Deliver anti-PD-L1 into brain by p-hydroxybenzoic acid to enhance immunotherapeutic effect for glioblastoma

被引：42

作者：

Guo, Haiyan ^{[1
,2
]}

Wang, Ruifeng ^{[1
,2
]}

Wang, Dongli ^{[1
,2
]}

Wang, Songli ^{[1
,2
]}

Zhou, Jianfen ^{[1
,2
]}

Chai, Zhilan ^{[1
,2
]}

Yao, Shengyu ^{[1
,2
]}

Li, Jinyang ^{[1
,2
]}

Lu, Linwei ^{[3
,4
]}

Liu, Yu ^{[1
,2
]}

Xie, Cao ^{[1
,2
]}

Lu, Weiyue ^{[1
,2
,3
,4
,5
,6
,7
,8
]}

机构：

[1] Fudan Univ, Sch Pharm, Dept Pharmaceut, Shanghai 201203, Peoples R China

[2] Fudan Univ, Key Lab Smart Drug Delivery, Minist Educ & PLA, Shanghai 201203, Peoples R China

[3] Fudan Univ, Huashan Hosp, Dept Integrat Med, Shanghai 200041, Peoples R China

[4] Fudan Univ, Inst Integrat Med, Shanghai 200041, Peoples R China

[5] Fudan Univ, State Key Lab Med Neurobiol, Inst Brain Sci, Shanghai 200032, Peoples R China

[6] Fudan Univ, MOE Frontiers Ctr Brain Sci, Shanghai 200032, Peoples R China

[7] Fudan Univ, Minghang Hosp, Zhongshan Hosp, Minhang Branch, Shanghai 201199, Peoples R China

[8] Fudan Univ, Minghang Hosp, Inst Fudan Minghang Acad Hlth Syst, Shanghai 201199, Peoples R China

来源：

JOURNAL OF CONTROLLED RELEASE | 2020年 / 320卷

基金：

中国国家自然科学基金;

关键词：

Immune checkpoint inhibitor; p-Hydroxybenzoic acid; Conjugate; Brain-targeting; Glioblastoma; OPEN-LABEL; CANCER; METASTASES; BIOMARKERS; MELANOMA; SYSTEM;

D O I：

10.1016/j.jconrel.2020.01.005

中图分类号：

O6 [化学];

学科分类号：

0703 ;

摘要：

In glioblastoma with typical immunosuppressive characteristics, immune checkpoint inhibitors treatment showed unsatisfactory clinical effects, attributable to the exclusion of antibodies by blood-brain barrier (BBB) to a large extent. Herein, a conjugate of anti-programmed death ligand 1 antibody (alpha PDL1) and the targeting moiety p-hydroxybenzoic acid (pHA) was designed to realize crossing BBB of antibody based on the dopamine receptor mediated transcytosis. Conjugation with pHA did not influence the binding affinity of alpha PDL1 with PD-L1 protein, thus maintaining the capability of PD pathway blockade. Importantly, pHA-alpha PDL1 crossed BBB, demonstrated by the increased distribution in both the brain and the glioma after intravenous administration of pHA-alpha PDL1. Compared with the unmodified alpha PDL1, pHA-alpha PDL1 prolonged the survival time and suppressed tumor growth more effectively in an orthotopic glioblastoma model by activating glioma-infiltrating T cells. Our results suggested the potential of the antibody-pHA conjugate to improve efficacy for cerebral diseases by providing a potential platform for macromolecules to play therapeutics role in the brain.

引用

页码：63 / 72

页数：10

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