quantum dots due to which they are classified neither as an extended solid structure or single molecular entity. The properties of quantum dots that can be tuned by controlling the size and composition of particles are brightness of the spectrum, photo- and chemical stability of particles, width of emission spectrum, etc. [53]. Fluorescence and FRET-based biosensors used for ultrasensitive detection of biomolecules like acids, enzymes, sugars, antibodies, and antigens are generally synthesized using quantum dot [71]. These particles are generally fabricated from elements of Group II (e.g., Zn, Cd), VI (e.g., Se, S), III–V, and IV–VI of the periodic table. The quantum dots can be synthesized by heating/combustion method, hydrothermal technique, microwave/ultrasonic-assisted method, electrochemical synthesis, acid oxidation, arc discharge, laser ablation, and plasma treatment [46]. The application of quantum dots in drug delivery is limited due to inherent toxicity of cadmium and lead present in these particles. Despite formulation of Cd- and Pb-free quantum dots, not much decrease in the toxicity has been observed.
2.2.4 Self-Emulsifying Drug Delivery Systems (SEDDS)
Self-emulsifying drug delivery systems are self-emulsifying oil formulations consisting of isotropic mixtures of one or more oil, surfactants, co-surfactant, hydrophilic solvents, and co-solvents and have droplet size in the range of 100 to 300 nm [72]. SEDDS upon mild agitation and dilution with aqueous media form fine oil-in-water (o/w) type self-microemulsifying drug delivery system (SMEDDS) (droplet size of less than 50 nm) [73]. In vivo, the gastrointestinal motility provides the agitation necessary for micro-emulsification and is instrumental in increasing the rate and extent of availability of poorly water-soluble drugs. The physical stability of SEDDS makes them superior to orally administered emulsions; moreover, they can be encapsulated in standard soft gelatin capsules. Further, the SEDDS protect the drug in gut environment and control the release of drugs resulting in improved oral bioavailability [47]. The excipients used in SEDDS have been extensively reviewed by Nardin and Killner [74].
2.2.5 Polymer-Based Nanoparticles
Polymeric nanoparticles are nano-sized particles in the size range of 100–1000 nm, prepared using polymers. Both polymers of natural or synthetic origin can be used in the fabrication of polymeric nanoparticles as shown in Table 2.2. These carrier systems facilitate the release of active pharmaceutical ingredient in a controlled and sustained manner and hence find vast applications in the novel drug delivery systems [75]. Solvent evaporation method, polymerization, co-precipitation, solvent diffusion, and spontaneous emulsification methods are commonly used for the formulation of polymeric nanoparticles. Generally, non-toxic, biocompatible, and biodegradable polymers are used in the fabrication of polymeric nanoparticles, which protect the active pharmaceutical ingredient against degradation in the formulation as well as in vivo. The properties of nanoparticles can be engineered depending on their application in specific diseases like tuberculosis, cancer, Alzheimer’s, etc. Chawla et al. prepared and studied oral delivery of polymeric nanoparticles of first line anti-tubercular drugs encapsulated in PLGA. In vivo uptake studies of PLGA nanoparticles showed significantly higher intracellular concentration of drugs in alveolar macrophages in comparison to free drug suspension. Biodistribution studies using rhodamine labeled nanoparticles were also carried out to validate the results of cellular uptake studies, and extensive accumulation of nanoparticles was observed in macrophage-rich regions [76, 77].
Table 2.2 Schematic representation of classification of polymer based on their origin.
| Polymers | |||
|---|---|---|---|
| Natural | Synthetic | Biodegradable | Non-biodegradable |
| ChitosanGelatinSodium alginateAlbumin | Polyethylene glycol (PEG)Poly-lactide co-glycolic acid (PLGA)Polyglycolic acid (PGA)Polylactic acid (PLA)PolycynoacrylatesPolyglutamatePolyanhydrides | ChitosanGelatinSodium alginateAlbuminPoly lactide co glycolic acid (PLGA)Polyglycolic acid (PGA)Polylactic acid (PLA)Polycynoacrylates | PolyanhydridesPolymethyl methacrylatesEudragit |
Advancements in material design have led to development of stimuli-responsive polymeric nanoparticles incorporated with stimuli-responsive components. pH and temperature have attracted potential interest in the field of stimuli-responsive nanoparticles. pH inside human body varies greatly (different organelles have different intracellular pH profiles; endosomes and lysosomes show pH values of 6.8–4.5) [78]; even a minor change in physiological setup induces changes in microenvironment pH notwithstanding the diseased states. Tumorous cells are known to have acidic environment in comparison to the surrounding microenvironment; likewise, psoriatic skin cells are known to have different pH values than the normal skin cells [79, 80]. Therefore, pH responsive polymeric nanoparticles are extensively explored for the programmed release of drugs at the diseased site. The drug release from pH-responsive polymeric nanoparticles is based on acid-catalyzed hydrolysis. Some charged polymers undergo pH-dependent conformational changes that lead to cell membrane destabilization and hence aid in drug release and cellular uptake of the drug molecules [78]. Drug–polymer conjugates linked via pH-sensitive bonds such as anhydrides, hydrazones, cis-aconityl, and acetals also help in releasing drug molecules at specific pH environment. This approach confers stability to the drug conjugate under normal circulation and releases drug at the specific site [78-81]. Polymeric nanoparticles of poly(vinylpyrrolidone-co-dimethylmaleic anhydride) containing pH-sensitive group dimethylmaleic anhydride were designed to release drug at pH 6.0 and 7.0, and experimental data showed no drug release expected at these pH conditions [82]. Reducing size changes the physical and chemical properties of the matter, and as a result, its behavior towards temperature also changes. This property of nanoparticles has fascinated the scientists to formulate thermoresponsive carriers for delivery of drugs at target site. Thermoresponsive polymers exhibit a critical solution temperature (CST) that defines the solvation behavior of the polymer based on polymer–polymer and polymer–solvent interactions. Accordingly, thermoresponsive polymers exhibit lower critical solution temperature (LCST) and upper critical solution temperature (UCST). Below LCST and above UCST, the polymer is immiscible in solvent [83, 84]. For example, poly(N-isopropylacrylamide), poly(N,N-diethylacrylamide), poly(N-vinlycaprolactam), and poly(ethylene glycol) exhibit LCST over a range of 30–32°C, 25–32°C, 25–35°C, and 80–85°C, respectively. Studies have shown that critical solution temperature is a property dependent on molecular weight and architecture of the polymer [84]. Thermoresponsive polymers are widely used for the fabrication of timed release drug formulations that release drug on the application of specific temperature. One reaching the specific temperature threshold, there is swelling of polymer chains, which in return allow the drug to come out of the polymeric matrix [83]. Rejinold et al. developed curcumin loaded thermoresponsive nanoparticles of chitosan and poly(N-vinylcaprolactam) and reported a significantly higher drug release as well as toxicity (to cancer cells) above LCST as compared to that observed at below LCST [76].
Surface modified nanoparticles provide a successful means for improving the selective efficacy of drug therapeutics. Ligand targeted nanocarriers allow cell-specific drug delivery by 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
