A BRD4 PROTAC nanodrug for glioma therapy via the intervention of tumor cells proliferation,apoptosis and M2 macrophages polarization

作     者：Tingting Yang Yuzhu Hu Junming Miao Jing Chen Jiagang Liu Yongzhong Cheng Xiang Gao Tingting Yang;Yuzhu Hu;Junming Miao;Jing Chen;Jiagang Liu;Yongzhong Cheng;Xiang Gao

作者机构：Department of Neurosurgery and Institute of NeurosurgeryState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengdu 610041China Department of Medical OncologyState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalWest China Medical SchoolSichuan University and Collaborative Innovation Center for BiotherapyChengdu 610041China 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2022年第12卷第6期

页      面：2658-2671页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 10[医学] 100602[医学-中西医结合临床] 

基　　金：supported by the National Natural Science Foundation of China(No.82172630,81972347 and 82003493) the Key R&D Projects of the Science and Technology Department of Sichuan Province(No.2020YFS0213,China) the 1·3·5 Project for Disciplines of Excellence,West China Hospital,Sichuan University(No.ZYJC21022,No.ZYYC21001 and 2019HXFH017,China)。 

主　　题：Glioma BRD4 ARV-825 Micelle M2 macrophage 

摘      要：Glioma is a primary aggressive brain tumor with high recurrence rate.The poor efficiency of chemotherapeutic drugs crossing the blood-brain barrier(BBB) is well-known as one of the main challenges for anti-glioma therapy.Moreover,massive infiltrated tumor-associated macrophages(TAMs) in glioma further thwart the drug efficacy.Herein,a therapeutic nanosystem(SPP-ARV-825) is constructed by incorporating the BRD4-degrading proteolytic targeting chimera(PROTAC) ARV-825 into the complex micelle(SPP) composed of substance P(SP) peptide-modified poly(ethylene glycol)-poly(D,L-lactic acid)(SP-PEG-PDLL A) and methoxy poly(ethylene glycol)-poly(D,L-lac tic acid)(mPEG-PDLL A,PP),which could penetrate BBB and target brain tumor.Subsequently,released drug engenders antitumor effect via attenuating cells proliferation,inducing cells apoptosis and suppressing M2 macrophages polarization through the inhibition of IRF4 promoter transcription and phosphorylation of STAT6,STAT3 and AKT.Taken together,our work demonstrates the versatile role and therapeutic efficacy of SPP-ARV-825 micelle against glioma,which may provide a novel strategy for glioma therapy in future.