期刊
CHEMISTRY OF MATERIALS
卷 28, 期 18, 页码 6742-6752出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.chemmater.6b03236
关键词
-
资金
- National Natural Science Foundation of China [21474077, 51233003]
Multidrug resistance (MDR) is one of the main causes of the failure in cancer chemotherapy. To address this challenge, this work develops a tumor-triggered nanomedicine (HA-MSDOX-KLA; comprised of a tumor active targeting segment (hyaluronic acid, HA) and two programmed therapeutic agents, MMP-substrate peptide (CPLGLAGG) conjugated doxorubicin (designated as MSDOX) and proapoptotic peptide (KLAKLAK)(2) (designated as KLA)) with switchable morphology transformation that significantly enhances tumor-specific accumulation and retention for overcoming MDR. Morphology changes could be triggered by tumor overexpressed matrix metalloproteinases (MMPs), achieving elevated drug accumulation and prolonged intracellular drug retention. Additionally, the adjunctive release of proapoptotic peptide KLA would targetedly induce the dysfunction of mitochondria with decreased adenosine 5'-triphosphate (ATP) generation to further inhibit the drug efflux. In vitro and in vivo studies demonstrate that, compared with free doxorubicin (DOX), the functionalized HA-MSDOX-KLA shows a 6.1-fold and 4.5-fold increase in anti-MDR efficacy on MCF-7/ADR cancer cells and MCF-7/ADR tumor-bearing mice, respectively. We believe that this strategy will open a new window of designing transformable nanomedicine for combating drug resistance in tumor treatments.
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