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

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Abstract

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.

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Funding

This work was supported by National Natural Science Foundation of China (32070927), Natural Science Foundation of Shandong Province (ZR2023MC121), and Science and Technology Innovation Development Planning of Yantai (2023JCYJ060, 2023JCYJ064).

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Authors and Affiliations

  1. School of Pharmacy, Collaborative Innovation Center of Advanced Drug Delivery System and Biotech Drugs, Universities of Shandong, Key Laboratory of Molecular Pharmacology and Drug Evaluation (Yantai University), Ministry of Education, Yantai University, Yantai, 264005, China

    Hui Liu, Yating Du, Aiping Wang & Yuanlei Fu

  2. Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Yantai, 264000, China

    Hui Liu, Yating Du, Desheng Zhan, Yan Li, Jianpeng Yin & Yuanlei Fu

  3. Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, 264117, China

    Wenjun Yu, Haiqiang Cao & Yuanlei Fu

Authors
  1. Hui Liu
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  2. Yating Du
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  4. Wenjun Yu
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  5. Yan Li
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  7. Jianpeng Yin
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  8. Haiqiang Cao
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  9. Yuanlei Fu
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Contributions

Hui Liu: conceptualization, writing — original draft, writing — review and editing. Yating Du: writing — original draft, writing — review and editing. Yuanlei Fu: conceptualization, writing — review and editing, supervision. Haiqiang Cao: conceptualization, writing — review and editing, supervision. Jianpeng Yin: investigation, resources, visualization, writing — review and editing. Desheng Zhan: writing — review and editing. Wenjun Yu: writing — review and editing. Yan Li: writing — review and editing. Aiping Wang: writing — review and editing.

Corresponding authors

Correspondence to Jianpeng Yin, Haiqiang Cao or Yuanlei Fu.

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All the animal experiments reported in this paper were approved by the Committee on the Ethics of Animal Experiments of the Yantai Institute of Materia Medica, and were performed in strict accordance with the guidelines of the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

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Hui Liu, Yating Du, and Desheng Zhan contributed equally to this study.

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Liu, H., Du, Y., Zhan, D. et al. Oxaliplatin lipidated prodrug synergistically enhances the anti-colorectal cancer effect of IL12 mRNA. Drug Deliv. and Transl. Res. (2024). https://doi.org/10.1007/s13346-024-01540-x

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