| Sequestration of drugs, into protected nanoparticles, affords delivery to tumors and avoidance of toxicity to healthy tissues. The unifying theme of this thesis is the formation of therapeutic nanoparticles by kinetically controlled, block copolymer directed precipitation. Advantages of drug-delivery via nanoparticles are demonstrated with two nitric oxide (NO) prodrugs: PABA/NO and Double JS-K formulated with biocompatible polyethylene oxide stabilized polymers. The prodrug operates by releasing cytotoxic NO when activated by the antioxidant glutathione in cells. Premature activation of free drug in circulation, before it has been targeted, has been a major barrier limiting effective administration of this class of compounds. By protecting the drug in a nanoparticle capsule, we are able to increase the stability by 20 fold in vitro. Promising in vitro results led to the animal studies on human lung cancer xenografts in mice, and a highly suppressed tumor growth is observed after the i.v. administration of drug loaded nanoparticles.;The delivery of nucleic acid, small interfering RNA (siRNA), has been a major challenge for therapeutics based on RNA interference (RNAi). A major obstacle has been the ability to avoid enzymatic degradation in circulation and to deliver siRNA into cells. Again, the protection of siRNA in nanoparticle capsules is seen as the most promising route for delivery. Our goal is to formulate siRNA-lipid nanoparticles (LNPs) in range of 50-150 nm and improve cellular uptake and performance in vivo. Electrostatic interaction between siRNA and cationic lipids enables the formation of hydrophobic multi-layer vesicles, which are sterically stabilized by PEG lipids to yield 70-150 nm sized LNPs. The relationship between the components brought together in the self-assembly process and the final structure of the LNPs has been elaborately discussed.;The underlying principles behind anti-solvent precipitation method have been used to formulate polymeric nanoparticles of drugs: itraconazole, odanacatib and amphotericin B; and fluorescent dyes: pyrene and hostasol yellow. Drug solubility and particle size are identified as important variables governing the interfacial stability of nanoparticles. As bioavailability of pharmaceutical materials depends on their physical state (crystalline vs. amorphous), we used fluorescence to characterize the drug distribution and kinetics of rearrangement in nanoparticle cores. Using Flory Huggins theory of the thermodynamics of polymer mixtures, the conditions under which stable drug formulations could be prepared and conditions in which drug aggregation occurs have been demonstrated. The understanding helped us to formulate a more highly dispersed form of the antifungal drug, amphotericin B, by formulating a core comprising amphotericin B and vitamin E.;The anti-solvent precipitation route, to formulate nanoparticles, is a kinetically driven process unlike the traditional routes based on the solubilization of drug molecules into the polymeric micelles. A thermodynamic model has been used to explain the low-loading values obtained with traditional routes as the solubilization of drug in the polymeric core is limited by the high Laplace pressure associated with the interfacial curvature. The model links the physical properties of drugs and polymers to the thermodynamic parameters, governing the entropy, enthalpy and Laplace pressure, to discuss various experimental observations on drug loading cited in the literature. |
