Introduction

Cyclodextrins are cyclic oligomers obtained from starch by enzymatic degradation and were discovered in 1891 by the French pharmacist Villiers (Crini et al. 2021). Cyclodextrins have remarkable capability to establish supramolecular host–guest interactions because of their toroidal shape and non-polar inside (Morin-Crini et al. 2021; Petitjean et al. 2021). Cyclodextrin molecules contribute distinguished advantages due to their novel architectural features to form inclusion complexes with several kinds of molecules like ions, protein, and oligonucleotides (Lysik and Wu-Pong 2003). Inclusion complexes are formed when the “guest” molecule, usually a drug, is partially or fully included inside the “host’s cavity” (Szente and Szejtli 1999). Owing to the hydrophobic cavity, cyclodextrins as ghosts offer the guest a suitable environment for interaction (Fig. 1). The outer hydrophilic surface of cyclodextrins is compatible with water, which allows hydrogen bonding cohesive interactions (Challa et al. 2005). Cyclodextrin-conjugated nanoparticles offer numerous advantages such as enhanced drug solubility, improved encapsulation efficiency, and drug loading and serve as drug carriers to a specific target site such as cancer cells with minimum toxicity to normal cells, greater surface area over microparticles, and higher stability over liposomes.

Fig. 1
figure 1

Inclusion complex of cyclodextrins. A complex is formed when the “guest” molecule, such as a drug, is partially or fully included inside the host’s cavity. Cyclodextrins have various practical applications in different fields such as pharmaceuticals, food, cosmetics, hygiene and toiletries, agrochemistry, catalysis, chromatography, biotechnology, nanotechnology, medical imaging, textile industry, and soil and water treatment

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This review discusses cyclodextrin-based nanoparticles to explain their versatility and high potential for advanced drug delivery, protein and peptide delivery, and gene delivery. It also highlights the role of cyclodextrins in specific types of nanoparticles such as gold, silver, and magnetic, polymeric, and lipid-based nanoparticles. Additionally, pharmaceutical applications of amphiphilic cyclodextrin nanoparticles and miscellaneous administration routes of cyclodextrin-based nanoparticles are also discussed. This article is an abridged version of the chapter published by Pandey (2020) in the series Environmental Chemistry for a Sustainable World.

Cyclodextrin nanoparticles as drug delivery system

The cyclodextrins have the exceptional ability to trap a guest molecule inside of their hydrophobic cavity and have been significantly exploited by pharmaceutical researchers to enhance the bioavailability, aqueous solubility, and stability of several therapeutic agents (Arora et al. 2019). Cyclodextrin-based nanoparticles can improve bioavailability, modify drug metabolism, reduce toxicity, and increase the biological half-life of drugs after systemic administration (Bilensoy 2011; Crini et al. 2018). Cyclodextrins act as true carriers by dissolving and delivering hydrophobic drug molecules through the aqueous exterior of lipophilic biological membrane barriers, e.g., mucosa. In general, only dissolved drug molecules can partition into the barrier and then penetrate through the mucosa. In addition, cyclodextrins are known to self-assemble to form nanosized aggregates in aqueous solutions and thus have the potential of being developed into novel drug delivery systems (Messner et al. 2010). This characteristic is promising for a broad range of nanotechnology domains such as drug delivery, cancer therapy, gene delivery, and biosensing. Cyclodextrin-based nanoparticles facilitate a novel drug delivery system with the advantages of both components: The cyclodextrin molecules offer enhanced water solubility and drug loading, while the nanoparticles afford targeted drug delivery.

Anticancer drugs

Nanotechnology-based drug delivery system provides an exceptional platform for the delivery of anticancer agents to enhance their targeting ability and bioavailability. Oral administration of paclitaxel is still considered one of the most suitable and safe modes of delivery. Hamada et al. (2006) studied the aqueous solubility behavior of anticancer agent paclitaxel employing 11 kinds of cyclodextrins and the bioactivity of the paclitaxel–cyclodextrin inclusion complex. They have reported that 2,6-dimethyl-β-cyclodextrin was most effective, and paclitaxel showed significant solubility in 2,6-dimethyl-β-cyclodextrin aqueous solution. Moreover, this inclusion complex revealed a 1.23-fold polymerization activity as paclitaxel in a tubulin assay. One of the main advantages of loading anticancer drugs into nanoparticles is to enhance their cellular uptakes by bypassing the different multidrug-resistant mechanisms. For example, paclitaxel isolated from Taxus brevifolia is a potent anticancer agent approved for the treatment of a large number of solid tumors. But hydrophobic nature of paclitaxel results in low bioavailability. Therefore, to overcome the issue of hydrophobicity, Bilensoy et al. (2008a, b) have developed amphiphilic cyclodextrin as a nanoparticulate carrier system for paclitaxel drug delivery. This yielded nanospheres via nanoprecipitation technique with good cytotoxicity against L929 cells, high encapsulation efficiency, prolonged drug release, and a threefold increase in the loading capacity of nanoparticles when formed directly from the inclusion complex. In another approach, Agüeros et al. (2009) investigated the concept of utilizing cyclodextrin–polyanhydride nanoparticles for oral delivery of paclitaxel. The addition of cyclodextrin increases the solubility of paclitaxel by developing an inclusion complex, and the use of polyanhydride enhances intestinal permeability. In conclusion, cyclodextrin-based nanoparticles improve solubility and increase the targeting ability and bioavailability of anticancer drugs.

Proteins and peptides

Cyclodextrin complexation represents an effective strategy for improving protein therapy by stabilizing them against aggregation, thermal denaturation, and degradation. Proteins are mostly hydrophilic and too bulky to be wholly included in the cavity of cyclodextrins. Nevertheless, the hydrophobic side chains in the peptides may penetrate into the cavity of the oligosaccharide, leading to the formation of non-covalent inclusion complexes, which improves the stability of proteins. Da Silveira et al. (1998) have prepared and evaluated nanoparticulate systems of progesterone composed of poly(isobutyl cyanoacrylate) and cyclodextrins for enhancing the loading of the particles with substances. The authors have demonstrated that an increase in hydroxypropyl-β-cyclodextrin concentration resulted in small nanoparticles of size less than 50 nm and a 50-fold increase in progesterone loading compared to nanoparticles prepared without cyclodextrins. Cyclodextrins are believed to enhance nasal absorption of peptides by opening tight junctions and/or solubilizing membrane components (Merkus et al. 1999). In light of these facts, Zhang et al. (2011) fabricated a novel nanoparticle system based on the coupling of cyclodextrin and hyperbranched polyglycerols to enhance the nasal transport of insulin. The in vitro release study showed significant release rate of insulin under acidic conditions than physiological conditions. In vitro cytotoxic evaluation against Caco-2 cells exhibited that hyperbranched polyglycerol-β-cyclodextrin had significant biocompatibility. Moreover, the capacity of hyperbranched polyglycerol-β-cyclodextrin nanoparticles to penetrate the nasal mucosal epithelia was proved by confocal laser scanning microscopy. Glutathione is the main thiolated small peptide in mammalian cells used to treat drug poisoning and protection against cytotoxic chemotherapy and radiation trauma. However, glutathione inclusion and preservation into conventional pharmaceutical dosage forms are challenging tasks due to low and variable oral bioavailability, non-enzymatic pH-dependent oxidation, chemical and enzymatic degradation of glutathione in the jejunum (Langie et al. 2007). Therefore, to resolve these issues, Trapani et al. (2010) have developed new nanoparticles containing chitosan or cyclodextrin and demonstrated that chitosan nanoparticles containing the anionic cyclodextrin sulfobutylether 7 m-β-cyclodextrin seem to be significant potential oral glutathione carriers, as they combine enhanced glutathione loading along with the ability to improve glutathione permeabilization through the intestine, as observed in a frog intestinal sac model. More recently, He et al. (2019) reported a novel oral protein delivery system of ovalbumin with improved intestinal permeability and enhanced antigen stability. Results of the in vivo study of nanoparticles revealed that ovalbumin-loaded cyclodextrin/chitosan nanoparticles possess the capacity to induce an intestinal mucosal immune response and could serve as a potential antigen-delivery system for oral vaccination. The above examples reveal that cyclodextrin-containing nanoparticles significantly increase drug-loading capacity and enhance stability and intestinal permeability of protein and peptide molecules.

Cyclodextrin nanoparticles as gene delivery systems

Gene therapy offers advantages over conventional protein therapy such as improved bioavailability and reduced systemic toxicity. Therefore, to avoid the toxicity issue of viral vectors, researchers have developed cyclodextrin-based nanoparticles as non-viral vectors. Teijeiro-Osorio et al. (2009) first investigated a new generation of hybrid polysaccharide nanocarriers composed of chitosan and anionic cyclodextrins, to evaluate their ability to penetrate epithelial cells and improve gene expression in the Calu-3 cell culture model. Furthermore, hybrid chitosan and anionic cyclodextrins nanoparticles were developed and loaded with plasmid deoxyribonucleic model that encodes the expression of secreted alkaline phosphatase. Results of cellular uptake studies revealed that the nanoparticles were efficiently internalized by the cells and confirm their potential as gene vectors. The application of small interfering ribonucleic acid (siRNAs) is a promising approach to restrict the mutation of protein. The major hindrance in siRNA-based strategies is the lack of efficient and non-toxic transportation vectors to ensure target delivery to the nervous system. This stimulated Godinho et al. (2013) to develop modified amphiphilic β-cyclodextrins as novel siRNA neuronal carriers. The results showed that the cyclodextrin formed nanosize particles significantly reduced the expression of the huntingtin gene in rat striatal cells and human Huntington’s disease primary fibroblasts. These findings firmly support the utility of modified β-cyclodextrins as safe and effective siRNA delivery vectors. In another study to facilitate the delivery of siRNA, cationic cyclodextrin conjugated with polyethylene glycol chain to expedite the attachment of targeting group anisamide. Parenteral administration of anisamide-tagged PEGylated (polyethylene glycol chain conjugated) cyclodextrin nanoparticles presented notable tumor inactivation with diminished toxicity when investigated preclinically in a rodent prostate tumor model, hence serving as an excellent drug delivery system of siRNA delivery for prostate cancer therapy (Guo et al. 2012). The siRNAs generally exhibit weak cell penetration with limited stability; the inclusion of cyclodextrins as a key excipient can aid in the delivery of oligonucleotides. Zokaei et al. (2019) recently developed chitosan β-cyclodextrin complexes as a tropical agent. These polymer cyclodextrin complexes loaded with the messenger ribonucleic acid (mRNA) cleaving DNAzyme that targets the mRNA of the multidrug resistance protein 1 (MDR1) gene in the doxorubicin-resistant breast cancer cell line (MCF-7/DR). Results proved the downregulation of MDR1 mRNAs in MCF-7/DR/DNZ by a real-time polymer chain reaction, compared to the MCF-7/DR as control. To sum up, results substantiate chitosan β-cyclodextrin complexes in association with chemotherapy drug for cancer therapy and notably valuable at the delivery of DNAzyme in reviving chemosensitivity. These findings reveal that cyclodextrin-based nanoparticles are promising non-toxic transportation vectors that facilitate safe, effective, and targeted gene delivery.

Role of cyclodextrin in magnetic nanoparticles

The magnetic nanoparticles offer several advantages over other types of nanomaterials, such as narrow size distribution, high colloidal stability, low toxicity, and high specific surface area to render them suitable for biomedical applications (Ahmed et al. 2014). Additionally, magnetic nanoparticles displayed the phenomenon of superparamagnetism: They are promptly magnetized under the influence of the external magnetic field and vice versa. This unique characteristic allows the nanoparticles to localize at the targeted site in vivo in response to the externally applied magnetic field. Silica is generally added to the surface of the nanoparticles to prevent their oxidation that leads to demagnetization, which subsequently maintains the stability of magnetic nanoparticles. Wang et al. (2003) first proved the role of cyclodextrin to enhance the stability of magnetic nanoparticles in an aqueous medium. They have modified the surface properties of these magnetic nanoparticles through the formation of an inclusion complex between surface-bound surfactant molecules and α-cyclodextrin, thus improving oleic acid stabilized nanoparticles dispersion for a prolonged period in water. Banerjee and Chen (2007) have developed cyclodextrin-citrate-gum Arabic modified magnetic nanoparticles for hydrophobic drug delivery. The results showed that cyclodextrin-citrate-gum Arabic-modified magnetic nanoparticles exhibited a considerable adsorption capability for ketoprofen as compared to gum Arabic-modified magnetic nanoparticles. Therefore, this system seems to be a very promising vehicle for the administration of hydrophobic drugs. A decade later, Chen et al. (2017) have amalgamated double-layer polymer-coated magnetic targeted nanoparticles (coated with β-cyclodextrin and polymer chitosan) to ensure stability and biocompatibility of the nanoparticles and effective drug delivery of ibuprofen, a hydrophobic drug delivery. They noted that nanocarriers exhibited sufficient magnetic properties, high drug-loading capacity, and significant in vitro drug release. Recently, the same authors have developed β-cyclodextrin-based magnetic nanocarriers via a molecular docking technique. Herein, the introduction of the molecular docking technique establishes a method to fast select an effective β-cyclodextrin-based surface coating for the development of high-performance magnetic nanoparticles (Chen et al. 2019). In another study, Ding et al. (2015) developed a novel hydrogel of poorly soluble drug 5-fluorouracil, based on chitosan crosslinked carboxymethyl-β-cyclodextrin polymer-modified Fe3O4 magnetic nanoparticles. Experimental results showed that the nanocarriers displayed a high loading efficiency and pH-dependent swelling and diffusion-controlled drug release. This report tentatively proposed the mechanism of 5-fluorouracil encapsulated into the magnetic chitosan nanoparticles. Camptothecin, a hydrophobic anticancer agent, acts by inhibiting the enzyme topoisomerase I. The primary mechanism of action of camptothecin involves cell death at the S-phase of the cell cycle (Behera and Padhi 2020). The bioactive lactone form of camptothecin rapidly hydrolyzes to the inactive carboxylate form under physiological conditions, thus limiting the delivery and therapeutic application of camptothecin in cancer therapy (Pandey 2021). Therefore, to overcome these limitations, Enoch et al. (2018) synthesized β-cyclodextrin-based magnetic nanoparticles of camptothecin. The fabricated nanoparticles showed superparamagnetic behavior. Further research showed that coating the magnetic nanoparticles with the cyclodextrin–tethered polymer improves the drug-loading capacity, sustained drug release, and enhanced cytotoxicity. Wang et al. (2018) fabricated a magnetic and pH-sensitive composite nanoparticulate system prepared by double emulsion technique and incorporating acetylated β-cyclodextrin as a key ingredient to recognize the pH response and Fe3O4 as a component to realize magnetic response. Results showed irreversible pH response property and reversible magnetic responsive properties at different pH environments for the composite nanoparticle. Moreover, drug release behavior exhibited pH-dependent property through preliminary in vitro evaluation. In conclusion, cyclodextrin-containing magnetic nanoparticles significantly improve the solubility of hydrophobic drugs, increase stability, modify drug release, and enhance the cytotoxicity of anticancer drugs.

Role of cyclodextrin in polymeric nanoparticles

The inclusion property of cyclodextrin renders polymeric nanoparticles to conveniently deliver hydrophobic molecules to the targeted site by encapsulating the drugs in the hydrophobic cyclodextrin cavity. The polymeric nanoparticles have cyclodextrin casting outer shells, while the core of the polymeric nanoparticles is composed of natural or synthetic polymer. Thus, the drugs can be loaded in the core of the polymeric nanoparticles, or they can be conjugated with the cyclodextrin in the outer shell. Nanoparticulate systems can be prepared either by dispersion of preformed polymers or polymerization. Among the polymers used in nanoparticle preparation are poly(cyanoacrylates) which are particularly interesting because of their biodegradability and very simple polymerization process. One of the major drawbacks of this type of nanoparticle is related to the difficulty of entrapping in hydrophobic drugs. Da Silveira et al. (1998) first proposed cyclodextrin to overcome this problem. The authors proposed the possibility of preparing nanoparticles of poly-(isobutyl cyanoacrylate) in the presence of hydroxypropyl-β-cyclodextrin by anionic polymerization of isobutyl cyanoacrylate. Later, Ren et al. (2009) dissolved adamantane-end-capped poly(ε-caprolactone) and poly(vinylpyrrolidone)-cyclodextrin in N-methyl-2-pyrrolidone, a common solvent for both polymers. Further addition of this mixed polymer solution in solvent results in self-assembled polymeric nanoparticles. The summary of various major cyclodextrin-based polymeric nanoparticles loaded with pharmaceuticals including natural compounds and techniques of drug inclusion is illustrated in Table 1.

Table 1 Formulation of various cyclodextrin-based polymeric nanoparticles loaded with pharmaceuticals including natural compounds and techniques of drug inclusion to facilitate the improved drug stability, sustained, controlled, and targeted drug delivery including encapsulation of hydrophilic and hydrophobic compound
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Cyclodextrin-based lipid nanoparticles

Lipids generally obtained from the natural origin are non-toxic, biodegradable, and biocompatible. These properties make lipids superior to polymers. Hence, the lipid-based nanoparticulate system provides a better platform for safe and effective drug delivery (Chaudhari et al. 2020). The association of cyclodextrin into lipid nanoparticle formulations not only promotes the hydrophobic drug loading within the aqueous components of the lipid cyclodextrin nanoparticles but also maintains the targetability of nanoparticles. To ensure stable encapsulation, McCormack and Gregoriadis (1994) suggested an approach wherein cyclodextrin/drug inclusion complexes are embedded into liposomes. This strategy is designated as drug-in-cyclodextrin-in-liposome. Arima et al. (2006) developed PEGylated (polyethylene glycol chain conjugated) liposomes entrapping the doxorubicin complex with γ-cyclodextrin and evaluated the antitumor effect of doxorubicin in rodents bearing colon-26 tumor cells. The findings of the study displayed retardation in tumor growth and an increase in drug retention. Curcumin, a well-known bioactive compound, possesses antibacterial, anti-inflammatory, antioxidant, and antitumor activity. But, curcumin exhibits instability and poor solubility. Therefore, to resolve these issues, Dhule et al. (2012) fabricated curcumin-loaded cyclodextrin-based liposomal nanoparticles and studied them to treat osteosarcoma. The resulting 2-hydroxypropyl-γ-cyclodextrin/curcumin–liposome complex exhibits promising cytotoxic potential. Ji et al. (2016) practiced the use of cyclodextrin to enhance the tumor-targeting ability of the lipid nanoparticles on the outside of the liposomal wall. The surface of the liposome consisted of pirfenidone-loaded β-cyclodextrin linked with a cleavable peptide, along with arginyl–glycyl–aspartic acid peptide to target pancreatic tumor cells, while the interior of the liposome carried the chemotherapeutic agent gemcitabine. Results showed this integrated nanomedicine effectively targets and kills pancreatic tumor cells, moreover, facilitating a promising strategy for the improvement of pancreatic cancer therapy. Solid lipid nanoparticles represent an alternative carrier system to conventional colloidal carriers due to their specific features such as the use of natural fabrication components, size and related narrow distribution, enhanced stability, and increased permeation through biological barriers. Skiba et al. (1993) first described the development and application of a novel cyclodextrin-based dispersible colloidal system in the form of spherical particles of matrix type with size ranging from 90 to 900 nm (nanospheres), which might contain an active pharmaceutical ingredient. This nanoparticulate system was used as a carrier for numerous pharmaceuticals and cosmetic agents. Nanostructured lipid carriers represent an upgraded generation of lipid nanoparticles, which overcome the major drawback of solid lipid nanoparticles, particularly the tendency of discharge of the drug during storage as an outcome of their highly ordered crystalline composition. A summary of recently developed cyclodextrin-based solid lipid nanoparticles, lipid nanoparticles, and their therapeutic applications is illustrated in Table 2.

Table 2 Formulations of cyclodextrin-based solid lipid nanoparticles and lipid nanoparticles loaded with various drugs, utilizing the advantages of both cyclodextrin and nanolipid carriers by incorporating the drug–cyclodextrin inclusion complex into the lipid nanoparticles
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Role of cyclodextrins in gold and silver nanoparticles

In recent years, gold and silver nanoparticles have been widely investigated for nanomedicine due to their superior optical, chemical, and biological properties. Gold and silver cyclodextrin nanoparticles are commonly produced by connecting cyclodextrin to the metallic core using a linker, such as adamantane, which forms a strong stable complex with the cyclodextrins. Liu et al. (1998) first developed a novel technique for the surface derivatization of gold colloidal particles to prepare gold colloidal particles of diameter higher than 10 nm. They demonstrated aqueous solubilization of aliphatic thiols by α-cyclodextrin, which effectively binds to the aliphatic chains and carries the hydrophobic thiol molecules to the surface of the gold particles. Wang et al. (2016a, b) described an easy method to produce the host–guest assembly of gold nanoparticles induced by intracellular glutathione. Results showed that the synthesized aggregates retained for a long time in cancer cells and provoke apoptosis of cells when exposed to near-infrared irradiation. β-cyclodextrin-functionalized gold nanoparticles are more efficient in anticancer therapy when incorporated with anticancer agents. For example, Bakar et al. (2015) reported decreased breast cancer cell (MCF-7) proliferation by complexing various ligands (pinoresinol, lariciresinol, and secoisolariciresinol), with thiolated-β-cyclodextrin and decorating them on the exterior of gold nanoparticles. Conventional anticancer molecules such as doxorubicin, paclitaxel, and docetaxel were incorporated into the β-cyclodextrin-functionalized gold nanoparticles and targeted to cancer cells. The findings of cell line studies showed that the doxorubicin-loaded β-cyclodextrin gold nanoparticles enhanced the cellular uptake and exerted a significant antiproliferative effect. Similarly, Wang et al. (2016a, b) constructed a twofold nanoparticulate delivery system based on host–guest nanoplatforms loaded with anticancer agent docetaxel and genetic material siRNA using gold nanorods coated with polyethylenimine-grafted β-cyclodextrin. The developed gold nanoparticles upon exposure to near-infrared laser irradiation generate a significant hyperthermia effect to trigger siRNA and docetaxel release from the cyclodextrin and remarkably inhibit lung metastasis of 4T1 breast tumors. In another study, Gannimani et al. (2016) coupled the antibacterial properties of silver nanoparticles and hydrophobic drug carrier characteristic of cyclodextrin to fabricate supramolecules to provide cutting-edge for antibacterial efficacy of chloramphenicol. Likewise, Gaurav et al. (2015) utilized β-cyclodextrin to solubilize clotrimazole, an antifungal agent, and then attach to albumin-stabilized silver nanoparticles. These hybrid nanoparticles exerted a synergistic effect when evaluated for antifungal activity against candida yeast cells. Zhai et al. (2017) investigated the uptake of biocompatible nanoparticles into viable cells in a microfluidic chip by utilizing surface-enhanced Raman spectroscopy, which modified the surface of β-cyclodextrin-capped silver nanoparticles using para-amino thiophenol and folic acid. The para-amino thiophenol molecules serve as the Raman reporter, while the folic acid fragments have a high proclivity for folate receptors that are over-expressed on the surface cancerous cells so that the nanoparticles can penetrate the cells and be observed by the Raman reporter. The above findings delineate that surface functionalization of gold and silver nanoparticles by cyclodextrins improves solubility, enhances permeability, and modifies drug release with retaining safety and efficacy.

Pharmaceutical applications of amphiphilic cyclodextrin nanoparticles

The potential use of cyclodextrin in a biological system needs amphiphilic properties because natural cyclodextrin has relatively low solubility both in water and in organic solvents, thus limiting their uses in pharmaceutical formulations. Amphiphilic or ionizable cyclodextrins can modify the rate or time of drug release and bind to the surface membrane of cells that may be used for the enhancement of drug absorption across biological barriers (Bilensoy and Hincal 2009). According to the chemical structure of the amphiphilic cyclodextrin, different carrier systems could be obtained such as solid lipid nanoparticles, bilayer vesicles, liposomes, and nanoparticles (Donohue et al. 2002). Their unique properties can improve the drug-loading capacity, cellular interaction and tumoral penetration, drug release profiles, and cytotoxicity of drug delivery systems. Table 3 summarizes the various potential pharmaceutical applications of amphiphilic cyclodextrin-based nanoparticles such as anticancer, cholesterol-targeted, folate-targeted, and amphiphilic cyclodextrin nanoparticles for gene delivery.

Table 3 The historical landmarks of amphiphilic cyclodextrins-based nanoparticles containing anticancer, antimicrobial drugs including gene delivery to facilitate improved drug-loading capacity, significant cytotoxicity, and vectorized gene delivery
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Miscellaneous

As per the biopharmaceutical classification system of drugs, poor drug solubility or poor mucosa permeability attributes of drugs limit their pharmaceutical applications. These cyclodextrin-based polymeric nanoparticles represent a more reliable drug delivery system when compared with control nanoparticles; they displayed homogeneous bioadhesive interactions with the gastrointestinal mucosa due to the presence of several hydroxyl groups in cyclodextrin nanoparticles, which would promote hydrogen bonding with the gut, subsequently enhancing the bioadhesive potential (Agüeros et al. 2011). Furthermore, Luppi et al. (2011) examined the potential of different cyclodextrins in nasal drug delivery using albumin nanoparticles for the treatment of the most common neurodegenerative disorder Alzheimer’s disease to validate their effect on the drug release, mucoadhesiveness of nanoparticles, and permeability of model drug tacrine. Maestrelli et al. (2006) synthesized chitosan nanoparticles in the presence of cyclodextrin as a nanocarrier system for transdermal drug delivery of the triclosan (an antifungal agent) and furosemide (a diuretic). This nanocarrier system exhibited fast release followed by a delayed release of drug. It confirms the inclusion of the drug inside the cyclodextrin cavity and later encapsulation inside the chitosan polymer. Similarly, Khalil et al. (2012) formulated nanoparticles of warfarin, an anticoagulant drug, by loading it in chitosan–cyclodextrin-complexed nanoparticle systems for transdermal drug delivery. The results of in vitro release studies and ex vivo permeation studies of nanoparticles paved the new way for the delivery of hydrophobic drugs. Datz et al. (2018) have synthesized a new β-cyclodextrin-based biocompatible and multifunctional substance that cross-linked with rigid organic linker molecules to yield thermostable, readily water-dispersible particles having a nanosize range approximately 150 nm. In the next step, these nanoparticles covalently linked with dye molecules to enable effective tracking of them during in vitro cell experiments. Results showed the successful nuclei staining with Hoechst 33,342 dye, including effective cell killing with the doxorubicin cargo molecules and , therefore, representing a promising approach for the development of novel theranostic systems. The above examples confirm that cyclodextrin-based nanoparticles significantly enhance the bioadhesive potential and permeability of drug molecules and, thus, act as a promising carrier for nasal and transdermal drug delivery.

Conclusion

There is a significant discussion about the potential advantages, characteristics, and therapeutic applications of cyclodextrin-based nanoparticles reported in previous years. Cyclodextrin-based polymeric nanoparticles, including new generation nanoparticles such as magnetic, gold, and silver nanoparticles, have emerged as an effective nanocarrier system for advanced drug delivery such as anticancer drugs, peptides, proteins, deoxyribonucleic acid, and other genetic material. They facilitate improved drug-loading capacity, inclusion complex ability, increased aqueous solubility, targeted drug delivery, and significant cytotoxicity against different cancer cell lines. Cyclodextrin-containing nanoparticles have shown their potential to improve the loading capacity of liposomes, solid lipid nanoparticles, and nanostructured lipid carriers. The chemical modification of cyclodextrin polymers is a unique strategy to explore their potential pharmaceutical applications. Some cyclodextrin-containing nanoparticles, such as CRLX101, a tumor-targeted nanopharmaceuticals, and CALAA-01 for siRNA delivery, are among the most promising nanotherapeutics in clinical phase II trials for cancer diseases (Weiss et al. 2011; Zuckerman et al. 2014). Apart from these promising research findings, safety, efficacy, pharmacokinetic evaluation for cyclodextrin-based nanoparticles in the body, and mechanism of elimination of nanoparticles need to be further investigated.