PEG化是延长阳离子脂质体在血液中循环时间的常用方法。然而，PEG化与"PEG困境"相关，阻碍其与肿瘤细胞的结合和摄取。可切除的PEG产物是解决这个问题的可能方案。在当前研究中，制备了表面结合基质金属蛋白酶-2（MMP-2）敏感的八肽链-PEG衍生物的多柔比星加载的阳离子脂质体（Dox-CLs），并将其与非PEG化和PEG化的脂质体进行了尺寸、表面电荷、药物包封和释放、摄取、体内药代动力学和抗癌活性方面的比较。假设在肿瘤微环境中过度表达的MMP-2诱导PEG脱屏蔽，增加保护脂质体与细胞膜的相互作用，提高其被肿瘤细胞/血管摄取。MMP2响应型Dox-CLs的粒径约为115-140nm，表面电荷约为+25mv，封装效率约为85-95%。体外细胞毒性评估显示，相比于其不可切除的PEG包被对照物和Caelyx®，可切除的PEG可水解脂质体摄取和细胞毒性显著增强。此外，鸡子绒膜寻常疣膜实验证实Dox-CLs具有出色的抗血管生成能力，可靶向和预防肿瘤的新生血管形成。另外，体内研究显示PEG可水解Dox-CLs对小鼠结肠癌具有显著的治疗效果，且血液学和组织病理学毒性可忽略。总之，我们的结果表明，MMP2响应型Dox-CLs可能成为改善肿瘤药物传递和摄取的有前途的方法。

PEGylation is a commonly used approach to prolong the blood circulation time of cationic liposomes. However, PEGylation is associated with the "PEG dilemma", which hinders binding and uptake into tumor cells. The cleavable PEG products are a possible solution to this problem. In the current research, doxorubicin-loaded cationic liposomes (Dox-CLs) surface-conjugated with a matrix metalloproteinase-2 (MMP-2)-sensitive octapeptide linker-PEG derivative were prepared and compared to non-PEGylated and PEGylated CLs in terms of size, surface charge, drug encapsulation and release, uptake, in vivo pharmacokinetics, and anticancer efficacy. It was postulated that PEG deshielding in response to the overexpressed MMP-2 in the tumor microenvironment increases the interaction of protected CLs with cellular membranes and improves their uptake by tumor cells/vasculature. MMP2-responsive Dox-CLs had particle sizes of ∼115-140 nm, surface charges of ∼+25 mV, and encapsulation efficiencies of ∼85-95%. In vitro cytotoxicity assessments showed significantly enhanced uptake and cytotoxicity of PEG-cleavable CLs compared to their non-cleavable PEG-coated counterparts or Caelyx®. Also, the chick chorioallantoic membrane assay showed great antiangiogenesis ability of Dox-CLs leading to target and prevent tumor neovascularization. Besides, in vivo studies showed an effective therapeutic efficacy of PEG-cleavable Dox-CLs in murine colorectal cancer with negligible hematological and histopathological toxicity. Altogether, our results showed that MMP2-responsive Dox-CLs could be served as a promising approach to improve tumor drug delivery and uptake.