Li Jinyang, Lu Jiasheng, Guo Haiyan, Zhou Jianfen, Wang Songli, Jiang Kuan, Chai Zhilan, Yao Shengyu, Wang Xiaoyi, Lu Linwei, Xie Cao, Chen Yi, Lu Weiyue
Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery (Fudan University), Ministry of Education and PLA, Shanghai 201203, China.
The Institutes of Integrative Medicine of Fudan University, Shanghai 200041, China.
Acta Pharm Sin B. 2021 Jan;11(1):283-299. doi: 10.1016/j.apsb.2020.07.024. Epub 2020 Aug 13.
AL3810, a molecular dual inhibitor of the vascular endothelial growth factor receptor (VEGFR) and fibroblast growth factor receptor (FGFR), has earned the permission of phase II clinical trial for tumor treatment by China FDA. As a reversible ATP-competitive inhibitor, AL3810 targets ATP-binding site on intracellular region of VEGFR and FGFR, whereas, AL3810 lacking interplay with extracellular region of receptors rendered deficient blood-brain tumor barrier (BBTB) recognition, poor brain penetration and unsatisfactory anti-glioma efficacy. Integrin v3 overexpressed on capillary endothelial cells of BBTB as well as glioma cells illuminated ligand-modified liposomes for pinpoint spatial delivery into glioma. The widely accepted peptide c(RGDyK)-modified liposome loading AL3810 of multiple dosing caused hypothermia, activated anti-c(RGDyK)-liposome IgG and IgM antibody and pertinent complements C3b and C5b-9, and experienced complement-dependent opsonization. We newly proposed a pentapeptide mn with superb v3-binding affinity and tailored AL3810-loaded mn-modified liposome that afforded impervious blood circulation, targeting ability, and glioma therapeutic expertise as vastly alleviated immune opsonization on the underpinning of the finite antibodies and complements assembly. Stemming from attenuated immunogenicity, peptide mn strengthened liposome functions as a promising nanocarrier platform for molecular targeting agents.
AL3810是一种血管内皮生长因子受体（VEGFR）和成纤维细胞生长因子受体（FGFR）的分子双重抑制剂，已获得中国食品药品监督管理总局批准进行肿瘤治疗的II期临床试验。作为一种可逆的ATP竞争性抑制剂，AL3810作用于VEGFR和FGFR细胞内区域的ATP结合位点，然而，由于AL3810与受体细胞外区域缺乏相互作用，导致其对血脑肿瘤屏障（BBTB）的识别不足、脑渗透性差以及抗胶质瘤疗效不理想。整合素v3在BBTB的毛细血管内皮细胞以及胶质瘤细胞上过度表达，这为将配体修饰的脂质体精准地空间递送至胶质瘤提供了依据。广泛使用的载有多剂量AL3810的肽c(RGDyK)修饰脂质体可导致体温过低，激活抗c(RGDyK)脂质体IgG和IgM抗体以及相关补体C3b和C5b-9，并经历补体依赖性调理作用。我们新提出了一种具有超强v3结合亲和力的五肽mn，并定制了载有AL3810的mn修饰脂质体该脂质体具有良好的血液循环、靶向能力和胶质瘤治疗效果，因为在有限的抗体和补体组装基础上极大地减轻了免疫调理作用。由于免疫原性减弱，肽mn增强了脂质体作为分子靶向剂的有前景的纳米载体平台的功能。
