College of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China.
Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui Province Key Laboratory of R&D of Chinese Medicine, Anhui University of Chinese Medicine, Hefei, Anhui 230038, China.
Nano Lett. 2020 Jun 10;20(6):4153-4161. doi: 10.1021/acs.nanolett.0c00152. Epub 2020 May 28.
Cancer metastasis is the main cause of chemotherapeutic failure. Inhibiting the activity of matrix metalloproteinases (MMPs) is a common strategy for reducing metastasis. However, broad-spectrum MMP-inhibitors (MMPI) may cause undesired side effects. Here, we screened a selective MMP2 inhibitor (CCKIGLFRWR) and linked it with doxorubicin (DOX) to produce an amphiphilic peptide-drug conjugate (PDC). Then novel core-shell nanoparticles were self-assembled from PDC core and modified polylysine (MPL) shell. When the particles were passively targeted to the tumor site, the PDC core was exposed for charge switch of the MPL shell, aggregated for its transformation behavior, and specially adhered to the cell membrane. The disulfide bond between the MMPI peptide and DOX was broken via a low concentration of glutathione-mediated reduction in tumor microenvironment. DOX could effectively enter the tumor cells. Meanwhile, the MMPI peptide could selectively inhibit the activity of the MMP2 and effectively inhibit tumor metastasis.
癌症转移是化疗失败的主要原因。抑制基质金属蛋白酶（MMPs）的活性是减少转移的常用策略。然而，广谱 MMP 抑制剂（MMPI）可能会引起不良反应。在这里，我们筛选了一种选择性 MMP2 抑制剂（CCKIGLFRWR）并将其与阿霉素（DOX）相连，以产生两亲性肽-药物偶联物（PDC）。然后，新型核壳纳米粒子自组装于 PDC 核和修饰聚赖氨酸（MPL）壳。当粒子被动靶向肿瘤部位时，PDC 核暴露，MPL 壳的电荷发生转换，聚集，发生转变行为，并特异性黏附于细胞膜。在肿瘤微环境中，低浓度谷胱甘肽介导还原作用，打破了 MMP 肽和 DOX 之间的二硫键。DOX 可以有效地进入肿瘤细胞。同时，MMPI 肽可以选择性地抑制 MMP2 的活性，并有效地抑制肿瘤转移。
