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differentiating the healthy cells from the diseased one, which have varied or over-expression of cell surface receptors. For example, folate receptors are overexpressed in several human tumors, and thus attaching folate to the surface of nanoparticles can help target drug carriers to the diseased site only, thereby avoiding unwanted toxicity and side effects to healthy cells. Likewise, G protein-coupled receptors such as endothelin receptors, chemokine receptors, and lysophosphatidic acid receptors have been implicated in the tumorigenesis and metastasis of multiple human cancers. Zhong et al. have at length reviewed the active targeting of polymeric nanoparticles for cancer chemotherapy [85].

2.3 Various Applications of Nanoparticulate Carriers

      Nanoparticulate carriers are versatile moieties that have multifunctional applications in drug delivery and diagnostics like use as carriers of drug molecules, proteins, genes, DNA, antibiotics, etc.; and use as biosensors and contrast agents in MRI, CT scan, phototherapy, and fluorescent biological labels. They can also be used for ligand targeted delivery, tissue engineering and regenerative medicine, phagokinetic studies, hyperthermia for destruction of tumor cells, etc. Few other applications that have not been discussed in the previous sections are being discussed below.

      2.3.1 Tissue Engineering and Regenerative Medicine

      The transplantation procedures of tissues and organs have limited success rates because of poor availability of donors, high rejection of transplant, and immune reactions to these exogenous bodies. Due to these drawbacks, the focus has shifted to design and synthesis of artificial three-dimensional (3D) scaffolds, which resemble the original biological organs/tissues [86]. Tissue regeneration by using nanoscaffolds loaded with a robust population of specialized cells called stem cells is capable of cell renewal and differentiation, thereby reestablishing disrupted cell functions and structure. Nanoscaffolds are a three-dimensional structure composed of fine biodegradable polymeric fibers, which provide the microenvironment for tissue regeneration by mimicking the behavior of extracellular matrix. Damaged cells also adhere to the scaffold and begin to rebuild tissue through minute pores present in the scaffold. As the tissue grows, the scaffolds are absorbed into the body and disappear completely leaving healthy cells in its place [87].

2.3.2 Delivery of Proteins

      To overcome the challenges related to the delivery of proteins and peptides, the nanoparticulate carriers provide an amicable solution. The stability of nanoparticulate carriers in biological fluids makes them appropriate cargo for proteins and peptides, besides providing added protection to encapsulated proteins and peptides against enzymatic degradation. Veronesi et al. developed PLGA NPs loaded with thyrotropin-releasing hormone (TRH) for intranasal administration and observed significant reduction in the severity of seizures studied in animal seizure models and suggested its application in suppression of epileptogenesis [88]. Neuroprotective peptide-NAPVSIPQ (NAP) encapsulated in lactoferrin (Lf) conjugated PEG-PCL nanoparticle (Lf-NP) when administered to Alzheimer’s disease animal model showed significant neuroprotection and improvement in memory, which was corroborated by assay of acetylcholinesterase, choline acetyltransferase activity, and neuronal degeneration in the mice hippocampus [89]. The nanoparticles can also be used for the detection of proteins like the gold nanoparticles, which are used in immunohistochemistry to study protein–protein interaction. Surface modifications with antibodies and photoactive dyes can be done to provide multiplexing capabilities. These probes can be used to recognize not only small molecules but also proteins [90].

      2.3.3 Delivery of Vaccines

      Nano-vaccines are an upcoming concept in immunotherapy. Till date, injectable route has been used to deliver vaccines because of their strong potential to induce immune response in comparison to mucosal vaccines. Mucosal nano-vaccines (developed using either nanomaterial adjuvants or delivery carriers) initiate strong humoral and cell-mediated responses, besides enhanced delivery of potentially protective viral epitopes [91]. Generally, organic material carriers like cationic polymers and liposome derivatives have been used as they are biodegradable, biocompatible, non-toxic, and non-immunogenic and provide large surface area, being non-viral at the same time. The nanomaterial-based adjuvants for use in vaccines have been reviewed by Han et al. [92]. Nanoparticles of Newcastle disease virus (NDV) encapsulated in N-2-hydroxypropyl trimethyl ammonium chloride chitosan (NDV/La Sota-N-2-HACC-NPs) showed very low toxicity, higher safety, sustained release, and stronger immune responses (cellular, humoral, and mucosal) as compared to marketed product [93]. Positive indicative results were reported for orally administered PLG-encapsulated CS6 antigen from E. coli to induce mucosal IgA responses in humans [89, 94]. Even lipid-based delivery systems such as human liposomes, immuno-stimulating complexes (ISCOMs), virosomes, and proteosomes have shown encouraging results in mucosal vaccination approach in preclinical models [95, 96].

      2.3.4 Gene Therapy

Gene therapy is the microlevel therapeutics that works at molecular level by “switching genes on or off” through the use of nucleic acid-based drugs (NABDs), example of which include oligodeoxynucleotides, plasmid DNA, ribozymes, siRNA, miRNA, and related chemically synthesized molecules. As these molecules are biodegradable, so stability of vectors carrying them is indispensible for them to reach the target cell/tissue, which is defective or mutated. Nanoparticulate carriers can play a crucial role in gene therapy by providing safe, non-toxic, non-viral carriers. Recently, United States Food and Drug Administration (FDA) has approved the first ever siRNA-lipid based formulation for human use under the trade name Onpattro^™ for hereditary amyloidosis [97]. Cationic lipids and cationic polymers have also been used for gene therapy by formation of lipoplexes and polyplexes, respectively [98-99]. Lipoplexes are cationic lipid-based non-viral gene delivery systems formed via electrostatic interaction with the negatively charged phosphate groups present in nucleic acids. Similarly, polyplexes are formed using cationic polymers. The methods generally used for the preparation of nanoparticulate carriers can also be used for the preparation of these carriers.

      2.3.5 Phagokinetic Studies

      Albrecht-Buehler studied cell motility based upon observation of phagokinetic track, which can be described as a path generated by the cell as it passes over a layer of “biological markers” and engulfs them, leaving behind a halo (blank spot) equivalent to the area it has navigated [100]. This method provides a mechanism of studying and integrating the cell motility while preserving the history of individual paths. Opto-electrical methods can be used for studying these tracks [101]. Initially, the tracks were studied using the luminescence technique, which has very short-lived intensity as it quenches very fast. Colloidal quantum dots, with tunable light emitting properties, have emerged as a suitable alternative for biological labeling experiments wherein these colloidal semiconductor nanocrystals are spontaneously ingested by a wide variety of cells and remain intact within the cells for weeks enabling the tracking of phagokinetic tracks within cells [102].

2.4 Modes of Transport of Nanoparticulate Carriers

Nanocarriers have the capability to cross the different biological barriers via various routes as shown in Figure 2.2a. The fate of nanoparticle is decided upon reaching the circulation either through lymphatic system or hematogenous system. The nanocarriers can be transported both actively and passively across the membranes in the body. Surface modified nanocarriers decorated with ligands/antibodies that bind to specific receptors expressed on the cell surface especially in cancer/tumor and deliver the selectivity of drug delivery is called active targeting of nanocarriers [103]. The intrinsic imbalance of the angiogenic receptors and growth factors results in disorganized cell surface with leaky vasculature and compromised lymphatic drainage resulting in enhanced permeability and retention effect (EPR). Nanoparticles with molecular weight above 50 kDa can undergo enhanced EPR effect and passively accumulate in the tumor cells. Further, nanocarriers with size and surface modified to provide prolonged circulation time (PEGylated nanocarriers) escape capture by reticuloendothelial

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