Engineering Surface-Functionalized, Intelligent Hydrogel Nanoparticles with Tunable Release Properties
Translational Medicine and Bioengineering Conference
Saturday, October 28, 2017 - 6:30pm to 7:30pm
The nanogels are comprised of a: (i) cationic monomer, 2-(diethylamino)ethyl methacrylate, that imparts a pH-response by ionization of amine pendant groups, (ii) tetraethylene glycol dimethacrylate crosslinker to improve drug retention, (iii) n-alkyl methacrylate monomer to improve drug loading through CA-polymer interactions, and (iv) surface-grafted poly(ethylene glycol) or hyaluronic acid to impart serum stability. The impact of n-alkyl methacrylate monomer inclusion was investigated through systematic variation of monomer steric bulk and chain length. The physical properties of resulting nanogels were compared using dynamic light scattering, zeta potential, titration, pyrene fluorescence, and hemolysis as a function of pH to elicit the influence of polymer composition on swelling ratio, surface charge, pKa, hydrophile-hydrophobe phase transition, and cell membrane disruption capability. The therapeutic delivery potential of the nanogels was optimized and analyzed using paclitaxel and carboplatin.
Nanogel-mediated combination therapy offers many advantages including the ability to signal different pathways in the cancer cells, maximize the therapeutic efficacy against specific targets, target different phases of the cell cycle, and overcome efflux-driven mechanisms of resistance. Further, it allows PK/PD to be dictated by the in vivo distribution and cellular uptake of the nanogels rather than the physicochemical properties of free CAs, ensuring optimal synergistic ratios are delivered to the cytosol. We demonstrated that both the grafted monomer and hydrophobic monomer composition can be varied to enable precise control over the nanogel surface and core characteristics to enable effective, controlled delivery. The nanogel molecular architecture was rationally designed to entrap cargos with widely varying physicochemical properties and to release the cargo only in response to a specific environmental cue. Further, control over the nanogel functionalization was demonstrated, and the surface properties were optimized to avoid clearance mechanisms and increase circulation time while still maintaining the necessary characteristics to promote cellular uptake. Ultimately, the tunability of our multicomponent nanogel system can be exploited to enable long-circulation and effective transport of the drugs to the tumor site.