Composite nanogels for the triggerable release of chemotherapeutics
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The development of external stimuli responsive nanoparticles has progressed greatly since its inception in the seventies. However, apart from some clinical success for slow release delivery via liposomes, the technology has stalled for the delivery of chemotherapeutics due to a myriad of problems with cytocompatibility and premature diffusion of drug payload. The solution to cytocompatibility has been the coating of the system with polyethylene glycol. New methods have been developed to attach polyethylene glycol (PEG) tethers to the surface of otherwise unreactive particles. Surface hydrolysis of acrylamide containing polymers can be used to produce carboxylic acid functional groups near the surface of the polymeric nanoparticles. These nanoparticles can then be functionalized with PEG via EDC/NHS chemistry. The use of surface hydrolysis not only allows for reaction with these neutral polymers, but also provides greater control of PEG localization and leads to an unintrusive method to add the much needed stealth coating. In order to address the issue with premature release, new polymer systems have been developed. These systems are based around theory of hydrophobic interaction in order to improve the polymer/drug interaction in order to limit the unwanted diffusional release of drug payload. This interaction was addressed in a number of ways, focusing on both compartmentalization and copolymerization in order to develop nanogels that can entrap and withhold more drug from the surrounding area. An in depth look into the interactions that encourage drug uptake in these systems was performed by altering the copolymer chosen for these systems. This work looks into effects on phase transition, functional groups, hydrophobicity, and any structural changes that occur as a result of the polymerization scheme. After drawing conclusions on the interactions that encourage drug uptake, complex systems were devised to take advantage of these interactions. Core shell systems were designed to take advantage of the convective release of lower critical solution systems while still utilizing the mechanisms that improve drug retention. These systems were synthesized by two methods, emulsion polymerization and micelle crosslinking. These systems have been showed to improve the drug interaction and retention of doxorubicin as a model chemotherapeutic.