Farnesylthiosalicylic Acid-derivatized PEI-based Nanocarrier for Improved Tumor Vaccination

Vaccines hold huge potential for cancer immunotherapy by activating and stimulating our immune system. Cancer vaccines that make use of mutant tumor antigens represent a promising therapeutic strategy by stimulating immune responses against tumors to generate long-term anti-tumor immunity. However, vaccines have shown limited clinical efficacy in high risk cancer patients, which mostly due to the inefficient delivery. In this study, we will focus on vaccine delivery assisted by nanoparticles for cancer immunotherapy. Nanoparticle-mediated vaccination can efficiently deliver neoantigenic nucleic acids into lymphoid organs and antigen presenting cells. The intracellular release of vaccine and cross-presentation of antigens can be fine-tuned via polymer engineering. Polyethylenimine (PEI) was conjugated with farnesylthiosalicylic acid (FTS), an inhibitor of RAS signaling and the resulting amphiphilic conjugate could self-assemble to form micelles. Subsequent interaction with nucleic acids led to formation of polymer/nucleic acid complexes of well-controlled structure. Tumor transfection via PEI-FTS was much more effective than that by PEI, other PEI variants or naked DNA alone. Significant transfection was also observed in draining lymph nodes. In vivo delivery of an ovalbumin (OVA, a model antigen) expression plasmid by PEI-FTS led to a significant growth inhibition of OVA-expressing B16F10 melanoma. PEI-FTS represents a promising transfection agent for effective gene delivery to tumors and draining lymph nodes to mediate neoantigen vaccination.