面部两亲切的脂质高度敏化脂质体对分泌磷脂酶A2
Facial Amphiphile-Modified Lipids Highly Sensitize Liposomes toward Secretory Phospholipase A2
影响因子:4.50000
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
摘要
肿瘤中已提出上调分泌的磷脂酶A2（SPLA2）是一种刺激，以触发从脂质体中释放药物以获得治疗作用。但是，目前开发SPLA2响应性脂质体的策略仅考虑酶的偏好受到有限的膜损伤作用，酶水解引起的膜破坏性效应以及由于过度使用SPLA2偏爱的脂质而导致的安全性问题。在这里，引入了基于酶促提取的膜 - 二亲和面部两亲物（FAS）（FAS）在脂质膜中的过渡。 FA修饰的脂质的酶促降解，这是从膜上提取脂质的过程，通过SPLA2，旋转，旋转和分离的FAS沉降的SN-2酯键的裂解，导致了从Liposomes造成有效负载的巨大外由，从唇质上产生了secris效应。在存在SPLA2的情况下，含有FA改良脂质的奥沙利铂（L-OHP）负载脂质体表现出增强的药物释放，可比的体外细胞毒性和极好的体内抗肿瘤效不适性和降低的Colo205-抗蛋白酶的不良综合症，与传统的spla2 labe spla2层相比。 SECRIS效应的发现为治疗SPLA2阳性肿瘤的工程脂质体平台创造了新的途径。
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.