Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, Department of Pharmaceutics, School of Pharmacy, Fudan University, Shanghai 201203, China.
ACS Nano. 2013 Mar 26;7(3):2860-71. doi: 10.1021/nn400548g. Epub 2013 Mar 12.
Tumor microenvironment, such as the lowered tumor extracellular pH (pHe) and matrix metalloproteinase 2 (MMP2), has been extensively explored, which promotes the development of the microenvironment-responsive drug delivery system. Utilizing these unique features, an activatable cell-penetrating peptide (designated as dtACPP) that is dual-triggered by the lowered pHe and MMP2 has been constructed, and a smart nanoparticle system decorating with dtACPP has been successfully developed, which could dual-load gene drug and chemotherapeutics simultaneously. After systemic administration, dtACPP-modified nanoparticles possess passive tumor targetability via the enhanced permeability and retention effect. Then dtACPP would be activated to expose cell-penetrating peptide to drive the nanoparticles' internalization into the intratumoral cells. As angiogenesis and tumor cells might be mutually improved in tumor growth, so combining antiangiogenesis and apoptosis is meaningful for oncotherapy. Vascular endothelial growth factor (VEGF) is significant in angiogenesis, and anti-VEGF therapy could decrease blood vessel density and delay tumor growth obviously. Chemotherapy using doxorubicin (DOX) could kill off tumor cells efficiently. Here, utilizing dtACPP-modified nanoparticles to co-deliver plasmid expressing interfering RNA targeting VEGF (shVEGF) and DOX (designated as dtACPPD/shVEGF-DOX) results in effective shutdown of blood vessels and cell apoptosis within the tumor. On the premise of effective drug delivery, dtACPPD/shVEGF-DOX has demonstrated good tumor targetability, little side effects after systemic administration, and ideal antitumor efficacy.
肿瘤微环境，如降低的肿瘤细胞外 pH 值（pHe）和基质金属蛋白酶 2（MMP2），已经被广泛研究，这促进了微环境响应型药物输送系统的发展。利用这些独特的特性，构建了一种双响应性的细胞穿透肽（命名为 dtACPP），它可以被降低的 pHe 和 MMP2 双重激活，并成功开发了一种带有 dtACPP 的智能纳米颗粒系统，该系统可以同时双重装载基因药物和化疗药物。在系统给药后，dtACPP 修饰的纳米颗粒通过增强的通透性和保留效应具有被动的肿瘤靶向性。然后，dtACPP 会被激活，暴露出细胞穿透肽，从而驱动纳米颗粒进入肿瘤内细胞的内化。由于血管生成和肿瘤细胞在肿瘤生长中可能相互促进，因此联合抗血管生成和细胞凋亡对肿瘤治疗具有重要意义。血管内皮生长因子（VEGF）在血管生成中具有重要意义，抗 VEGF 治疗可以明显降低血管密度并延迟肿瘤生长。使用多柔比星（DOX）进行化疗可以有效地杀死肿瘤细胞。在这里，利用 dtACPP 修饰的纳米颗粒共递送靶向 VEGF 的干扰 RNA 质粒（shVEGF）和 DOX（命名为 dtACPPD/shVEGF-DOX）可有效关闭肿瘤内的血管和细胞凋亡。在有效药物递送的前提下，dtACPPD/shVEGF-DOX 具有良好的肿瘤靶向性、系统给药后副作用小和理想的抗肿瘤疗效。
