Abstract
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-Gln, AVPIAQ) and cathepsin B-cleavable peptide (Phe-Arg-Arg-Gly, FRRG) to a doxorubicin (DOX), resulting in SMAC-FRRG-DOX that allows self-assembled into nanoparticles. The resulting DD-NPs were specifically cleaved to pro-apoptotic 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.
Original language | English |
---|---|
Article number | 120347 |
Journal | Biomaterials |
Volume | 261 |
DOIs | |
State | Published - Dec 2020 |
Bibliographical note
Funding Information:This work was supported from the National Research Foundation (NRF) of South Korea, funded by the Ministry of Science (NRF-2019R1A2C3006283) of Republic of Korea, the KU-KIST Graduate School of Converging Science and Technology (Korea University), and the Intramural Research Program of KIST.
Funding Information:
This work was supported from the National Research Foundation ( NRF ) of South Korea, funded by the Ministry of Science (NRF-2019R1A2C3006283) of Republic of Korea, the KU-KIST Graduate School of Converging Science and Technology ( Korea University ), and the Intramural Research Program of KIST .
Publisher Copyright:
© 2020 Elsevier Ltd
Keywords
- Cancer nanomedicine
- Drug resistance
- Prodrug
- Synergetic effect