Synergistic metabolic modulation of fibroblast-like synoviocytes via targeted dual prodrug nanoparticles to mitigate rheumatoid arthritis  

作　　者：Shaobing Li Juntao Lin Chengxinqiao Wang Junhan Liu Yupeng Wang Yan Chen Dongfang Zhou 

机构地区：[1]Department of Ultrasonic Diagnosis,Zhujiang Hospital,NMPA Key Laboratory for Research and Evaluation of Drug Metabolism&Guangdong Provincial Key Laboratory of New Drug Screening&Guangdong-HongkongMacao Joint Laboratory for New Drug Screening,School of Pharmaceutical Sciences,Southern Medical University,Guangzhou 510515,China [2]Key Laboratory of Mental Health of the Ministry of Education,Southern Medical University,Guangzhou 510515,China

出　　处：《Acta Pharmaceutica Sinica B》2025年第1期542-556,共15页药学学报(英文版)

基　　金：supported by grants from the National Key Research and Development Program of China(2022YFC3601900/2022YFC3601902);the National Natural Science Foundation of China(22275081,82372117);the Guangdong Basic and Applied Basic Research Foundation(2024A1515011462,2022A1515011292 and 2024A1515010464);the China Postdoctoral Science Foundation(2022M711532 and 2022T150302).

摘　　要：Elevated glucose metabolism is a prominent characteristic of fibroblast-like synoviocytes(FLS)in rheumatoid arthritis(RA).However,the efficacy of inhibiting a single target of glucose metabolism in FLS using small molecular inhibitors is limited for RA treatment.Herein,the synergistic inhibition of FLS’survival,proliferation,and activation by combining two glucose metabolism inhibitors,diclofenac(DC)and lonidamine(LND)was first verified.Subsequently,DC and LND were individually conjugated to cystamine-modified hyaluronic acid(HA)to prepare two polymer-prodrug conjugates.A HAP-1 peptide-modified dual polymer-prodrug conjugates-assembled nanoparticles system(HAP1 NPDCþLND)was further tailored in the optimal synergistic ratio for targeted and synergistic metabolic modulation of FLS to alleviate RA symptoms.Upon targeted uptake by FLS in inflamed joints,^(HAP-1) NP_(DC+LND) released DC and LND within the intracellular reductive microenvironment,where DC hinders glucose uptake and LND suppresses glycolytic enzymes to eliminate FLS synergistically.Additionally,the secretion of lactic acid and pro-inflammatory factors from FLS were reduced,thereby disrupting the crosstalk between FLS and pro-inflammatory macrophages.Finally,^(HAP-1)NP_(DCþLND)demonstrated promising efficacy in a mouse model of collagen-induced arthritis(CIA).Overall,this research provides valuable insights into novel therapeutic strategies for the safe and effective of treatment RA through targeted and synergistic metabolic modulation of FLS.

关 键 词：Dual prodrug nanoparticles Metabolic modulation Fibroblast-like synoviocytes Rheumatoid arthritis Glucose transporter member 1 Glycolytic enzyme Lactic acid Synovial microenvironment 

分 类 号：R59[医药卫生—内科学]