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Lack of specificity in traditional chemotherapeutic administration typically leads to significant dose-limiting toxicities and requires patients to wait for long periods between treatments. During this time, cancer cells have an opportunity to recover from treatment and develop drug resistance. To improve treatment and reduce toxicity to healthy tissues, novel nanoscale hydrogel carriers (nanogels) for the controlled intracellular delivery of chemotherapeutics have recently been developed. These nanogels entrap multiple chemotherapeutics and release the cargo only in response to a specific environmental stimulus. Nanoparticle-mediated combination therapy offers many advantages including the ability to signal different pathways in cancer cells, maximize therapeutic efficacy against specific targets, and overcome efflux-driven mechanisms of resistance.

In this project, pH-sensitive nanogels were designed to remain collapsed during circulation in the bloodstream (pH 7.4) and to swell during endocytosis (pH < 6.5) in order to release the cargo. Several factors of the polymerization were investigated in order to create a set of nanogels with varying molecular architecture, size, and surface properties. Furthermore, the impact of including an alkyl-methacrylate monomer was studied through systematic variation of monomer chain length and steric bulk. Physical properties of resulting nanogels were compared using dynamic light scattering, zeta potential, pyrene fluorescence, hemolysis, and cell compatibility to elicit the influence of polymer composition on swelling ratio, surface charge, pKa, hydrophile-hydrophobe phase transition, and cell membrane disruption capability. Delivery potential was analyzed using paclitaxel (hydrophobic) and carboplatin (hydrophilic) chemotherapeutics.

All nanogels exhibited well-defined and controllable particle size, morphology, and composition. The inclusion of an alkyl-methacrylate monomer significantly altered the resulting nanogel physical properties. Varying both chain length and steric bulk allowed for precise control over the thermodynamic response (relative swelling ratio), dynamic behavior (nanogel pKa and membrane disruption potential), and drug-polymer interaction (therapeutic delivery potential). Nanogels synthesized with increased steric bulk exhibited favorable behavior for intracellular delivery and demonstrated a 10-fold increase in delivery potential.

Ultimately, these multi-component nanogel systems demonstrated a tunability to entrap cargos with widely varying physicochemical properties. Further, the molecular architecture of these nanogels can be rationally designed to release the cargo only in response to the intracellular environment for improved targeted specificity in drug delivery. Current and future work includes mechanistic studies of the cellular internalization pathways, and optimizing the nanogel composition and surface properties for improved uptake.