Intestinal TGR5-targeted carrier-drug conjugate improves glycemic control in mice and pigs
文献类型：期刊论文
| 作者 | Zhang, Yaqi7,8,9; Huang, Hui6,8,9; Wang, Yaying7,8,9; Li, Xiang7,8,9; Hou, Peizhou7,8,9; Yu, Miaorong8,9; Zhang, Zhuan5,8,9; Guo, Shiyan8,9; Liu, Chang7,8,9; Zhang, Zilong8,9 |
| 刊名 | SCIENCE TRANSLATIONAL MEDICINE
 |
| 出版日期 | 2025-11-19 |
| 卷号 | 17期号:825页码:17 |
| ISSN号 | 1946-6234 |
| DOI | 10.1126/scitranslmed.ado5177 |
| 英文摘要 | Numerous G protein-coupled receptors (GPCRs) expressed in the gastrointestinal tract serve as crucial transducers to regulate a variety of physiological functions upon activation. Takeda G protein-coupled receptor 5 (TGR5), a prominent gastrointestinal GPCR expressed on enteroendocrine L cells, is activated by intestinal bile acids and plays a role in glucose utilization. However, the development of TGR5 agonists has been hindered by the hepatobiliary toxicity associated with long-term supplementation with exogenous agonists. Here, we designed and characterized a biomimetic receptor agonist, which we termed TGR5-targeted carrier-drug conjugate (TGR5-CaDC), that combined the TGR5-activating capabilities of deoxycholic acid, a TGR5 agonist, with the nonabsorbable properties of a carrier. Unlike traditional agonists or carrier-based drug delivery systems, nonabsorbable TGR5-CaDC remained localized in the intestines of mice and pigs, providing high surface concentrations of TGR5 agonists in addition to ensuring strong L cell specificity and TGR5 affinity. TGR5-CaDC treatment also promoted TGR5 cluster aggregation, signal amplification, and increased glucagon-like peptide 1 secretion. Notably, TGR5-CaDC demonstrated sustained glycemic effects with reduced toxicity compared with deoxycholic acid alone or liraglutide in diabetic mice and Bama minipigs. By targeting extracellular binding domains and mimicking native ligand-receptor binding patterns, the design concept underlying this carrier-drug conjugate has the potential for applications in a variety of GPCR-mediated gastrointestinal diseases. |
| WOS关键词 | BILE-ACID RECEPTOR ; GLUCAGON-LIKE PEPTIDE-1 ; SILICA NANOPARTICLES ; TGR5 ACTIVATION ; SECRETION ; CELL ; GLUCOSE ; GUT ; METABOLISM ; DELIVERY |
| 资助项目 | National Science Fund of Distinguished Young Scholars[82025032] ; National Key R&D Program of China[2024YFA1210100] ; National Natural Science Foundation of China[82430111] ; National Natural Science Foundation of China[22425703] ; National Key Research and Development Program[2022YFA1302902] ; Science and Technology Commission of Shanghai Municipality[23HC1401200] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDB0830000] ; Space Application System of China Manned Space Program ; Research Grant for Pudong Health Bureau of Shanghai[YC-2023-0401] ; Shanghai Municipal Science and Technology Major Project[TM202301D002] |
| WOS研究方向 | Cell Biology ; Research & Experimental Medicine |
| 语种 | 英语 |
| WOS记录号 | WOS:001617842000004 |
| 出版者 | AMER ASSOC ADVANCEMENT SCIENCE |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/322037]  |
| 专题 | 国家级研究中心_原创新药研究全国重点实验室 |
| 通讯作者 | Zhou, Hu; Gan, Yong |
| 作者单位 | 1.Shanghai Univ Med & Hlth Sci, Zhoupu Hosp, Dept Sci Res, Shanghai 201318, Peoples R China 2.Sichuan Univ, West China Hosp, NHC Key Lab Transplant Engn & Immunol, Chengdu 610041, Peoples R China 3.Sichuan Univ, West China Hosp, Prote Metab Anal Platform, Chengdu 610041, Peoples R China 4.ShanghaiTech Univ, Sch Biomed Engn, Shanghai 201210, Peoples R China 5.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China 6.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou 310024, Peoples R China 7.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 8.Chinese Acad Sci, Ctr Pharmaceut, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 9.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 10.Natl Inst Food & Drug Control, NMPA Key Lab Qual Res & Evaluat Pharmaceut Excipi, Beijing 100050, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhang, Yaqi,Huang, Hui,Wang, Yaying,et al. Intestinal TGR5-targeted carrier-drug conjugate improves glycemic control in mice and pigs[J]. SCIENCE TRANSLATIONAL MEDICINE,2025,17(825):17. |
| APA | Zhang, Yaqi.,Huang, Hui.,Wang, Yaying.,Li, Xiang.,Hou, Peizhou.,...&Gan, Yong.(2025).Intestinal TGR5-targeted carrier-drug conjugate improves glycemic control in mice and pigs.SCIENCE TRANSLATIONAL MEDICINE,17(825),17. |
| MLA | Zhang, Yaqi,et al."Intestinal TGR5-targeted carrier-drug conjugate improves glycemic control in mice and pigs".SCIENCE TRANSLATIONAL MEDICINE 17.825(2025):17. |
入库方式： OAI收割
来源：上海药物研究所
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