2. Academic Validation
  3. Intratumoral delivery of IL-12 and IL-27 mRNA using lipid nanoparticles for cancer immunotherapy

Intratumoral delivery of IL-12 and IL-27 mRNA using lipid nanoparticles for cancer immunotherapy

  • J Control Release. 2022 May;345:306-313. doi: 10.1016/j.jconrel.2022.03.021.
Jin-Qing Liu 1,  Chengxiang Zhang 2,  Xinfu Zhang 2,  Jingyue Yan 2,  Chunxi Zeng 3,  Fatemeh Talebian 1,  Kimberly Lynch 1,  Weiyu Zhao 2,  Xucheng Hou 2,  Shi Du 2,  Diana D Kang 2,  Binbin Deng 4,  David W McComb 5,  Xue-Feng Bai 6,  Yizhou Dong 7
Affiliations

Affiliations

  • 1 Department of Pathology, College of Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States.
  • 2 Division of Pharmaceutics & Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, United States.
  • 3 Department of Pathology, College of Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States; Division of Pharmaceutics & Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, United States.
  • 4 Center for Electron Microscopy and Analysis, The Ohio State University, Columbus, OH, United States.
  • 5 Center for Electron Microscopy and Analysis, The Ohio State University, Columbus, OH, United States; Department of Materials Science and Engineering, The Ohio State University, Columbus, OH, United States.
  • 6 Department of Pathology, College of Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, United States. Electronic address: Xue-Feng.Bai@osumc.edu.
  • 7 Division of Pharmaceutics & Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, United States; Department of Radiation Oncology, Department of Biomedical Engineering, The Center for Clinical and Translational Science, The Comprehensive Cancer Center, Dorothy M. Davis Heart & Lung Research Institute, Center for Cancer Engineering, Center for Cancer Metabolism, Pelotonia Institute for Immune-Oncology, The Ohio State University, Columbus, OH, United States. Electronic address: dong.525@osu.edu.
PMID: 35301053 DOI: 10.1016/j.jconrel.2022.03.021
Abstract

Cytokines are important immunotherapeutics with approved drugs for the treatment of human cancers. However, systemic administration of cytokines often fails to achieve adequate concentrations to immune cells in tumors due to dose-limiting toxicity. Thus, developing localized therapy that directly delivers immune-stimulatory cytokines to tumors may improve the therapeutic efficacy. In this study, we generated novel lipid nanoparticles (LNPs) encapsulated with mRNAs encoding cytokines including IL-12, IL-27 and GM-CSF, and tested their anti-tumor activity. We first synthesized ionizable lipid Materials containing di-amino groups with various head groups (DALs). The novel DAL4-LNP effectively delivered different mRNAs in vitro to tumor cells and in vivo to tumors. Intratumoral injection of DAL4-LNP loaded with IL-12 mRNA was most potent in inhibiting B16F10 melanoma tumor growth compared to IL-27 or GM-CSF mRNAs in monotherapy. Furthermore, intratumoral injection of dual DAL4-LNP-IL-12 mRNA and IL-27 mRNA showed a synergistic effect in suppressing tumor growth without causing systematic toxicity. Most importantly, intratumoral delivery of IL-12 and IL-27 mRNAs induced robust infiltration of immune effector cells, including IFN-γ and TNF-α producing NK and CD8+ T cells into tumors. Thus, intratumoral administration of DAL-LNP loaded with IL-12 and IL-27 mRNA provides a new treatment strategy for Cancer.

Keywords

Cancer immunotherapy; Cytokines; Diamino lipid-derived nanoparticles (DAL-LNPs); mRNA therapeutics.

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