(625a) Stimuli-Responsive Nanoscale Hydrogels for the Co-Delivery of Chemotherapeutic Agents
Prepared nanogels are comprised of: (i) a hydrophilic, cationic monomer 2-(diethylamino)ethyl methacrylate (DEAEMA) that imparts the pH-response by ionization of amine pendant groups; (ii) a tetraethylene glycol dimethacrylate (TEGDMA) crosslinker to improve chemotherapeutic agent retention; (iii) an alkyl methacrylate monomer to improve chemotherapeutic agent-polymer interactions; and (iv) surface-grafted poly(ethylene glycol) methacrylate (PEGMA) to impart serum stability. Nanogels were synthesized using a UV-initiated oil-in-water emulsion polymerization with a 2.5 mol% crosslinking density3. Hydrogel properties were investigated through systematic variation of monomer functionality and chain length. The physical properties of the resulting nanogels were compared using dynamic light scattering, zeta potential, titration, pyrene fluorescence, and red blood cell hemolysis as a function of pH to elicit the influence of polymer composition on swelling ratio, surface charge, pKa, relative hydrophobicity and hydrophile-hydrophobe phase transition, and erythrocyte membrane disruption capability. The therapeutic delivery potential was analyzed using hydrophobic and hydrophilic chemotherapeutic agents.
The nanogels resulted in well-defined and controllable particle size, morphology, and composition. We demonstrated the tunability of our multicomponent nanogel systems to entrap varied molecular cargos, and showed that the molecular architecture can be rationally designed to respond intelligently to different environments. Inclusion of a hydrophobic monomer significantly altered the resulting nanogel physical properties. Varying both the 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). We also demonstrated that the zeta potential changes drastically as a function of grafted PEGMA coverage on the surface of the nanogel, while the isoelectric point of the network core remains constant. The volume swelling ratio (VSR) of the nanogels was significantly influenced by the amount of PEGMA, with an increased percentage relating to a decreased VSR. Ultimately, we found that optimizing both the grafted monomer and hydrophobic monomer composition leads to varying nanogel surface and core characteristics, respectively, that may be exploited to enable long-circulation of the nanogels and effective transport of the drugs to the tumor site.
Acknowledgements: This work was supported by a grant from the National Institutes of Health (R01-EB-000246-22). AMW is supported by an NSF Graduate Research Fellowship. AS, NAS, and BC equally contributed to the work.
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