首页|Precise delivery of obeticholic acid via nanoapproach for triggering natural killer T cell-mediated liver cancer immunotherapy

Precise delivery of obeticholic acid via nanoapproach for triggering natural killer T cell-mediated liver cancer immunotherapy

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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 nano-particles 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 pre-pared via ultrasonic emulsification method,with a diameter of 184 nm and good stability.In vivo bio-distribution 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 medica-tion of free OCA.Immunologic analysis revealed that the OCA-NE resulted in augmented secretion of CXCL16 and IFN-y,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

Obeticholic acidFamesoid X receptorNanoemulsionLiver sinusoidal endothelial cellsLiver cancer

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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Department of Gastrointestinal and Colorectal Surgery, China-Japan Union Hospital of Jilin University,Changchun 130033, China

Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China

Key Laboratory of Zoonosis, Chinese Ministry of Education, College of Basic Medical Science, Jilin University,Changchun 130021, China

Jilin Biomedical Polymers Engineering Laboratory, Changchun 130022, China

Second Hospital of Shandong University, Jinan 250000, China

Second Hospital of Jilin University, Changchun 130041, China

State Key Laboratory of Inorganic Synthesis and Preparative Chemistry, College of Chemistry, Jilin University,Changchun 130012, China

Division of Pharmacoengineering and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA

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This work was financially supported by the National Natural Science Foundation of ChinaThis work was financially supported by the National Natural Science Foundation of ChinaThis work was financially supported by the National Natural Science Foundation of ChinaThis work was financially supported by the National Natural Science Foundation of ChinaMinistry of Science and Technology of ChinaProgram of Scientific Development of Jili

51673189519732155183301051520105004Project 2018ZX09711003-012

2020

药学学报(英文版)

药学学报(英文版)

CSTPCDCSCDSCI
ISSN：
年,卷(期)：2020.10(11)
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