Li Peishan, Li Jiaxin, Cheng Jinmei, Huang Junyi, Li Jinhui, Xiao Jisheng, Duan Xiaopin
Department of General Surgery, Zhujiang Hospital; Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China.
Department of General Surgery, Zhujiang Hospital; Cancer Research Institute, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong 510515, China; Department of Cardiology, Heart Center, Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease; Translational Medicine Research Center, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, China.
J Control Release. 2025 Jan 10;377:277-287. doi: 10.1016/j.jconrel.2024.11.032. Epub 2024 Nov 21.
Liposomes, especially polyethylene glycol (PEG)-modified long-circulating liposomes, have been approved for market use, due to good biocompatibility, passive tumor targeting, and sustained drug release. PEG-modified long-circulating liposomes address issues such as poor stability and rapid clearance by the reticuloendothelial system. However, they still face challenges like hindering drug uptake by tumor cells and preventing tumor penetration. Inspired by the hypoxic tumor microenvironment, we constructed a hypoxia-responsive liposome (PAO-L) to enhance the intracellular uptake and photodynamic therapy (PDT) effect of chlorin e6 (Ce6). The intelligent hypoxia-cleavable PEG-AZO-OA (PAO) was prepared by coupling PEG and octadecylamine (OA) to hypoxia-sensitive azobenzene-4,4'-dicarboxylic acid (AZO) through amide reaction. The synthesized PAO was further incorporated into Ce6-loaded liposomes to enhance the circulation stability, while promote the tumor penetration and internalization by the responsive shedding of PEG from liposome surface upon reaching the hypoxic tumor tissue. PAO-L mediated PDT significantly inhibited the growth of B16F10 and 4T1 tumors, as well as lung metastasis of 4T1 breast cancer. The excellent therapeutic effect and good tolerability make PAO-L a promising candidate for enhanced PDT.
脂质体，尤其是聚乙二醇（PEG）修饰的长循环脂质体，因其良好的生物相容性、被动肿瘤靶向性和药物缓释性已被批准用于市场。PEG修饰的长循环脂质体解决了诸如稳定性差和被网状内皮系统快速清除等问题。然而，它们仍然面临着阻碍肿瘤细胞摄取药物和阻止肿瘤渗透等挑战。受缺氧肿瘤微环境的启发，我们构建了一种缺氧响应脂质体（PAO-L），以增强氯e6（Ce6）的细胞内摄取和光动力疗法（PDT）效果。通过酰胺反应将PEG和十八胺（OA）与缺氧敏感的偶氮苯-4,4'-二羧酸（AZO）偶联制备了智能缺氧可裂解的PEG-AZO-OA（PAO）。将合成的PAO进一步掺入负载Ce6的脂质体中，以提高循环稳定性，同时在到达缺氧肿瘤组织时通过PEG从脂质体表面的响应性脱落促进肿瘤渗透和内化。PAO-L介导的PDT显著抑制了B16F10和4T1肿瘤的生长以及4T1乳腺癌的肺转移。优异的治疗效果和良好的耐受性使PAO-L成为增强PDT的有前途的候选者。
