关键词: 乳腺癌, 4T1细胞, 阿帕替尼, ZIF-8, 增殖, 凋亡

Abstract: Objective To construct the apatinib@zeolitic imidazolate framework-8 (A@ZIF-8) nanoparticles, and to investigate the effect of A@ZIF-8 on the proliferation and apoptosis of mouse breast cancer 4T1 cells. Methods The zeolitic imidazolate framework-8 (ZIF-8) was prepared by a physical agitation method, the apatinib was loaded into ZIF-8 by the one-step method to construct the A@ZIF-8. The particle size and morphological characteristics of ZIF-8 and A@ZIF-8 were observed by transmission electron microscope (TEM) and scanning electron microscope (SEM), the Zeta potentials were measured by laser particle size analyzer. CCK-8 assay and flow cytometry were used to detect the effects of A@ZIF-8 on the proliferation and apoptosis of 4T1 cells. One mouse was randomly selected from 13 Balb/c female mice for A@ZIF-8 in vitro hemolysis experiment. The remaining mice were randomly divided into the control group (n=6) and the A@ZIF-8 group (n=6), and sacrificed on the 14th day after the first tail vein injection. Blood was collected for blood routine and blood biochemical index detection, and HE staining was used to observe the changes of organs, including heart, liver, spleen, lung, kidney and others, to evaluate the biological safety of A@ZIF-8. Results Both TEM and SEM showed that compared with the control group, the particle size of ZIF-8 increased after loaded with apatinib and the Zeta potential increased significantly (all P<0.001), indicating that A@ZIF-8 was successfully constructed. CCK-8 assay showed that the inhibitory effect of A@ZIF-8 on 4T1 cell proliferation increased with the increase of its concentration, IC₅₀=27.69 μg/mL. Flow cytometry showed that the apoptosis rate of the A@ZIF-8 group was higher than that of control group (P<0.001). Hemolysis test showed that the A@ZIF-8 was not prone to hemolysis in mice. After injection of A@ZIF-8 solution, the blood routine, liver function, kidney function and other indicators of mice were within the normal range, and no cell structure damage was found in HE staining of mouse vital organs under microscope. Conclusions The A@ZIF-8 constructed in this study can inhibit the proliferation of breast cancer 4T1 cells and promote cell apoptosis, with good biosafety, which is expected to be used for the treatment of breast cancer in vivo.

Key words: Breast cancer, 4T1 cells, Apatinib, ZIF-8, Proliferation, Apoptosis