KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul 02841, Republic of Korea; Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.
Biomedical Research Institute, Korea Institute of Science and Technology (KIST), Seoul 02792, Republic of Korea.
J Control Release. 2021 Feb 10;330:920-932. doi: 10.1016/j.jconrel.2020.10.065. Epub 2020 Nov 2.
Multiple combination therapies with chemotherapeutic drugs and inhibitors of drug resistance have been effective in the clinical cases, but concerns have been raised about the severe toxicity of these chemotherapeutic drugs. Herein, we report a potent and safe combination strategy of cancer-specific doxorubicin (DOX) prodrug nanoparticles (PNPs) and B-cell lymphoma-2 (Bcl-2) anti-apoptotic inhibitor, Navitoclax, to overcome acquired drug resistance during chemotherapy. The cancer-specific PNPs were constructed by conjugating cathepsin B-specific cleavable peptide (Phe-Arg-Arg-Gly; FRRG) to DOX, resulting in FRRG-DOX that self-assembled into nanoparticles and the FRRG-DOX nanoparticles were further stabilized with the FDA-approved pharmaceutical excipient, Pluronic F68. The resulting PNPs are specifically cleaved and metabolized to free DOX in cathepsin B-overexpressing cancer cells, but they exhibited minimal cytotoxicity in cathepsin B-deficient normal cells. As expected, free DOX and PNPs induced overexpression of Bcl-2 in MDA-MB-231 cells, due to acquired drug resistance in a cell culture system. However, combination therapy with PNPs and Navitoclax showed the outstanding synergetic cytotoxicity by decreasing the expression level of Bcl-2. In MDA-MB231 breast tumor-bearing mice, intravenously injected PNPs efficiently accumulated in targeted tumor tissues via enhanced permeability and retention (EPR) effect. When combined with orally administered Navitoclax, PNPs exhibited more potent therapeutic efficacy in aquired drug resistant models than free DOX plus Navitoclax, whereas PNPs greatly reduced systemic toxic side effects in normal organs. Our cancer-specific PNP-based combination therapy with Bcl-2 inhibitor may provide a promising approach for the potent and safe treatment of acquired drug-resistant cancers.
多种联合化疗药物和耐药抑制剂在临床病例中已被证实有效，但人们对这些化疗药物的严重毒性表示担忧。在此，我们报告了一种强效且安全的联合策略，即使用癌症特异性阿霉素（DOX）前药纳米颗粒（PNPs）和 B 细胞淋巴瘤-2（Bcl-2）抗凋亡抑制剂 Navitoclax，以克服化疗过程中获得的耐药性。癌症特异性 PNPs 通过将组织蛋白酶 B 特异性裂解肽（Phe-Arg-Arg-Gly；FRRG）与 DOX 缀合构建而成，得到的 FRRG-DOX 自组装成纳米颗粒，并进一步用 FDA 批准的药物赋形剂 Pluronic F68 稳定。所得的 PNPs 在组织蛋白酶 B 过表达的癌细胞中特异性裂解和代谢为游离的 DOX，但在组织蛋白酶 B 缺乏的正常细胞中表现出最小的细胞毒性。正如预期的那样，游离 DOX 和 PNPs 在 MDA-MB-231 细胞中诱导 Bcl-2 的过表达，这是由于细胞培养系统中的获得性耐药。然而，PNPs 与 Navitoclax 的联合治疗通过降低 Bcl-2 的表达水平显示出出色的协同细胞毒性。在 MDA-MB231 乳腺癌荷瘤小鼠中，静脉注射的 PNPs 通过增强的通透性和保留（EPR）效应有效地在靶向肿瘤组织中积累。当与口服给予的 Navitoclax 联合使用时，PNPs 在获得性耐药模型中的治疗效果比游离 DOX 加 Navitoclax 更强，而 PNPs 大大降低了正常器官的全身毒性副作用。我们基于癌症特异性 PNP 的联合治疗与 Bcl-2 抑制剂可能为治疗获得性耐药癌症提供一种有前途的方法。
