Oxaliplatin lipidated prodrug synergistically enhances the anti-colorectal cancer effect of IL12 mRNA

Abstract

Chemotherapy drugs are the main way to treat cancer, but there are strong toxic side effects in anti-tumor, of which oxaliplatin (OXA) is a commonly used platinum anti-tumor chemotherapy drug, colorectal cancer (CRC), non-small cell lung cancer and gastric cancer and other malignant tumors have a good therapeutic effect, but OXA also has strong side effects such as peripheral neurotoxicity, bone marrow suppression, etc. Therefore, by modifying the structure of OXA and introducing long alkyl chains in the platinum coordination of OXA, we greatly improve the fat solubility of the drug, which is more conducive to the drug crossing the bio lm and improving the anti-tumor e cacy. In addition to chemotherapy, cytokines are one of the earliest immunotherapies used in the treatment of human cancer, based on this, we prepared a new type of lipid nanoparticles (LNPs), wrapped with cytokines encoding interleukin-12 (IL12), which can directly deliver immune stimulation to tumors, and accumulate in tumors, improve the local immune environment of tumors, and directly or indirectly kill tumors. In this study, we combined the administration of modi ed prodrug OXA-LIP and mRNA-LNP, through in vivo pharmacodynamics and cytotoxicity experiments proving that combined administration can play a long-term anti-tumor effect, chemotherapy, and immunotherapy combination therapy is a very potential anti-tumor method, the combination of the two can play a synergistic effect, reduce the toxic side effects in tumor treatment, and the advantages in biological safety and anti-tumor activity provide broad application prospects for anticancer.