Rational design of stimuli responsive nanoparticle systems for the controlled, intracellular delivery of immunotherapeutic and chemotherapeutic agents

Advanced cancer therapeutic treatment strategies are rapidly evolving due to a better fundamental understanding of cancer cell biology and the complex tumor microenvironment. The development of tailored nanomedicine as a delivery platform for synergistic combination cancer treatment has grown in popularity over single faceted traditional chemotherapeutic or immunotherapeutic strategies. Chemotherapy and immunotherapy combined can target the heterogeneous cancer tumor from multiple pathways to augment the antitumor efficacy and prevent tumor metastasis and reoccurrence. Nanomedicine can be utilized synergistically to amplify antitumor immune responses of immunotherapy and minimize off-target toxicities of chemotherapy. However, the combination of multiple therapeutic strategies also compounds the obstacles that need to be overcome, such as the sequential biological barriers that the nanoplatform faces during delivery. Thus, the goal of this project was to develop a delivery platform that will facilitate the intracellular delivery of multiple cancer therapeutic agents for the treatment of colorectal cancer.

Biodegradable, cationic nanogels were synthesized via a UV-initiated free radical emulsion polymerization to impart environmentally responsive behavior for the intracellular delivery of loaded therapeutics. The 2-(diethylamino) ethyl methacrylate-based copolymeric nanogels exhibited pH responsive behavior that was optimized for the pH gradient of the tumor microenvironment and endosomal compartments of cancer cells. Then, the cationic nanogels were assessed for their ability to load and release various chemotherapeutic and immunotherapeutic agents. Finally, the copolymeric nanoparticle system was evaluated in vitro for biocompatibility, cellular internalization, and therapeutic efficacy. This combination treatment strategy will provide an excellent foundation for the rational design and development of the next generation of drug delivery systems.