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Encapsulating drug molecules, and selectively delivering those drugs to a disease site, is a complex multi-step challenge that requires the consideration of several interrelated parameters. We have developed stimuli sensitive nanogels that offer the size, stability, release kinetics, and drug loading capabilities necessary for efficient delivery. Our nanogel design is versatile and can be adapted to drug, gene, and protein delivery with little manipulation to its structure. In this thesis, we improve on the nanogel design by addressing a critical step in material based drug delivery, which is endosomal escape. We show how both functional groups on the delivery system as well as its architecture are important factors in deciding its escape from the endosome. Further, we expand the scope of nanogels for siRNA delivery using systematic design approaches. We demonstrate by employing concepts of supramolecular chemistry, adopted from our nanogel designs, we can systematically design a delivery vehicle of lower toxicity while achieving better complexation to siRNA, in comparison to simple polycationic homopolymers. Finally, we further improve upon our nanogel designs so as to allow for better biodegradability and biocompatibility by synthesizing nanogels using biocompatible GRAS building blocks.

Polymeric drug delivery has received tremendous attention in recent years. Polymeric drug delivery vehicles can be designed to deliver therapeutic agents either in a well-controlled manner or in response to a trigger. Drug delivery aims to ensure that the therapeutic agent reaches its target in the required quantity with minimal side effect. In this thesis, crosslinked polymers have been used to achieve controlled drug release. We have synthesized polymeric hydrogels from amino acid-derived monomers. Due to the hydrophilic nature of hydrogels, it is difficult to efficiently load hydrophobic drugs and hydrophilic drugs generally show a burst release. Various approaches have been developed in this work to tune and modulate the swelling, loading and release properties of hydrogels. The use of hydrogels as molecular separation systems to isolate, purify and concentrate compounds has been a well-known technique. However, the existing procedures mostly separate molecules by size exclusion and generally suffer selectivity with small molecules. We attempt to improve separation of molecules based on their charges. Nanogels have become very versatile vehicles for drug delivery. They are nanometer sized particles and can be administered parenterally to overcome the problems associated with the administration of drugs via the oral route i.e. degradation by digestive enzymes and first pass effect. Nanogel analogs of the hydrogels have been synthesized and evaluated for drug delivery.

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Proteins and nanoparticles (NPs) provide a promising platform for supramolecular interaction. We are currently exploring both fundamental and applied aspects of this interaction. On the fundamental side, we have fabricated a series of water-soluble anionic and cationic NPs to interact with cationic and anionic proteins respectively. A Varity of studies such as, activity assay, fluorescence titration, isothermal titration calorimetry etc. were carried out to quantify the binding properties of these functional NPs with those proteins. Those studies reveal the prospect of tuning the affinity between the nanoparticles and proteins by the surface modification. On the application side, we have used this protein-nanoparticle interaction in protein refolding where we successfully refolded the thermally denatured proteins toward its native structure. We have also applied this particle-protein recognition to create a biocompatible protein sensor using a protein-NP conjugate. Green fluorescent protein and a series of cationic NPs were used for a protein sensor for the identification of protein analytes through displacement process. We have extended this application even in sensing the proteins in human serum.

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