This is a revised proposal for an R21 Exploratory / Developmental Bioengineering Research Grant (EBRG) under PA-10-010 as an investigator-initiated application for developing a nanocomposite drug delivery system. The proposed drug delivery system consists of a degradable, thermally-responsive hydrogel nanosphere encapsulating a single domain paramagnetic iron oxide nanoparticle to release drug by swelling once magnetically-triggered. AC inductive heating of the magnetic nanoparticle conducts heat into the surrounding 'nanogel', which forces it to swell and imbibe physiological solvent. The swollen gel then releases incorporated drug agents for localized therapeutic delivery by diffusion and convective currents created during cyclical swelling and collapsing. The carriers will be designed for optimal in vivo targeting utility based on size, shape, charge, deformability, hydrophilicity, and degradability. Additionally, nanogel carriers will be surface modified for immune 'stealthing'to prolong circulation times, and with antibodies to facilitate active targeting. This composite drug delivery system can be used to concentrate therapeutics locally with release initiated by an external triggering mechanism and with enhanced medical imaging contrast if desired. In the development of this system, several fundamental challenges regarding nanogel drug delivery will be addressed. Specifically, the impact of temperature excursions and volume swelling responses will be examined to determine their impact on carrier stability, active targeting, and on non-specific protein adsorption. Furthermore, a novel testing apparatus will be fabricated that allows for swelling kinetics experiments as a function of carrier size. This will allow predictions to be made as to time to equilibrium and solute transport times with very small particulate carriers. Specific antibodies have been selected to enhance uptake by targeted cells overexpressing the desired receptor. Finally, nanocarriers will be tested in vitro to establish cytocompatibility, uptake performance, and required magnetic field strengths for triggering.
Drug therapies such as anticancer chemotherapeutics utilize toxic drugs which are typically administered systemically and therefore cause substantial unwanted side effects. Using nanocarriers, it is possible to deliver highly concentrated doses of these drugs at the anatomical locations where therapeutic benefit is greatest. An advanced nanocarrier system can be molecularly-targeted to the affected tissues, verified by imaging, and triggered externally for maximum control over treatment with greatly improved success rates.
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