面部两亲性脂质高度敏感脂质体对分泌性磷脂酶A2的响应增强

Facial Amphiphile-Modified Lipids Highly Sensitize Liposomes toward Secretory Phospholipase A2

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MOLECULAR PHARMACEUTICS

影响因子:4.5

分区:医学2区 / 药学2区医学：研究与实验3区

发表日期:2024 Nov 04

作者: Yanjiao Liu, Xingang Yao, Cheng Wen, Dan Li, Jiawen Zhang, Baomin Xi, Brian S Cummings, Guodong Zhu

DOI: 10.1021/acs.molpharmaceut.4c00271

摘要

肿瘤中上调的分泌性磷脂酶A2（sPLA2）被提出作为触发脂质体药物释放的刺激。然而，当前开发的sPLA2响应性脂质体策略仅考虑底物偏好，受限于酶促水解引起的膜破坏效果有限以及过度使用sPLA2偏好脂质导致的安全性问题。在此，提出一种基于酶促提取和脂质膜中面部两亲性（FAs）转变的膜不稳定机制。酶促降解FAs修饰脂质的过程，包括底物提取、sn-2酯键断裂、FAs的旋转和界面沉积，导致脂质体中药物的巨大外流，称为SECRIS效应。在sPLA2存在下，载有FAs修饰脂质的奥沙利铂（L-OHP）脂质体表现出增强的药物释放、等效的体外细胞毒性，以及在Colo205荷瘤小鼠中优异的体内抗肿瘤效果和减少的不良反应。SECRIS效应的发现为开发针对sPLA2阳性肿瘤的脂质体平台开辟了新路径。

Abstract

Upregulated secretory phospholipase A2 (sPLA2) in tumors has been proposed as a stimulus to trigger drug release from liposomes for therapeutic effects. However, the current strategy for developing sPLA2-responsive liposomes merely considering substrate preference suffers from limited membrane disruptive effects induced by enzymatic hydrolysis and safety issues resulting from the overuse of sPLA2-preferred lipids. Here, a membrane-destabilizing mechanism based on enzymatic extraction and the transition of facial amphiphiles (FAs) within lipid membranes was introduced. Enzymatic degradation of FA-modified lipids, a process involving substrate extraction of lipids from membranes and cleavage of sn-2 ester bonds by sPLA2, rotation, and interface settling of detached FAs, caused tremendous efflux of payloads from liposomes, termed the SECRIS effect. In the presence of sPLA2, oxaliplatin (L-OHP) loaded liposomes containing FA-modified lipids showed enhanced drug release, comparable in vitro cytotoxicity, and excellent in vivo antitumor efficacy and reduced adverse syndromes in Colo205-bearing mice compared to conventional sPLA2-labile formulations. The discovery of the SECRIS effect creates a new pathway to engineer liposome platforms for the treatment of sPLA2-positive tumors.