5-FU@DHA-UIO-66-NH(2) potentiates chemotherapy sensitivity of breast cancer cells through a microRNA let-7a-dependent mechanism

BACKGROUND: Drug delivery systems with magnetization facilitate the accumulation of drug at the target site. This study aimed to explore the mechanism by which docosahexaenoic acid (DHA)-modified porous metal-organic framework (MOF) UIO-66-NH(2) loads chemotherapeutic drug 5-fluorouracil (5-FU) and reduces the chemotherapy resistance of breast cancer (BC) cells. METHODS: UIO-66-NH(2) was synthesized and DHA with carboxyl end was used to modify the surface of UIO-66-NH(2). 5-FU was incorporated to UIO-66-NH(2) or DHA-UIO-66-NH(2) by a post-synthesis method. The loading and release of 5-FU by @DHA-UIO-66-NH(2) was investigated with ultraviolet (UV) spectroscopy. RT-qPCR was conducted to detect the expression of let-7a in cells. The uptake of DHA-UIO-66-NH(2) by MCF-7 BC cells was observed by confocal laser scanning microscope (CLSM). Cell counting kit-8 (CCK-8), flow cytometry, and live/dead cell staining were applied to investigate the effects of 5-FU@DHA-UIO-66-NH(2) on BC cells, and a BC mouse model was established to explore its effects on tumorigenesis. HE staining and routine blood index analysis were applied for determination of the biological safety of 5-FU@DHA-UIO-66-NH(2). RESULTS: 5-FU@DHA-UIO-66-NH(2) was successfully constructed and characterized. The loading amount of DHA-UIO-NH(2) for 5-FU reached 30.31%. DHA-UIO-66-NH(2) was effectively taken up by MCF-7 cells. Further, 5-FU@DHA-UIO-66-NH(2) exhibited stronger inhibitory effects on MCF-7 cell viability in vitro as well as tumorigenesis in vivo than 5-FU and 5-FU@UIO-66-NH(2). DHA up-regulated let-7a to reduce the resistance of MCF-7 cells to 5-FU. Moreover, the biosafety of 5-FU@DHA-UIO-66-NH(2) was identified. CONCLUSIONS: 5-FU@DHA-UIO-66-NH(2) increased the level of let-7a in BC cells, repressed cell viability and augmented apoptosis, and thus reduced the chemotherapy resistance of BC cells.