Abstract
Tuberculosis (TB) remains a significant global health challenge, necessitating innovative approaches for effective treatment. Conventional TB therapy encounters several limitations, including extended treatment duration, drug resistance, patient noncompliance, poor bioavailability, and suboptimal targeting. Advanced drug delivery strategies have emerged as a promising approach to address these challenges. They have the potential to enhance therapeutic outcomes and improve TB patient compliance by providing benefits such as multiple drug encapsulation, sustained release, targeted delivery, reduced dosing frequency, and minimal side effects. This review examines the current landscape of drug delivery strategies for effective TB management, specifically highlighting lipid nanoparticles, polymer nanoparticles, inorganic nanoparticles, emulsion-based systems, carbon nanotubes, graphene, and hydrogels as promising approaches. Furthermore, emerging therapeutic strategies like targeted therapy, long-acting therapeutics, extrapulmonary therapy, phototherapy, and immunotherapy are emphasized. The review also discusses the future trajectory and challenges of developing drug delivery systems for TB. In conclusion, nanomedicine has made substantial progress in addressing the challenges posed by conventional TB drugs. Moreover, by harnessing the unique targeting abilities, extended duration of action, and specificity of advanced therapeutics, innovative solutions are offered that have the potential to revolutionize TB therapy, thereby enhancing treatment outcomes and patient compliance.
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Introduction
Tuberculosis (TB), a chronic granulomatous disease caused by Mycobacterium tuberculosis (M. tuberculosis) that typically infects the lungs, is one of the most prevalent contagious infections [1]. This aerosol-based transmissible disease is among the top infectious diseases worldwide [2,3,4]. In India alone, 26% of global cases have been reported, the most significant number of TB cases for any individual country [5]. It is considered the second deadliest infection after COVID-19. This infection is prevalent in all age groups worldwide and is curable as well as preventable. According to the WHO, early diagnosis and proper treatment have saved more than 74 million lives in the past two decades [6]. When the infection is untreated, the TB bacteria multiply and progress to other organs, which can result in fatal outcomes. Many patients diagnosed with TB are prescribed a standardized treatment regimen containing first-line anti-tubercular drugs (ATDs). The nonadherence of patients to ATDs leads to the generation of a newer strain known as multidrug resistant (MDR)-TB [7]. This occurs due to random chromosomal mutations and genetic changes in the bacterium. MDR bacilli are resistant to two important first-line drugs, isoniazid (INH) and rifampicin (RIF), and are treated using second-line ATDs, such as amikacin, capreomycin, and fluoroquinolones. Extensively drug-resistant (XDR)-TB is a more dangerous strain than MDR-TB. The treatment of XDR-TB is more difficult, as patients are resistant to many of the second-line drugs. Highly potent antibiotics, such as thioridazine, have severe side effects and are used for the treatment of XDR-TB [8].
Due to their size, the tubercle bacilli can reach the pulmonary alveoli, further becoming phagocytized by the alveolar macrophages (AM) [9, 10]. The bacilli then multiply in the alveolar sacs. The granulomas formed in these regions have heterogeneous size distributions and varying cellular compositions. When the bacterial load reaches a maximum, it can alter the morphology of granulomas, eventually spreading to other organs through the bloodstream and lymphatic system, resulting in extrapulmonary TB [11]. Thus, apart from the most common form of pulmonary TB, it can practically affect all human body organs, particularly the pleura, lymph nodes, abdomen, genitourinary tract, skin, meninges, joints, and bones [12, 13]. A schematic diagram of the pathogenesis of TB infection is shown in Fig. 1.
The treatment of TB patients is performed by using the TB-DOTS (directly observed treatment, short-course) treatment regimen. This regimen involves the use of various ATDs. The majority of the drugs used for therapy have severe adverse effects. The drugs' cure rates are as high as 95% in clinical trials, but they perform significantly worse in clinical conditions. The main reason for this is the lengthy duration of treatment and high dropout rates. The long duration of treatments and the serious adverse effects of the drugs impair patients' physical and mental endurance throughout therapy [16, 17]. Such instances cause patient relapse while also contributing to the development of bacterial resistance. Furthermore, there are several TB subpopulations, each with its physiology within the host. It can exist in two states that react to drugs differently: an active dividing state and a dormant/inactive state. It can alter drug metabolism, which also affects how effectively the therapy cycle functions [18, 19].
Due to tremendous improvements in treatment strategies, the number of patients infected with this disease is declining. The main reason for such a decline is the early and accurate diagnosis of the disease by various conventional and advanced techniques, such as chest X-ray, sputum microscopy, culturing method, nucleic acid amplification, ultralow dose chest CT (Clinical trials.gov identifier: NCT03220464), QuantiFERON (Clinical trials.gov identifier: NCT00982969), Nanodisk MS assay (Clinical trials.gov identifier: NCT03271567), and automated molecular diagnosis platform (Clinical trials.gov identifier: NCT04988984). However, due to the emergence of variant strains, the eradication of TB has not been achievable [20]. In this context, improved treatments with appropriate routes of administration are needed to shorten TB treatment duration, enhance efficacy, reduce adverse effects, and prevent resistance [9].
The significant challenges of clinical efficacy for TB include drug-resistant strains of M. tuberculosis, standard treatment duration (6–9 months), delayed diagnosis, and reduced therapeutic response with immunocompromised patients, which leads to more severe disease and a higher risk of complications that affect clinical outcomes [12, 21]. TB therapy is often delivered through various routes to ensure effective treatment. The main challenges associated with the oral route include slower onset of action, hepatic first-pass metabolism and rapid gastrointestinal absorption [9]. The parenteral and pulmonary routes for TB therapy displayed the highest bioavailability compared to oral administration. In particular, inhaled formulations are considered suitable for improving the pharmacodynamic profile of a drug [22]. Remarkably, lower doses of TB drugs can be delivered through inhalation and still result in effective treatments, thus reducing the chance of toxicity and enhancing localized drug concentrations [23]. With nanotechnology projected to simplify dosing and minimize adverse events, it can contribute significantly to the elimination of TB, especially by eradication of mycobacteria in those who do not have an active disease (latent TB), thereby preventing the progression to active disease [14, 24].
Advanced drug delivery strategies could improve bioavailability, patient compliance and the efficacy of TB treatment. As summarized in Table 1, with the dearth of new drug approvals for ATDs, except for bedaquiline, delamanidin, and pretomanid, which have come up in more than 40 years, innovative drug delivery strategies for existing drugs could be considered promising to enhance patient compliance [25,26,27,28]. Novel drug delivery systems (NDDSs) aid in optimizing the concentration of the active compound in the patient's plasma. Promising strategies for optimizing drug delivery could be based on modern systems such as nanoparticles, liposomes, microemulsions, niosomes, dendrimers and liquid crystalline systems [3, 25, 29]. By developing inexpensive and easy-to-administer delivery systems that offer extended drug release, dosing frequency could be reduced, thereby improving patient adherence. Direct targeting by selectivity toward both AM and tubercle bacilli may counteract the ability of intracellular pathogens to evade antibiotic treatments [30]. Thus, NDDSs can help optimize drug delivery to the target site, maximizing drug absorption and minimizing unwanted side effects [31]. Moreover, drug delivery systems can be optimized for a suitable route of administration to safeguard the therapeutic agents from immediate host metabolism and clearance, which can aid in therapeutic dose reduction [32]. A well-designed drug carrier can also demonstrate controlled drug release characteristics as per different metabolic and physicochemical responses [33]. These delivery systems also have a high possibility of treating nontubercular infections in the future [34, 35].
Here, we have reviewed the recent advances in drug delivery and therapeutics to effectively treat TB by overcoming the existing hurdles associated with TB therapy. We have discussed promising preclinical developments and their future perspectives, along with the challenges that must be addressed for impactful clinical translation.
Advanced drug delivery strategies
Designing NDDSs includes approaches for achieving and optimizing the continuous delivery of drugs in a precise and reproducible manner to the target site. A major focus has been on targeted drug delivery and minimizing undesirable effects. They are of various types depending upon the formulation, dosage form, and mechanism of drug delivery. Various types of delivery systems and routes of administration for TB are represented in Fig. 2.
Nanocarriers offer prominent advantages, such as drug release in the presence of specific triggers, providing temporal control of drug exposure, enhanced drug uptake in target cells, improved efficacy against intracellular pathogens, and protection of labile therapeutic agents from harsh physiological conditions such as low pH or enzymatic degradation [61]. In particular, polymers such as poly(lactic-co-glycolic acid) (PLGA), poly(caprolactone), poly(anhydrides), poly(orthoesters), poly(cyanoacrylates), and poly(amides) have opened avenues to modify drug release patterns by altering the monomer hydrophobicity, polymer chain length and particle size [62]. However, encapsulation of both hydrophobic and hydrophilic drugs is possible with liposomes to achieve sustained release [14].
Recent advances in nanotechnology have brought carriers into the limelight, which can specifically target AM [30]. Modulation of the physical properties of drug carriers, such as surface composition, charge, shape, particle size, hydrophobicity, and zeta potential, can modify drug internalization by AM. Another approach has been to use ligands on the nanocarrier that interact with specific receptors on macrophages, termed active targeting or ligand-mediated targeting. Strategies that do not rely on specific ligands have been called passive targeting. For passive targeting of AM, polymer- and polysaccharide-based carriers, as well as liposomes, solid lipid nanoparticles (SLNs), and gold nanorods, have been utilized for numerous agents, mostly INH and RIF [30]. Polysaccharides and their derivatives, including chitosan, inulin, alginate, and CD, have seen increased applications owing to their biocompatibility, biodegradability, hydrophilicity, mucoadhesive properties, use in modifying carrier surface charge, and target specificity [63,64,65,66].
Despite the beneficial prospects of these modern and fabricated drug delivery systems, safety and toxicity need to be verified, as they comprise different types of material [67, 68]. These technological solutions need to support scalability and reproducibility, aiding clinical translation beyond laboratory optimization by overcoming manufacturing, regulatory and financial challenges [69]. In particular, the reformulation of existing drugs for enhanced efficacy and safety needs to be cost-effective [70]. Furthermore, the synthesis and storage conditions need to be conducive to conditions in low-resource countries [71]. Importantly, process optimization is of utmost significance in the case of nanomedicines that are likely to be 3D constructs of multiple components with preferred spatial arrangements, with any deviation adversely affecting the composition [72, 73]. Table 2 provides a summary of drug delivery systems and their key findings incorporating anti-tubercular drugs.
Lipid-based drug delivery systems
Liposomes
The efficiency of drug delivery by liposomal systems has mainly been studied using M. avium and M. tuberculosis models. In a mouse model, liposomal rifabutin was demonstrated to slow the pathogenic course of TB infection. Formulations containing dipalmitoyl phosphatidylcholine and dipalmitoyl phosphatidylglycerol were able to reduce TB progression in the lungs and lowered the bacterial loads in the spleen and liver, implying that liposomal-loaded ATDs could be a promising approach for treating extrapulmonary TB [104]. Similarly, liposomal clofazimine showed higher antibacterial activity than free clofazimine against the M. avium complex in mice, even when the treatment was initiated after the dissemination of the infection [108].
RIF and INH-encapsulated liposomes reduced pulmonary inflammation and enhanced the survival of TB-induced mice. Liposome formulation improved RIF penetration across the alveolar epithelium, extending pulmonary residence time and lowering systemic drug toxicity [116]. Mannan-anchored liposomes containing RIF, INH, and pyrazinamide can be delivered to the lungs using a dry powder inhaler (DPI) for the treatment of pulmonary TB with high entrapment efficiency and sustained drug release [117].
The liposome-in-hydrogel technique was found to be promising for treating bone TB locally. Liposomes entrapped with INH served dual functions of pulmonary medication transport and alveolar stabilization. DPIs containing ligand-anchored pH-sensitive liposomes for the simultaneous delivery of INH and ciprofloxacin demonstrated the greatest accumulation in the lung. Liposomes can aid in the pulmonary administration of ATDs, which could be an attractive alternative to improve TB therapy [74, 118, 119].
Asymmetric liposomes made up of phosphatidylserine at the outer surface resembling apoptotic bodies and phosphatidic acid at the inner layer could be used to boost innate antimycobacterial activity in phagocytes while limiting the inflammatory response [120]. Liposomes containing dipalmitoyl phosphatidylcholine and cholesterol were reported to inactivate M. tuberculosis and multidrug-resistant (MDR) -M. tuberculosis, with action dependent on the incubation period and low dose [121]. Phosphatidylcholine-cholesterol-cardiolipin liposome formulation and levofloxacin are efficacious against M. tuberculosis bacilli [103]. Liposomes may potentially be useful as part of a gene vaccine for TB treatment, as evidenced by the efficacy of a peptide-DNA-cationic liposome pseudoternary complex [122].
Niosomes
INH integrated with niosomes was found to be effective against TB, with 62% cellular absorption by macrophages and 65% drug localization to the target organ, compared to 15% with the supplied free INH [123]. Liposomal preparations of azole antifungals such as clotrimazole and econazole were shown to be effective against M. tuberculosis and latent bacilli, while fluoroquinolones such as moxifloxacin accumulated more efficiently in AM when delivered in the context of niosomes [123].
Chowdhury et al. [208] and El-Ridy et al. investigated niosomal formulations of RIF and ofloxacin for the treatment of drug-resistant TB, finding 81.76% entrapment efficiency and regulated release for up to 15 days. El-Ridy et al. formulated ethambutol-containing niosomes that demonstrated regulated release and a reduction in nonspecific toxicity [99]. After intratracheal injection, RIF-loaded niosomes demonstrated enhanced accumulation and 90% RIF release in 48 h, with 65% localization [125]. Niosomes containing cholesterol and Triton X-100 successfully targeted RIF in Wistar rats, INH in J744A.1 mouse macrophages, and ethambutol in Swiss albino mice infected with M. tuberculosis H37Rv [76, 126]. In guinea pigs, pyrazinamide encapsulated in niosomes demonstrated significant drug entrapment efficiency. Subcutaneous treatment with niosomal ethambutol formulated with Span 60, Span 85, cholesterol, diacetyl phosphate, and stearyl amine resulted in prolonged drug release in Swiss albino mouse lungs and lowered bacterial counts in guinea pigs infected with M. tuberculosis H37Rv by i.m. injection [99, 127].
For highly lipophilic drugs, such as BM859, which demonstrated significant antimycobacterial action against M. tuberculosis H37Rv, niosomes are a preferable method of drug delivery. Sadhu et al. developed ethionamide niosomes with sufficient stability for intravenous injection [128, 129]. Niosomes loaded with hydrophilic D-cycloserine and lipophilic ethionamide kill drug-resistant TB by releasing 96% of ethionamide and 97% of D-cycloserine [130]. Antimycobacterial drugs encapsulated in tyloxapol niosomes have a high drug loading efficiency, and the isatin-INH hybrid WF-208 has a fourfold higher MIC against H37Rv M. tuberculosis [131,132,133].
Liquid crystals
Liquid crystals are an ideal mechanism of drug delivery for ATDs. Liquid crystal-based zidovudine, ciprofloxacin, and fluconazole formulations are some of the recent developments in the antimicrobial field, making them a possible approach for delivering ATDs as well [135]. K. Dua et al. synthesized RIF-based liquid crystals with higher solubility and stability in acidic environments than the free drug, allowing for lower dose frequency and increased bioavailability. RIF is poorly water soluble and degrades in the stomach, resulting in limited bioavailability [136]. Tran et al. created two RIF-loaded nanoparticles using neutral lipid monoolein and the cationic lipid N-(1-(2,3-Dioleoyloxy)propyl)-N,N,N-trimethylammonium methyl-sulfate (DOTAP), which decreased the MIC of RIF against S. aureus. The cationic charge helped in increased solubility and greater membrane fusion, as explained in Fig. 3 [91]. Kim et al. developed a liquid crystal-based aptasensor for IFN detection that has higher sensitivity and a lower detection limit than enzyme linked immunosorbent assay (ELISA). They created an improved biosensor that uses immobilized antigen ESAT-6 to detect anti-TB antibodies (anti-ESAT-6) [137]. Bedaquiline-loaded cubosomes based on nanocarriers have been demonstrated to be effective in the treatment of non-small cell lung cancer (NSCLC) by sustained release over 72 h [138].
Polymer-based drug delivery systems
Polymer micelles
Because of their capacity to stabilize and protect the drug, prolong the therapeutic activity, and enclose hydrophobic pharmaceuticals, polymeric micelles are used as drug carriers. They can also be utilized to deliver multiple ATDs into infected macrophages while causing fewer negative effects [139, 140]. Tripodo et al. created RIF-delivering micelles based on inulin functionalized with vitamin E (INVITE) and its succinylated derivative (INVITESA). It demonstrated strong mucoadhesion to mucin and equivalent antibacterial activities against gram-positive bacteria [94].
RIF- and INH-loaded N-(2-hydroxypropyl)methacrylamide-poly(lactic acid) micelles allow prolonged drug release, improving effectiveness against resistant and sensitive pathogens. Kaur et al. revealed different polymeric micelle-based delivery methods for ATDs for drug-resistant TB, including polyethylene oxide-polypropylene oxide (PEO-PPO), polyvinyl-caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (PCL-PVAc-PEG), and chitosan-graft-poly-ε-caprolactone (CS-g-PCL). PEO-PPO decreased the MIC value, PCL-PVAc-PEG improved RIF solubility and physical stability, and CS-g-PCL provided INH with pH-dependent release, improved cellular internalization, and decreased cytotoxicity [141].
Yuan et al. created interconnected hydrogel micelles for the delayed release of weakly water-soluble RIF using biodegradable polymers such as guar gum, chitosan, and polycaprolactone. In vitro release experiments revealed that 90% of the medication was released in 12 days, and 97% of the encapsulation was effective [142]. Sheth et al. encapsulated RIF and INH in pluronic, which increased activity and sustained release against M. tuberculosis. Grotz et al. developed an inhalable nanocarrier based on RIF-loaded polymeric micelles to improve water solubility [96, 143].
Chitosan-based polymer drug delivery systems
Chitosan can be used as a vaccine delivery mechanism in the treatment of TB. Negatively charged particles, such as PLGA, can be coated with chitosan to transfer them efficiently to the mucosal membrane [144, 145]. Gu et al. recently proved that a combination of dihydroartemisinin and chitosan might overcome M. tuberculosis RIF resistance. This combination worked best at lower chitosan concentrations, but at greater concentrations, the bacteria were deprived of nutrition [146]. Chitosan biguanidine nanoparticles developed using a one-pot green synthesis method can be used as carrier systems for ATDs. It was demonstrated that chitosan biguanidine nanoparticles have enhanced pharmacological activity owing to targeted delivery [147].
Alginate-based polymer drug delivery systems
For MDR-TB, hydrophilic ATDs such as amikacin and moxifloxacin were encapsulated in alginate-entrapped PLGA nanoparticles. When these nanoparticles were fed to macrophages infected with M. tuberculosis, antibacterial activity was detected [148]. For the administration of RIF in combination with ascorbic acid, a nanocarrier system comprised of alginate coated with Tween 80 and chitosan was created [149]. Alginate-cellulose nanocrystal hybrid nanoparticles have demonstrated significant antimycobacterial action and moderate oral medication delivery difficulties [93]. Anti-TB action has also been shown in nanostructured polyelectrolyte complexes synthesized from sodium alginate and chitosan. Alginate particles have been investigated as a means of encapsulating live mycobacterium particles for use in inhalable vaccinations [150, 151].
Nagpal et al. proposed coating live mycobacterium with alginate to improve dendritic cell activation and maturation [150]. When alginate-coated chitosan nanoparticles were delivered intranasally and subcutaneously, they released the PPE17 antigen, which produced effective immune responses in mice [152]. Pregelatinized sodium alginate and chitosan can be used for the development of nanoparticles of INH and pyrazinamide and could be an interesting approach for TB treatment [153]. To improve stability and long-term release, polypeptidic micelles containing bedaquiline were coated with sodium alginate [154].
Zn-alginate beads show excellent biocompatibility and no fatal cytotoxicity when utilized as carriers for RIF administration [155]. Alginate has been employed as a stabilizer in the manufacture of silver nanoparticles, which have the ability to attack M. tuberculosis and sterilize nonreplicating persistent TB [156]. It has been discovered that calcium ion-sodium alginate-piperine-based microspheres improve entrapment efficiency and extend the release and oral bioavailability of INH [82].
Cyclodextrin-based polymer drug delivery systems
CDs are cyclic oligosaccharides with D-glucose units linked by β-1,4-glucosidic linkages [157]. Because of the constrained rotation around the bonds joining the glucopyranose units, they form a toroidal structure [158,159,160]. β-Cyclodextrins (β-CD) have the potential to be an effective carrier system for ATD delivery. An in vivo investigation found that administering unloaded β-CD via endotracheal or intranasal routes reduced the bacterial burden. Loaded with ethionamide and boosted with BDM43266, the bacilli activity was tenfold increased and selective. This can be used to combine several medications into a single formulation [95].
RIF is insoluble and permeable, but this can be addressed by creating an inclusion combination with hydroxypropyl- β -CD (HP- β -CD). To simplify dose modification and treatment adherence, Javier Suárez-González et al. developed a combined-dose oral pediatric formulation including INH and RIF. HP- β -CD has also been employed to create a powdered RIF dosage form for direct lung-focused distribution [95].
The bioavailability and deposition performance of clofazimine were increased by combining it with β-CD and L-leucine [110]. Curdlan nanoparticles containing RIF and levofloxacin were used to target M. tuberculosis-infected macrophages [161]. In mice, the combination of ethionamide with the booster BDM41906 decreases mycobacterial load [112]. Christian and Werner successfully complexed an INH-hydrazone-phthalocyanine compound in β-CD encapsulated in soybean lecithin liposomes. It demonstrated pH-dependent drug release that is appropriate for site-specific delivery [162]. Anjani et al. discovered that CD inclusion complexes improved antibacterial action, with 60% drug release in 2 h [139].
Dendrimer-based drug delivery systems
Polymers commonly used for the preparation of dendrimers are poly(amidoamine) (PAMAM) and poly(propylene imine) (PPI) [163,164,165]. Others include polyglycerol, poly(ether hydroxylamine) (PEHAM), poly(ester amine) (PEA), and melamine [166]. Dendrimers behave like unimolecular micelles that facilitate the delivery of both hydrophilic and hydrophobic drugs [167,168,169]. Cationic dendrimers can be used as nonviral gene carriers [170].
The RIF-PAMAM complex can be used as a carrier for drugs to acidic sites, as normal RIF can lead to solubility issues [171]. When a maximum of twenty RIF molecules were loaded in fourth-generation PAMAM dendrimers, a sustained release profile was observed at neutral pH, whereas simultaneous release was triggered at acidic pH. Incorporating RIF into G3 PAMAM prolonged its release compared to first- and second-generation PAMAM due to the entrapment of RIF in the branched chains of G3 PAMAM along with the high density, high molecular weight, and size of G3 PAMAM [173].
The solubilization of drugs is due to hydrophobic-hydrophilic interactions, the interaction between ions, and encapsulation of hydrophobic drugs into crevices of dendritic architecture, as demonstrated by Karthikeyan R et al. using known concentrations of PEGylated PPI dendrimers [174]. Fourth- and fifth-generation PEGylated PPIs also demonstrated an increase in the entrapment of RIF [175]. Furthermore, targeting of AM was studied using RIF with fifth-generation ethylenediamine (EDA)-PPI dendrimers based on mannosylation to selectively target macrophages. The outcome was that the concentration of the drug in the macrophages exceeded the plasma concentration, making it a promising approach for the treatment of TB [85].
Poorly aqueous or hydrophobic drugs can be encapsulated within the core of PEHAM dendrimers to improve their solubility, which further increases the bioavailability of the drug [176, 177]. Since the cationic groups present in the PEHAM dendrimers are toxic to RBCs, methods such as glycosylation and acetylation are extensively employed to overcome the toxicity [178, 179]. ATDs can also be encapsulated in polymers to increase their half-life and attain enhanced bioavailability and a sustained release profile [180].
Polymeric-microparticulate drug delivery systems
The inclusion of RIF and INH into polylactic acid microparticles (MPs) at a 1:1 ratio increased the drug concentration in macrophages, lowering the dosage frequency and toxicity [181]. For the detection and treatment of pulmonary TB, monocyte-derived MPs can be utilized to target AM. To release entrapped pharmaceuticals, sodium alginate, a linear copolymer of α-guluronic acid and α-mannuronic acid, creates a meshwork with divalent cations [182]. Recently, β-1,3/1,6 glucan particles (GPs) produced from yeast have been used to deliver anti-TB medicines to macrophages [183, 184]. Macrophages and other phagocytic cells can recognize the β-1,3-D glucan surface makeup. Particulate glucan is biodegradable and biocompatible, and the United states Food and Drug Administration (FDA) considers it generally recognized as safe (GRAS). In a study, RIF DPI was developed that had the ability to overcome drug resistance as well as reduce the time needed for therapy [185].
INH-administered mannitol microspheres containing iron(III) trimesate metal organic framework (MOF) MIL-100 nanoparticles demonstrated adequate encapsulation efficiency and aerodynamics for pulmonary delivery. In vitro testing in human alveolar adenocarcinoma basal epithelial cells revealed effective internalization, indicating that it is suited for deep lung ATD administration [80]. Fucoidan microparticles loaded with ATDs demonstrated good affinity, aerodynamic features, and no cytotoxicity to lung epithelial cells or THP-1 macrophages [186]. ATDs suppressed 95% of microbial growth and triggered cytokine-mediated macrophage activation even when used as a single formulation [187]. Chitosan polymeric MP loaded with INH and rifabutin showed comparable and increased efficacy against M. bovis [188].
Host defense peptide (HDP) microencapsulation with INH demonstrated enhanced and additive antimycobacterial effects, resulting in a lower dosage concentration. Antimycobacterial action was also demonstrated by encapsulated astaxanthin [189, 190]. Following oral dosing, epigallocatechin gallate (EGCG) exhibited a modest therapeutic effect, while microencapsulated EGCG with trehalose sugar (EGCG-t-MS) demonstrated dose-dependent death of TB bacteria in mouse macrophages. In vivo, pulmonary delivery of EGCG for 6 weeks resulted in lower bacterial loads, less inflammation, and fewer granulomas than orally administered EGCG. Combination therapy with EGCG-t-MS with a subtherapeutic dose of regular ATDs demonstrated efficacy comparable to full-dose therapy [191].
The bioavailability of RIF-loaded poly lactic co glycolic acid (PLGA) microsphere powders after intratracheal aerosolization was 92%. Other RIF, INH, pyrazinamide, rifabutin, and linezolid microencapsulated formulations have been studied as prospective NDDSs for prolonged release, infrequent dosage, and adequate bioavailability [192, 193]. Anisimova et al. discovered that INH, streptomycin, and RIF encapsulated in poly(butyl cyanoacrylate) (PBCA) and poly(isobutyl cyanoacrylate) (PIBCA) accumulated more intracellularly in monocytes than free drugs [148]. INH, streptomycin, and RIF encapsulated in PBCA and PIBCA accumulated intracellularly, producing a more effective response [131]. Table 3 represents a summary of drug delivery systems for anti-tubercular drug combinations and new approaches.
Floating drug delivery methods are low-density devices that allow the drug to float on top of the stomach juice, boosting retention time and bioavailability. Quercetin-loaded RIF floating microspheres were developed to treat TB and maintain RIF release in the stomach, and they were found to be stable after six months [194]. RIF stability can be increased by integrating it into sustained-release microporous floating microspheres and gastric-resistant INH sustained-release microspheres. Microporous floating sustained release microspheres were created using emulsification and evaporation techniques, resulting in increased RIF bioavailability [195]. Because one drug can be enteric coated to release in the stomach and the other in the ileum, floating delivery systems are useful for ATD fixed-dose combos. Studies have shown that more RIF is absorbed from the stomach even in the presence of INH [196].
Inorganic nanoparticles
Gold nanoparticles
Gold nanoparticles (GNPs) have several applications in targeted drug delivery due to their small size, biocompatibility, and lack of cytotoxicity. Green synthesized GNP with herbs may be beneficial in the treatment of TB. The various types of GNPs and their general synthesis methods are depicted in Fig. 4. GNP exhibits bactericidal activity [216]. With respect to TB, GNP was able to inhibit M. tuberculosis with an MIC of 10 µg/ml but was ineffective against RIF-resistant M. tuberculosis [217]. Gold nanoparticles synthesized using the bacterium Zoogloia ramigera exhibited good antibacterial activity and can be utilized for TB treatment. The antibacterial properties were studied using MIC and minimum bactericidal concentration methods [218]. Mesoporous silica nanoparticles (MSNs) containing gold nanoparticles (MSNs@GNP) can inhibit M. tuberculosis growth and produce a synergistic effect against M. tuberculosis, making it safe for TB treatment [219]. Another important application of GNP is in TB diagnosis. A ferromagnetic GNP-based immune detection system was developed for the detection of M. tuberculosis and to differentiate M. bovis [220]. GNPs loaded with quadruplex DNA motifs can aid in the diagnosis of M. tuberculosis in sputum [15, 221]. Magnetic beads and GNP-based immuno-PCR assays were developed to detect M. tuberculosis antigen [222].
Silica nanoparticles
Silica nanoparticles have the ability to be taken up by macrophages and produce immunological benefits [223]. Polyethyleneimine (PEI)-coated MSNs loaded with RIF exhibited effective targeted intracellular delivery with decreased cytotoxicity [224, 225]. MSNs loaded with first-line ATDs can kill M. tuberculosis-infected macrophages [201, 226]. MSNs containing NZX (mycobacterial peptide) can effectively treat TB by killing MDR strains of M. tuberculosis [227]. Tenland et al. found that MSNs can increase antibacterial activity against M. bovis and M. tuberculosis H37Rv in vitro and in vivo [227]. NapFab, an antimicrobial peptide isolated from bronchoalveolar lavage, showed excellent antimycobacterial activity when introduced into dendritic MSNs. MSNs can be used as carriers for the delivery of silver nanoparticles to target sites because they have very high bactericidal potency. A 2D hexagonal MSN containing silver bromide also showed good antimycobacterial activity [228].
M. tuberculosis produces extracellular vesicles that can cause immunomodulatory responses. Nanodrug delivery systems such as MSNs can mimic endogenous vesicles and act as carriers of the vesicle-associated proteins Ag85B, LprG, and LprA. They have been studied for the development of vaccines against TB [229]. Acetophenone helps MSNs deliver clofazimine to the target site [230]. Oral drug delivery of antitubercular nitroimidazopyrazinone analogs-pretomanid and MCC7433 from the bicyclic nitroimidazole class can be improved by MSNs. The MCM-41 type of SNP was used as a carrier for the transport of poorly water-soluble bicyclic nitroimidazole compounds [231]. MSNs are a promising multifunctional drug delivery system due to their high drug loading capacity and stability [232].
Carbon nanotubes
Carbon nanomaterials have gained popularity due to their unique features, which include physiochemical, thermal, optical, and electrical properties. Carbon nanotubes are the most well-known structures with a continuous cylinder formed of graphene [233]. Zomorodbakhsh et al. 2020 linked INH with multiwall carbon nanotubes (MWCNTs), which demonstrated greater lethality against M. tuberculosis even at considerably lower concentrations than the free drug [79]. Chen et al. developed chitosan nanotubes based on INH nanoparticles to increase medication release time, accelerate TB ulcer healing, and minimize inflammation and cytotoxicity [78]. Tudose et al., Moradi et al. and Pi et al. used a graphene oxide carrier system with various surface modifications for the delivery of ATDs and were found to have superior control over drug release [97, 198, 206].
More et al. developed a graphene oxide-based air-dried hydrogel containing para-amino salicylic acid for targeting MDR TB, whereas Vatanparast et al. revealed that AlN- and AlP-doped graphene quantum dots (GQDs) can be utilized to transport INH [7, 77, 114]. INH- and fluoxetine-conjugated MWCNTs increased the antimycobacterial activity and were capable of regulating the expression of the INH resistance genes inhA and katG, as shown in the schematic representation in Fig. 5 [207]. Carbon nanomaterials have been used to create electrochemical biosensors for M. tuberculosis detection, such as an amperometric DNA biosensor and a microfluidic multiplexed platform based on carbon nanotubes [234].
Emulsion-based drug delivery systems
Microemulsions
Microemulsions can be utilized to deliver targeted drugs, control release, and improve ATD bioavailability. Mehta et al. [202] formulated a highly stable Tween 80 microemulsion using RIF and INH [235]. Tween-based microemulsions of ATDs such RIF, INH, and pyrazinamide were found to be less hazardous and irritating, with INH releasing faster in the continuous phase and RIF releasing faster in the droplet phase [202]. The encapsulation efficiency, shape, antimycobacterial activity, particle size, and zeta potential have all been improved using modified microemulsion procedures [100, 236]. These medication delivery technologies can significantly reduce dose frequency while increasing bioavailability. Kaur et al. developed a Brig 96 microemulsion to work in combination with lipophilic and hydrophilic drugs [203]. Microemulsions of INH, pyrazinamide, and RIF exhibited good antibacterial characteristics [237].
Using the microemulsion process, calcium phosphate nanocontainers can be loaded with 1,3-benzothiazine-4-one, a new antimycobacterial drug that results in an increase in local drug concentration at the site of mycobacterial infection. Eugenol, an active chemical ingredient, was also combined with Tween 20 as a surfactant to improve therapeutic efficacy against M. tuberculosis [238]. According to Talegaonkar et al., microemulsions enhanced drug solubility and absorption, making RIF more effective and less toxic [239]. Microemulsions were also discovered to be promising for the regulated administration of ATDs as well as the destruction of drug-resistant strains of M. tuberculosis [240].
Nanoemulsion
M. tuberculosis can affect the eyes and cause an ocular infection resulting in permanent vision loss [98]. In this case, ATDs have to overcome the obstacle of the blood‒retinal barrier for effective drug movement, decreasing bioavailability. A solution could be the formulation of drugs into nanoemulsions by using excipients such as chitosan and polymyxin B [241]. For instance, a cationic RIF nanoemulsion was produced by high-pressure homogenization in a way that does not affect the therapeutic efficiency of the drug while enhancing bioavailability and other pharmacokinetic parameters [98]. Nanoemulsions were also used to develop a thermostable adjuvanted vaccine against TB by the "design of experiment (DoE)” approach [211].
Hydrogels
Hydrogel-forming microneedle arrays were designed for the transdermal delivery of ATDs, enabling the administration of high doses of ATDs [242]. Transdermal injection of hydrogel-based medicines has been proven to improve antibiotic activity against M. tuberculosis infection. For in vitro permeation, three distinct drug reservoirs were developed and combined with hydrogel-forming microneedle arrays. When the microneedle arrays were paired with polyethylene glycol tablets, immediately compressed tablets, and lyophilized tablets, the maximum penetration of RIF, ethambutol, INH, and pyrazinamide was attained [81].
More et al. formulated a graphene-based hydrogel that contained PAS and had good biocompatibility and antimycobacterial capabilities [7]. Wan et al. synthesized a variety of cationic peptide amphiphiles capable of self-assembling hydrogels [243]. A graphene oxide air-dried hydrogel designed to target M. tuberculosis also showed excellent antibacterial activity [7]. Polyvinyl alcohol (PVA) is nontoxic and has a high effectiveness for the encapsulation of hydrophilic pharmaceuticals, and a PVA-chitosan-tripolyphosphate hydrogel was developed for the extended release of ATDs. In a phosphate buffer solution (pH 7.4), a formulation of 80% PVA—20% chitosan hydrogel matrix demonstrated the maximum rate of drug release in a short period of time, with varied release patterns for RIF, INH, ethambutol, and pyrazinamide [204, 205].
Hydrogel interconnecting micelles made with guar gum/chitosan/polycaprolactone can serve as effective carriers for poorly water-soluble medicines such as RIF [142]. TB-Gel is an injectable and nonimmunogenic amphiphilic-based drug delivery technology with a low molecular weight. In an experimental mouse model, it was found to be more effective than oral delivery of a combination of four medicines in lowering mycobacterial infection [18]. Because of their swelling behavior, wide size range, and biocompatibility, hydrogels are effective in resolving these problems [244].
3D-printed formulations
3D printing techniques could truly advance the application of modern drug delivery systems in TB treatment by precision in the fabrication of scaffolds with well-controlled inner structures and pore morphologies, as depicted in Fig. 6 [245]. The prospects could be enhanced by the use of biocompatible and biodegradable polymers, such as polycaprolactone, as the binder for 3D printing [246].
A 3D-printed scaffold containing drugs such as INH and RIF can minimize the occurrence of drug resistance in osteoarticular TB [199]. In osteoarticular TB debridement procedures, drugs are placed into mesoporous and bioactive ceramics that bond with poly(3hydroxybutyrate-co-3-hydroxyhexonate) (PHBHHx) [246].
A bioengineered delivery system, such as 3D-printed tablets with discrete compartmentalization for RIF and INH, has the advantage of reducing drug degradation, allowing for successful combination treatment [247]. Bilayered tablets with two different ATDs, INH and RIF, can be designed and manufactured using a 3D-printed scaffold. The pH-sensitive polymer in which these medicines are contained determines the site of release. These methods can reduce pH-dependent deterioration and improve therapeutic efficiency [200].
Quercetin, a flavonoid, has been found to limit the growth of M. tuberculosis H37Rv. To combat the devastating effects of pulmonary TB, 3D printing technology was employed to create medicinal skin patches. Pharmacokinetic studies in rats revealed the viability of creating 3D-printed medicinal skin patches that may deliver plasma levels for up to 18 days following a single application [248, 249].
Advanced therapeutic strategies
Targeted therapy
Among polymers, biocompatible PLGA has found profound use in the fabrication of controlled ATD delivery systems because of the ease in achieving the desired dose and release kinetics by modification of the lactide to glycolide ratio, molecular weight, and drug concentration [250,251,252]. With regard to tissue-resident macrophage targeting for the delivery of ATDs, the surface of the drug carrier is functionalized with ligands, including mannosylated molecule, β-glucan, curdlan (β-1,3 glucose), folic acid, hyaluronic acid, tuftsin peptide, and phosphoserine conjugate, that can be recognized by corresponding receptors on macrophages, such as mannosyl receptor (CD206), dectin-1 receptor, folate receptor, tuftsin receptor, hyaluronic acid receptor, fucosyl and scavenger receptor, Fc receptor, transferrin receptor, formyl peptide receptor (FPR), and other lectin-like receptors [30, 253, 254] represented in Fig. 7. Among them, drug carriers made of modified mannose are the most common and can be added to liposomes, SLN, and polymer micelles [255,256,257] Studies have shown that cubosomal lipid nanocarriers exhibit higher drug delivery efficiency as well as bioavailability than conventional formulations. They are not only effective against free bacilli but also have the ability to deliver drugs to intracellular bacilli [258]. Thus, the identification of better sets of ligands with higher binding affinity for macrophage-based receptors might result in enhanced targeting efficiency. A promising approach could be heteromultivalent targeting, in which different types of ligands bind to different macrophage receptors simultaneously [259]. With respect to targeting and drug accumulation at sites of infection, future studies need to focus on the translation of preclinical data into humans in relation to the severity of infection, the fraction of drug at off-target sites, and the drug targeting index [14, 260].
Pulmonary TB is the most common form of TB, and inhalable carriers of ATDs have been a major focus of research and were found to significantly increase targeting in the lungs, reducing undesirable toxic side effects and enabling delivery to AM [9, 14]. Liposomes [261], microparticles [186, 187, 262], microencapsulation [80], liquid crystals [263], hydrogels [244], polymeric micelles [96] and even hybrid systems [264] have been promising for inhalational TB therapy. The formulations need to be optimized to penetrate mucous layers and biofilms and overcome sequestration, rapid deactivation by enzymes, and elimination by coughing [265, 266]. In addition to passing through the acidic gastric environment, pulmonary administration could be particularly beneficial for controlled release within AM. However, for translatable pulmonary administration of ATDs, challenges need to be resolved, including the use of better and safer excipients, drug encapsulation efficiency, process and production scalability, and developing formulations with optimum size and morphology for deep lung deposition [124, 267,268,269]. If sufficient drugs can be delivered through the inhaled route, it would be of immense benefit to TB patients considering the acceptance of portable, cost-effective and easy-to-operate inhalers [23].
Unlike the conventional administration of drugs, nanomaterial-based systems offer significant benefits, such as ease of administration, minimal side effects, and addressing the pharmacodynamics and pharmacokinetic limitations of many potential drug molecules [270]. Recently, transforming growth factor (TGF)-β1-specific siRNA nanoliposomes loaded with INH, RIF, and pyrazinamide have demonstrated the potential for improving spinal TB chemotherapy [271]. With the adoption of a phage-based delivery system for endogenous type III-A CRISPR‒Cas antimicrobials against M. tuberculosis, nanoenabled CRISPR‒Cas-powered strategies might also be developed for the treatment of TB [272,273,274]. Thus, nanotechnology holds immense potential in developing novel and targeted delivery systems for new therapies as well as existing drugs. This could be of interest, particularly in the development of inhaled or orally delivered nanocarriers for extended release of ATDs, which in turn can reduce the required dosing frequency to improve patient adherence. Drug depot systems can be of remarkable benefit, particularly for the treatment of TB in children, if balance can be achieved between the ease and safety of administration [275,276,277].
Long-acting therapeutics
Long-acting therapeutics can be formulated using prodrugs that have low aqueous solubility, inhibit rapid dissolution and drug release, and have a reasonably long half-life, enabling slow elimination from the body and high potency, allowing low drug doses to be injected [278,279,280]. In this regard, drugs such as bedaquiline, which has a longer half-life (24 h), higher lipophilicity (logP 7.3), and lower MIC for M. tuberculosis (0.03 μg/ml), were found to be suitable for use in a long-acting injectable (LAI) formulation [278, 281, 282]. Remarkably, one intramuscular injection of long-acting bedaquiline at 160 mg/kg demonstrated significant antitubercular activity for 12 weeks in p mouse models. Moreover, physiologically based pharmacokinetic modeling identified delamanid and rifapentine as potential LAI candidates suitable for monthly intramuscular administration at doses of 1500 mg and 250 mg, respectively [282]. A promising development is the one-time large-dose controlled release delivery system resident in the gastrointestinal tract. It offers numerous advantages over currently available injectable depot formulations, including ease of administration, lack of immunologic reactions, and the ability to accommodate multigram-level dosing in line with current TB treatment regimens [283].
In another approach, a thermoresponsive matrix containing an extended-release polymer was used to encapsulate drug molecules to improve the duration of action. Significant efficacy was achieved using sustained release intramuscular injection loaded with tin protoporphyrin (SnPPIX), a heme oxygenase-1 inhibitor, in murine models of pulmonary TB [284].
Furthermore, notable technological advancements for TB include developments in oral and subcutaneous systems [285]. Solid nanoparticles (SNPs) are widely studied for the oral delivery of antimicrobials, including SLNs, polymeric nanoparticles, MSNs, and hybrid nanoparticles [286]. SLN has been tested in rodents with the goal of improving the bioavailability of RIF and the combination of INH, RIF, and pyrazinamide [14, 287]. MSNs were able to enhance the activity of orally delivered poorly soluble antibacterial agents against TB, such as pretomanid and MCC7433, a novel nitroimidazopyrazinone analog [231]. SLN was also proposed as a suitable drug delivery platform with short-term sustained release upon intramuscular and subcutaneous administration [288].
Extrapulmonary TB therapy
ATD delivery for TB bone defects has been another area of focus in TB research, as bone TB has the highest incidence among extrapulmonary TB, accounting for approximately 35–50%. Even though surgery is available, the remaining M. tuberculosis around the trauma can multiply, leading to TB ulcer and sinus formation and even causing bone TB recurrence and bacterial infection. This, along with poor local blood supply that causes difficult access to ATDs, complicates the scenario [289]. A probable solution could be loading ATDs into scaffolds through various drug-loading techniques to improve the efficiency of anti-TB treatment [290]. As carbon nanotubes have strong penetrability across physiological barriers to enter tissues, chitosan/carbon nanotube nanoparticles were constructed to achieve slow release of INH. It was found to significantly promote the healing of TB ulcers and could be developed as a new treatment for secondary wounds of bone TB [78].
Another approach that has shown promising potential for osteoarticular TB therapy is biocompatible mesoporous bioactive glass/metal–organic framework (MBG/MOF) scaffolds fabricated by a 3D printing technique using polycaprolactone [246]. MBG is considered a promising material owing to its bone repair potential in relation to its high surface area and better bioactivity, along with its superior drug loading and release ability [291,292,293]. The biomedical applications of MOFs are related to their tunable porosity, biocompatibility and biodegradability, making them an attractive drug delivery system with a modifiable degradation rate for controlled drug delivery [294, 295].
In comparison, the cutaneous administration of ATDs is poorly explored. Skin can be considered a good route for the treatment of cutaneous TB, usually caused by atypical mycobacterium species, namely, M. leprae, M. hemophilum, and M. ulcerans. TB represents only 1–1.5% of extrapulmonary cases, affecting mainly the face, torso, and neck areas [296]. However, the incidence of extrapulmonary TB is increasing in the context of MDR-TB. Recently, van Staden et al. proposed the utility of self-double-emulsifying drug delivery systems (SDEDDS) containing clofazimine for topical delivery in the treatment of cutaneous TB [297]. The benefit of SDEDDS for dermal administration of clofazimine is that, with lower drug concentrations, it could provide consistent drug delivery profiles that will be cytotoxic toward M. tuberculosis, which can help to suppress drug resistance [298]. As a topical delivery, it might be able to reduce the unpleasant discoloration associated with oral administration of clofazimine [299]. The improved drug loading capacity of SDEDDS may be further utilized to treat active TB or resistant TB infections by either including higher concentrations of clofazimine or incorporating fixed-dose drug combinations with other drugs known to act synergistically [300].
The possibility of INH delivery by the skin route has also been evaluated, as this route could avoid the hepatic first-pass effect, thereby reducing hepatotoxicity that leads to poor patient compliance [301]. The selection of excipients is based on the intended use. For example, limonene was found to be the better excipient for transdermal formulations based on the enhancement of INH absorption, while transcutol and menthol were found to be more appropriate for topical systems. Inclusion of transcutol led to increased skin accumulation of the drug, termed the "intracutaneous depot", created by swelling of stratum corneum intercellular lipids that retained the drugs, along with a simultaneous decrease in transdermal permeation. Interestingly, the incorporation of limonene resulted in transdermal absorption of INH that was sufficient to ensure a systemic therapeutic effect [301]. Moreover, to achieve transdermal drug delivery, cutting-edge anti-TB drug delivery systems are being explored, such as 3D printed quercetin-coupled polyvinylpyrrolidone (PVP) skin patches for the treatment of destructive pulmonary TB [249].
Another avenue is ophthalmic drug delivery for the treatment of ocular TB, in which eyes and orbital tissues are affected, leading to ocular morbidity and visual loss [98, 302]. Even though it is a comparatively rare extrapulmonary manifestation, ocular TB may be the first presentation of TB in initially asymptomatic patients, especially since 92% of patients with ocular TB present without evidence of concomitant pulmonary TB [303,304,305]. A RIF-loaded cationic nanoemulsion with specific surface modification employing chitosan and polymyxin B was found to be promising to overcome the hurdle of the blood‒retinal barrier of the eye that hinders the availability of ATD delivered by the systemic route [30, 98].
Phototherapy
An emerging technology with promising application in TB therapy is combining ATDs with other treatment modalities, such as photodynamic and photothermal therapies [306, 307]. For instance, a targeted antibiotic-delivering nanoassembly was shown to exert chemo-photothermal therapy [307]. The core of the nanoassembly was composed of near-infrared (NIR) active gold nanorods (GNRs) coated with MSNs, which served as the carrier for bedaquiline. The assembly was wrapped within a thermosensitive liposome (TSL) conjugated to the mycobacteria-targeting peptide NZX, which mediated adhesion of the final nanoassembly on the mycobacterial surface and had intrinsic antibacterial activity. Upon NIR exposure, TSL undergoes a phase transition, becoming permeable due to the heat generated from the GNRs, releasing encapsulated bedaquiline. Hyperthermia also plays a role in increasing bacterial cell membrane permeability, causing leakage of bacterial cell contents and subsequent bacterial cell death. The final nanoassembly demonstrated remarkable antibacterial activity against M. smegmatis, which was 20-fold more efficacious than the free drug equivalent. Moreover, it successfully inhibited the growth of intracellular mycobacteria residing in lung cells, underlying its potential to treat latent pulmonary TB. The engineered nanoassembly was able to (1) control remote trigger release of encapsulated ATD upon exposure to NIR laser by melting of TSL, (2) increase internalization into infected host cells through TSL coating and offer targeted ATD delivery to the bacterial cell surface by NZX targeting peptide, thereby reducing off-target toxicity, and (3) demonstrate synergistic antibacterial activity due to encapsulated ATD and photothermal activity [307]. Furthermore, combined chemo-photothermal therapy based on an enzyme-responsive nanosystem could be a promising approach to combat drug-resistant bacteria[308]. Even photodynamic therapy could be a new option for the treatment of MDR- and XDR-TB, as it was able to inactivate M. tuberculosis clinical strains regardless of the drug resistance levels of the bacilli [8].
Immunotherapy
The immune system significantly impacts TB recognition, occurrence, development, and outcome. The disease's progression depends on genetics and environmental factors. In the initial stages, innate immune clearance is involved, while macrophages, neutrophils, dendritic cells, T cells, and NK cells form the first line of defense [309]. The interaction between host immunity and mycobacterial invasiveness affects the immune system response. If the invasiveness of bacilli is weak, macrophages eliminate it, generating trained immunity. If mycobacterial invasiveness is balanced with host immunity, bacilli may replicate, spread, and become active TB. TB-specific immunotherapy is needed to regulate the immune system's anti-TB response. Cytokines such as IL-2, IL-24, and IL-32 can be therapeutic targets against TB [310,311,312,313,314]. IL-2, a Th1 immune response cytokine, induces differential gene expression in peripheral blood mononuclear cells (PBMCs) stimulated by TB. Administration of rhuIL-2 immunoadjuvant enhances CD4 + T-cell proliferation and NK cell proliferation, improving the sputum bacterium-negative rate in MDR-TB patients. A multicenter clinical trial on rhuIL-2 as an adjuvant therapy for MDR-TB is being conducted in China (ClinicalTrials.gov Identifier: NCT03069534). IL-24, a novel tumor suppressor, inhibits IL-24 expression in human PBMCs, increasing susceptibility to TB [314,315,316,317]. NK cells, T cells, and macrophages play a crucial role in combating TB. IL-24 activates CD8 + T cells, producing IFN-γ and IL-32, which induce inflammatory cytokines such as IL-1, IL-6, IL-8, and TNF-α. Heat-killed TB stimulates PBMCs to produce IL-32, enhancing clearance by monocyte macrophages. Anti-TB antibodies also have protective effects on anti-TB immunity [318,319,320,321]. Antimicrobial peptides, small molecule peptides, can enter cells through the skin and placenta exhibiting bactericidal and immunotherapeutic effects on TB [322].
Antigens can alert immune cells and precipitate an immunological reaction [323]. If these antigens can be engineered in such a way that they target proteins of M. tuberculosis, such as ESAT-6, CFP-10, and TB 7.7, these antigens can be used effectively against TB bacilli [324]. Accordingly, amino acid polymers that self-assembled to form a hollow core-shaped nanobead were administered to TB patients and produced different cytokines, including IFN-γ, INF-α, IL-2, CCL3, and CCL11 [325]. The biopolyester and polyhydroxybutyrate beads were biocompatible, thereby minimizing adverse reactions. The evaluation of the engineered antigen was performed by interferon release assay [326]. This delivery system could not only be used for ATD delivery but also for TB diagnosis, especially in patients showing tuberculin skin test negative (TSTn) results, as it contains short overlapping synthetic peptides such as in the QuantiFERON-TB Gold in Tube test (QFT-GIT) [327].
Conclusion and future perspectives
In conclusion, advanced drug delivery approaches have the potential to revolutionize TB therapy by addressing the challenges associated with traditional treatment methods. By developing inexpensive and easy-to-administer delivery systems that offer extended drug release, dosing frequency could be reduced, thereby improving patient adherence. Direct targeting by selectivity toward both AM and tubercle bacilli using suitably designed drug carriers and specific ligands may counteract the ability of intracellular pathogens to evade antibiotic treatments. With better penetration of ATDs into lung cavities and necrotic lesions, the success rate of TB therapy could be increased. In recent years, there has been a rise in TB cases, particularly resistant forms, across the globe. Various strategies for combating TB have been established at different levels, including the WHO’s End-TB Strategy and the UN’s Sustainable Development Goals (SDGs) [328]. The ‘3P Project’ aims to unite researchers to develop a treatment strategy that lasts for at most one month for all forms of TB infections [329]. Remarkably, the Medicines Patent Pool (MPP) has facilitated the clinical development of promising investigational treatments for TB, such as sutezolid, a linezolid analog [330]. In addition to the prospect of new drugs for TB, a favorable approach has been to improve the aspects of drug delivery through technologies that can offer the flexibility to adopt better routes of administration, multiple drug encapsulation, sustained drug release, targeted drug delivery, enhanced permeability and retention along with a lower incidence of side effects [331]. This indeed has the potential to overcome patient nonadherence to long and frequent dosing regimens [275]. The challenges that need to be addressed with some of the current ATDs are their poor solubility, instability in gastric acid, and inability to penetrate AM, where the bacilli reside [14, 332].
Recently, a significant breakthrough has been made in the treatment of TB through the use of siRNA-loaded nanoparticles, which effectively silence genes specific to M. tuberculosis. Additionally, a lyophilized formulation of the emulsion-adjuvanted subunit ID93 with GLA-SE, a recombinant subunit antigen combined with a squalene emulsion containing glucopyranosyl lipid A (GLA), has shown promise in a phase 1 clinical trial (Clinical trials.gov identifier: NCT03722472). This thermostable vaccine formulation demonstrated safety and immunogenicity in healthy adults. Similar technology-based formulations have also undergone clinical trials (Clinical trials.gov identifiers: NCT01599897, NCT01927159, NCT02465216, NCT02508376, and NCT03722472), and updates on these trials and development status can be accessed through The Working Group on New TB Vaccines (WGNV) database (https://newtbvaccines.org/tb-vaccine-pipeline/).
Another formulation, a liposome suspension known as RUTI®, containing a mixture of antigens, is actively recruiting patients for phase 2 clinical trials (Clinical trials.gov identifier: NCT04919239). These advancements highlight the potential of advanced drug delivery strategies in addressing the challenges of TB treatment. Despite the promising research activity, progress in clinical trials has been relatively slow.
To further advance the field, it is imperative to focus on addressing research gaps related to drug delivery systems for TB management. These gaps include the need for targeted delivery to specific cells and tissues, enhancing drug bioavailability, optimizing drug release kinetics from delivery systems, ensuring biocompatibility and biodegradability, addressing immunogenicity concerns, enabling personalized medicine approaches, exploring combination therapy benefits, considering cost-effectiveness, navigating regulatory approval processes, promoting successful clinical translations and validations, and fostering interdisciplinary collaboration.
In conclusion, while recent developments in TB treatment using advanced drug delivery strategies are encouraging, continued efforts are required to bridge the gap between research advancements and clinical application. By focusing on the aspects, the field of TB drug delivery can overcome challenges and contribute to more effective and accessible treatment options for patients worldwide.
Data availability
Not applicable.
Abbreviations
- AM:
-
Alveolar macrophages
- ATDs:
-
Anti-tubercular drugs
- CCL11:
-
Chemokine (C-C motif) ligand 11
- CCL3:
-
Chemokine (C-C motif) ligand 3
- CDs:
-
Cyclodextrins
- CFU:
-
Colony-forming units
- CRISPR:
-
Clustered regularly interspaced short palindromic repeats
- CS-g-PCL:
-
Chitosan-graft-poly-ε-caprolactone
- DNA:
-
Deoxyribose nucleic acid
- DoE:
-
Design of experiment
- DOTAP:
-
1,2-dioleyl-3-trimethyl-ammonium-propane
- DOTAP:
-
N-(1-(2,3-Dioleoyloxy)propyl)-N,N,Ntrimethylammonium methyl-sulfate
- DOTS:
-
Directly observed treatment short-course
- DprE1:
-
Decaprenylphosphoryl-β-d-ribose 2’-epimerase
- DPI:
-
Dry powder inhaler
- EGCG:
-
Epigallocatechin gallate
- EGCG-t-MS:
-
Microencapsulated EGCG with trehalose sugar
- ELISA:
-
Enzyme-linked immunosorbent assay
- FDA:
-
Food and Drug Administration
- FPR:
-
Formyl peptide receptor
- GLA:
-
Glucopyranosyl lipid A
- GNPs:
-
Gold nanoparticles
- GNR:
-
Gold nanorods
- GPs:
-
Glucan particles
- GRAS:
-
Generally Recognized As Safe
- GQDs:
-
Graphene quantum dots
- HDP:
-
Host defence peptide
- HP- β -CD:
-
Hydroxypropyl- β -CD
- IFN-γ:
-
Interferon gamma
- IL-2:
-
Interleukin 2
- I.M:
-
Intramuscular
- INH:
-
Isoniazid
- INVITE:
-
Inulin functionalized with vitamin E
- INVITESA:
-
Inulin functionalized with a vitamin E succinylated derivative
- I.V:
-
Intravenous
- LAI:
-
Long-acting injectables
- MBG:
-
Mesoporous bioactive glass
- MDR:
-
Multidrug resistant
- MIC:
-
Minimum inhibitory concentration
- MO:
-
Monoolein
- MOF:
-
Metal organic framework
- MP:
-
Microparticles
- MPP:
-
Medicines Patent Pool
- MSNs:
-
Mesoporous silica nanoparticles
- MWCNTs:
-
Multiwall carbon nanotubes
- NPs:
-
Nanoparticles
- NDDS:
-
Novel drug delivery systems
- NIR:
-
Near infrared
- NSCLC:
-
Non-small cell lung cancer
- PAMAM:
-
Poly(amidoamine)
- PBCA:
-
Poly(butyl cyanoacrylate)
- PBMCs:
-
Peripheral blood mononuclear cells
- PCL:
-
Poly-caprolactone
- PEA:
-
Poly(ester amine)
- PEG:
-
Polyethylene glycol
- PEHAM:
-
Poly(ether hydroxylamine)
- PEI:
-
Polyethyleneimine
- PEO-PPO:
-
Polyethylene oxide- polypropylene oxide
- PHBHHx:
-
Poly(3hydroxybutyrate-co-3-hydroxyhexonate)
- PIBCA:
-
Poly(isobutyl cyanoacrylate)
- PLGA:
-
Polylactic co glycolic acid
- PPI:
-
Poly (propylene imine)
- PVA:
-
Polyvinyl alcohol
- PVP:
-
Polyvinylpyrrolidone
- QFT-GIT:
-
QuantiFERON-TB Gold in Tube test
- RIF:
-
Rifampicin
- SDEDDS:
-
Self-double-emulsifying drug delivery systems
- SDGs:
-
Sustainable development goals
- si RNA:
-
Small interfering RNA
- SLNs:
-
Solid lipid nanoparticles
- SNPs:
-
Solid nanoparticles
- TB:
-
Tuberculosis
- TGF:
-
Transforming growth factor
- TSL:
-
Thermosensitive liposome
- TSTn:
-
Tuberculin skin test negative
- XDR:
-
Extensive drug resistance
- β -CD:
-
β -Cyclodextrins
References
Zignol M, Gemert Wv, Falzon D, Sismanidis C, Glaziou P, Floyd K, Raviglione M. Surveillance of anti-tuberculosis drug resistance in the world: an updated analysis, 2007–2010. Bull World Health Organ. 2012;90:111–9.
Migliori GB, Raviglione MC. Essential tuberculosis. Cham: Springer; 2021.
Shukla R, Sethi A, Handa M, Mohan M, Tripathi PK, Kesharwani P. Dendrimer-based drug delivery systems for tuberculosis treatment. In: Kesharwani Prashant, editor. Nanotechnology based approaches for tuberculosis treatment. Amsterdam: Elsevier; 2020.
Organization WH: Global tuberculosis report 2013: World Health Organization; 2013.
WHO G: Global tuberculosis report 2020. Glob Tuberc Rep 2020.
Tuberculosis. https://www.who.int/news-room/fact-sheets/detail/tuberculosis
More MP, Chitalkar RV, Bhadane MS, Dhole SD, Patil AG, Patil PO, Deshmukh PK. Development of graphene-drug nanoparticle based supramolecular self assembled pH sensitive hydrogel as potential carrier for targeting MDR tuberculosis. Mater Technol. 2019;34(6):324–35.
Sung N, Back S, Jung J, Kim K-H, Kim J-K, Lee JH, Ra Y, Yang HC, Lim C, Cho S. Inactivation of multidrug resistant (MDR)-and extensively drug resistant (XDR)-Mycobacterium tuberculosis by photodynamic therapy. Photodiagn Photodyn Ther. 2013;10(4):694–702.
Costa A, Pinheiro M, Magalhães J, Ribeiro R, Seabra V, Reis S, Sarmento B. The formulation of nanomedicines for treating tuberculosis. Adv Drug Deliv Rev. 2016;102:102–15.
Vinod V, Pushkaran AC, Kumar A, Mohan CG, Biswas R. 2021 Interaction mechanism of Mycobacterium tuberculosis GroEL2 protein with macrophage Lectin-like, oxidized low-density lipoprotein receptor-1: an integrated computational and experimental study. Biochimica et Biophysica Acta Gen Subj. 1865;1:129758.
Krishnan N, Robertson BD, Thwaites G. The mechanisms and consequences of the extra-pulmonary dissemination of Mycobacterium tuberculosis. Tuberculosis. 2010;90(6):361–6.
Sia IG, Wieland ML. Current concepts in the management of tuberculosis. In: Beckman Thomas J, editor. Mayo clinic proceedings. Amsterdam: Elsevier; 2011.
Vinod V, Vijayrajratnam S, Vasudevan AK, Biswas R. The cell surface adhesins of Mycobacterium tuberculosis. Microbiol Res. 2020;232:126392.
Kirtane AR, Verma M, Karandikar P, Furin J, Langer R, Traverso G. Nanotechnology approaches for global infectious diseases. Nat Nanotechnol. 2021;16(4):369–84.
Paulose RR, Kumar VA, Sharma A, Damle A, Saikumar D, Sudhakar A, Koshy AK, Venu RP. An outcome-based composite approach for the diagnosis of intestinal tuberculosis: a pilot study from a tertiary care centre in South India. J Royal Coll Phys Edinb. 2021;51(4):344–50.
Saktiawati AM, Sturkenboom MG, Stienstra Y, Subronto YW, Kosterink JG, van der Werf TS, Alffenaar J-WC. Impact of food on the pharmacokinetics of first-line anti-TB drugs in treatment-naive TB patients: a randomized cross-over trial. J Antimicrob Chemother. 2016;71(3):703–10.
Prameswari A. The evaluation of directly observed treatment short-course (DOTS) implementation for TB in hospital X. J Medicoeticolegal dan Manaj Rumah Sakit. 2018;7(2):93–101. https://doi.org/10.18196/jmmr.7261.
Pal S, Soni V, Kumar S, Jha SK, Medatwal N, Rana K, Yadav P, Mehta D, Jain D, Sharma P. A hydrogel-based implantable multidrug antitubercular formulation outperforms oral delivery. Nanoscale. 2021;13(31):13225–30.
Connolly LE, Edelstein PH, Ramakrishnan L. Why is long-term therapy required to cure tuberculosis? PLoS Med. 2007;4(3):e120. https://doi.org/10.1371/journal.pmed.0040120.
Gygli SM, Borrell S, Trauner A, Gagneux S. Antimicrobial resistance in Mycobacterium tuberculosis: mechanistic and evolutionary perspectives. FEMS Microbiol Rev. 2017;41(3):354–73.
Seung KJ, Keshavjee S, Rich ML. Multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis. Cold Spring Harbor Perspect Med. 2015. https://doi.org/10.1101/cshperspect.a017863.
Hickey A, Durham P, Dharmadhikari A, Nardell E. Inhaled drug treatment for tuberculosis: past progress and future prospects. J Control Release. 2016;240:127–34. https://doi.org/10.1016/j.jconrel.2015.11.018.
Braunstein M, Hickey AJ, Ekins S. Why wait? The case for treating tuberculosis with inhaled drugs. Pharm Res. 2019;36(12):1–6.
Organization WH. Latent tuberculosis infection: updated and consolidated guidelines for programmatic management. Geneva: World Health Organization; 2018.
Brhane Y, Gabriel T, Adane T, Negash Y, Mulugeta H, Ayele M. Recent developments and novel drug delivery strategies for the treatment of tuberculosis. Int J Pharm Sci Nanotechnol. 2019;12(3):4524–30.
Cohen J: Approval of novel TB drug celebrated—with restraint. In: American Association for the Advancement of Science; 2013.
Liu Y, Matsumoto M, Ishida H, Ohguro K, Yoshitake M, Gupta R, Geiter L, Hafkin J. Delamanid: from discovery to its use for pulmonary multidrug-resistant tuberculosis (MDR-TB). Tuberculosis. 2018;111:20–30.
Keam SJ. Pretomanid: first approval. Drugs. 2019;79(16):1797–803.
Kaur K, Gupta A, Narang R, Murthy R. Novel drug delivery systems: desired feat for tuberculosis. J Adv Pharm Technol Res. 2010;1(2):145.
Gairola A, Benjamin A, Weatherston JD, Cirillo JD, Wu HJ. Recent developments in drug delivery for treatment of tuberculosis by targeting macrophages. Adv Ther. 2022. https://doi.org/10.1002/adtp.202100193.
Borah Slater K, Kim D, Chand P, Xu Y, Shaikh H, Undale V. A current perspective on the potential of nanomedicine for anti-tuberculosis therapy. Trop Med Infect Dis. 2023;8(2):100.
Shirsath NR, Goswami AK. Nanocarriers based novel drug delivery as effective drug delivery: a review. Curr Nanomater. 2019;4(2):71–83.
Dhanjal DS, Mehta M, Chopra C, Singh R, Sharma P, Chellappan DK, Tambuwala MM, Bakshi HA, Aljabali AA, Gupta G. Novel controlled release pulmonary drug delivery systems: current updates and challenges. In: Azar Ahmad Taher, editor. Modeling and control of drug delivery systems. Amsterdam: Elsevier; 2021.
Gopalaswamy R, Shanmugam S, Mondal R, Subbian S. Of tuberculosis and non-tuberculous mycobacterial infections–a comparative analysis of epidemiology, diagnosis and treatment. J Biomed Sci. 2020;27(1):1–17.
Suresh P, Kumar A, Biswas R, Vijayakumar D, Thulasidharan S, Anjaneyan G, Kunoor A, Biswas L. Epidemiology of nontuberculous mycobacterial infection in tuberculosis suspects. Am J Trop Med Hyg. 2021. https://doi.org/10.4269/ajtmh.21-0095.
Singh C, Koduri L, Bhatt TD, Jhamb SS, Mishra V, Gill MS, Suresh S. In vitro-in vivo evaluation of novel co-spray dried rifampicin phospholipid lipospheres for oral delivery. AAPS PharmSciTech. 2017;18(1):138–46.
Denti P, Jeremiah K, Chigutsa E, Faurholt-Jepsen D, PrayGod G, Range N, Castel S, Wiesner L, Hagen CM, Christiansen M. Pharmacokinetics of isoniazid, pyrazinamide, and ethambutol in newly diagnosed pulmonary TB patients in Tanzania. PLoS ONE. 2015;10(10):e0141002.
Saifullah B, Chrzastek A, Maitra A, Naeemullah B, Fakurazi S, Bhakta S, Hussein MZ. Novel anti-tuberculosis nanodelivery formulation of ethambutol with graphene oxide. Molecules. 2017;22(10):1560.
Zhang M, Sala C, Hartkoorn RC, Dhar N, Mendoza-Losana A, Cole ST. Streptomycin-starved Mycobacterium tuberculosis 18b, a drug discovery tool for latent tuberculosis. Antimicrob Agents Chemother. 2012;56(11):5782–9.
Pijck J, Hallynck T, Soep H, Baert L, Daneels R, Boelaert J. Pharmacokinetics of amikacin in patients with renal insufficiency: relation of half-life and creatinine clearance. J Infect Dis. 1976;134(Supplement_2):S331–41. https://doi.org/10.1093/infdis/135.Supplement_2.S331.
Bunn PA. Kanamycin. Med Clin North Amer. 1970;54(5):1245–56. https://doi.org/10.1016/S0025-7125(16)32590-1.
Stein GE, LeBel M, Flor SC, Zinny M. Bioavailability and pharmacokinetics of oral ofloxacin formulations in normal subjects. Current Med Research Opinion. 1991;12(8):479–84. https://doi.org/10.1185/03007999109111658.
Fish DN, Chow AT. The clinical pharmacokinetics of levofloxacin. Clin Pharmacokin. 1997;32:101–19. https://doi.org/10.2165/00003088-199732020-00002.
Naidoo A, Naidoo K, McIlleron H, Essack S, Padayatchi N. A review of moxifloxacin for the treatment of drug-susceptible tuberculosis. J Clin Pharmacol. 2017;57(11):1369–86.
Begg EJ, Robson RA, Saunders DA, Graham GG, Buttimore RC, Neill AM, Town GI. The pharmacokinetics of oral fleroxacin and ciprofloxacin in plasma and sputum during acute and chronic dosing. British J Clin Pharmacol. 2000;49(1):32–8. https://doi.org/10.1046/j.1365-2125.2000.00105.x.
Drusano GL, Standiford HC, Plaisance K, Forrest A, Leslie J, Caldwell J. Absolute oral bioavailability of ciprofloxacin. Antimicro Agents Chemo. 1986;30(3):444–6. https://doi.org/10.1128/aac.30.3.444.
Traunmüller F, Zeitlinger M, Zeleny P, Müller M, Joukhadar C. Pharmacokinetics of single-and multiple-dose oral clarithromycin in soft tissues determined by microdialysis. Antimicro Agents Chemo. 2007;51(9):3185–9. https://doi.org/10.1128/aac.00532-07.
Patel DS, Sharma N, Patel MC, Patel BN, Shrivastav PS, Sanyal M. Development and validation of a selective and sensitive LC–MS/MS method for determination of cycloserine in human plasma: application to bioequivalence study. J Chrom B. 2011;879(23):2265–73. https://doi.org/10.1016/j.jchromb.2011.06.011.
Peloquin CA, Henshaw TL, Huitt GA, Berning SE, Nitta AT, James GT. Pharmacokinetic evaluation of para-aminosalicylic acid granules. Pharmaco J Human Pharmacol Drug Therapy. 1994;14(1):40–6. https://doi.org/10.1002/j.1875-9114.1994.tb02787.x.
Abdelwahab MT, Wasserman S, Brust JC, Gandhi NR, Meintjes G, Everitt D, Diacon A, Dawson R, Wiesner L, Svensson EM, Maartens G. Clofazimine pharmacokinetics in patients with TB: dosing implications. J Antimicro Chemo. 2020;75(11):3269–77. https://doi.org/10.1093/jac/dkaa310.
Dharmadhikari AS, Kabadi M, Gerety B, Hickey AJ, Fourie PB, Nardell E. Phase I, single-dose, dose-escalating study of inhaled dry powder capreomycin: a new approach to therapy of drug-resistant tuberculosis. Antimicrobial agents and chemotherapy. 2013;57(6):2613–9. https://doi.org/10.1128/aac.02346-12.
Ahmad M, Madni AU, Usman M. In-vitro release and pharmacokinetics of anti-tubercle drug ethionamide in healthy male subjects. J Bioanal Biomed. 2009;1:046–9. https://doi.org/10.4172/1948-593X.1000010.
Venkatesan K. Clinical pharmacokinetic considerations in the treatment of patients with leprosy. Clin Pharmaco. 1989;16:365–86. https://doi.org/10.2165/00003088-198916060-00003.
Yun HY, Chang MJ, Jung H, Chang V, Wang Q, Strydom N, Yoon YR, Savic RM. Prothionamide dose optimization using population pharmacokinetics for multidrug-resistant tuberculosis patients. Antimicro Agents Chemo. 2022;66(9):e01893–21. https://doi.org/10.1128/aac.01893-21.
Holdiness MR. Clinical pharmacokinetics of the antituberculosis drugs. Clin Pharmaco. 1984;9:511–44. https://doi.org/10.2165/00003088-198409060-00003.
Zitkova L, Tousek J. Pharmacokinetics of cycloserine and terizidone. Chemotherapy. 1974;20(18):28. https://doi.org/10.1159/000221787.
Skinner MH, Hsieh M, Torseth J, Pauloin D, Bhatia GU, Harkonen S, Merigan TC, Blaschke TF. Pharmacokinetics of rifabutin. Antimicro Agents Chemo. 1989;8:1237–41. https://doi.org/10.1128/aac.33.8.1237.
Stalker DJ, Jungbluth GL. Clinical pharmacokinetics of linezolid, a novel oxazolidinone antibacterial. Clin Pharmaco. 2003;42:1129–40. https://doi.org/10.2165/00003088-200342130-00004.
Chahine EB, Karaoui LR, Mansour H. Bedaquiline: a novel diarylquinoline for multidrug-resistant tuberculosis. Annals Pharmaco. 2014;48(1):107–15. https://doi.org/10.1177/1060028013504087.
Salinger DH, Subramoney V, Everitt D, Nedelman JR. Population pharmacokinetics of the antituberculosis agent pretomanid. Antimicro Agents Chemo. 2019;63(10):e00907–19. https://doi.org/10.1128/aac.00907-19.
Biswas B, Misra TK, Ray D, Majumder T, Bandyopadhyay TK, Bhowmick TK. Current therapeutic delivery approaches using nanocarriers for the treatment of tuberculosis disease. Int J Pharm. 2023. https://doi.org/10.1016/j.ijpharm.2023.123018.
Langer R. Drug delivery and targeting. Nature. 1998;392(6679 Suppl):5–10.
Mosaiab T, Farr DC, Kiefel MJ, Houston TA. Carbohydrate-based nanocarriers and their application to target macrophages and deliver antimicrobial agents. Adv Drug Deliv Rev. 2019;151:94–129.
Afinjuomo F, Abdella S, Youssef SH, Song Y, Garg S. Inulin and its application in drug delivery. Pharmaceuticals. 2021;14(9):855.
Putri KSS, Ramadhani LS, Rachel T, Suhariyono G, Surini S. Promising chitosan-alginate combination for rifampicin dry powder inhaler to target active and latent tuberculosis. J Appl Pharm Sci. 2022;12(5):098–103.
Longuinho MM, Leitão SG, Silva RS, Silva PE, Rossi AL, Finotelli PV. Lapazine loaded alginate/chitosan microparticles: enhancement of anti-mycobacterium activity. J Drug Deliv Sci Technol. 2019;54:101292.
Wolfram J, Zhu M, Yang Y, Shen J, Gentile E, Paolino D, Fresta M, Nie G, Chen C, Shen H. Safety of nanoparticles in medicine. Curr Drug Targets. 2015;16(14):1671–81.
Khairnar SV, Pagare P, Thakre A, Nambiar AR, Junnuthula V, Abraham MC, Kolimi P, Nyavanandi D, Dyawanapelly S. Review on the scale-up methods for the preparation of solid lipid nanoparticles. Pharmaceutics. 2022;14(9):1886.
Junnuthula V, Kolimi P, Nyavanandi D, Sampathi S, Vora LK, Dyawanapelly S. Polymeric micelles for breast cancer therapy: recent updates, clinical translation and regulatory considerations. Pharmaceutics. 2022;14(9):1860.
Sundar S, Chakravarty J. Liposomal amphotericin B and leishmaniasis: dose and response. J Global Infect Dis. 2010;2(2):159.
Mitchell SL, Carlson EE. Tiny things with enormous impact: nanotechnology in the fight against infectious disease. ACS Infect Dis. 2018;4(10):1432–5.
Desai N. Challenges in development of nanoparticle-based therapeutics. AAPS J. 2012;14(2):282–95.
Ioannidis J, Kim B, Trounson A. How to design preclinical studies in nanomedicine and cell therapy to maximize the prospects of clinical translation. Nat Biomed Eng. 2018;2(11):797–809.
Chimote G, Banerjee R. In vitro evaluation of inhalable isoniazid-loaded surfactant liposomes as an adjunct therapy in pulmonary tuberculosis. J Biomed Mater Res B Appl Biomater. 2010;94(1):1–10.
Karki R, Mamatha G, Subramanya G, Udupa N. Preparation, characterization and tissue disposition of niosomes containing isoniazid. Rasayan J Chem. 2008;1(2):224–7.
Singh G, Dwivedi H, Saraf SK, Saraf SA. Niosomal delivery of isoniazid-development and characterization. Trop J Pharm Res. 2011. https://doi.org/10.4314/tjpr.v10i2.66564.
Vatanparast M, Shariatinia Z. Computational studies on the doped graphene quantum dots as potential carriers in drug delivery systems for isoniazid drug. Struct Chem. 2018;29(5):1427–48.
Chen G, Wu Y, Yu D, Li R, Luo W, Ma G, Zhang C. Isoniazid-loaded chitosan/carbon nanotubes microspheres promote secondary wound healing of bone tuberculosis. J Biomater Appl. 2019;33(7):989–96.
Zomorodbakhsh S, Abbasian Y, Naghinejad M, Sheikhpour M. The effects study of isoniazid conjugated multi-wall carbon nanotubes nanofluid on Mycobacterium tuberculosis. Int J Nanomed. 2020;15:5901.
Fernández-Paz C, Fernández-Paz E, Salcedo-Abraira P, Rojas S, Barrios-Esteban S, Csaba N, Horcajada P, Remuñán-López C. Microencapsulated isoniazid-loaded metal-organic frameworks for pulmonary administration of antituberculosis drugs. Molecules. 2021;26(21):6408.
Anjani QK, Permana AD, Cárcamo-Martínez Á, Domínguez-Robles J, Tekko IA, Larrañeta E, Vora LK, Ramadon D, Donnelly RF. Versatility of hydrogel-forming microneedles in in vitro transdermal delivery of tuberculosis drugs. Eur J Pharm Biopharm. 2021;158:294–312.
Telange DR, Pandharinath RR, Pethe AM, Jain SP, Pingale PL. Calcium ion-sodium alginate-piperine-based microspheres: evidence of enhanced encapsulation efficiency, bio-adhesion, controlled delivery, and oral bioavailability of isoniazid. AAPS PharmSciTech. 2022;23(4):1–18.
Jain C, Vyas S. Preparation and characterization of niosomes containing rifampicin for lung targeting. J Microencapsul. 1995;12(4):401–7.
Jain C, Vyas S, Dixit V. Niosomal system for delivery of rifampicin to lymphatics. Indian J Pharm Sci. 2006. https://doi.org/10.4103/0250-474X.29622.
Kumar PV, Asthana A, Dutta T, Jain NK. Intracellular macrophage uptake of rifampicin loaded mannosylated dendrimers. J Drug Target. 2006;14(8):546–56.
Takenaga M, Ohta Y, Tokura Y, Hamaguchi A, Igarashi R, Disratthakit A, Doi N. Lipid microsphere formulation containing rifampicin targets alveolar macrophages. Drug Deliv. 2008;15(3):169–75.
Patil JS, Devi VK, Devi K, Sarasija S. A novel approach for lung delivery of rifampicin-loaded liposomes in dry powder form for the treatment of tuberculosis. Lung India. 2015;32(4):331.
Bellini RG, Guimarães AP, Pacheco MA, Dias DM, Furtado VR, de Alencastro RB, Horta BA. Association of the anti-tuberculosis drug rifampicin with a PAMAM dendrimer. J Mol Graph Model. 2015;60:34–42.
Parmar R, Misra R, Mohanty S. In vitro controlled release of Rifampicin through liquid-crystalline folate nanoparticles. Colloids Surf, B. 2015;129:198–205.
Rajabnezhad S, Casettari L, Lam JK, Nomani A, Torkamani MR, Palmieri GF, Rajabnejad MR, Darbandi MA. Pulmonary delivery of rifampicin microspheres using lower generation polyamidoamine dendrimers as a carrier. Powder Technol. 2016;291:366–74.
Tran N, Hocquet M, Eon B, Sangwan P, Ratcliffe J, Hinton TM, White J, Ozcelik B, Reynolds NP, Muir BW. Non-lamellar lyotropic liquid crystalline nanoparticles enhance the antibacterial effects of rifampicin against Staphylococcus aureus. J Colloid Interface Sci. 2018;519:107–18.
Ola M, Bhaskar R, Patil GR. Liquid crystalline drug delivery system for sustained release loaded with an antitubercular drug. J Drug Deliv Ther. 2018;8(4):93–101.
Thomas D, Latha M, Thomas KK. Synthesis and in vitro evaluation of alginate-cellulose nanocrystal hybrid nanoparticles for the controlled oral delivery of rifampicin. J Drug Deliv Sci Technol. 2018;46:392–9.
Tripodo G, Perteghella S, Grisoli P, Trapani A, Torre ML, Mandracchia D. Drug delivery of rifampicin by natural micelles based on inulin: physicochemical properties, antibacterial activity and human macrophages uptake. Eur J Pharm Biopharm. 2019;136:250–8.
Suárez-González J, Santoveña-Estévez A, Soriano M, Fariña JB. Design and optimization of a child-friendly dispersible tablet containing isoniazid, pyrazinamide, and rifampicin for treating tuberculosis in pediatrics. Drug Develop Indus Pharm. 2020;46(2):309–17. https://doi.org/10.1080/03639045.2020.1717516.
Grotz E, Tateosian NL, Salgueiro J, Bernabeu E, Gonzalez L, Manca ML, Amiano N, Valenti D, Manconi M, García V. Pulmonary delivery of rifampicin-loaded soluplus micelles against Mycobacterium tuberculosis. J Drug Deliv Sci Technol. 2019;53:101170.
Pi J, Shen L, Shen H, Yang E, Wang W, Wang R, Huang D, Lee B-S, Hu C, Chen C. Mannosylated graphene oxide as macrophage-targeted delivery system for enhanced intracellular M. tuberculosis killing efficiency. Mater Sci Eng C. 2019;103:109777.
Henostroza MAB, Melo KJC, Yukuyama MN, Löbenberg R, Bou-Chacra NA. Cationic rifampicin nanoemulsion for the treatment of ocular tuberculosis. Colloids Surf A. 2020;597:124755.
El-Ridy MS, Yehia SA, Kassem MA-E-M, Mostafa DM, Nasr EA, Asfour MH. Niosomal encapsulation of ethambutol hydrochloride for increasing its efficacy and safety. Drug Deliv. 2015;22(1):21–36.
Nemati E, Mokhtarzadeh A, Panahi-Azar V, Mohammadi A, Hamishehkar H, Mesgari-Abbasi M, Ezzati Nazhad Dolatabadi J, de la Guardia M. Ethambutol-loaded solid lipid nanoparticles as dry powder inhalable formulation for tuberculosis therapy. AAPS PharmSciTech. 2019;20(3):1–9.
Vladimirsky M, Ladigina G. Antibacterial activity of liposome-entrapped streptomycin in mice infected with Mycobacterium tuberculosis. Biomed Pharmacotherap. 1982;36(8–9):375–7.
Cynamon MH, Swenson CE, Palmer GS, Ginsberg RS. Liposome-encapsulated-amikacin therapy of Mycobacterium avium complex infection in beige mice. Antimicrob Agents Chemother. 1989;33(8):1179–83. https://doi.org/10.1128/aac.33.8.1179.
Gaidukevich S, Mikulovich YL, Smirnova T, Andreevskaya S, Sorokoumova G, Chernousova L, Selishcheva A, Shvets V. Antibacterial effects of liposomes containing phospholipid cardiolipin and fluoroquinolone levofloxacin on Mycobacterium tuberculosis with extensive drug resistance. Bull Exp Biol Med. 2016;160(5):675–8.
Gaspar M, Cruz A, Penha A, Reymão J, Sousa A, Eleutério C, Domingues S, Fraga A, Longatto Filho A, Cruz M. Rifabutin encapsulated in liposomes exhibits increased therapeutic activity in a model of disseminated tuberculosis. Int J Antimicrob Agents. 2008;31(1):37–45.
Gaspar MM, Neves S, Portaels F, Pedrosa J, Silva MT, Cruz MEM. Therapeutic efficacy of liposomal rifabutin in a Mycobacterium avium model of infection. Antimicrob Agents Chemother. 2000;44(9):2424–30.
Sandler ED, Ng V, Hadley W. Clofazimine crystals in alveolar macrophages from a patient with the acquired immunodeficiency syndrome. Arch Pathol Lab Med. 1992;116(5):541–3.
Mehta RT. Liposome encapsulation of clofazimine reduces toxicity in vitro and in vivo and improves therapeutic efficacy in the beige mouse model of disseminated Mycobacterium avium-M. intracellulare complex infection. Antimicrob Agents Chemother. 1996;40(8):1893–902.
Kansal RG, Gomez-Flores R, Sinha I, Mehta RT. Therapeutic efficacy of liposomal clofazimine against Mycobacterium avium complex in mice depends on size of initial inoculum and duration of infection. Antimicrob Agents Chemother. 1997;41(1):17–23.
Adams LB, Sinha I, Franzblau SG, Krahenbuhl JL, Mehta RT. Effective treatment of acute and chronic murine tuberculosis with liposome-encapsulated clofazimine. Antimicrob Agents Chemother. 1999;43(7):1638–43.
de Castro RR, Todaro V, da Silva LCRP, Simon A, do Carmo FA, de Sousa VP, Rodrigues CR, Sarmento B, Healy AM, Cabral LM. Development of inhaled formulation of modified clofazimine as an alternative to treatment of tuberculosis. J Drug Deliv Sci Technol. 2020;58:101805.
Kisich K, Gelperina S, Higgins M, Wilson S, Shipulo E, Oganesyan E, Heifets L. Encapsulation of moxifloxacin within poly (butyl cyanoacrylate) nanoparticles enhances efficacy against intracellular Mycobacterium tuberculosis. Int J Pharm. 2007;345(1–2):154–62.
Costa-Gouveia J, Pancani E, Jouny S, Machelart A, Delorme V, Salzano G, Iantomasi R, Piveteau C, Queval CJ, Song O-R. Combination therapy for tuberculosis treatment: pulmonary administration of ethionamide and booster co-loaded nanoparticles. Sci Rep. 2017;7(1):1–14.
Garcia-Contreras L, Padilla-Carlin DJ, Sung J, VerBerkmoes J, Muttil P, Elbert K, Peloquin C, Edwards D, Hickey A. Pharmacokinetics of ethionamide delivered in spray-dried microparticles to the lungs of guinea pigs. J Pharm Sci. 2017;106(1):331–7.
De Maio F, Palmieri V, Santarelli G, Perini G, Salustri A, Palucci I, Sali M, Gervasoni J, Primiano A, Ciasca G. Graphene oxide-linezolid combination as potential new anti-tuberculosis treatment. Nanomaterials. 2020;10(8):1431.
Sercombe L, Veerati T, Moheimani F, Wu S, Sood A, Hua S. 2015 Advances and challenges of liposome assisted drug delivery. Front Pharmacol. 2015;6:286.
Orozco LC, Quintana FO, Beltrán RM, de Moreno I, Wasserman M, Rodriguez G. The use of rifampicin and isoniazid entrapped in liposomes for the treatment of murine tuberculosis. Tubercle. 1986;67(2):91–7.
Bhardwaj A, Kumar L, Narang RK, Murthy RS. Development and characterization of ligand-appended liposomes for multiple drug therapy for pulmonary tuberculosis. Artificial cells, nanomedicine, and biotechnology. 2013;41(1):52–59. https://doi.org/10.3109/10731199.2012.702316.
Liu P, Guo B, Wang S, Ding J, Zhou W. A thermo-responsive and self-healing liposome-in-hydrogel system as an antitubercular drug carrier for localized bone tuberculosis therapy. Int J Pharm. 2019;558:101–9.
Bhardwaj A, Grobler A, Rath G, Kumar Goyal A, Kumar Jain A, Mehta A. Pulmonary delivery of anti-tubercular drugs using ligand anchored pH sensitive liposomes for the treatment of pulmonary tuberculosis. Curr Drug Deliv. 2016;13(6):909–22.
Greco E, Quintiliani G, Santucci MB, Serafino A, Ciccaglione AR, Marcantonio C, Papi M, Maulucci G, Delogu G, Martino A. Janus-faced liposomes enhance antimicrobial innate immune response in Mycobacterium tuberculosis infection. Proc Natl Acad Sci. 2012;109(21):E1360–8.
Miretti M, Juri L, Cosiansi MC, Tempesti TC, Baumgartner MT. Antimicrobial effects of ZnPc delivered into liposomes on multidrug resistant (MDR)-mycobacterium tuberculosis. ChemistrySelect. 2019;4(33):9726–30.
Rosada RS, Silva CL, Santana MHA, Nakaie CR, de la Torre LG. Effectiveness, against tuberculosis, of pseudo-ternary complexes: peptide-DNA-cationic liposome. J Colloid Interface Sci. 2012;373(1):102–9.
Bekraki AI. Liposomes-and niosomes-based drug delivery systems for tuberculosis treatment. In: Kesharwani Prashant, editor. Nanotechnology based approaches for tuberculosis treatment. Amsterdam: Elsevier; 2020.
Patil K, Bagade S, Bonde S, Sharma S, Saraogi G. Recent therapeutic approaches for the management of tuberculosis: challenges and opportunities. Biomed Pharmacother. 2018;99:735–45. https://doi.org/10.1016/j.biopha.2018.01.115.
Kaur IP, Singh H. Nanostructured drug delivery for better management of tuberculosis. J Control Release. 2014;184:36–50.
Bibhas C, Narahari N. Exploring the use of lipid based nano-formulations for the management of tuberculosis. J Nanosci Curr Res. 2017;2(112):2572–813.
Bibhas C, Subas C, Gitanjali M, Narahari N. Exploring the use of lipid based nano-formulations for the management of tuberculosis. J Nanosci Curr Res. 2017;2(112):2572–813.
Hanieh PN, Consalvi S, Forte J, Cabiddu G, De Logu A, Poce G, Rinaldi F, Biava M, Carafa M, Marianecci C. Nano-based drug delivery systems of potent MmpL3 inhibitors for tuberculosis treatment. Pharmaceutics. 2022;14(3):610.
Sadhu PK, Saisivam S, Debnath SK. Design and characterization of niosomes of ethionamide for multi drug resistance tuberculosis. 2019.
Kulkarni P, Rawtani D, Barot T. Formulation and optimization of long acting dual niosomes using box-Behnken experimental design method for combinative delivery of ethionamide and D-cycloserine in tuberculosis treatment. Colloids Surf A. 2019;565:131–42.
Hussain A, Singh S, Das SS, Anjireddy K, Karpagam S, Shakeel F. Nanomedicines as drug delivery carriers of anti-tubercular drugs: from pathogenesis to infection control. Curr Drug Deliv. 2019;16(5):400–29.
Van Zyl L, Viljoen JM, Haynes RK, Aucamp M, Ngwane AH, du Plessis J. Topical delivery of artemisone, clofazimine and decoquinate encapsulated in vesicles and their in vitro efficacy against Mycobacterium tuberculosis. AAPS PharmSciTech. 2019;20(1):1–11.
Eldehna WM, El Hassab MA, Abdelshafi NA, Sayed FA-Z, Fares M, Al-Rashood ST, Elsayed ZM, Abdel-Aziz MM, Elkaeed EB, Elsabahy M. Development of potent nanosized isatin-isonicotinohydrazide hybrid for management of Mycobacterium tuberculosis. Int J Pharm. 2022;612:121369.
Emami F, Vatanara A, Park EJ, Na DH. Drying technologies for the stability and bioavailability of biopharmaceuticals. Pharmaceutics. 2018;10(3):131.
Marzaman AN, Roska TP, Sartini S, Utami RN, Sulistiawati S, Enggi CK, Manggau MA, Rahman L, Shastri VP, Permana AD. Recent advances in pharmaceutical approaches of antimicrobial agents for selective delivery in various administration routes. Antibiotics. 2023;12(5):822. https://doi.org/10.3390/antibiotics12050822.
Dua K, Rapalli VK, Shukla SD, Singhvi G, Shastri MD, Chellappan DK, Satija S, Mehta M, Gulati M, Pinto TDJA. Multi-drug resistant Mycobacterium tuberculosis & oxidative stress complexity: emerging need for novel drug delivery approaches. Biomed Pharmacother. 2018;107:1218–29.
Kim SY, Park MS, Kim YS, Kim SK, Chang J, Lee HJ, Cho SN, Kang YA. The responses of multiple cytokines following incubation of whole blood from TB patients, latently infected individuals and controls with the TB antigens ESAT‐6, CFP‐10 and TB 7.7. Scand J Immunol. 2012;76(6):580–86. https://doi.org/10.1111/j.1365-3083.2012.02776.x.
Patil SM, Sawant SS, Kunda NK. Inhalable bedaquiline-loaded cubosomes for the treatment of non-small cell lung cancer (NSCLC). Int J Pharm. 2021;607:121046.
Anjani QK, Domínguez-Robles J, Utomo E, Font M, Martínez-Ohárriz MC, Permana AD, Cárcamo-Martínez Á, Larrañeta E, Donnelly RF. Inclusion complexes of rifampicin with native and derivatized cyclodextrins: in silico modeling, formulation, and characterization. Pharmaceuticals. 2021;15(1):20.
Amarnath Praphakar R, Sam Ebenezer R, Vignesh S, Shakila H, Rajan M. Versatile pH-responsive chitosan-g-polycaprolactone/maleic anhydride–isoniazid polymeric micelle to improve the bioavailability of tuberculosis multidrugs. ACS Appl Bio Mater. 2019;2(5):1931–43.
Kaur J, Mishra V, Singh SK, Gulati M, Kapoor B, Chellappan DK, Gupta G, Dureja H, Anand K, Dua K. Harnessing amphiphilic polymeric micelles for diagnostic and therapeutic applications: breakthroughs and bottlenecks. J Control Release. 2021;334:64–95.
Yuan X, Praphakar RA, Munusamy MA, Alarfaj AA, Kumar SS, Rajan M. Mucoadhesive guargum hydrogel inter-connected chitosan-g-polycaprolactone micelles for rifampicin delivery. Carbohyd Polym. 2019;206:1–10.
Sheth U, Tiwari S, Bahadur A. Preparation and characterization of anti-tubercular drugs encapsulated in polymer micelles. J Drug Deliv Sci Technol. 2018;48:422–8.
Garg NK, Dwivedi P, Jain A, Tyagi S, Sahu T, Tyagi RK. Development of novel carrier (s) mediated tuberculosis vaccine: more than a tour de force. Eur J Pharm Sci. 2014;62:227–42.
Danhier F, Ansorena E, Silva JM, Coco R, Le Breton A, Préat V. PLGA-based nanoparticles: an overview of biomedical applications. J Control Release. 2012;161(2):505–22.
Gu X, Cheng Q, He P, Zhang Y, Jiang Z, Zeng Y. Dihydroartemisinin-loaded chitosan nanoparticles inhibit the rifampicin-resistant mycobacterium tuberculosis by disrupting the cell wall. Front Microbiol. 2021. https://doi.org/10.3389/fmicb.2021.735166/full.
Abdallah HM, Elella MHA, Abdel-Aziz MM. One-pot green synthesis of chitosan biguanidine nanoparticles for targeting M. tuberculosis. Int J Biol Macromol. 2023;232:123394.
Anisimova YV, Gelperina SI, Peloquin CA, Heifets LB. Nanoparticles as antituberculosis drugs carriers: effect on activity against Mycobacterium tuberculosis in human monocyte-derived macrophages. J Nanopart Res. 2000;2:165–71. https://doi.org/10.1023/A:1010061013365.
Scolari IR, Páez PL, Sánchez-Borzone ME, Granero GE. Promising chitosan-coated alginate-tween 80 nanoparticles as rifampicin coadministered ascorbic acid delivery carrier against Mycobacterium tuberculosis. AAPS PharmSciTech. 2019;20(2):1–21.
Nagpal PS, Kesarwani A, Sahu P, Upadhyay P. Aerosol immunization by alginate coated mycobacterium (BCG/MIP) particles provide enhanced immune response and protective efficacy than aerosol of plain mycobacterium against M. tb. H37Rv infection in mice. BMC Infect Dis. 2019;19(1):1–14.
Kesarwani A, Sahu P, Jain K, Sinha P, Mohan KV, Nagpal PS, Singh S, Zaidi R, Nagarajan P, Upadhyay P. The safety and efficacy of BCG encapsulated alginate particle (BEAP) against M. tb H37Rv infection in macaca mulatta: a pilot study. Sci Rep. 2021;11(1):1–10.
Najafi A, Ghazvini K, Sankian M, Gholami L, Amini Y, Zare S, Khademi F, Tafaghodi M. T helper type 1 biased immune responses by PPE17 loaded core-shell alginate-chitosan nanoparticles after subcutaneous and intranasal administration. Life Sci. 2021;282:119806.
Kushwaha K, Dwivedi H. Interfacial phenomenon based biocompatible alginate-chitosan nanoparticles containing isoniazid and pyrazinamide. Pharm Nanotechnol. 2018;6(3):209–17.
Soria-Carrera H, Lucía A, De Matteis L, Aínsa JA, de la Fuente JM, Martín-Rapún R. Polypeptidic micelles stabilized with sodium alginate enhance the activity of encapsulated bedaquiline. Macromol Biosci. 2019;19(4):1800397.
Latha M, Kurienthomas K. Zinc-alginate beads for the controlled release of rifampici. Orient J Chem. 2018;34(1):428.
Chen C-C, Chen Y-Y, Yeh C-C, Hsu C-W, Yu S-J, Hsu C-H, Wei T-C, Ho S-N, Tsai P-C, Song Y-D. Alginate-capped silver nanoparticles as a potent anti-mycobacterial agent against mycobacterium tuberculosis. Front Pharmacol. 2021. https://doi.org/10.3389/fphar.2021.746496/full.
Liu Z, Ye L, Xi J, Wang J, Feng Z-G. Cyclodextrin polymers: structure, synthesis, and use as drug carriers. Prog Poly Sci. 2021;118:101408.
Abdellatif FHH, Abdellatif MM. Utilization of sustainable biopolymers in textile processing. In: Ibrahim Nabil, Hussain Chaudhery Mustansar, editors. Green chemistry for sustainable textiles. Amsterdam: Elsevier; 2021.
Tiwari G, Tiwari R, Rai AK. Cyclodextrins in delivery systems: applications. J Pharm Bioall Sci. 2010;2(2):72–9.
Crini G. A history of cyclodextrins. Chem Rev. 2014;114(21):10940–75.
Basha RY, TS SK, Doble M. Dual delivery of tuberculosis drugs via cyclodextrin conjugated curdlan nanoparticles to infected macrophages. Carbohydr Polym. 2019;218:53–62.
Nkanga CI, Krause RWM. Encapsulation of isoniazid-conjugated phthalocyanine-in-cyclodextrin-in-liposomes using heating method. Sci Rep. 2019;9(1):1–16.
Maiti PK, Çaǧın T, Wang G, Goddard WA. Structure of PAMAM dendrimers: generations 1 through 11. Macromolecules. 2004;37(16):6236–54.
Kaur D, Jain K, Mehra NK, Kesharwani P, Jain NK. A review on comparative study of PPI and PAMAM dendrimers. J Nanopart Res. 2016;18(6):1–14.
Bapat RA, Joshi CP, Bapat P, Chaubal TV, Pandurangappa R, Jnanendrappa N, Gorain B, Khurana S, Kesharwani P. The use of nanoparticles as biomaterials in dentistry. Drug Discov Today. 2019;24(1):85–98.
Madaan K, Kumar S, Poonia N, Lather V, Pandita D. Dendrimers in drug delivery and targeting: drug-dendrimer interactions and toxicity issues. J Pharm Bioall Sci. 2014;6(3):139.
Chauhan AS. Dendrimers for drug delivery. Molecules. 2018;23(4):938.
Menjoge AR, Kannan RM, Tomalia DA. Dendrimer-based drug and imaging conjugates: design considerations for nanomedical applications. Drug Discov Today. 2010;15(5–6):171–85.
Wang J, Li B, Qiu L, Qiao X, Yang H. Dendrimer-based drug delivery systems: history, challenges, and latest developments. J Biol Eng. 2022;16(1):1–12.
Parekh H. The advance of dendrimers-a versatile targeting platform for gene/drug delivery. Curr Pharm Des. 2007;13(27):2837–50.
Choudhary S, Gupta L, Rani S, Dave K, Gupta U. Impact of dendrimers on solubility of hydrophobic drug molecules. Front Pharmacol. 2017;16(8):261. https://doi.org/10.3389/fphar.2017.00261.
Bodewein L, Schmelter F, Di Fiore S, Hollert H, Fischer R, Fenske M. Differences in toxicity of anionic and cationic PAMAM and PPI dendrimers in zebrafish embryos and cancer cell lines. Toxicol Appl Pharmacol. 2016;305:83–92.
Bellini RG, Guimarães AP, Pacheco MA, Dias DM, Furtado VR, de Alencastro RB, Horta BA. Association of the anti-tuberculosis drug rifampicin with a PAMAM dendrimer. J Mol Graph Model. 2015;60:34–42. https://doi.org/10.1016/j.jmgm.2015.05.012.
Karthikeyan R, Koushik O, Kumar V. Surface modification of cationic dendrimers eases drug delivery of anticancer drugs. Nanosci Nanotechnol. 2016;10:108.
Kaur M, Garg T, Narang R. A review of emerging trends in the treatment of tuberculosis. Artif Cells Nanomed Biotechnol. 2016;44(2):478–84.
Srinivasan M, Rajabi M, Mousa SA. Multifunctional nanomaterials and their applications in drug delivery and cancer therapy. Nanomaterials. 2015;5(4):1690–703.
Zohuri G. Polymer science: a comprehensive reference. Amsterdam: Elsevier; 2012.
Leng Z-H, Zhuang Q-F, Li Y-C, He Z, Chen Z, Huang S-P, Jia H-Y, Zhou J-W, Liu Y, Du L-B. Polyamidoamine dendrimer conjugated chitosan nanoparticles for the delivery of methotrexate. Carbohyd Polym. 2013;98(1):1173–8.
Jain A, Jain K, Mehra NK, Jain N. Lipoproteins tethered dendrimeric nanoconstructs for effective targeting to cancer cells. J Nanopart Res. 2013;15(10):1–18.
Bernkop-Schnürch A, Scholler S, Biebel RG. Development of controlled drug release systems based on thiolated polymers. J Control Release. 2000;66(1):39–48.
Muttil P, Kaur J, Kumar K, Yadav AB, Sharma R, Misra A. Inhalable microparticles containing large payload of anti-tuberculosis drugs. Eur J Pharm Sci. 2007;32(2):140–50.
Sharma S, Khuller G, Garg S. Alginate-based oral drug delivery system for tuberculosis: pharmacokinetics and therapeutic effects. J Antimicrob Chemother. 2003;51(4):931–8.
Soto E, Kim YS, Lee J, Kornfeld H, Ostroff G. Glucan particle encapsulated rifampicin for targeted delivery to macrophages. Polymers. 2010;2(4):681–9.
Upadhyay TK, Fatima N, Sharma D, Saravanakumar V, Sharma R. Preparation and characterization of beta-glucan particles containing a payload of nanoembedded rifabutin for enhanced targeted delivery to macrophages. EXCLI J. 2017;16:210.
Rawal T, Kremer L, Halloum I, Butani S. Dry-powder inhaler formulation of rifampicin: an improved targeted delivery system for alveolar tuberculosis. J Aero Med Pulm Drug Delivery. 2017;30(6):388–98. https://doi.org/10.1089/jamp.2017.1379.
Cunha L, Rosa da Costa AM, Lourenço JP, Buttini F, Grenha A. Spray-dried fucoidan microparticles for pulmonary delivery of antitubercular drugs. J Microencapsul. 2018;35(4):392–405.
Cunha L, Rodrigues S, Rosa da Costa AM, Faleiro ML, Buttini F, Grenha A. Inhalable fucoidan microparticles combining two antitubercular drugs with potential application in pulmonary tuberculosis therapy. Polymers. 2018;10(6):636.
Cunha L, Rodrigues S, da Costa AMR, Faleiro L, Buttini F, Grenha A. Inhalable chitosan microparticles for simultaneous delivery of isoniazid and rifabutin in lung tuberculosis treatment. Drug Dev Ind Pharm. 2019. https://doi.org/10.1080/03639045.2019.1608231.
Sharma A, Vaghasiya K, Ray E, Gupta P, Singh AK, Gupta UD, Verma RK. Mycobactericidal activity of some micro-encapsulated synthetic host defense peptides (HDP) by expediting the permeation of antibiotic: a new paradigm of drug delivery for tuberculosis. Int J Pharm. 2019;558:231–41.
Vasudevan S, Venkatraman A, Yahoob SAM, Jojula M, Sundaram R, Boomi P. Biochemical evaluation and molecular docking studies on encapsulated astaxanthin for the growth inhibition of Mycobacterium tuberculosis. J Appl Biol Biotechnol. 2021;9(1):3–9.
Sharma A, Vaghasiya K, Ray E, Gupta P, Gupta UD, Singh AK, Verma RK. Targeted pulmonary delivery of the green tea polyphenol epigallocatechin gallate controls the growth of mycobacterium tuberculosis by enhancing the autophagy and suppressing bacterial burden. ACS Biomater Sci Eng. 2020;6(7):4126–40.
Gaspar MC, Grégoire N, Sousa JJ, Pais AA, Lamarche I, Gobin P, Olivier J-C, Marchand S, Couet W. Pulmonary pharmacokinetics of levofloxacin in rats after aerosolization of immediate-release chitosan or sustained-release PLGA microspheres. Eur J Pharm Sci. 2016;93:184–91.
Vidyadevi B. Direct lungs targeting: an alternative treatment approach for pulmonary tuberculosis. Asian J Pharm (AJP). 2021. https://doi.org/10.2237/ajp.v15i04.4212.
Pingale PL, Amrutkar SV. Quercetin loaded rifampicin-floating microspheres for improved stability and invitro drug release. Pharmacophore. 2021;12(3):95–9. https://doi.org/10.51847/yBXnl2bSUH.
Mwila C, Walker RB. Improved stability of rifampicin in the presence of gastric-resistant isoniazid microspheres in acidic media. Pharmaceutics. 2020;12(3):234.
Luciani-Giacobbe LC, Lorenzutti AM, Litterio NJ, Ramírez-Rigo MV, Olivera ME. Anti-tuberculosis site-specific oral delivery system that enhances rifampicin bioavailability in a fixed-dose combination with isoniazid. Drug Delivery Trans Re. 2021;11:894–908. https://doi.org/10.1007/s13346-020-00847-9.
Upadhyay S, Khan I, Gothwal A, Pachouri PK, Bhaskar N, Gupta UD, Chauhan DS, Gupta U. Conjugated and entrapped HPMA-PLA nano-polymeric micelles based dual delivery of first line anti TB drugs: improved and safe drug delivery against sensitive and resistant Mycobacterium tuberculosis. Pharm Res. 2017;34(9):1944–55.
Moradi S, Taran M, Mohajeri P, Sadrjavadi K, Sarrami F, Karton A, Shahlaei M. Study of dual encapsulation possibility of hydrophobic and hydrophilic drugs into a nanocarrier based on bio-polymer coated graphene oxide using density functional theory, molecular dynamics simulation and experimental methods. J Mol Liq. 2018;262:204–17.
Zhu M, Li K, Zhu Y, Zhang J, Ye X. 3D-printed hierarchical scaffold for localized isoniazid/rifampin drug delivery and osteoarticular tuberculosis therapy. Acta Biomater. 2015;16:145–55.
Tabriz AG, Nandi U, Hurt AP, Hui H-W, Karki S, Gong Y, Kumar S, Douroumis D. 3D printed bilayer tablet with dual controlled drug release for tuberculosis treatment. Int J Pharm. 2021;593:120147.
Clemens DL, Lee B-Y, Xue M, Thomas CR, Meng H, Ferris D, Nel AE, Zink JI, Horwitz MA. Targeted intracellular delivery of antituberculosis drugs to Mycobacterium tuberculosis-infected macrophages via functionalized mesoporous silica nanoparticles. Antimicrob Agents Chemother. 2012;56(5):2535–45.
Mehta S, Kaur G, Bhasin K. Tween-embedded microemulsions—physicochemical and spectroscopic analysis for antitubercular drugs. AAPS PharmSciTech. 2010;11(1):143–53.
Kaur G, Mehta S, Kumar S, Bhanjana G, Dilbaghi N. Coencapsulation of hydrophobic and hydrophilic antituberculosis drugs in synergistic Brij 96 microemulsions: a biophysical characterization. J Pharm Sci. 2015;104(7):2203–12.
Mulia K, Chadarwati S, Rahyussalim A, Krisanti E. Preparation and characterization of polyvinyl alcohol-chitosan-tripolyphosphate hydrogel for extended release of anti-tuberculosis drugs. IOP Conf Ser Mater Sci Eng. 2019. https://doi.org/10.1088/1757-899X/703/1/012010.
Krisanti EA, Gofara TZ, Rahyussalim AJ, Mulia K. Polyvinyl alcohol (PVA)/chitosan/sodium tripolyphosphate (STPP) hydrogel formulation with freeze-thaw method for anti-tuberculosis drugs extended release. AIP Conf Proc. 2021. https://doi.org/10.1063/5.0063175.
Tudose M, Anghel EM, Culita DC, Somacescu S, Calderon-Moreno J, Tecuceanu V, Dumitrascu FD, Dracea O, Popa M, Marutescu L. Covalent coupling of tuberculostatic agents and graphene oxide: a promising approach for enhancing and extending their antimicrobial applications. Appl Surf Sci. 2019;471:553–65.
Sheikhpour M, Delorme V, Kasaeian A, Amiri V, Masoumi M, Sadeghinia M, Ebrahimzadeh N, Maleki M, Pourazar S. An effective nano drug delivery and combination therapy for the treatment of tuberculosis. Sci Rep. 2022;12(1):1–11.
Chowdhury P, Shankar U. Formulation and evaluation of Rifampicin and Ofloxacin niosomes for Drugresistant TB on Logarithmic-phase cultures of Mycobacterium tuberculosis. Int J Res Pharma Sci (IJRPS). 2016;3(4):628–33.
Ferraz-Carvalho RS, Pereira MA, Linhares LA, Lira-Nogueira MC, Cavalcanti IM, Santos-Magalhães NS, Montenegro LM. Effects of the encapsulation of usnic acid into liposomes and interactions with antituberculous agents against multidrug-resistant tuberculosis clinical isolates. Mem Inst Oswaldo Cruz. 2016;111:330–4.
Yousefi A, Khodaverdi E, Atyabi F, Dinarvand R. Thermosensitive drug permeation through liquid crystal-embedded cellulose nitrate membranes. PDA J Pharm Sci Technol. 2010;64(1):54–62.
Kramer RM, Archer MC, Orr MT, Cauwelaert ND, Beebe EA, Po-wei DH, Dowling QM, Schwartz AM, Fedor DM, Vedvick TS. Development of a thermostable nanoemulsion adjuvanted vaccine against tuberculosis using a design-of-experiments approach. Int J Nanomed. 2018;13:3689.
de Almeida A, Caleffi-Ferracioli K, de Regiane B, Scodro L, Baldin VP, Montaholi DC, Spricigo LF, Nakamura-Vasconcelos SS, Hegeto LA, Sampiron EG, Costacurta GF, dos Diego A, Yamazaki S, de Gauze FG, Siqueira VL, Cardoso RF. Eugenol and derivatives activity against Mycobacterium tuberculosis, nontuberculous mycobacteria and other bacteria. Future Microbiol. 2019;14:331–44.
Zhang G, Sheng L, Hegde P, Li Y, Aldrich CC. 8-cyanobenzothiazinone analogs with potent antitubercular activity. Med Chem Res. 2021;30(2):449–58.
Kumar U, Singh RK. Clinical efficacy of beta-sitosterol as adjuvant therapy for the treatment of tuberculosis in children. Int J Paediatr Geriatr. 2021;4(1):141–3. https://doi.org/10.33545/26643685.2021.v4.i1c.144.
Rudolph D, Redinger N, Schaible UE, Feldmann C. Transport of lipophilic anti-tuberculosis drug benzothiazone-043 in Ca3 (PO4) 2 nanocontainers. ChemNanoMat. 2021;7(1):7–16.
Gupta A, Pandey S, Yadav JS. A review on recent trends in green synthesis of gold nanoparticles for tuberculosis. Adv Pharm Bull. 2021;11(1):10.
Govindaraju K, Vasantharaja R, Suganya KU, Anbarasu S, Revathy K, Pugazhendhi A, Karthickeyan D, Singaravelu G. Unveiling the anticancer and antimycobacterial potentials of bioengineered gold nanoparticles. Process Biochem. 2020;96:213–9.
Srivastava N, Mukhopadhyay M. Biosynthesis and characterization of gold nanoparticles using Zooglea ramigera and assessment of its antibacterial property. J Cluster Sci. 2015;26(3):675–92.
Sun C, Zhang X, Wang J, Chen Y, Meng C. Novel mesoporous silica nanocarriers containing gold; a rapid diagnostic tool for tuberculosis. BMC Complement Med Ther. 2021;21(1):1–7.
Gilbride B, Moreira GMSG, Hust M, Cao C, Stewart L. Catalytic ferromagnetic gold nanoparticle immunoassay for the detection and differentiation of Mycobacterium tuberculosis and Mycobacterium bovis. Anal Chim Acta. 2021;1184:339037.
Li J, Hu K, Zhang Z, Teng X, Zhang X. Click DNA cycling in combination with gold nanoparticles loaded with quadruplex DNA motifs enable sensitive electrochemical quantitation of the tuberculosis-associated biomarker CFP-10 in sputum. Microchim Acta. 2019;186(9):1–7.
Singh N, Dahiya B, Radhakrishnan VS, Prasad T, Mehta PK. Detection of Mycobacterium tuberculosis purified ESAT-6 (Rv3875) by magnetic bead-coupled gold nanoparticle-based immuno-PCR assay. Int J Nanomed. 2018;13:8523.
Sadanandan P, Payne NL, Sun G, Ashokan A, Gowd SG, Lal A, Kumar MKS, Pulakkat S, Nair SV, Menon KN. Exploiting the preferential phagocytic uptake of nanoparticle-antigen conjugates for the effective treatment of autoimmunity. Nanomed Nanotechnol Biol Med. 2022;40:102481.
Saravanan V, Ramachandran M, Prasanth V: Exploring various Silver Nanoparticles and Nanotechnology. 2022.
Mamaeva V, Sahlgren C, Lindén M. Mesoporous silica nanoparticles in medicine—recent advances. Adv Drug Deliv Rev. 2013;65(5):689–702.
Hwang J, Son J, Seo Y, Jo Y, Lee K, Lee D, Khan MS, Chavan S, Park C, Sharma A. Functional silica nanoparticles conjugated with beta-glucan to deliver anti-tuberculosis drug molecules. J Ind Eng Chem. 2018;58:376–85.
Tenland E, Pochert A, Krishnan N, Umashankar Rao K, Kalsum S, Braun K, Glegola-Madejska I, Lerm M, Robertson BD, Lindén M. Effective delivery of the anti-mycobacterial peptide NZX in mesoporous silica nanoparticles. PLoS ONE. 2019;14(2):e0212858.
Beitzinger B, Gerbl F, Vomhof T, Schmid R, Noschka R, Rodriguez A, Wiese S, Weidinger G, Ständker L, Walther P. Antimicrobial peptides: delivery by dendritic mesoporous silica nanoparticles enhances the antimicrobial activity of a napsin-derived peptide against intracellular Mycobacterium tuberculosis (Adv. Healthcare Mater. 14/2021). Adv Healthcare Mater. 2021;10(14):2170066.
Montalvo-Quirós S, Gómez-Graña S, Vallet-Regí M, Prados-Rosales RC, González B, Luque-Garcia JL. Mesoporous silica nanoparticles containing silver as novel antimycobacterial agents against Mycobacterium tuberculosis. Colloids Surf, B. 2021;197:111405.
Chen W, Cheng C-A, Lee B-Y, Clemens DL, Huang W-Y, Horwitz MA, Zink JI. Facile strategy enabling both high loading and high release amounts of the water-insoluble drug clofazimine using mesoporous silica nanoparticles. ACS Appl Mater Interfaces. 2018;10(38):31870–81.
Ang CW, Tan L, Qu Z, West NP, Cooper MA, Popat A, Blaskovich MA. Mesoporous silica nanoparticles improve oral delivery of antitubercular bicyclic nitroimidazoles. ACS Biomater Sci Eng. 2021. https://doi.org/10.1021/acsbiomaterials.1c00807.
Selvarajan V, Obuobi S, Ee PLR. Silica nanoparticles—a versatile tool for the treatment of bacterial infections. Front Chem. 2020;8:602.
Bhushan B, Luo D, Schricker SR, Sigmund W, Zauscher S. Handbook of nanomaterials properties. Berlin: Springer; 2014.
Chen Y, Guo S, Zhao M, Zhang P, Xin Z, Tao J, Bai L. Amperometric DNA biosensor for Mycobacterium tuberculosis detection using flower-like carbon nanotubes-polyaniline nanohybrid and enzyme-assisted signal amplification strategy. Biosens Bioelectron. 2018;119:215–20.
Buya AB, Witika BA, Bapolisi AM, Mwila C, Mukubwa GK, Memvanga PB, Makoni PA, Nkanga CI. Application of lipid-based nanocarriers for antitubercular drug delivery: a review. Pharmaceutics. 2021;13(12):2041.
Mehta S, Kaur G, Bhasin K. Entrapment of multiple anti-Tb drugs in microemulsion system: quantitative analysis, stability, and in vitro release studies. J Pharm Sci. 2010;99(4):1896–911.
Rajput A, Mandlik S, Pokharkar V. Nanocarrier-based approaches for the efficient delivery of anti-tubercular drugs and vaccines for management of tuberculosis. Front Pharmacol. 2021. https://doi.org/10.3389/fphar.2021.749945/full.
Eleleemy M, Amin BH, Nasr M, Sammour OA. A succinct review on the therapeutic potential and delivery systems of Eugenol. Arch Pharm Sci Ain Shams University. 2020;4(2):290–311.
Talegaonkar S, Azeem A, Ahmad FJ, Khar RK, Pathan SA, Khan ZI. Microemulsions: a novel approach to enhanced drug delivery. Recent Patents Drug Delivery Form. 2008;2(3):238–57. https://doi.org/10.2174/187221108786241679.
Sheikh BA, Bhat BA, Alshehri B, Mir RA, Mir WR, Parry ZA, Mir MA. Nano-drug delivery systems: possible end to the rising threats of tuberculosis. J Biomed Nanotechnol. 2021;17(12):2298–318.
Kompella UB, Kadam RS, Lee VH. Recent advances in ophthalmic drug delivery. Ther Deliv. 2010;1(3):435–56.
Raina N, Pahwa R, Bhattacharya J, Paul AK, Nissapatorn V, de Lourdes PM, Oliveira SM, Dolma KG, Rahmatullah M, Wilairatana P. Drug delivery strategies and biomedical significance of hydrogels: translational considerations. Pharmaceutics. 2022;14(3):574.
Wan Y, Liu L, Yuan S, Sun J, Li Z. pH-responsive peptide supramolecular hydrogels with antibacterial activity. Langmuir. 2017;33(13):3234–40.
Ahmad N, Pandey M, Mohamad N, Chen XY, Amin MCIM. Hydrogels for pulmonary drug delivery. In: Dua Kamal, Hansbro Philip M, Wadhwa Ridhima, Haghi Mehra, Pont Lisa G, Williams Kylie A, editors. Targeting chronic inflammatory lung diseases using advanced drug delivery systems. Amsterdam: Elsevier; 2020.
Guvendiren M, Molde J, Soares RM, Kohn J. Designing biomaterials for 3D printing. ACS Biomater Sci Eng. 2016;2(10):1679–93.
Zhao S, Zhu M, Zhang J, Zhang Y, Liu Z, Zhu Y, Zhang C. Three dimensionally printed mesoporous bioactive glass and poly (3-hydroxybutyrate-co-3-hydroxyhexanoate) composite scaffolds for bone regeneration. J Mater Chem B. 2014;2(36):6106–18. https://doi.org/10.1039/c4tb00838c.
Malakar TK, Chaudhari VS, Dwivedy SK, Murty US, Banerjee S. 3D printed housing devices for segregated compartmental delivery of oral fixed-dose anti-tubercular drugs adopting print and fill strategy. Print Addit Manuf. 2021. https://doi.org/10.1089/3dp.2021.0037.
Sasikumar K, Ghosh AR, Dusthackeer A. Antimycobacterial potentials of quercetin and rutin against Mycobacterium tuberculosis H37Rv. 3 Biotech. 2018;8(10):1–6.
Chaudhari VS, Malakar TK, Murty US, Banerjee S. Extruded filaments derived 3D printed medicated skin patch to mitigate destructive pulmonary tuberculosis: design to delivery. Expert Opin Drug Deliv. 2021;18(2):301–13.
Marcianes P, Negro S, Barcia E, Montejo C, Fernández-Carballido A. Potential active targeting of gatifloxacin to macrophages by means of surface-modified PLGA microparticles destined to treat tuberculosis. AAPS PharmSciTech. 2020;21(1):1–14.
Shah S, Cristopher D, Sharma S, Soniwala M, Chavda J. Inhalable linezolid loaded PLGA nanoparticles for treatment of tuberculosis: design, development and in vitro evaluation. J Drug Deliv Sci Technol. 2020;60:102013.
Operti MC, Bernhardt A, Grimm S, Engel A, Figdor CG, Tagit O. PLGA-based nanomedicines manufacturing: technologies overview and challenges in industrial scale-up. Int J Pharm. 2021;605:120807.
Baranyai Z, Soria-Carrera H, Alleva M, Millán-Placer AC, Lucía A, Martín-Rapún R, Aínsa JA, de la Fuente JM. Nanotechnology-based targeted drug delivery: an emerging tool to overcome tuberculosis. Adv Ther. 2021;4(1):2000113.
Roy A, Agnivesh PK, Sau S, Kumar S, Kalia NP. Tweaking host immune responses for novel therapeutic approaches against Mycobacterium tuberculosis. Drug Discov Today. 2023. https://doi.org/10.1016/j.drudis.2023.103693.
Hamed A, Osman R, Al-Jamal KT, Holayel SM, Geneidi A-S. Enhanced antitubercular activity, alveolar deposition and macrophages uptake of mannosylated stable nanoliposomes. J Drug Deliv Sci Technol. 2019;51:513–23.
Vieira AC, Chaves LL, Pinheiro M, Lima SAC, Ferreira D, Sarmento B, Reis S. Mannosylated solid lipid nanoparticles for the selective delivery of rifampicin to macrophages. Artif Cells Nanomed Biotechnol. 2018;46(sup1):653–63.
Galdopórpora JM, Martinena C, Bernabeu E, Riedel J, Palmas L, Castangia I, Manca ML, Garcés M, Lázaro-Martinez J, Salgueiro MJ. Inhalable mannosylated rifampicin-curcumin co-loaded nanomicelles with enhanced in vitro antimicrobial efficacy for an optimized pulmonary tuberculosis therapy. Pharmaceutics. 2022;14(5):959.
Sarkar S, Dyett B, Lakic B, Ball AS, Yeo LY, White JF, Soni S, Drummond CJ, Conn CE. Cubosome lipid nanocarriers as a drug delivery vehicle for intracellular mycobacterium tuberculosis infections. ACS Appl Mater Interfaces. 2023;15(18):21819–29.
Worstell NC, Singla A, Saenkham P, Galbadage T, Sule P, Lee D, Mohr A, Kwon JS-I, Cirillo JD, Wu H-J. Hetero-multivalency of Pseudomonas aeruginosa lectin LecA binding to model membranes. Sci Rep. 2018;8(1):1–11.
Siegel RA, Kirtane AR, Panyam J. Assessing the benefits of drug delivery by nanocarriers: a partico/pharmacokinetic framework. IEEE Trans Biomed Eng. 2016;64(9):2176–85.
Garcia-Contreras L, Sethuraman V, Kazantseva M, Hickey A. Efficacy of combined rifampicin formulations delivered by the pulmonary route to treat tuberculosis in the guinea pig model. Pharmaceutics. 2021;13(8):1309.
Sharma PR, Dravid AA, Kalapala YC, Gupta VK, Jeyasankar S, Goswami A, Agarwal R. Cationic inhalable particles for enhanced drug delivery to M. tuberculosis infected macrophages. Biomater Adv. 2022;133:112612.
Gangadhar KN, Changsan V, Buatong W, Srichana T. Phase behavior of rifampicin in cholesterol-based liquid crystals and polyethylene glycol. Eur J Pharm Sci. 2012;47(5):804–12.
Truzzi E, Capocefalo A, Meneghetti F, Maretti E, Mori M, Iannuccelli V, Domenici F, Castellano C, Leo E. Design and physicochemical characterization of novel hybrid SLN-liposome nanocarriers for the smart co-delivery of two antitubercular drugs. J Drug Deliv Sci Technol. 2022;70:103206.
Roy I, Vij N. Nanodelivery in airway diseases: challenges and therapeutic applications. Nanomed Nanotechnol Biol Med. 2010;6(2):237–44.
Han C, Romero N, Fischer S, Dookran J, Berger A, Doiron AL. Recent developments in the use of nanoparticles for treatment of biofilms. Nanotechnol Rev. 2017;6(5):383–404.
Misra A, Hickey AJ, Rossi C, Borchard G, Terada H, Makino K, Fourie PB, Colombo P. Inhaled drug therapy for treatment of tuberculosis. Tuberculosis. 2011;91(1):71–81.
Pham D-D, Fattal E, Tsapis N. Pulmonary drug delivery systems for tuberculosis treatment. Int J Pharm. 2015;478(2):517–29.
Tan ZM, Lai GP, Pandey M, Srichana T, Pichika MR, Gorain B, Bhattamishra SK, Choudhury H. Novel approaches for the treatment of pulmonary tuberculosis. Pharmaceutics. 2020;12(12):1196.
Ghosh S, Ghosh S, Sil PC. Role of nanostructures in improvising oral medicine. Toxicol Rep. 2019;6:358–68.
Yang Z, Niu N, Lou C, Wang X, Wang C, Shi Z. Preparation, characterrization, and in-vitro cytotoxicity of nanoliposomes loaded with anti-tuberculous drugs and TGF-β1 siRNA for improving spinal tuberculosis therapy. BMC Infect Dis. 2022. https://doi.org/10.1186/s12879-022-07791-8.
Jiang Z, Wei J, Peng N, Li Y. Genetic engineering of a phage-based delivery system for endogenous III-A CRISPR-cas system against mycobacterium tuberculosis. In: Tofazzal Islam M, Molla Kutubuddin Ali, editors. CRISPR-cas methods. New York: Springer; 2021.
Dubey AK, Kumar Gupta V, Kujawska M, Orive G, Kim N-Y, Li C-Z, Kumar Mishra Y, Kaushik A. Exploring nano-enabled CRISPR-Cas-powered strategies for efficient diagnostics and treatment of infectious diseases. J Nanostruct Chem. 2022. https://doi.org/10.1007/s40097-022-00472-7.
Babunovic GH, DeJesus MA, Bosch B, Chase MR, Barbier T, Dickey AK, Bryson BD, Rock JM, Fortune SM. CRISPR interference reveals that all-trans-retinoic acid promotes macrophage control of mycobacterium tuberculosis by limiting bacterial access to cholesterol and propionyl coenzyme A. MBio. 2022;13(1):e03683-e3621.
Verma M, Furin J, Langer R, Traverso G. Making the case: developing innovative adherence solutions for the treatment of tuberculosis. BMJ Glob Health. 2019;4(1):e001323.
Furin J, Tommasi M, Garcia-Prats AJ. Drug-resistant tuberculosis: will grand promises fail children and adolescents? Lancet Child Adolesc Health. 2018;2(4):237–8.
Harausz EP, Garcia-Prats AJ, Seddon JA, Schaaf HS, Hesseling AC, Achar J, Bernheimer J, Cruz AT, D’Ambrosio L, Detjen A. New and repurposed drugs for pediatric multidrug-resistant tuberculosis Practice-based recommendations. Am J Respir Crit Care Med. 2017;195(10):1300–10.
Swindells S, Siccardi M, Barrett SE, Olsen DB, Grobler JA, Podany AT, Nuermberger E, Kim P, Barry C, Owen A. Long-acting formulations for the treatment of latent tuberculous infection: opportunities and challenges. Int J Tuberc Lung Dis. 2018;22(2):125–32.
Park EJ, Amatya S, Kim MS, Park JH, Seol E, Lee H, Shin Y-H, Na DH. Long-acting injectable formulations of antipsychotic drugs for the treatment of schizophrenia. Arch Pharmacal Res. 2013;36(6):651–9.
Kaushik A, Ammerman NC, Tyagi S, Saini V, Vervoort I, Lachau-Durand S, Nuermberger E, Andries K. Activity of a long-acting injectable bedaquiline formulation in a paucibacillary mouse model of latent tuberculosis infection. Antimicrob Agents Chemother. 2019;63(4):e00007-00019.
Diacon A, Donald P, Pym A, Grobusch M, Patientia R, Mahanyele R, Bantubani N, Narasimooloo R, De Marez T, Van Heeswijk R. Randomized pilot trial of eight weeks of bedaquiline (TMC207) treatment for multidrug-resistant tuberculosis: long-term outcome, tolerability, and effect on emergence of drug resistance. Antimicrob Agents Chemother. 2012;56(6):3271–6.
Rajoli RK, Podany AT, Moss DM, Swindells S, Flexner C, Owen A, Siccardi M. Modelling the long-acting administration of anti-tuberculosis agents using PBPK: a proof of concept study. Int J Tuberc Lung Dis. 2018;22(8):937–44.
Verma M, Vishwanath K, Eweje F, Roxhed N, Grant T, Castaneda M, Steiger C, Mazdiyasni H, Bensel T, Minahan D. A gastric resident drug delivery system for prolonged gram-level dosing of tuberculosis treatment. Sci Transl Med. 2019;11(483):6267.
Adeleke OA, Fisher L, Moore IN, Nardone GA, Sher A. A long-acting thermoresponsive injectable formulation of tin protoporphyrin sustains antitubercular efficacy in a murine infection model. ACS Pharmacol Transl Sci. 2020;4(1):276–87.
Sadeghi I, Byrne J, Shakur R, Langer R. Engineered drug delivery devices to address global health challenges. J Control Release. 2021;331:503–14.
Raza A, Sime FB, Cabot PJ, Maqbool F, Roberts JA, Falconer JR. Solid nanoparticles for oral antimicrobial drug delivery: a review. Drug Discov Today. 2019;24(3):858–66.
Singh H, Jindal S, Singh M, Sharma G, Kaur IP. Nano-formulation of rifampicin with enhanced bioavailability: development, characterization and in-vivo safety. Int J Pharm. 2015;485(1–2):138–51.
Elbrink K, Van Hees S, Chamanza R, Roelant D, Loomans T, Holm R, Kiekens F. Application of solid lipid nanoparticles as a long-term drug delivery platform for intramuscular and subcutaneous administration: in vitro and in vivo evaluation. Eur J Pharm Biopharm. 2021;163:158–70.
Pigrau-Serrallach C, Rodríguez-Pardo D. Bone and joint tuberculosis. Eur Spine J. 2013;22(4):556–66.
Hua L, Qian H, Lei T, Liu W, He X, Zhang Y, Lei P, Hu Y. Anti-tuberculosis drug delivery for tuberculous bone defects. Expert Opin Drug Deliv. 2021;18(12):1815–27.
Zhang J, Zhao S, Zhu Y, Huang Y, Zhu M, Tao C, Zhang C. Three-dimensional printing of strontium-containing mesoporous bioactive glass scaffolds for bone regeneration. Acta Biomater. 2014;10(5):2269–81.
Zhao S, Zhang J, Zhu M, Zhang Y, Liu Z, Ma Y, Zhu Y, Zhang C. Effects of functional groups on the structure, physicochemical and biological properties of mesoporous bioactive glass scaffolds. J Mater Chem B. 2015;3(8):1612–23.
Wu C, Chang J. Multifunctional mesoporous bioactive glasses for effective delivery of therapeutic ions and drug/growth factors. J Control Release. 2014;193:282–95.
Miller SR, Heurtaux D, Baati T, Horcajada P, Grenèche J-M, Serre C. Biodegradable therapeutic MOFs for the delivery of bioactive molecules. Chem Commun. 2010;46(25):4526–8.
Giménez-Marqués M, Hidalgo T, Serre C, Horcajada P. Nanostructured metal–organic frameworks and their bio-related applications. Coord Chem Rev. 2016;307:342–60.
Semaan R, Traboulsi R, Kanj S. Primary Mycobacterium tuberculosis complex cutaneous infection: report of two cases and literature review. Int J Infect Dis. 2008;12(5):472–7.
van Staden D, Haynes RK, Viljoen JM. Adapting clofazimine for treatment of cutaneous tuberculosis by using self-double-emulsifying drug delivery systems. Antibiotics. 2022;11(6):806.
Xu Y, Wu J, Liao S, Sun Z. Treating tuberculosis with high doses of anti-TB drugs: mechanisms and outcomes. Ann Clin Microbiol Antimicrob. 2017;16(1):1–13.
Ammerman NC, Swanson RV, Bautista EM, Almeida DV, Saini V, Omansen TF, Guo H, Chang YS, Li S-Y, Tapley A. Impact of clofazimine dosing on treatment shortening of the first-line regimen in a mouse model of tuberculosis. Antimicrob Agents Chemother. 2018;62(7):e00636-e618.
van Staden D, Haynes RK, Viljoen JM. Adapting clofazimine for treatment of cutaneous tuberculosis by using self-double-emulsifying drug delivery systems. Antibiotics. 2022;11(6):806. https://doi.org/10.3390/antibiotics11060806.
Caon T, Campos CEM, Simões CMO, Silva MAS. Novel perspectives in the tuberculosis treatment: administration of isoniazid through the skin. Int J Pharm. 2015;494(1):463–70.
Basu S, Monira S, Modi RR, Choudhury N, Mohan N, Padhi TR, Balne PK, Sharma S, Panigrahi SR. Degree, duration, and causes of visual impairment in eyes affected with ocular tuberculosis. J Ophthalmic Inflam Infect. 2014;4(1):1–5.
Bennett JE, Dolin R, Blaser MJ: Mandell, douglas, and bennett’s principles and practice of infectious diseases E-book: Elsevier Health Sciences; 2019.
Agrawal R, Gunasekeran DV, Raje D, Agarwal A, Nguyen QD, Kon OM, Pavesio C, Gupta V. Global variations and challenges with tubercular uveitis in the collaborative ocular tuberculosis study. Invest Ophthalmol Vis Sci. 2018;59(10):4162–71.
Agrawal R, Ludi Z, Betzler BK, Testi I, Mahajan S, Rousellot A, Kempen JH, Smith JR, McCluskey P, Nguyen QD. The collaborative ocular tuberculosis study (COTS) calculator—a consensus-based decision tool for initiating antitubercular therapy in ocular tuberculosis. Eye. 2022. https://doi.org/10.1038/s41433-022-02147-7.
Zhang Z, Liu J, Wan C, Liu P, Wan H, Guo Z, Tong J, Cao X. Successful treatment of tuberculosis verrucosa cutis with fester as primary manifestation with photodynamic therapy and anti-tubercular drugs. Photodiagn Photodyn Ther. 2022;38:102763.
Patel U, Rathnayake K, Jani H, Jayawardana KW, Dhakal R, Duan L, Jayawardena SN. Near-infrared responsive targeted drug delivery system that offer chemo-photothermal therapy against bacterial infection. Nano Select. 2021;2(9):1750–69.
Liu Y, Lin A, Liu J, Chen X, Zhu X, Gong Y, Yuan G, Chen L, Liu J. Enzyme-responsive mesoporous ruthenium for combined chemo-photothermal therapy of drug-resistant bacteria. ACS Appl Mater Interfaces. 2019;11(30):26590–606.
Sia JK, Georgieva M, Rengarajan J. Innate immune defenses in human tuberculosis: an overview of the interactions between Mycobacterium tuberculosis and innate immune cells. J Immunol Res. 2015. https://doi.org/10.1155/2015/747543.
Cadena AM, Flynn JL, Fortune SM. The importance of first impressions: early events in Mycobacterium tuberculosis infection influence outcome. MBio. 2016;7(2):e00342-e316.
Divangahi M, Aaby P, Khader SA, Barreiro LB, Bekkering S, Chavakis T, van Crevel R, Curtis N, DiNardo AR, Dominguez-Andres J. Trained immunity, tolerance, priming and differentiation: distinct immunological processes. Nat Immunol. 2021;22(1):2–6.
Gong W, Wu X. Differential diagnosis of latent tuberculosis infection and active tuberculosis: a key to a successful tuberculosis control strategy. Front Microbiol. 2021. https://doi.org/10.3389/fmicb.2021.745592.
Khan N, Vidyarthi A, Javed S, Agrewala JN. Innate immunity holding the flanks until reinforced by adaptive immunity against Mycobacterium tuberculosis infection. Front Microbiol. 2016;7:328.
Mi J, Liang Y, Liang J, Gong W, Wang S, Zhang J, Li Z, Wu X. The research progress in immunotherapy of tuberculosis. Front Cell Infect Microbiol. 2021. https://doi.org/10.3389/fcimb.2021.763591.
Johnson B, Bekker LG, Ress S, Kaplan G. Recombinant interleukin 2 adjunctive therapy in multidrug-resistant tuberculosis. In: Chadwick Derek J, Cardew Gail, editors. Genetics and tuberculosis: novartis foundation symposium 217. Hoboken: Wiley Online Library; 1998.
Kim YG, Baltabekova AZ, Zhiyenbay EE, Aksambayeva AS, Shagyrova ZS, Khannanov R, Ramanculov EM, Shustov AV. Recombinant vaccinia virus-coded interferon inhibitor B18R: expression, refolding and a use in a mammalian expression system with a RNA-vector. PLoS ONE. 2017;12(12):e0189308.
Ma Y, Chen H-D, Wang Y, Wang Q, Li Y, Zhao Y, Zhang X-L. Interleukin 24 as a novel potential cytokine immunotherapy for the treatment of Mycobacterium tuberculosis infection. Microbes Infect. 2011;13(12–13):1099–110.
Netea MG, Lewis EC, Azam T, Joosten LA, Jaekal J, Bae S-Y, Dinarello CA, Kim S-H. Interleukin-32 induces the differentiation of monocytes into macrophage-like cells. Proc Natl Acad Sci. 2008;105(9):3515–20.
Li W, Deng W, Xie J. The biology and role of interleukin-32 in tuberculosis. J Immunol Res. 2018. https://doi.org/10.1155/2018/1535194.
Teitelbaum R, Glatman-Freedman A, Chen B, Robbins JB, Unanue E, Casadevall A, Bloom BR. A mAb recognizing a surface antigen of Mycobacterium tuberculosis enhances host survival. Proc Natl Acad Sci. 1998;95(26):15688–93.
Hamasur B, Haile M, Pawlowski A, Schröder U, Källenius G, Svenson SB. A mycobacterial lipoarabinomannan specific monoclonal antibody and its F (ab′) 2 fragment prolong survival of mice infected with Mycobacterium tuberculosis. Clin Exp Immunol. 2004;138(1):30–8.
AlMatar M, Makky EA, Yakıcı G, Var I, Kayar B, Köksal F. Antimicrobial peptides as an alternative to anti-tuberculosis drugs. Pharmacol Res. 2018;128:288–305.
Saeed AF, Wang R, Ling S, Wang S. Antibody engineering for pursuing a healthier future. Front Microbiol. 2017;8:495.
Gutiérrez-Ortega A, Moreno DA, Ferrari SA, Espinosa-Andrews H, Ortíz EP, Milián-Suazo F, Alvarez AH. High-yield production of major T-cell ESAT6-CFP10 fusion antigen of M. tuberculosis complex employing codon-optimized synthetic gene. Int J Biol Macromol. 2021;171:82–8. https://doi.org/10.1016/j.ijbiomac.2020.12.179.
Bianchi L, Galli L, Moriondo M, Veneruso G, Becciolini L, Azzari C, Chiappini E, de Martino M. Interferon-gamma release assay improves the diagnosis of tuberculosis in children. Pediatr Infect Dis J. 2009;28(6):510–4.
Zhang X, Liu X-Y, Yang H, Chen J-N, Lin Y, Han S-Y, Cao Q, Zeng H-S, Ye J-W. A polyhydroxyalkanoates-based carrier platform of bioactive substances for therapeutic applications. Front Bioeng Biotechnol. 2021. https://doi.org/10.3389/fbioe.2021.798724/full.
Saracino A, Scotto G, Fornabaio C, Martinelli D, Faleo G, Cibelli D, Tartaglia A, Di Tuwo R, Fazio V, Prato R. QuantiFERON®-TB gold in-tube test (QFT-GIT) for the screening of latent tuberculosis in recent immigrants to Italy. New Microbiol. 2009;32(4):369.
Patil TS, Deshpande AS. Innovative strategies in the diagnosis and treatment of tuberculosis: a patent review (2014–2017). Expert Opin Ther Pat. 2018;28(8):615–23.
Brigden G, Castro JL, Ditiu L, Gray G, Hanna D, Low M, Matsoso MP, Perry G, Spigelman M, Swaminathan S. Tuberculosis and antimicrobial resistance–new models of research and development needed. Bull World Health Organ. 2017;95(5):315–315.
Pool MP. The medicines patent pool announces first license for tuberculosis treatment. Geneva: UNITAID; 2017.
Bekale RB, Du Plessis S-M, Hsu N-J, Sharma JR, Sampson SL, Jacobs M, Meyer M, Morse GD, Dube A. Mycobacterium tuberculosis and interactions with the host immune system: opportunities for nanoparticle based immunotherapeutics and vaccines. Pharm Res. 2019;36(1):1–15.
Verma N, Arora V, Awasthi R, Chan Y, Jha NK, Thapa K, Jawaid T, Kamal M, Gupta G, Liu G. Recent developments, challenges and future prospects in advanced drug delivery systems in the management of tuberculosis. J Drug Deliv Sci Technol. 2022. https://doi.org/10.1016/j.jddst.2022.103690.
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AYN AG AMN RKS AJ AKV PS would like to acknowledge the support by Amrita Vishwa Vidyapeetham. VJ expresses his gratitude to the Finnish Cultural Foundation (Ingrid, Toini and Olavi Martelius foundation) and the Helsinki University Library for funding.
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AYN AG AMN RKS AJ VJ performed the literature search and data analysis. AYN AG AMN RKS AJ AKV PS VJ drafted the manuscript. AKV PS VJ created the backbone, and AKV PS VJ SD critically revised the work. All authors agreed on the submission.
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Nair, A., Greeny, A., Nandan, A. et al. Advanced drug delivery and therapeutic strategies for tuberculosis treatment. J Nanobiotechnol 21, 414 (2023). https://doi.org/10.1186/s12951-023-02156-y
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DOI: https://doi.org/10.1186/s12951-023-02156-y