Folic Acid-Modified miR-491-5p-Loaded ZIF-8 Nanoparticles Inhibit Castration-Resistant Prostate Cancer by Regulating the Expression of EPHX1

Epoxide hydrolase 1 (EPHX1) has been reported to be related to the development of several tumors. However, the regulation of castration-resistant prostate cancer (CRPC) development by EPHX1 has not been reported. We used proteomic technology and found that the EPHX1 protein was highly expressed in CRPC tissues and the CRPC cell line C4-2. We performed screening and found that EPHX1 is a direct target of miR-491-5p. High miR-491-5p expression significantly reduced the EPHX1 level in C4-2 cells and inhibited C4-2 cell proliferation and migration. Zeolite imidazolate framework-8 (ZIF-8) has good thermal stability, a simple synthesis method, tumor site stability, and specific acid responsiveness. We synthesized ZIF-8 nanodrug vectors to deliver miR-491-5p into C4-2 cells. After loading miR-491-5p into ZIF-8, we modified the ZIF-8 surface with folic acid (FA) as the target group (FA@ZIF-8). Our synthesized nanodrug carrier showed less cytotoxicity to C4-2 cells even at 200 μg/ml. Modified FA could increase the efficiency of nanomaterial entry into C4-2 cells. FA@miR-491-5p@ZIF-8 could stably release miR-491-5p for a long period in both phosphate-buffered saline (pH 7.4) and acetate buffer (pH 4.8), and miR-491-5p was released faster at the beginning of the experiment in acetate buffer (pH 4.8). FA@miR-491-5p@ZIF-8 significantly reduced C4-2 cell proliferation and migration, and FA@miR-491-5p@ZIF-8 had a better effect than miR-491-5p alone. In vivo, FA@miR-491-5p@ZIF-8 significantly inhibited CRPC growth in nude mice. Overall, we verified that miR-491-4p regulated CRPC development by targeting EPHX1. The drug nanocarrier FA@miR-491-5p@ZIF-8 not only significantly reduced C4-2 CRPC cell proliferation and migration but also significantly inhibited CRPC growth. Our research provides a theoretical basis for treatment and treatment strategies for CRPC.