Hydroxy-α-sanshool-loaded adipose-targeted mesoporous silica nanoparticles induce white adipose browning and reduce obesity by activating TRPV1  

羟基-α-山椒素介孔硅脂肪靶向纳米粒通过激活TRPV1受体促使白色脂肪棕色化

作　　者：Qing Zhang Chengxun He Juan Guo Dandan Tang Die Qian Chuan Zheng Chunjie Wu Wei Peng 张青;何承勋;郭娟;汤丹丹;钱碟;郑川;吴纯洁;彭伟(成都中医药大学药学院西南特色中药资源国家重点实验,中医药创新研究院/交叉学科研究院,成都市611130;密歇根大学安娜堡分校分子与整合生理学,美国密歇根,48109;成都中医药大学附属医院代谢性疾病中医药调控四川省重点实验室,成都市610072;成都中医药大学四川省经典名方二次创新开发工程研究中心,成都市611930)

机构地区：[1]State Key Laboratory of Southwestern Chinese Medicine Resources,School of Pharmacy,Innovative Institute of Chinese Medicine and Pharmacy/Academy for Interdiscipline,Chengdu University of Traditional Chinese Medicine,Chengdu 611130,China RESEARCH ARTICLE [2]Department of Molecular&Integrative Physiology,University of Michigan,Ann Arbor,Michigan 48109,USA [3]TCM Regulating Metabolic Diseases Key Laboratory of Sichuan Province,Hospital of Chengdu University of Traditional Chinese Medicine,Chengdu 610072,China [4]Sichuan Provincial Engineering Research Center of Innovative Re-development of Famous Classical Formulas,Tianfu TCM Innovation Harbour,Chengdu University of Traditional Chinese Medicine,Chengdu 611930,China

出　　处：《Bio-Design and Manufacturing》2025年第2期288-309,I0005-I0011,共29页生物设计与制造(英文)

基　　金：supported by the Natural Science Foundation of Sichuan Province(No.2022NSFSC0720);Research Center for the Development of the Comprehensive Health Industry and Rural Revitalization of Sichuan TCM(No.DJKYB202306);State Administration of Traditional Chinese Medicine of Sichuan Province of China(No.2020HJZX001).

摘　　要：Obesity has become a global threat to health;however,the available drugs for treating obesity are limited.We investigated the anti-obesity effect of hydroxy-α-sanshool(HAS),an amide derived from the fruit of Zanthoxylum bungeanum,which promotes the management of obesity by triggering the browning of white adipose tissue(WAT)targeting the membrane receptor of transient receptor potential vanilloid 1(TRPV1).However,HAS easily undergoes configuration transformation and oxidative degradation.The short peptide CKGGRAKDC or adipose-targeting sequence(ATS)binds specifically to prohibitin on the surface of WAT cells and can be used as recognition assembly to enhance adipocyte targetability.Furthermore,mesoporous silica nanoparticles(MSNs)are widely used in drug delivery systems because of their large specific surface area and pore volume.Therefore,HAS-loaded adipose-targeted MSNs(MSNs-ATS)were developed to enhance the adipocyte targetability,safety,and efficacy of HAS,and tested on mature 3T3-L1 cells and obese mouse models.MSNs-ATS showed higher specificity for adipocyte targetability without obvious toxicity.HAS-loaded MSNs-ATS showed anti-obesity effects superior to those of HAS alone.In conclusion,we successfully developed adipocyte-targeted,HAS-loaded MSNs with good safety and anti-obesity effects.肥胖已经成为威胁全球人类健康的疾病,然而当前临床能够用于治疗肥胖的药物却很少。在前期研究中,我们报道了从花椒中分离出的酰胺类化合物羟基-α-山椒素(HAS)通过激活TRPV1受体促进白色脂肪棕色化,从而具有显著的减肥作用。然而,HAS因其特殊的化学结构,容易发生结构转化和被氧化。介孔硅纳米粒(MSNs)因其高比表面积、表面孔径和孔道体积大等优点,被普遍用于药物递送系统的研究。此外,脂肪靶向小肽ATS(CKGGRAKDC)能特异性地靶向结合脂肪细胞表面的抑制素蛋白(prohibitin),可以被用于改善增加介孔硅的脂肪靶向性。因此,本研究中我们将HAS装在ATS修饰的介孔硅上,构建了HAS的脂肪靶向介孔硅纳米粒(HAS@MSNs-ATS)以提高HAS的脂肪靶向性。研究结果表明,相比于HAS,HAS@MSNs-ATS在体内外均表现出更强的脂肪组织靶向性,且未观察到明显的毒副作用。总之,在本文中我们成功构建了一种安全有效的HAS脂肪靶向介孔硅纳米递药系统。

关 键 词：Hydroxy-α-sanshool Adipocyte targetability Mesoporous silica nanoparticles White adipose tissue browning OBESITY 

分 类 号：R58[医药卫生—内分泌]