Evaluation of PLGA containing anti-CTLA4 inhibited endometriosis progression by regulating CD4 + CD25 + Treg cells in peritoneal fluid of mouse endometriosis model

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• 作者：Qi Liu^a ; Pingchuan Ma^b ; Lanxia Liu^c ; Guilei Ma^c ; Jingjing Ma^c ; Xiaoxuan Liu^c ; Yijin Liu^a ; Wanjun Lin^b ; Yingjun Zhu^b ; ^{zhuyj8072@sina.com}
• 关键词：PLGA ; Anti-CTLA-4 ; CD4  ; +  ; CD25  ; +  ; Treg cells ; Endometriosis model ; Checkpoint inhibitors (CPI)
• 刊名：European Journal of Pharmaceutical Sciences
• 出版年：2017
• 出版时间：1 January 2017
• 年：2017
• 卷：96
• 期：Complete
• 页码：542-550
• 全文大小：1171 K
• 卷排序：96

文摘

Our study investigated poly(lactic-co-glycolic acid) (PLGA) as protein delivery vehicles encapsulate CTLA-4-antibody (anti-CTLA-4) which is essential for CD4 + CD25 + Treg cells suppressive function exposing superior potential for inhibiting endometriosis progress in mouse model than single anti-CTLA-4. Anti-CTLA-4 loaded PLGA combined to ligands CTLA-4 in surface of CD4 + CD25 + Treg cells which distributed in peritoneal fluid of mouse endometriosis model. The particle size, zeta potential of the anti-CTLA-4 loaded nanoparticles was detected by dynamic light scattering. Morphology of nanoparticles was evaluated by transmission electron microscopy (TEM). Confocal laser scanning microscopy (CLSM) indicated distribution of anti-CTLA-4 with PLGA or without in peritoneal fluid. Cumulative anti-CTLA-4 release from nanoparticles was evaluated by Micro BCA assay. The percentage of CD4 + CD25 + Treg cells in peritoneal fluid was demonstrated by flow cytometer. In vitro experiment we co-culture ectopic endometrial cells (EEC) with isolated CD4 + CD25 + Treg cells in peritoneal fluid (PF), proliferation and invasion of ectopic endometrial cells (EEC) was measured by BrdU ELISA assay and Matrigel invasion assay. In comparison with anti-CTLA-4 without nanoparticles, the bioconjugates PLGA/anti-CTLA-4 were tolerated in peritoneal fluid with a controlled release of anti-CTLA-4 in 3, 7, 14 days. Moreover, PLGA/anti-CTLA-4 had superior protective regulation ability to reduce level of CD4 + CD25 + Treg cells in peritoneal fluid. Most strikingly, in vitro experiment, PLGA/anti-CTLA-4 exhibited better ability in inhibiting proliferation and invasion of ectopic endometrial cells in co-culture system compared with anti-CTLA-4. Progressively, PLGA/anti-CTLA-4 had better suppressive activity to inhibited IL-10 and TGF-beta secreted by CD4 + CD25 + Treg cells which indicating that PLGA/anti-CTLA-4 suppressed cells proliferation and invasion through reduced IL-10 and TGF-beta production. Thus, PLGA/anti-CTLA-4 may be a potential strategy for endometriosis therapy.