International Journal of Nanomedicine (Aug 2024)

Delivery of a STING Agonist Using Lipid Nanoparticles Inhibits Pancreatic Cancer Growth

  • Shaji SG,
  • Patel P,
  • Mamani UF,
  • Guo Y,
  • Koirala S,
  • Lin CY,
  • Alahmari M,
  • Omoscharka E,
  • Cheng K

Journal volume & issue
Vol. Volume 19
pp. 8769 – 8778

Abstract

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Sherin George Shaji,1 Pratikkumar Patel,1 Umar-Farouk Mamani,1 Yuhan Guo,1 Sushil Koirala,1 Chien-Yu Lin,1 Mohammed Alahmari,1 Evanthia Omoscharka,2 Kun Cheng1 1Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, USA; 2Department of Pathology, University Health/Truman Medical Center, School of Medicine, University of Missouri-Kansas City, Kansas, MO, USACorrespondence: Kun Cheng, Email [email protected]: The tumor microenvironment (TME) of pancreatic cancer is highly immunosuppressive and characterized by a large number of cancer-associated fibroblasts, myeloid-derived suppressor cells, and regulatory T cells. Stimulator of interferon genes (STING) is an endoplasmic reticulum receptor that plays a critical role in immunity. STING agonists have demonstrated the ability to inflame the TME, reduce tumor burden, and confer anti-tumor activity in mouse models. 2’ 3’ cyclic guanosine monophosphate adenosine monophosphate (2’ 3’-cGAMP) is a high-affinity endogenous ligand of STING. However, delivering cGAMP to antigen-presenting cells and tumor cells within the cytosol remains challenging due to membrane impermeability and poor stability.Methods: In this study, we encapsulated 2’ 3’-cGAMP in a lipid nanoparticle (cGAMP-LNP) designed for efficient cellular delivery. We assessed the properties of the nanoparticles using a series of in-vitro studies designed to evaluate their cellular uptake, cytosolic release, and minimal cytotoxicity. Furthermore, we examined the nanoparticle’s anti-tumor effect in a syngeneic mouse model of pancreatic cancer.Results: The lipid platform significantly increased the cellular uptake of 2’ 3’-cGAMP. cGAMP-LNP exhibited promising antitumor activity in the syngeneic mouse model of pancreatic cancer.Discussion: The LNP platform shows promise for delivering exogenous 2’ 3’-cGAMP or its derivatives in cancer therapy.Keywords: 2’ 3’-cGAMP, cold tumor, innate immunotherapy, lipid nanoparticle, cytosolic delivery

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