Sequential delivery of PD-1/PD-L1 blockade peptide and IDO inhibitor for immunosuppressive microenvironment remodeling via an MMP-2 responsive dual-targeting liposome  

作　　者：Chuan Hu Yujun Song Yiwei Zhang Siqin He Xueying Liu Xiaotong Yang Tao Gong Yuan Huang Huile Gao 

机构地区：[1]Key Laboratory of Drug Targeting and Drug Delivery Systems,West China School of Pharmacy,Sichuan University,Chengdu 610041,China

出　　处：《Acta Pharmaceutica Sinica B》2023年第5期2176-2187,共12页药学学报（英文版）

基　　金：the National Natural Science Foundation of China(82173762,China);111 Project(B18035,China);the Fundamental of Research Funds for the Central Universities(China);the Key Research and Development Program of Science and Technology Department of Sichuan Province(2022JDJQ0050,China);Project of Chengdu Science and Technology Bureau(2020-GH03-00003-HZ)。

摘　　要：Intelligent responsive drug delivery system opens up new avenues for realizing safer and more effective combination immunotherapy.Herein,a kind of tumor cascade-targeted responsive liposome(NLG919@Lip-pep1)is developed by conjugating polypeptide inhibitor of PD-1 signal pathway(AUNP-12),which is also a targeted peptide that conjugated with liposome carrier through matrix metalloproteinase-2(MMP-2)cleavable peptide(GPLGVRGD).This targeted liposome is prepared through a mature preparation process,and indoleamine-2,3-dioxygenase(IDO)inhibitor NLG919 was encapsulated into it.Moreover,mediated by the enhanced permeability and retention effect(EPR effect)and AUNP-12,NLG919@Lip-pep1 first targets the cells that highly express PD-L1 in tumor tissues.At the same time,the over-expressed MMP-2 in the tumor site triggers the dissociation of AUNP-12,thus realizing the precise block of PD-1 signal pathway,and restoring the activity of T cells.The exposure of secondary targeting moduleⅡVRGDC-NLG919@Lip mediated tumor cells targeting,and further relieved the immunosuppressive microenvironment.Overall,this study offers a potentially appealing paradigm of a high efficiency,low toxicity,and simple intelligent responsive drug delivery system for targeted drug delivery in breast cancer,which can effectively rescue and activate the body's anti-tumor immune response and furthermore achieve effective treatment of metastatic breast cancer.

关 键 词：Immunotherapy Cascade targeting LIPOSOME MMP-2 responsive Breast cancer ICBs IDO inhibitors Immunosuppressive microenvironment 

分 类 号：R730.3[医药卫生—肿瘤]