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

Publisher: Springer Country of Publication: United States NLM ID: 101540061 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2190-3948 (Electronic) Linking ISSN: 2190393X NLM ISO Abbreviation: Drug Deliv Transl Res Subsets: MEDLINE

Original Publication: New York : Springer

Oxaliplatin*/administration & dosage ; Oxaliplatin*/pharmacology ; Oxaliplatin*/pharmacokinetics ; Prodrugs*/administration & dosage ; Prodrugs*/pharmacology ; Prodrugs*/pharmacokinetics ; Colorectal Neoplasms*/drug therapy ; Interleukin-12*/genetics ; Antineoplastic Agents*/pharmacology ; Antineoplastic Agents*/administration & dosage ; Antineoplastic Agents*/pharmacokinetics ; Antineoplastic Agents*/therapeutic use ; Antineoplastic Agents*/chemistry ; RNA, Messenger*/metabolism ; RNA, Messenger*/genetics ; Mice, Nude*; Animals ; Humans ; Mice ; Mice, Inbred BALB C ; Cell Line, Tumor ; Lipids/chemistry ; Lipids/administration & dosage ; Drug Synergism ; Xenograft Model Antitumor Assays

Colorectal cancer (CRC) is the fourth most common cancer in the world, with the second highest incidence rate after lung cancer. Oxaliplatin (OXA) is a broad-spectrum anti-tumor agent with significant therapeutic efficacy in colorectal cancer, and as a divalent platinum analog, it is not selective in its distribution in the body and has systemic toxicity with continued use. Interleukin-12 (IL12) is an immunostimulatory cytokine with cytokine monotherapy that has made advances in the fight against cancer, limiting the clinical use of cytokines due to severe toxicity. Here, we introduced a long alkyl chain and N-methyl-2,2-diaminodiethylamine to the ligand of OXA to obtain OXA-LIP, which effectively reduces its toxicity and improves the uptake of the drug by tumor cells. We successfully constructed IL12 mRNA and used LNPs to deliver IL12 mRNA, and in vivo pharmacodynamic studies demonstrated that OXA-LIP combined with IL12 mRNA had better tumor inhibition and higher biosafety. In addition, it was investigated by pharmacokinetic experiments that the OXA-LIP drug could accumulate in nude mice at the tumor site, which prolonged the half-life and enhanced the anti-tumor efficiency of OXA. It is hoped that these results will provide an important reference for the subsequent research and development of OXA-LIP with IL12 mRNA, as well as provide new therapeutic approaches for the treatment of colon cancer.
(© 2024. Controlled Release Society.)

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32070927 National Natural Science Foundation of China; ZR2023MC121 Department of Science and Technology of Shandong Province; 2023JCYJ060 Yantai Science and Technology Bureau; 2023JCYJ064 Yantai Science and Technology Bureau

Keywords: Chemotherapy immunotherapy combination; IL12 mRNA; Lipid nanoparticles; Oxaliplatin; Prodrug

04ZR38536J (Oxaliplatin)
0 (Prodrugs)
187348-17-0 (Interleukin-12)
0 (Antineoplastic Agents)
0 (RNA, Messenger)
0 (Lipids)

Date Created: 20240308 Date Completed: 20241001 Latest Revision: 20241008

20241009

10.1007/s13346-024-01540-x

38457025