Abstract
Nanotechnology advancements have led to the development of its allied fields, such as nanoparticle synthesis and their applications in the field of biomedicine. Nanotechnology driven innovations have given a hope to the patients as well as physicians in solving the complex medical problems. Nanoparticles with a size ranging from 0.2 to 100 nm are associated with an increased surface to volume ratio. Moreover, the physico-chemical and biological properties of nanoparticles can be modified depending on the applications. Different nanoparticles have been documented with a wide range of applications in various fields of medicine and biology including cancer therapy, drug delivery, tissue engineering, regenerative medicine, biomolecules detection, and also as antimicrobial agents. However, the development of stable and effective nanoparticles requires a profound knowledge on both physico-chemical features of nanomaterials and their intended applications. Further, the health risks associated with the use of engineered nanoparticles needs a serious attention.
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Introduction
The multidisciplinary unit, comprising the principles of physics, chemistry, engineering and biology to design and synthesize the nanoscale materials or devices is termed as nanotechnology. Nanotechnology deals with the development of nanoscale sized objects including materials, devices and/or systems [1]. The rapid progress in nanotechnology has shown a new hope in promoting human and veterinary health and in addressing the deadliest diseases in the future. Currently, it is well accepted with a great concern of potential health risks. The exposure of nanoparticles (NPs) causes inflammation, toxicity, apoptosis, oxidative stress and lung inflammation leading to pulmonary diseases [2, 3]. Further, the presence of ultrafine particles at extra-pulmonary sites including heart, liver, brain, and also in the systemic circulation have been observed to cause intestinal pulmonary fibrosis, metal fume fever, mesothelioma, and ardystil syndrome [3,4,5]. Nanomaterials typically have a size in the scale of 0.2–100 nm with an increased surface to volume ratio [2]. The NPs are of two different types such as non-engineered NPs which are found in the environment and derived from natural events (erosion, and volcanic eruptions) and engineered NPs (ENPs) produced by human using different materials [6]. The physico-chemical and biological properties of ENPs including strength, flexibility, performance and durability have drawn an attention from various fields such as medicine, biology, and engineering.
The properties of NPs, such as size, shape, surface morphology and particle diameter affect the physical stability and also the performance of NPs in vivo [7]. The surface area of NPs increases with the decreased size and the increased surface to volume ratio is correlated to their increased antimicrobial activity. Different types of ENPs ranging in size from 0.5 to 1000 nm have been synthesized and characterized for their applicability in biomedical fields. Furthermore, the efficiency of ENPs also depends on the surface characteristic features such as surface charge and hydrophobicity. The surface Zeta potential values of NPs helps in the determination of surface charge and surface hydrophobicity [8]. The interaction of NPs with the bioactive compounds depends on the NPs surface charge, intensity and also the electrostatic interaction between them [7]. Depending upon the dimensions, ENPs can be classified as one-dimensional (thin films), two-dimensional (carbon nanotubes) and three-dimensional (dendrimers, quantum Dots) NPs [7, 9]. Many different types of NPs have been developed and characterized for use in drug/bioactive agent delivery system which include liposomes [10], polymeric NPs [11] nanocapsules [12, 13], polymeric micelles [14], and dendrimers [15, 16]. Properties and synthesis of these NPs is discussed in Sect. 2.1. The effectiveness of ENPs in a biological system is mainly correlated to their properties, such as shape, size, configuration, surface charge, and chemical and biological interactions. Application of ENPs in imaging, phototherapy, and drug delivery require a stable and explicit control over NPs interaction with cells, which are mostly provided by the surface properties of NPs [17]. Moreover, the stability and size control issues remains as a challenge during the synthesis of ENPs [18].
The development of advanced techniques, such as transmission electron microscope (TEM) including low- and high-resolution TEM (LRTEM and HRTEM), photon-correlation spectroscopy (PCS), scanning electron microscopy (SEM), atomic force microscopy (AFM), laser doppler anemometry (LDA) have significantly influenced the development of nanomaterials and their characterization. The difference in the surface to volume ratio allows ENPs to exhibit different chemical, physical, electrical, optical, mechanical, and magnetic properties [19, 20]. The physico-chemical and biological properties of ENPs can be modified depending on various applications [1, 21].
NPs possess a specialized property known as stimuli response release system in which the release of bioactive agents can be controlled by various physical and chemical parameters [22, 23]. Different types of stimuli, such as temperature [24], magnetic fields [25, 26], ultrasonic waves [27], pH [28], and light [29] have been investigated as effective stimuli to use in response release systems and this helps in the effective release of bioactive compounds at the target sites. The ENPs are utilized in various fields, such as optical, chemical and biological applications. In specific, they are widely used in the fields of optical devices, superconductors, catalysts, drug delivery, gene delivery, fuel cells, imaging of biosamples, biomolecules detection, tissue engineering, regenerative medicine, detection of pathogens, biosensors and also as alternatives against drug-resistant microbes [2, 30,31,32,33,34].
ENPs exhibit superior inhibitory activity against microbes [35,36,37]. Both organic as well as inorganic ENPs with potential applications in different fields of life science have been synthesized by several research groups. However, the inorganic ENPs have wide ranging applications when compared to organic ENPs due to their capacity to withstand adverse reaction conditions [21]. Several types of ENPs have been synthesized and characterized by different research groups and are shown in Table 1. Moreover, it has been observed that NPs play a promising role in the delivery of drugs and other bioactive agents with increased therapeutic and/or bioactive efficacy [38, 39]. The role of ENPs in medicine such as in vivo imaging, in vitro diagnostics, tissue engineering, regenerative medicine and also in the detection of biomolecules has been well established [40].
Antimicrobial drug resistance has forced to use alternative approaches for the treatment of various diseases. Amongst them, nanocomposites such as graphene oxide-silver nanocomposites, Ti-GO-Ag nanocomposite, Ag NPs/GO nanocomposites have been reported to be very effective antimicrobial agents [41,42,43]. The nanocomposites/NPs act on microbes by various ways, including DNA damage, inhibiting DNA replication, protein synthesis, release of reactive oxygen species (ROS) and cell wall/membrane disruption (Table 1). Furthermore, different types of nanomaterials, such as gold (Au), silver (Ag), silver oxide (Ag2O), titanium dioxide (TiO2), zinc oxide (ZnO), copper oxide (CuO), calcium oxide (CaO), magnesium oxide (MgO) and silica (Si) have been synthesized and characterized for their antimicrobial activity [2, 34]. The antimicrobial mechanism of ENPs depends on their bulk properties. NPs which process high surface area to volume ratio reduce the microbial adhesion and the formation of biofilms and are the viable approaches for the treatment of biofilm-associated infections [44]. The development and characterization of magnetic NPs (MNPs) has evolved as a significant field of research in medicine and biology. The growing interest in the MNPs is due to their easy preparation, smaller sizes, higher biocompatibility, low toxicity, high stability, simple chemical functionalization, efficient drug conjugation along with superior magnetic responsiveness [45]. Many different MNPs based on iron oxide have been developed and found potential applications in the field of drug delivery, magnetic resonance imaging, magnetic separation and biomolecules detection and also in the new and emerging fields of medicine, such as cell therapy, tissue engineering, and regenerative medicine.
The present review provides comprehensive and updated information related to various applications of ENPs in medicine and biology. The data in this review has been obtained by various search engines including Science Direct, Google Scholar, Scopus, Pub Med, Research Gate and SciFinder.
Applications of ENPs
Nanotechnology and the development of ENPs have revolutionized the fields of medicine and have given a ray of hope for physicians in combating the diseases which still do not have specific drugs. ENPs find potential applications in various fields of medicine and biology Different types of ENPs have been synthesized and characterized by several groups for this purpose. Some of the inorganic ENPs, such as aluminum NPs (AlNPs), copper NPs (CuNPs), CuONPs, AuNPs, AgNPs, MgONPs and carbon-based NPs have been synthesized, characterized and evaluated for their biological activity. Furthermore, advancements in the field of DNA nanotechnology and preparation of several different DNA-based NPs has been a significant impact in the field of medicine and biology such as drug delivery, and preparation of biosensors/biochips [46]. Various organic ENPs including quaternary ammonium compounds, chitosan, polysiloxanes, and triclosan have also been characterized for their biological activity [2]. Several different metalloid NPs such as polymercoated bismuth sulfide NPs, and cadmium telluride NPs have also been employed in the diagnostic assays [47]. The application of ENPs in various fields is represented schematically in Fig. 1.
Applications of engineered nanoparticles in different fields of medicine and biology
ENPs in cancer therapy
The most common and widely used mode of cancer treatments include surgical removal of an abnormal tissue, chemotherapy, biotherapy, radiation therapy alone and/or in combination with two or more different therapies. Though these conventional cancer therapies have improved the patient survivability, they carry certain limitations such as non-specific distribution of drugs, aqueous insolubility of drugs, and multidrug resistance [48, 49]. One of the major shortcoming of conventional therapy is non-specific distribution of drugs, which limits the therapeutic dosage, and also affects the normal cells, tissues and organs with severe side effects, and bring down the quality life of cancer patients [50]. Hence, designing a specific drug to target cancer cells/tissues accompanied by the controlled drug release helps to overcome the shortcomings of conventional cancer therapy and could benefit the cancer treatment significantly.
The development of NPs has offered a great benefit and interest in cancer therapy in addition to overcoming the limitations of conventional chemotherapies [51, 52]. ENPs have several advantages including the enhanced solubility of hydrophobic drugs, prolonged circulation time, capacity to carry higher payloads of drugs, minimized non-specific uptake, prevention of undesirable side effects, enhanced intracellular penetration, specific anticancer drug targeting and in cancer imaging [53, 54]. Drug carriers enter into cancer tissue compartments through openings/fenestrae between vascular endothelial cells and several different NPs can easily pass through these fenestrae [55]. The great advantage of ENPs is their specific drug delivery to target sites such as cancer cells or tumors, which in turn increases the drug concentration at the target site/s by avoiding the toxicity to normal cells. However, the factors such as, molecular weight and stability are attributed to the specific distribution, optimized blood circulation and finally accumulation within tumors. Moreover, the rate of leakage of NPs across tumor vascular fenestrae can also be controlled through several parameters such as shape, size and surface properties, concentration (in tumor blood vessel) of NPs, and blood vessel factors such as the size of fenestrae, density, and distribution [55]. Further, NPs have the great potential in overcoming the multiple drug resistance mechanism in cancer therapy [52]. In addition, ENPs can be tailored to carry therapeutic drugs as well as imaging probes or diagnostic agents simultaneously and also can be designed to target diseased tissues specifically to enable combination therapy to overcome multidrug resistance [56].
Cancer cells display greater affinity towards particles of certain size than healthy cells due to their faulty particle screening and the presence of immature blood vessels which may be leaky and the phenomenon is known as the enhanced permeation and retention (EPR) effect [57, 58]. Hence, the EPR effect allows NPs to accumulate more (100–200 times) into tumor cells/tissue than normal cells/tissues [40] and this mechanism is also considered as a “gold standard” for the designing of anticancer drugs and also for targeting the site of tissue inflammation [40, 59,60,61,62]. The approval of cisplatin as an antitumor agent by the Food and Drug Administration (FDA) in 1978 has generated interest in exploring other metals such as gold and gold-based compounds in cancer therapy [63]. The first clinical trial for NPs based anticancer drug delivery started in the mid-1980s, and in 1995, the first liposomal NPs encapsulated with doxorubicin drug had entered the pharmaceutical market. Since then, several new and novel ENPs have been approved or under the development as anticancer drug delivery systems and cancer therapy. Different types of ENPs have been explored in the cancer therapies which include inorganic ENPs, polymeric ENPs and conjugates, micelles, dendrimers, protein and bacterial carriers (Fig. 2). Several different ENPs have been approved as anticancer agents by FDA for metastatic breast cancers, ovarian cancers and Kaposi’s sarcomas [64].
Different types of engineered nanoparticles (ENPs) approved by FDA or under clinical trial for cancer therapy
Liposome NPs for cancer treatment
Liposomes find potential applications in the cancer treatment due to their unique characteristic features such as biocompatibility, biodegradability, lack of immune system activation, low toxicity, and the capability to encapsulate both hydrophobic and hydrophilic drugs. Thus, liposomes have gained a significant attention as carrier systems for the delivery of therapeutic agents [65]. Moreover, surfaces of liposomes are modifiable through several chemical linkages/strategies to acquire significant therapeutic functions, including site-specific drug delivery, enhanced accumulation at the target site, prolonged systemic circulation, and increased cellular internalization [66, 67]. The therapeutic potential of liposomes as carriers for payloads and drug delivery to the target sites has led to the development of several different liposomal formulations for cancer therapy [68]. Several such vesicular formulations have been approved by FDA including 1,2-distearoyl-sn- glycero-3-phosphoethanolamine(DSPE), egg yolk phosphatidylglycerol (EggPG), hydrogenated phosphatidylcholine from soybean lecithin (HSPC), and 1,2-distearoyl-glycero-3-phosphocholine (DSPC) [67].
Polyethylene glycolated (PEGylated) liposomes have greater advantages of stable drug entrapment, very low drug leakage for longer period of time, prolonged circulation in the blood and the capability to accumulate in target/tumor tissues through EPR effect [69,70,71]. The earlier study has reported that modified liposomes coated with Folate-poly(l-lysine) and carrying doxorubicin drug have shown twofold higher cytotoxicity than poly(l-lysine) coated liposomal DXR on KB cells [72]. This might be attributed to the occurrence of folate receptor-mediated endocytosis. Further, the evaluation of Folate receptor targeted liposomes as carriers of a chemotherapeutic drug; Vincristine (F-l-VIN) exhibited a significant receptor-specific cytotoxicity with an IC50value of 2.64 ± 0.14 μM on KB cancer cells compared to non-targeted liposomes [73]. PEGylated liposome loaded with doxorubicin is used in the treatment of different types of cancer and several nanosomes loaded with different drugs such as camptothecin, docetaxel, vitamin D analog and bryostatin-1 have also been developed by Aphios Corp. Woburn, MA 01801, USA and used in the treatment of multiple types of cancer [67].
Several researchers have effectively reported the use of liposomes, dendrimers and polymeric NPs in the combination therapy against cancers [74]. For example, attempts have been made to simultaneously deliver DNA and drugs via liposomes using cationic core–shell NPs, which were synthesized by self-assembling biodegradable amphiphilic copolymers. These ENPs are more advantageous than liposomes, because of their easy fabrication, and manipulation of their size and charges [75]. According to them, the cancer growth was more effectively suppressed by the co-delivery of paclitaxel along with a plasmid encoding for interleukin-12, compared to the individual delivery of paclitaxel or the plasmid as observed in a breast cancer animal model. Likewise, a formulation of combretastatin–doxorubicin nanocell was used to deliver combretastatin and doxorubicin to target lung carcinoma, melanoma and various other cancer types [76]. Such studies were further supported by few novel polymeric nano-formulations, such as poly [lactic-co-glycolic acid] NPs co-encapsulating vincristine and verapamil, polyalkylcyanoacrylate NPs co-encapsulating doxorubicin and cyclosporin A, poly [ethylene glycol]–poly [aspartate hydrazide] block copolymers–Dox–WOR NPs, PDMAEMA–PCL–PDMAEMA-based cationic micelles, against various cancer types [74, 77,78,79].
Polymer and polymer–drug conjugate NPs for cancer treatment
Polymeric NPs are generally colloidal solid systems and have the capability to dissolve, entrap, encapsulate, and adsorb therapeutic drug onto the constituent polymer matrix [80]. Polymeric NPs may vary from nanospheres to nanocapsules such as micelle [81], polymerosome [82, 83] dendrimers [84] and hyper-branched polymers [85]. Moreover, natural macromolecules including polysaccharides and polypeptides [86] have also been characterized as drug delivery systems. Different shapes/designs of polymeric ENPs may be attributed to the flexibility provided by polymers.
It is well known that polymeric ENPs have been extensively used in the encapsulation as well as delivery of drugs such as lipophilic and hydrophilic drugs for many years. The unique physical and chemical properties of the polymers, including dispersity index, molecular weight, crystallinity and hydrophobicity helps in the precise control of drug release kinetics and degradation of drugs [67]. Moreover, the surface chemistry of polymeric NPs can be modified and stabilized through conjugation, grafting, or adsorption of other hydrophilic polymer such as PEG, to improve the circulation half-life and also to reduce the hepatic uptake [87, 88]. PEG helps to protect NPs from the reticulo-endothelial system (RES); however, it is known to prevent the cellular uptake as well as intracellular drug release [89].
Modification of polymeric chains through side-chain grafting of chemotherapeutic drugs results in the formation of polymer–drug conjugates. Polymer–drug conjugates helps in the delivery of higher doses of drugs to the target sites. The entry of synthetic polymer–drug, HPMA-doxorubicin [N-(2-hydroxypropyl) methacrylamide] copolymer (PK1), into the phase II clinical trial for advanced breast cancer [90] has been a breakthrough and created a significant interest in the field of cancer therapeutics. Further, the pharmacokinetic study of PK1 has showed a distribution time (t1/2) and an elimination (t1/2) time of 1.8 and 93 h, respectively. In the Phase I clinical study PK1 exhibited antitumor activity against refractory cancers with maximum-tolerated dose of 320 mg/m2 and dose-limiting toxicities such as febrile neutropenia and mucositis [90]. Furthermore, several polymer–drug conjugates are in clinical phase and/or recommended for use in cancer therapy which include paclitaxel polymer conjugate (paclitaxel poliglumex) against lung cancer [91], and Oncaspar (PEG–l-asparaginase) for acute lymphoblastic leukemia [92]. Polymer drug conjugates in which drugs are grafted on the side chains of poly-amino acids have also been demonstrated with significant therapeutic efficacy along with high drug loading capability [67, 93, 94]. Moreover, several different linkers have been used to increase the drug loading capacity of polymeric–drug conjugates. It has been reported that the degradable linker, polyglutamate-glycine-camptothecin enhanced the drug loading capacity from 5 to 50%. Further, the use of glycine linker has significantly increased the drug loading capacity compared to polyglutamate-camptothecin alone; this may be due to the reduced steric hindrance by glycine linker [67].
Micelle and dendrimeric NPs for cancer treatment
Micelles are spherical structures with a hydrophobic core formed by amphipathic lipids or other molecules, including poly-amino acids or polymers. Polymeric micelles act as promising and perspective delivery molecules for cancer therapeutic drugs [95]. It has been reported that polymeric micelles ranging in size from 10 to 200 nm are known to enhance the accumulation of drugs within tumor cells due to the EPR effect [96, 97]. Several different micelle NPs have been developed and characterized such as, Genexol-PM, NK105, and Nk911 [67]. However, the first non-targeted polymeric micelle formulation approved for cancer therapy is Genexol-PM. Genexol-PM is a block copolymer micelle formulation of paclitaxel (Taxol) with a size of ~ 60 nm and drug (Paclitaxel) loading capacity of ~ 15% (w/w). It has been reported earlier that Genexol-PM exhibit higher paclitaxel concentration in the tumor tissue than Taxol alone [98]. Genexol-PM, which is in the phase II trial study, has shown antitumor activity in patients with non-small-cell lung cancer at the dose of 230 mg/m2 with low incidence y of toxicity [99]. Polymeric micelles loaded with thioridazine (THZ-MM) and doxorubicin (DOX-MM) have been synthesized and characterized to determine the antitumor activity. The size of these micelles were found to be ~ 89.6 nm (DOX-MM) and ~ 77.0 nm (THZ-MM), respectively, and the co-delivery and/or individual delivery of these micelles had shown significant anticancer activity against breast cancer stem cells [97].
Dendrimers ranges in size from 5 to 10 nm are globular macromolecules possessing well-defined branching architectures. The basic components of dendrimers are central core, branching units and terminal group, the availability of terminal functional groups helps in further surface modifications [100]. Therapeutic agents/drugs can be encapsulated or bound in the internal cavities or on surfaces of the dendrimers through electrostatic and/or hydrophobic interactions or through covalent attachment to the terminal functional groups. The availability of controlled synthetic mechanisms led to the development of different class of dendrimers which find potential applications in diagnostics, drug targeting and also in drug delivery. Several different types of dendrimers have been developed by several research groups such as polyamidoamine (PAMAM), Poly (propylene imine) (PPI), and Poly-l-lysine (PLL) dendrimers. Doxorubicin (DOX) conjugated to carboxyl-terminated PAMAM dendrimers decreased the tumor (lung metastasis) burden in a model and also increased the efficacy of DOX treatment against lung metastasis in mouse model [101]. Further, researchers have developed “avidimers” [67], containing methotrexate polyamidoamine targeted for tumor vasculature [102].
Protein and polymerosome NPs for cancer treatment
Proteins are considered as ideal molecules in the preparation of NPs due to their capability to interact with both solvent and the drug [103]. Moreover, protein-based NPs are biodegradable, less toxic, easily metabolizable, and allow surface modifications for the attachment of ligands and drugs for targeted delivery and efficacy [103, 104]. Several water soluble proteins including albumin, gelatin, elastin, legumin and water insoluble proteins such as zein, gliadin have been explored in the synthesis of NPs and have been characterized as drug delivery carriers in the cancer treatment [103].
Protein-based NPs have made a significant improvement in cancer therapy. Albumin is a natural molecule capable of transporting molecules (no-covalent interactions) across endothelial barriers. Albumin accumulates in the tumor due to its intrinsic targeting abilities and enhanced permeability and retention effect [67]. Several studies have demonstrated the increased uptake of albumin bound paclitaxel in endothelial cells as well as in the extra vascular space [105, 106]. The albumin bound drug NPs such as Abraxane, ABI-008, are albumin-bound paclitaxel are approved by FDA for metastatic breast cancer therapy [67] and ABI-009 is under clinical trial against non-hematologic malignancies [103]. An earlier study showed that albumin-bound paclitaxel NP formulation (ABI-007) has showed maximum-tolerated dose ranging from 100 to 150 mg/m2, the dose-limiting toxicities observed were neutropenia and peripheral neuropathy [105]. Albumin has been evaluated as a delivery system for the low water solubility drugs such as rapamycin at the concentration of ~ 2.5 mg/mL [103]. Abraxane in combination with other chemotherapeutics such as vorinostat and rapamycin have been tested against metastatic breast cancer, ovarian and prostate cancer.
Amphipathic polypeptide or synthetic polymers forms polymerosomes or polymer shell vesicles (with a diameter of about ~ 100 nm) through self-assembly. The morphology of polymerosomic NPs depends on hydrophilicity or hydrophobicity of polymers and structures may be bilayer, spherical, or cylindrical [67, 107]. Moreover, the thickness of the membrane core is determined by the hydrophilic/hydrophobic ratio and size of the di-block copolymer [107]. Polymerosome NPs exhibit significant stability and lateral fluidity and the release of polymerosomes depend on the destabilization and degradation of shell layer and polymer chain, respectively [67]. Ahmed et al. [108] reported that the polymerosome NPs loaded with doxorubicin and paclitaxel with a maximum-tolerated dose of 2.5 mg/kg, exhibited therapeutic effect on breast cancer tumor. Moreover, in comparison to formulations by free drug, the polymerosome NPS reduced tumor size within 5 days post-injection. A nano-dumbbell consisting of hydrophobic NP core and a hydrophilic polymerosome shell has been synthesized to use as transducers in photodynamic therapy [109]. In addition, the lipid shell polymerosomes loaded with zinc (II) phthalocyanine (photosensitizer used photodynamic therapy) was used to minimize corrosion and/or non-specific absorption during transportation [110].
Inorganic NPs for cancer treatment
The development of nanotechnology offered the development of metal and metal based ENPs with potential applications in biomedicine especially targeted drug therapy for cancer. Several inorganic NPs have been developed, characterized and evaluated for use in cancer therapy including AuNPs, AlNPs, CuNPs, and semiconductors such as quantum dots, carbon nanotubes, carbon dots and iron oxide, These molecules have been evaluated for therapeutic and diagnostic purposes in cancer therapy, however, only less number of inorganic ENPs have been translated into clinical practice presently [111]. The characteristic features of quantum dots such as size-dependent luminescence, stability against photo-bleaching and high fluorescence yields allow them to use in a wide range of medical and biological fields including cancer therapy, drug delivery, cell targeting/imaging, fluorescent probes and diagnostics [112]. The EPR effect is difficult to be used for tumor drug delivery due to heterogeneity of tumor vasculature, uptake by the RES and particle detection. However, PEGylation of NPs reduces uptake by RES and increases the EPR effect compared to free drugs [58]. Addition of tumor recognition molecules such as transferrin, epidermal growth factor, monoclonal antibodies, on the surface of NPs helps in the delivery of drugs at the tumor sites. It has been reported that, metal oxide NPs such as cobalt oxide NPs (CoONPs) modified by the addition of N-phosphonomethyl iminodiacetic acid (PMIDA) facilitated the binding/conjugation of cancer cell lysate antigen (Ag-PMIDA-CoONPs), These Ag-PMIDA-CoONPs were found to stimulate the immune responses against conjugated cancer lysate antigens only and acts as a antigen delivery system for antitumor vaccine [113], Furthermore, PMIDA-CoO NPs and chitosan-coated CoONPs were also reported to induce apoptosis/cell death through DNA damage, caspase activation and oxidative stress in leukemic cell lines [114, 115].
Inorganic ENPs made of transition metals d-block elements such as Ti, V, Cr, Re, Mn, Au, and Cu have found potential applications in photo activated chemotherapy for cancer and inorganic ENPs based cancer therapy is becoming significant and interesting field [116]. Further, the anticancer activity and photophysics of several inorganic elements such as Ti, V Cu, Fe, Pt, Rh, and Au have been well established [63]. However, further advancement in the characterization of these inorganic NPs and in vitro/in vivo study on different types of cancers would help in the potential application of these ENPs at the clinic.
Gold nanostructures with a particle size ranging from 2 to 500 nm are generally synthesized from the reduction of HAuCl4 assisted by various reducing/stabilizing agents under the different environmental conditions such as pH, pressure and temperature. The advantages of AuNPs synthesis is that their size and shape can be easily controlled during their synthesis. The ideal size between 1 and 150 nm with varied shape, and possessing distinctive chemical, physical, optical and electrical properties can be obtained readily [117,118,119]. AuNPs are the most stable materials and exhibit similar properties even when dilutions are changed and usually, they are non-toxic and exhibit both in vitro and in vivo biocompatibility. Because of this reason, they are widely employed in the biomedical applications especially for cancer diagnosis and therapy [120]. The most likely mechanism, by which AuNPs enter the cells, is by non-specific receptor-mediated endocytosis. In particular, AuNPs are effective as thermal destructive agents of cancerous cells owing to their effective photothermal heating capabilities and surface functionalization [121]. The photothermal therapy requires high photothermal conversion efficiency of NPs. The photothermal conversion efficiency of AuNPs depends on structural dimensions such as size and shape [122]. Several different AUNPs have been characterized and their potential applications in diagnosis and treatment of melanoma cancer have been determined [122]. Moreover, AuNPs based platforms have also been employed in the detection of circulating cancer markers such as vesicles, circulating tumor cells, proteins and nucleic acids as well [123]. Furthermore, in a recent study the green synthesized AuNPs were demonstrated with in vitro anticancer activity against MCF-7 cell lines at 74 μg/mL [124].
AuNPs are used in biomedicine as drug carriers, radio-sensitizers, and used in thermal therapy for cancers, diagnosis of cancers, and image analysis [119]. Au possess several advantages with synthetic versatility to the unique electronic and optical properties, AuNPs are widely employed for various biomedical applications. AuNPs have the ability to bind to amines and thiols, thus providing a suitable way for introducing several functional groups and may be employed as therapeutic agents when combined with therapeutic drugs or radionuclides, delivering genes/small-interfering RNAs, photo-acoustic imaging, and to target specific sites or proteins [119, 125,126,127,128,129].
In recent years, the available drugs are modified to enhance their pharmacokinetics to reduce non-specific toxicity and enable the delivery of drugs to target tissues at high doses. For instance, 5 nm AuNPs was used as a delivery agent bound with cetuximab as an active targeting agent in treating pancreatic cancers [130]. Likewise, AuNPs complexed with gemcitabine at low doses led to increased tumour growth inhibition (> 80%) in a pancreatic cancer model [130, 131]. Jiang et al. [132] synthesized AuNPs coated with citrate with sizes between 2 and 100 nm. These particles when bound with trastuzumab antibodies enabled to target and cross-link to human epidermal growth factor receptor (HER)-2 in human breast cancer cells. Hyperthermia induces apoptotic cell death and hence, used in cancer therapy in combination with radiotherapy and chemotherapy. AuNPs are very advantageous in this regard and an in vivo study has demonstrated that 100 nm sized Au nanoshells accumulated in human breast cancer cells (SK-BR-3) maximally within 24 h when injected intravenously. Interestingly, applying of laser showed an increase of 37 °C in nanoshell-treated mice, while in control mice there was only 9 °C increase. Also, there was no tissue damage found in the nanoshell group and mice survived up to 90 days without any tumour recurrence symptoms. Similarly, 110 nm sized PEGylated Au nanoshells and laser therapy were found effective in treating human prostate cancer [119, 133,134,135]. While, AuNPs improve the contrast and structural imaging modalities in Magnetic Resonance Imaging (MRI), positron emission tomography (PET) and computed tomography (CT) analysis and help to diagnose cancers. Molecular imaging studies provide in vivo data on the metabolic functions of cancers and allow easy identification of molecular markers [58, 136]. Most of the AuNPs studies in cancer diagnosis and therapy have shown positive effects. However, more studies are encouraged to investigate on the factors including shape, size, surface coating, and doses, influencing on the functional properties of AuNPs in addition to their observation in animal models.
ENPs and nanocomposites in tissue engineering and regenerative medicine
The development of biomaterials led to the evolution of advanced technology in the field of medicine known as tissue engineering (TE) and regenerative medicine (RM) and has revolutionized the field of medicine.
The fundamental components of TE include biomaterial scaffolds, cells, and signaling biomolecules [137]. Restoration of tissue function and/or repopulation of defect site by TE approach involve implantation of biomaterial scaffolds which are porous, biodegradable and seeded with adequate amount of normal cells [138, 139].
Growth factors (GFs) and differentiation factors (DFs) play a significant role in the proliferation, migration, maturation, and differentiation of functional precursors into mature functional tissues [140]. Hence, the success of RM and TE depend on the accurate presentation of GF’s/DF’s surrounding the healthy tissue and their concentration on the biomaterials during TE approach [141, 142]. Moreover, the effect of TE and RM also depends on the availability of effective and controlled release of GF’s/DF’s.
Several different types of biological nanomaterials including NPs, nanotubes, nanofibers, and fabricated nano-devices lesser than 100 nm dimension having potential applications in cell growth and tissue regeneration have been studied by several research groups. Biological nanomaterials explored in TE and RM must have the capability of eliciting several specific cell to cell interactions such as attachment, adhesion, multiplication, and differentiation. Hence, the selection of biomaterials is the most significant factor in the success of TE approach [143]. Biocompatibility surfaces coupled with suitable mechanical properties constitute the basic and fundamental requirements of biological materials explored in TE and RM. Several such biological materials have been investigated and characterized for use in TE and RM. However, it has been observed that no single biodegradable polymeric material can satisfy the basic and fundamental requirements. Therefore, the combination of biomaterials through addition of inorganic/biomolecules onto biodegradable polymeric matrices is an effective strategy to obtain nanocomposites having multifunctional and specific activity [143]. Several different polyester based nano composite materials have been developed to use in medical applications. The natural polymeric substances such as, silk [144], starch [145] and collagen [16] have been characterized for their potential application in medicine.
The advanced technology exploring the scaffolds and NPs loaded with bioactive agents has grown significantly which in turn led to the advancement in the field of TE and RM. The intended application of scaffold determines its composition and physical parameters. Many different natural and synthetic polymers have been characterized and used as TE scaffolds [138, 139]. The most commonly used TE scaffolds based natural polymers are gelatin, fibrin, collagen, polyhydroxyalkanoates, hyaluronic acid, chitosan and alginate [142]. Whereas, PLGA, PGA, PLA, PCL, PEG, PEG derivatives (poly (fumarate)) PEG copolymers such as poly (amido-amines), poly (vinyl alcohol), orpoly (urethanes) constitute the synthetic polymers used in TE scaffolds.
Several inorganic materials including cement, bioactive glass, calcium phosphate ceramics and ceramic/polymer composites have also been developed and found their application in bone TE [146, 147]. Many different conventional and advanced techniques have developed for the preparation of biological scaffolds used in TE approach which include melt molding, fiber bonding, solvent casting, gas foaming, particulate leaching, rapid prototyping phase separation, electrospinning, nanofabrication. Moreover, the surface-patterning techniques such as nano-imprint lithography, electron-beam lithography, photolithography, nano-contact and printing, have also been developed in the preparation of effective TE scaffolds. However, among all electrospinning is the most common and versatile technique used in the preparation of TE scaffolds having high surface area to volume ratio [40, 148]. Different ENPs coupled scaffolds have been characterized for use in bone and cartilage TE and RM.
ENPs and nanocomposites in drug delivery
The ENPs are capable of delivering the drug/bioactive agents in a controlled manner. Transient and sustained delivery of bioactive agents to the target/specific site is a major challenge in TE and RM approach. The controlled and sustained release of drug/bioactive agent by the ENPs provides several advantages which include protection of therapeutic molecule from degradation, maintenance of drug/bioactive agent concentration, along with targeted delivery and reduced side effects. Hence, the therapeutic efficacy of a drug/bioactive agent increases with the development of effective delivery systems, in this regard NPs acts as a promising device [38, 39]. However, an ideal NP carrier should be stable, biodegradable, non-immunogenic, and capable of releasing the drug/bioactive agent only at the target site in a cost-effective manner [149, 150]. The role of ENP’s in drug delivery has been well established and play significant and crucial role even in TE and RM also [140]. NPs are required to cross the physiological barriers of the system depending upon the application, target cells and route of administration [151]. Hence, the success and also the efficiency of NPs-based delivery system depends on the capability of transporting loaded bioactive agent through physiological barriers to reach the target site for optimum pharmacological activity. ENPs are internalized through different mechanisms such as phagocytosis, endocytosis, pinocytosis depending on the type of NPs and drug conjugate system.
The cell viability and internalization property varies from one cell type to another. Moreover, other parameters including composition, surface charge, size and concentration of NPs, and also incubation time influences the cell viability and internalization efficiency of NPs by the cell [40]. NPs based drug/bioactive agent delivery can be carried out through encapsulation using nanospheres developed from biodegradable (natural/synthetic) or non-degradable polymers. Poly(l-lactide) (PLA) or poly(l-lactide-co-glycolic) (PLGA) [152, 153] are the best examples for synthetic biodegradable NPs, while proteins and polysaccharides such as, collagen, gelatin, fibrin, alginate, and chitosan can be used as natural biodegradable polymers for NPs synthesis. Metals and metal oxides/sulfides such as, gold, hydroxyapatite, alumina and silica [154,155,156,157] constitute non-degradable NPs. The selection of polymeric material for the construction of NPs for delivery system depends on many factors including, size, surface chemistry and charge of the NPs, characteristic features of the dug/bioactive agent, dug/bioactive agent release profile, and also the biodegradability and biocompatibility of NPs [158]. The ENPs synthesized from biodegradable materials exhibit significant biocompatibility with negligible immunogenicity, apart from degradability.
The application of ENPs/nanocomposites in drug/bioactive agent delivery may improve the effective treatment of many diseases; one such is the cancer targeted drug delivery. Targeted drug delivery may be passive, active or physical targeting of cells, tissues, organs and even organelles. Organelle targeting drug delivery is an emerging and promising field of research due to its application in cancer therapy.
The passive targeting is based EPR effect (Sect. 2.1), is known to be influenced by several parameters including the shape, size, and surface charge of NPs which in turn influences penetration speed, circulation time, and also intracellular internalization mechanism [159, 160]. The surface properties of NPs could play significant role in their circulation in the blood vascular system and subsequent internalization by the cells [150]. Cancer cells tend to take up NPs with positive charge more readily than negatively charged NPs because of their negative charge on the surface [150]. Moreover, the geometry of NPs also influences the cellular uptake. Further, Li et al. established that internalization rate of PEGylated NPs spheres is faster compared to cubes, however, rods and disks exhibited slowest internalization rate [161]. Many different NP structures in which drugs are dissolved, entrapped, and/or conjugated on to the surface have been developed and several of them have received clinical approval and approved by FDA for instance; liposome mediated doxorubicin and daunorubicin delivery system, an albumin-bound NPs containing paclitaxel, abraxane against breast cancer [162].
However, active targeting is selective and can react only with target cells. In this process the NPs are functionalized with a ligand which has significant affinity towards molecule abundant on cancer cells. This increases the uptake specificity, delivery efficiency of NPs and sometimes protects the drug from enzymatic digestion. Active targeting mechanism directs the drug to a specific cell, organ, or organelle and can alter the normal distribution patterns of a carrier; however, passive targeting rely on the EPR effect and natural distribution of the drug [150]. Physical targeting involves navigation of drugs to the target site using external stimulation factors, such as magnetic fields and/or radiation such as photothermal therapy.
Several NP based photothermal agents have been tested in cancer therapy such as, AuNPs, graphene, carbon nanotubes. Several different mechanisms such as pH, heat and fictionalization/conjugation of NPs with polymer or PEG have been explored in the delivery of drugs. For instance, carbon nanotubes and graphene oxide conjugated with polymer is pH sensitive and kill cells photothermally [163], while graphene nanosheet coated with silica and functionalized with PEG have been reported to deliver doxorubicin [164]. The heat energy produced from MNPs due to their oscillation in a magnetic field is also explored in the cancer treatment (magnetic hyperthermia). However, the therapeutic effect and production of heat energy depend on distance between target cell and MNPs, strength of the magnetic field and sensitivity of target cell to magnetic field. Biological polymers such as, carbohydrates and proteins are coated onto MNPs to protect them against potential toxin release and corrosion. The imaging capabilities of MNPs offer great potentials in delivering MNPs based drug carriers to the target site (precision oncology), which in turn allows evaluation of distribution of the drug carrier and noninvasive imaging [45].The MNPs are mainly based on cobalt, nickel, magnetite (Fe3O4) or maghemite. However, iron oxides are most commonly employed due to its shape controllability and biological compatibility [150]. An earlier study showed that, iron oxide NPs obtained in the size of ~ 100 nm were found to be biocompatible and effective carrier for targeted drug delivery to cancer cell lines [165]. Many clinical trials have been conducted both in vivo and in vitro by photothermal therapy and also by magnetic hyperthermia [166]. It has also been reported that combinatorial effect of photothermal therapy and magnetic hyperthermia promotes effective internalization of NPs by tumor cells, rather than individual effect [167]. MNPs have potential significant applications in the field of in vivo human diagnostics and drug delivery and are already been used in the transportation of antimicrobial agents and anticancer drugs [168].
ENPs in biomolecules detection
Over the past few years, nanoscience and nano-biotechnological research advancements have focused towards the application of nanotechnology in biomolecular detection [135, 169]. The ENPs have significantly played a significant role in biomolecules detection. In specific, they have replaced the conventional molecular techniques and improved the sensitivity and accuracy of the identification. The thermal, optical, physical and electrochemical techniques have certainly improved in recognizing the molecules in solution when observed in the biosensing devices. NPs are widely used in developing new sophisticated sensing devises and assays which can improve the identification of nucleic acids and proteins [169, 170]. Several types of NPs including AuNPs, MNPs, quantum dots, silica NPs, inorganic phosphor NPs have been used in detecting viruses, hormones, specific antigens, thyroid-stimulating factors, DNA and other biomolecules [169, 171]. The physiological changes in the cell such as change in the type and concentration of metabolites may takes place due to pathological/disease condition or disorder, hence, the diagnosis of the disease and identification of its related physiological changes such as sensing and monitoring of the intracellular pH helps in understanding the disease biology [172]. Several nanoscale metal organic frame works (nMOFs) have been developed for the detection of several physiological changes in living cells, such as sensing the real time intracellular pH [173], intracellular oxygen quantification [174], and sensing nitric oxide concentration [175].
The advancement in the field of nanotechnology and development of novel NPs employed in the biomolecular detection could be a major breakthrough in the field of medicine which helps in the detection and diagnosis of many diseases which are still undetectable in the early stage such cancer through convention diagnostics. The availability of such advanced biomolecular diagnostics helps in the improvement of disease management along with the improvement in patient’s quality life.
ENPs and nanocomposites as antimicrobial agents
The improper or misuse of antimicrobials have caused the resistance property in microorganisms and is a present global challenge and causing a great threat to the patients infected with pathogenic microbes [2].There is a rise in the number of drug-resistant bacteria including methicillin-resistant Staphylococcus aureus (MRSA), and vancomycin-resistant enterococci which is a challenge to the medical practitioners..
Recent advancement in the area of nanobiotechnology has made the possibility of synthesizing nano-range molecules with incredible applications in the field of biomedicine and therapeutics. Further, these nanoscale nanocomposites possess excellent antimicrobial properties against various resistant microbes [2]. Hence, the antimicrobial property of ENPs can be employed as alternatives in treatment of drug-resistant microbes in the medical field. The possible mechanisms of antimicrobial action by ENPs are represented in Fig. 3 and Table 1.
Mode of action of engineered nanoparticles against microorganisms
Several inorganic NPs including silver NPs (AgNPs) have exhibited antimicrobial activity against diverse microbes. Silver ions have more affinity towards sulfur and phosphate groups and this might be significant in its antimicrobial activity. Silver ions (Ag+) released from NPs reacts with the proteins with sulphur components on the cell membrane. Ag+ produces ROS within the cell and are one of the main cause for cell death [176].The size of NPs is the key factor in deciding their efficacy against microbes. The size of < 10 nm produces holes/pores on cell membrane resulting in cell leakage and eventually will lead to microbial cell death [176, 177]. The minimum inhibitory concentration (MIC) values of AgNPs against pathogenic microbes differ with the type and sizes of the nanoparticles [2].
The biosynthesized AgNPs have been investigated against several pathogens with superior inhibitory potential [21, 178,179,180,181,182,183,184]. The AgNPs synthesized using Andrographis paniculata leaf extract exhibited higher antibacterial activity against Gram positive Enterococcus faecalis strains. Further, the surface zeta potential study revealed the key role of cell surface charge in bactericidal activity [185]. Further, the AgNPs synthesized using leaf extract of Ocimum gratissimum exhibited bactericidal activity against E. coli and S. aureus through ROS mediated cell surface damage [186]. Similarly, the surface of MgONPs has typically high pH and when bacterial cells interact with MgONPs, the high alkaline pH damages the cell membrane which is also called as alkaline effect [187,188,189]. Further, the antibacterial effect of MgONPs also depends on their size. The MgONPs less than 15 nm are known to exhibit superior bactericidal activity [187, 190]. MgONPs are effective against both Gram-negative and Gram-positive bacterial strains [191, 192]. In another study, it has been shown that MgONPs were effective against E. coli (MIC; 500 μg/mL), S. aureus (MIC; 1000 μg/mL), and Pseudomonas aeruginosa (MIC; 1000 μg/mL) [193]. Titanium dioxide inhibits bacterial strains by releasing ROS. In particular, the crystal surface of TiO2 interacts with fluids or water through photocatalytic reaction that generates the hydroxyl free radicals. The release of ROS then causes site specific DNA damages [2, 194,195,196,197]. ZnONPs show antimicrobial activity by generating hydrogen peroxides, and releasing Zn2+ ions. Also, ZnONPs release ROS including H2O2, OH−, and O22−. These ROS effectively damage the bacterial cell growth [198, 199]. The generation of hydrogen peroxides increases with the increased surface area of ZnONPs [2]. ZnONPs are shown to inhibit several kinds of Gram-negative and Gram-positive bacterial strains and are very effective against food borne pathogens [200, 201]. The inhibitory potential of iron oxide NPs is due to generation of singlet oxygen (1O2), superoxide radicals (O2–), hydroxyl radicals (OH−), and hydrogen peroxide (H2O2).
AuNPs were shown to possess anti-cancerous and antibacterial activity through photo thermal heating [21]. AuNPs and toluidine blue O (photosensitizer) have exhibited a synergistic antimicrobial activity against methicillin-resistant Staphylococcus aureus [202,203,204,205]. The bioactive molecules including antimicrobials, carbohydrates, antibodies, proteins, and oligonucleotides may be capped with AuNPs for better biological activities [206, 207], For example, the addition of vancomycin (antibiotic) to kill vancomycin-resistant enterococci [208, 209] and aminoglycosidic antibiotics to act against various bacterial pathogenic strains [210, 211]. AuNPs act on the bacterial cell by generating holes/pores in the cell wall/membrane and inhibit the transcription process through preventing the DNA uncoiling [212]. Several studies have reported the antimicrobial properties of copper (Cu) NPs (CuNPs) against several bacterial strains including Gram-positive Bacillus subtilis and S. aureus [213]. CuNPs produced through the biological process have been reported to possess higher inhibitory potential against drug-resistant human pathogens such as S. aureus and E.coli [214]. The antimicrobial property of CuNPs is due to their effective adhesion/attachment to the bacterial cell walls and causing the cell architecture damages [215]. Moreover, CuNPs have greater affinity towards carboxyl and amine groups found on B. subtilis cell surface and hence, they are highly effective against these strains [2].Copper ions released are reported to have the potential to disrupt biochemical processes inside bacterial cells [216] may also intercalate with nucleic acid strands and interact with DNA molecules. The mechanism of antimicrobial of AlNPs is due to the disruption of cell walls leading to cell death through ROS generated from the NPs [216]. However, aluminum NPs are regarded as scavengers of free radicals and appear to protect cells from the death due to oxidative stresses. However, this property is size independent and might depend upon the structure of the particles [2, 217]. Bismuth (Bi) NPs (BiNPs) are reported to function against several microbes. A study by Hernandez et al. [117, 218] reports the antibacterial and antifungal activity of BiNPs at < 1 and 2 mM concentrations, respectively. The BiNPs were reported to inhibit the drug-resistant bacterial strain, Helicobacter pylori significantly [219]. The mechanism of action was due to the inhibition of the bacterial growth by altering the amino acid metabolism and Krebs cycle [220]. Carbon nanotubes are shown to be effective against Gram-positive and Gram-negative bacterial strains including Salmonella enterica, E. coli, and Enterococcus faecium. Moreover, carbon NPs when complexed with silver inhibit multidrug-resistant microbes such as Acinetobacter baumannii, K. pneumonia, S. aureus, and Yersinia pestis [2, 221]. They cause cell wall disruption and DNA damages [222, 223]. Fullerenes, a soccer ball shaped carbon NPs have been investigated and showed antimicrobial activity against Salmonella spp., E. coli, Shewanella oneidensis and Streptococcus species [224,225,226]. Likewise, graphene oxides were also shown to effectively inhibit E. coli and S. aureus [227].
The organometallic polymers were reported to have effective inhibitory effect on several microbes. Experimental study has showed that peptide (lysine and phenylalanine) based NPs exhibit higher antimicrobial potential against P. aeruginosa, E. coli, Serratia marcescens and Candida albicans [2, 228]. Several different nanocomposites have been prepared and characterized for antibacterial activity for instance, AgNPs-graphene oxide (Ag NPs/GO) composites exhibited antibacterial activities against E. coli and S. aureus [43].Ag NPs decorated on thiol (-SH) grafted GO layers exhibited inhibitory effect against S. aureus and P. aeruginosa [42] and Ti substrates surface modified by GO thin film and AgNPs against Porphyromonas gingivalis and Streptococcus mutans [41]. Likewise, quaternary ammonium compounds are shown to inhibit microbes by interacting with the bacterial cell membrane. They cause cell membrane pores and denatures cellular proteins/enzymes [2, 229]. Polymers such as polysiloxane and triclosan are reported to possess superior activities against E. coli and S. aureus and Corynebacterium spp., respectively [230, 231].
Nanotechnology bids an excellent opportunity to inhibit viral multiplication and their global spread [2]. AgNPs have shown to possess antiviral properties against Hepatitis-B, HIV-1 (human immunodeficiency virus 1), HSV 1 (herpes simplex virus type 1) and monkeypox virus [2, 232, 233]. AgNPs exert antiviral activities by acting as a virucidal agent or by inhibiting the entry of virus particularly at early stage of viral replication. Also, NPs are reported to inhibit viral particles by binding on to their cell surfaces. After binding, they alter or denature the viral proteins [2]. AuNPs have also been reported to exhibit anti-HIV activity and with different anionic groups can inhibit influenza virus. The negatively charged AuNPs exhibit inhibitory effect against several influenza strains; this may be ascribed to the prevention of viral attachment. AgNPs capped with mercaptoethane sulfonate effectively inhibited HSV 1 infection [21]. These NPs prevent the infection by hindering the virus entry into the cell. The Au/Cu sulfide core/NPs shell system has shown antiviral activity against norovirus virus-like particles [234]. Likewise, TiO2, poly-l-lysine (PL), and DNA/RNA nanocomposite was shown to inhibit influenza A virus [235]. The surface modified NPs potentially inhibited viral infections [236]. More recently, NPs functionalized with zanamivir showed an effective activity against H1N1 influenza virus through apoptosis process [237]. Likewise, previously, it has been reported that AgNPs inhibit the replications in several viral particles such as herpes simplex virus, dengue virus 2, respiratory syncytial virus, parainfluenza virus 3, bean yellow mosaic virus, and H3N2 influenza [237, 238]. Fungal infections have tremendous contribution in increasing the mortality of immunocompromised patients [2]. Many investigations have showed that the NPs potential against fungi and fungal spores. The antifungal activity varies with particle sizes or zeta potentials. Zeta potential is believed to interact with negatively charged microbial surface and function as antifungal agents. Chitosan NPs are reported to have inhibitory effect on Candida albicans and Fusarium solani. The inhibitory effect may be credited to the occurrence of negatively charged sialic acid residues in cell the wall. Moreover, AgNPs also exhibit antifungal activity against C. albicans and Saccharomyces cerevisiae [2]. The synthesized amphotericin B-silver hybrid NPs have significantly inhibited the growth of C. albicans, F. culmorum and Aspergillus niger species [239]. Further, amphotericin B-copper (II) complex exhibited enhanced therapeutic potential against C. albicans, C. parapsilosis and A. niger [240]. Likewise, CuNPs synthesized chemically have shown antifungal activity against Fusarium spp [241]..
Limitations
The NPs can be synthesized by several ways such as, chemical, biological, mechanical method by milling and grinding technology, and gas phase synthesis. In most of these synthetic processes the size of the NPs does not exceed 100 nm. Furthermore, the chemical methods are not eco-friendly; however, the biological methods do not lead the production of any toxic agents and are eco-friendly [242]. The contact of ENPs with living cells/tissues is affected by various factors including their shape, size, and composition. The strong permeability of ENPs is a pre-requisite for its potential application as antimicrobial agent or an agent in drug delivery. Most of the synthesized NPs can penetrate membrane barriers and diffuse in the body. However, there are some possible health hazards of ENPs when they accumulate in cells, tissues and other cellular structures [2]. Synthesis and exposure of NPs with a diameter less than 100 nm may result in adverse side effect; however, the risk linked to NPs varies depending on NPs type [3, 201, 243]. The reactive oxygen species generated by NPs are major contributors in inflammation and toxicity, inducing oxidative stress, apoptosis and activation of signaling pathways. The NPs might escape the body’s defense mechanisms because of their nanoscale size and might result in toxic responses and inflammation [2, 3].
Several studies have reported the relationship between pulmonary inflammation and toxicity responses to ultrafine particles [2, 4]. Further, the consequence of ENPs on biological systems is not completely acknowledged. Therefore, complete understanding on the harmful effects/limitations on the use of NPs has to be addressed. Although intrinsic properties NPs offer lot of advantages some of those intrinsic characteristic features poses difficulties also. For example, the high surface area, of NPs favor particle agglomeration followed by formulation instability due to high surface Gibbs energy, and it is highly challenging to prevent [244]. Moreover, the independent control of these intrinsic parameters is also difficult and they might also influence stability issues including sedimentation [245]. Hence, it is difficult to generalize the protocols for NPs synthesis and for optimal cellular uptake. Moreover, it is highly essential to evaluate the potential negative impacts on environment as well as ecological systems due to the production of NPs in a larger scale. Furthermore, there may be unintended exposure of NPs by humans due to their bioavailability in different ecosystems and capability to move along the food webs [246]. Hence, thorough evaluation and regulation is required before the production of NPs in larger scale and also about their utility in biomedical fields.
Conclusion
The advent of nanotechnology and its allied fields revolutionized the field of medicine. Development of NPs represents an exciting, reliable and promising advancement in the field of medicine and biology. The potential application and use of ENPs in the treatment of wide range of bacterial, viral and fungal diseases, cancer therapy, drug delivery, tissue engineering, regenerative medicine, diagnostics, imaging and biomolecules detection has a significant effect on patient care and treatment. The development of advanced and effective ENPs and their applications in cancer treatment would help in overcoming the shortcomings of conventional cancer therapy and may provide a ray of hope for cancer patients in future. The rise of drug resistance property by microorganisms is another great threat, concern and challenge to the medical practitioners, which could also be overcome through advanced ENPs. The advancement of cutting edge nanomedicine offered the possibility and fascinating opportunities in NPs based bioimaging, early detection of diseases and targeted drug delivery for enhanced therapy. Various ENPs are shown to be effective against several pathogenic microorganisms, and are explored in cancer therapy, TE, RM, diagnostics and biomolecules detection. However, the effectiveness of ENPs in various fields of medicine and biology depends on the type of NPs, their size, stability, and composition. Though, ENPs possess numerous biological activities, their utilization is limited due to the facts such as toxicity, non-degradability, biocompatibility which may cause serious health risks. However, these limitations can be overcome through the use of eco-friendly approaches for NPs synthesis and is well appreciated also. Therefore, more studies are required to prove the effective utility of NPs in various fields of medicine and biology.
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Rudramurthy, G.R., Swamy, M.K. Potential applications of engineered nanoparticles in medicine and biology: an update. J Biol Inorg Chem 23, 1185–1204 (2018). https://doi.org/10.1007/s00775-018-1600-6
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DOI: https://doi.org/10.1007/s00775-018-1600-6