Shim, Man Kyu Moon, Yujeong Yang, Suah Kim, Jinseong Cho, Hanhee Lim, Seungho Yoon, Hong Yeol Seong, Joon-Kyung Kim, Kwangmeyung 2024-01-19T16:01:48Z 2024-01-19T16:01:48Z 2022-01-10 2020-12 0142-9612 https://pubs.kist.re.kr/handle/201004/117730 Chemotherapy has shown remarkable therapeutic efficacy for various types of cancer. However, drug resistance reduces the effectiveness and sensitivity of chemotherapy, leading treatment failure and cancer relapse in many clinical indications. Herein, we propose cancer-specific drug-drug nanoparticles (DD-NPs) that improve the therapeutic efficacy of chemotherapy against drug-resistant cancer. Cancer-specific and pro-apoptotic drug-drug conjugate was prepared by conjugating the pro-apoptotic peptide drug (SMAC; Ala-Val-Pro-Ile-Ala-Gin, AVPIAQ) and cathepsin B-cleavable peptide (Phe-Arg-Arg-Gly, FRRG) to a doxorubicin (DOX), resulting in SMAC-FRRGDOX that allows self-assembled into nanoparticles. The resulting DD-NPs were specifically cleaved to proapoptotic SMAC and cytotoxic DOX only in cathepsin B-overexpressing cancer cells, inducing a synergy of the pro-apoptotic activity with the chemotherapy. In MCF-7 breast tumor-bearing mice, intravenously injected DD-NPs highly accumulated at targeted tumor tissues via enhanced permeability and retention (EPR) effect, releasing SMAC and DOX, which showed a synergetic pro-apoptotic/chemotherapy. Furthermore, DD-NPs greatly suppressed tumor growth and improved overall survival in a metastatic lung cancer model. Collectively, these cancer-specific drug-drug nanoparticles may be a promising strategy to treat drug-resistant cancers with high cancer cell-specificity. English ELSEVIER SCI LTD BREAST-CANCER DELIVERY PROTEINS TEMOZOLOMIDE INHIBITOR TARGETS DESIGN Cancer-specific drug-drug nanoparticles of pro-apoptotic and cathepsin B-cleavable peptide-conjugated doxorubicin for drug-resistant cancer therapy Article 10.1016/j.biomaterials.2020.120347 1 BIOMATERIALS, v.261 BIOMATERIALS 261 scie scopus 000576748600003 2-s2.0-85090028475 Engineering, Biomedical Materials Science, Biomaterials Engineering Materials Science Article BREAST-CANCER DELIVERY PROTEINS TEMOZOLOMIDE INHIBITOR TARGETS DESIGN Drug resistance Prodrug Cancer nanomedicine Synergetic effect