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    2020-08-12

    r> 3.4. 5-FU- and rapamycin-loaded patches inhibited colon cancer growth in vitro
    As described above, traditionally, biological patches play an orga-nizational alternative role in repairing tissue defects. [15–17] Recently, biological patches have been used to repair tissue defects caused by extensive tumor resection [18–21]. However, according to our clinical experience, traditional biological patches effectively repair tissue de-fects, but also contribute to cancer Cytochalasin D and metastasis. Therefore, we loaded a traditional patch with a nanoscale anticancer drug mixture, and measured the therapeutic potential of this novel patch in vivo. We used BALB/c nude mice bearing sw480 human colon tumors implanted 2 weeks prior to treatment. The tumor-bearing mice were randomized into three different treatment groups (n = 5 per group). When tumor volumes reached 100 mm3, the groups were treated for two weeks as follows: 1) intravenous injections of mixtures of 5-FU and rapamycin (IOCV) every other day, 2) patches without drugs (control), 3) and patches loaded with drugs (1 mg/cm2) adjoining the tumor site. After treatment, the tumors were excised and photographed (Fig. 5A), and the tumor growth curves were recorded (Fig. 5B). We then performed IHC to analyze the expression of Ki-67 in the different groups. The
    Fig. 5. Enhanced antitumor effects of drug-loaded patches in vivo. A. Nude mice bearing Sw480 human colon tumors implanted 2 weeks prior to treatment received intravenous injections of mixtures of 5-FU and rapamycin (IOCV) every other day, patches without drugs (control), or drug-loaded patches (1 mg/cm2) for 2 weeks. Tumors were harvested and weighed after 2 weeks of treatment. N = 5 for each group. B. Tumor growth curves for the different experimental groups after treatment with the indicated substances. C. H&E-stain of major organs (Lung, Liver and Kidney) and IHC results of Ki67 in tumors. Scale bar =100 μm. D. Operation process of drug-loaded patch treatment. E. Blood biochemical analysis of mice in different groups.
    results showed that the group treated with the drug-loaded patches had the lowest Ki-67 expression (Fig. 5C), which indicated that the patch containing nanoscale drug formulations significantly inhibited tumor growth. To investigate the adverse effects associated with the patch, the livers, lungs, and kidneys of mice bearing sw480 human colon tumors treated with IOCV or patches loaded with nanoparticles were sectioned and examined by H&E staining (Fig. 5D). Paraffin sections of these organs were similar in all groups with no apparent damage or abnormal histological alterations observed in the two treatment groups compared to the control group, including no inflammatory infiltrates into the 
    tissues. This indicated the general safety of the patches to the major organs. Besides, we collected the blood of mice in each group after treatment to measure the biochemical indicators including ALT, AST, BUN and CREA. The results showed that drug-loaded patches didn’t cause liver and kidney damage (Fig. 5E). Thus, we concluded that the patches loaded with nanoparticles had minimal adverse effects asso-ciated with the liver and kidney. Furthermore, the general health of the mice was not affected by any of the treatments, and the animals showed no loss in weight, indicating that they were eating normally.
    4. Discussion
    LDDS-based combination drug therapy is an ideal therapeutic stra-tegies for the treatment of cancer and has become an attractive option. [22–24] A previous study reported the effects of 3D-printed patches loaded with a chemotherapy agent on tumor growth inhibition in a subcutaneous and orthotopic mouse model of pancreatic cancer [18]. The 3D printed patches were only loaded with one chemotherapy agent and the printed PLGA/PCL patches degraded over 4 months. Our results demonstrated that patches loaded with 5-FU-RAPA-PLA-NP exhibited improved therapeutic efficacy compared to patches with no drug. This improvement may have been due to sustained drug release from the patches at the target site causing local accumulation of higher con-centrations of the drugs in addition to the combined effects of 5-FU and rapamycin. 5-FU is the first-line chemotherapy for colon cancer. Hideo Shigematsu et al. reported that rapamycin enhanced the cytotoxic ef-fects of 5-FU by inhibiting the expression of thymidylate synthase (TS) in gastric cancer cells [25]. Furthermore, Kyung-Hun Lee et al. reported that RAD001, an inhibitor of mammalian target of rapamycin (mTOR), conferred sensitivity to 5-FU-resistant cell lines by downregulating TS, and inhibited the growth of gastric cancer cells [26]. In our study, co-treatment with 5-FU and rapamycin synergistically inhibited colon cancer cell growth.