Kim, Jinseong Shim, Man Kyu Yang, Suah Moon, Yujeong Song, Sukyung Choi, Jiwoong Kim, Jeongrae Kim, Kwangmeyung 2024-01-19T15:31:08Z 2024-01-19T15:31:08Z 2022-01-10 2021-02-10 0168-3659 https://pubs.kist.re.kr/handle/201004/117409 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. English ELSEVIER Combination of cancer-specific prodrug nanoparticle with Bcl-2 inhibitor to overcome acquired drug resistance Article 10.1016/j.jconrel.2020.10.065 1 JOURNAL OF CONTROLLED RELEASE, v.330, pp.920 - 932 JOURNAL OF CONTROLLED RELEASE 330 920 932 scie scopus 000626459100067 2-s2.0-85096406104 Chemistry, Multidisciplinary Pharmacology & Pharmacy Chemistry Pharmacology & Pharmacy Article Cancer-specific prodrug nanoparticles Bcl-2 inhibitor Combination therapy Inhibitor of drug resistance Drug resistance