Development of a heating activated drug delivery system to combine hyperthermia with chemotherapy

The current research project involves the development of thermally responsive graft oligomers based on PNIPAAm for heating-activated drug delivery. A thermosensitive grafted polymeric system which can be triggered to release the loaded drug with an increase in temperature was developed. The desirable carrier will have minimal release at 37°C so that the system can be localized (e.g., to cancer cells) prior to activation of the delivery of medication (which can be accomplished by magnetic hyperthermia). The grafted hydrogel system is shown to exhibit a desirable positive thermal response with an increased drug diffusion coefficient for temperatures higher than physiological temperature.;Drug release studies were conducted and drug diffusion coefficients for the release of model drugs from the hydrogels were estimated. Oligomers of (NIPAAm-co-AAm) which were grafted onto a non-thermally responsive PHEMA expanded below LCST hindering diffusion and collapsed above LCST allowing diffusion. The grafted system therefore showed slower release rates at physiological temperatures because of the expansion of incorporated PNIPAAm grafts and a higher release rates at temperatures above the LCST. The grafted system therefore can be used to achieve a positive thermoresponsive release. A mathematical model to predict drug diffusivities from the grafted gel as a function of varying system parameters such as mesh size, graft length and graft density was developed and validated with experimental results. The biocompatibilities of the oligomers synthesized for this research were tested using S2 cells and CD1 mice. Oligomers of (NIPAAm-co-AAm) did not show any signs of overt developmental toxicity or cytotoxicity.;Short chains or oligomers of (NIPAAm-co-acrylamide) or (NIPAAm-co-AAm) were copolymerized with 2-hydroxyethyl methacrylate, HEMA, and a crosslinking agent to form a grafted hydrogel system P(HEMA-g-(NIPAAm-co-AAm)). Oligomers were extensively characterized to determine their molecular weights, structure, composition, thermal response and kinetic response. Hydrogels were characterized for their lower critical solution temperatures, LCST by equilibrium swelling experiments, and mesh sizes by mechanical testing and equilibrium swelling data.