Precise delivery of obeticholic acid via nanoapproach for triggering natural killer T cell-mediated liver cancer immunotherapy |
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Authors: | Guofeng Ji Lushun Ma Haochen Yao Sheng Ma Xinghui Si Yalin Wang Xin Bao Lili Ma Fangfang Chen Chong Ma Leaf Huang Xuedong Fang Wantong Song |
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Affiliation: | 1. Department of Gastrointestinal and Colorectal Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, China;2. Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China;3. Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA;4. Key Laboratory of Zoonosis, Chinese Ministry of Education, College of Basic Medical Science, Jilin University, Changchun 130021, China;5. Second Hospital of Shandong University, Jinan 250000, China;6. Second Hospital of Jilin University, Changchun 130041, China;7. Jilin Biomedical Polymers Engineering Laboratory, Changchun 130022, China;8. State Key Laboratory of Inorganic Synthesis and Preparative Chemistry, College of Chemistry, Jilin University, Changchun 130012, China |
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Abstract: | Primary bile acids were reported to augment secretion of chemokine (C‒X‒C motif) ligand 16 (CXCL16) from liver sinusoidal endothelial cells (LSECs) and trigger natural killer T (NKT) cell-based immunotherapy for liver cancer. However, abundant expression of receptors for primary bile acids across the gastrointestinal tract overwhelms the possibility of using agonists against these receptors for liver cancer control. Taking advantage of the intrinsic property of LSECs in capturing circulating nanoparticles in the circulation, we proposed a strategy using nanoemulsion-loaded obeticholic acid (OCA), a clinically approved selective farnesoid X receptor (FXR) agonist, for precisely manipulating LSECs for triggering NKT cell-mediated liver cancer immunotherapy. The OCA-nanoemulsion (OCA-NE) was prepared via ultrasonic emulsification method, with a diameter of 184 nm and good stability. In vivo biodistribution studies confirmed that the injected OCA-NE mainly accumulated in the liver and especially in LSECs and Kupffer cells. As a result, OCA-NE treatment significantly suppressed hepatic tumor growth in a murine orthotopic H22 tumor model, which performed much better than oral medication of free OCA. Immunologic analysis revealed that the OCA-NE resulted in augmented secretion of CXCL16 and IFN-γ, as well as increased NKT cell populations inside the tumor. Overall, our research provides a new evidence for the antitumor effect of receptors for primary bile acids, and should inspire using nanotechnology for precisely manipulating LSECs for liver cancer therapy |
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Keywords: | Obeticholic acid Farnesoid X receptor Nanoemulsion Liver sinusoidal endothelial cells Liver cancer ALT" },{" #name" :" keyword" ," $" :{" id" :" kwrd0040" }," $$" :[{" #name" :" text" ," _" :" alanine aminotransferase AST" },{" #name" :" keyword" ," $" :{" id" :" kwrd0050" }," $$" :[{" #name" :" text" ," _" :" aspartate aminotransferase BUN" },{" #name" :" keyword" ," $" :{" id" :" kwrd0060" }," $$" :[{" #name" :" text" ," _" :" blood urea nitrogen CDCA" },{" #name" :" keyword" ," $" :{" id" :" kwrd0070" }," $$" :[{" #name" :" text" ," _" :" chenodeoxycholic acid Cr" },{" #name" :" keyword" ," $" :{" id" :" kwrd0080" }," $$" :[{" #name" :" text" ," _" :" creatinine FXR" },{" #name" :" keyword" ," $" :{" id" :" kwrd0090" }," $$" :[{" #name" :" text" ," _" :" farnesoid X receptor H&E" },{" #name" :" keyword" ," $" :{" id" :" kwrd0100" }," $$" :[{" #name" :" text" ," _" :" hematoxylin and eosin HCC" },{" #name" :" keyword" ," $" :{" id" :" kwrd0110" }," $$" :[{" #name" :" text" ," _" :" hepatocellular carcinoma HPLC" },{" #name" :" keyword" ," $" :{" id" :" kwrd0120" }," $$" :[{" #name" :" text" ," _" :" high-performance liquid chromatography HSCs" },{" #name" :" keyword" ," $" :{" id" :" kwrd0130" }," $$" :[{" #name" :" text" ," _" :" hepatic stellate cells IVIS" },{" #name" :" keyword" ," $" :{" id" :" kwrd0150" }," $$" :[{" #name" :" text" ," $$" :[{" #name" :" italic" ," _" :" in vivo" },{" #name" :" __text__" ," _" :" imaging system LSECs" },{" #name" :" keyword" ," $" :{" id" :" kwrd0160" }," $$" :[{" #name" :" text" ," _" :" liver sinusoidal endothelial cells NE" },{" #name" :" keyword" ," $" :{" id" :" kwrd0170" }," $$" :[{" #name" :" text" ," _" :" nanoemulsion NKT cells" },{" #name" :" keyword" ," $" :{" id" :" kwrd0180" }," $$" :[{" #name" :" text" ," _" :" natural killer T cells OCA" },{" #name" :" keyword" ," $" :{" id" :" kwrd0190" }," $$" :[{" #name" :" text" ," _" :" obeticholic acid PBC" },{" #name" :" keyword" ," $" :{" id" :" kwrd0200" }," $$" :[{" #name" :" text" ," _" :" primary biliary cholangitis TACE" },{" #name" :" keyword" ," $" :{" id" :" kwrd0210" }," $$" :[{" #name" :" text" ," _" :" transarterial chemoembolisation TSR" },{" #name" :" keyword" ," $" :{" id" :" kwrd0220" }," $$" :[{" #name" :" text" ," _" :" tumor suppression rate |
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