Zhao Xingyu, Li Yinghuan
School of Pharmaceutical Sciences, Capital Medical University, Beijing 100069, China.
Pharmaceuticals (Basel). 2025 Jul 15;18(7):1042. doi: 10.3390/ph18071042.
: PEGylated liposomes are widely recognized for their biocompatibility and capacity to extend systemic circulation via "stealth" properties. However, the PEG corona often limits tumor penetration and cellular internalization. Targeting matrix metalloproteinase-2 (MMP-2), frequently upregulated in breast cancer stroma, presents an opportunity to enhance tissue-specific drug delivery. In this study, we engineered MMP-2-responsive GPLGVRG peptide-modified cleavable PEGylated liposomes for targeted paclitaxel (PTX) delivery. : Molecular docking simulations employed the MMP-2 crystal structure (PDB ID: 7XJO) to assess GPLGVRG peptide binding affinity. A cleavable, enzyme-sensitive peptide-PEG conjugate (Chol-PEG-GPLGVRG-PEG) was synthesized via small-molecule liquid-phase synthesis and characterized by H NMR and MALDI-TOF MS. Liposomes incorporating this conjugate (S-Peps-PEG) were formulated to evaluate whether MMP-2-mediated peptide degradation triggers detachment of long-chain PEG moieties, thereby enhancing internalization by 4T1 breast cancer cells. Additionally, the effects of tumor microenvironmental pH (6.5) and MMP-2 concentration on drug release dynamics were investigated. : Molecular docking revealed robust GPLGVRG-MMP-2 interactions, yielding a binding energy of -7.1 kcal/mol. The peptide formed hydrogen bonds with MMP-2 residues Tyr A:23 and Arg A:53 (bond lengths: 2.4-2.5 Å) and engaged in hydrophobic contacts, confirming MMP-2 as the primary recognition site. Formulations containing 5 mol% Chol-PEG-GPLGVRG-PEG combined with 0.15 µg/mL MMP-2 (S-Peps-PEG +MMP) exhibited superior internalization efficiency and significantly reduced clonogenic survival compared to controls. Notably, acidic pH (6.5) induced MMP-2-mediated cleavage of the GPLGVRG peptide, accelerating S-Peps-PEG dissociation and facilitating drug release. : MMP-2-responsive, cleavable PEGylated liposomes markedly improve PTX accumulation and controlled release at tumor sites by dynamically modulating their stealth properties, offering a promising strategy to enhance chemotherapy efficacy in breast cancer.
聚乙二醇化脂质体因其生物相容性以及通过“隐身”特性延长全身循环的能力而被广泛认可。然而，聚乙二醇冠层通常会限制肿瘤渗透和细胞内化。靶向基质金属蛋白酶-2（MMP-2），其在乳腺癌基质中经常上调，为增强组织特异性药物递送提供了机会。在本研究中，我们设计了MMP-2响应性GPLGVRG肽修饰的可裂解聚乙二醇化脂质体用于靶向递送紫杉醇（PTX）。：分子对接模拟采用MMP-2晶体结构（PDB ID：7XJO）来评估GPLGVRG肽的结合亲和力。通过小分子液相合成法合成了一种可裂解的、酶敏感的肽-聚乙二醇缀合物（Chol-PEG-GPLGVRG-PEG），并通过1H NMR和MALDI-TOF MS进行了表征。制备了包含该缀合物的脂质体（S-Peps-PEG），以评估MMP-2介导的肽降解是否会触发长链聚乙二醇部分的脱离，从而增强4T1乳腺癌细胞的内化。此外，还研究了肿瘤微环境pH（约6.5）和MMP-2浓度对药物释放动力学的影响。：分子对接显示GPLGVRG与MMP-2之间存在强烈相互作用，结合能为-7.1 kcal/mol。该肽与MMP-2残基Tyr A:23和Arg A:53形成氢键（键长：2.4-2.5 Å）并参与疏水接触，证实MMP-2为主要识别位点。与对照组相比，含有5 mol% Chol-PEG-GPLGVRG-PEG并结合0.15 µg/mL MMP-2的制剂（S-Peps-PEG +MMP）表现出更高的内化效率和显著降低的克隆形成存活率。值得注意的是，酸性pH（约6.5）诱导MMP-2介导的GPLGVRG肽裂解，加速S-Peps-PEG解离并促进药物释放。：MMP-2响应性、可裂解聚乙二醇化脂质体通过动态调节其隐身特性，显著提高了PTX在肿瘤部位的积累和控释，为增强乳腺癌化疗疗效提供了一种有前景的策略。
