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.

中文翻译：

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缺氧反应性脂质体增强光敏剂的细胞内递送，以实现有效的光动力治疗


脂质体，尤其是聚乙二醇 （PEG） 修饰的长循环脂质体，由于具有良好的生物相容性、被动肿瘤靶向和持续的药物释放，已被批准用于市场。PEG 修饰的长循环脂质体解决了稳定性差和网状内皮系统快速清除等问题。然而，他们仍然面临阻碍肿瘤细胞吸收药物和阻止肿瘤渗透等挑战。受缺氧肿瘤微环境的启发，我们构建了缺氧反应性脂质体 （PAO-L） 以增强氯素 e6 （Ce6） 的细胞内摄取和光动力疗法 （PDT） 作用。通过酰胺反应将 PEG 和十八烷胺 （OA） 偶联到缺氧敏感的偶氮苯-4,4′-二羧酸 （AZO） 上，制备了智能缺氧可裂解的 PEG-AZO-OA （PAO）。合成的 PAO 进一步掺入负载 Ce6 的脂质体中，以增强循环稳定性，同时通过 PEG 到达缺氧肿瘤组织时从脂质体表面响应性脱落来促进肿瘤渗透和内化。PAO-L 介导的 PDT 显著抑制 B16F10 和 4T1 肿瘤的生长，以及 4T1 乳腺癌的肺转移。出色的治疗效果和良好的耐受性使 PAO-L 成为增强 PDT 的有前途的候选药物。