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Background: Recently, we reported that folate-appended methyl-b-cyclodextrin (FA-M-b-CyD) has tumor-selective antitumor effect via mitophagy. However, blood circulation of FA-M-b-CyD is poor. Objective: In the present study, to improve blood retention of FA-M-b-CyD, we prepared polyrotaxane with FA-M-b-CyD and evaluated its in vivo antitumor activity. Materials and Methods: To prepare FA-M-b-CyD polyrotaxane, polyrotaxane consisting of azide-b-CyD was prepared with Pluronic P123. Then, methylation of the polyrotaxane was performed with methyl iodide. To modify folate moieties, alkyne-folate was reacted with the polyrotaxane through a click reaction. To evaluate in vivo antitumor effects, FA-M-b-CyD polyrotaxane was repeatedly injected to BALB/c mice bearing Colon-26 cells (folate receptor positive cell), and tumor volume was measured. In addition, blood chemistry values after repeated intravenous injections of the polyrotaxane to BALB/c mice were also measured to estimate safety profiles. Results: According to the results of ¹H-NMR, FA-M-b-CyD polyrotaxane was successfully prepared. The number of M-b-CyD was 14/one polyrotaxane with 40% of coverage. The degrees of substitution of methyl group and folate moiety were 9/one b-CyD and 1.35/one b-CyD, respectively. Importantly, FA-M-b-CyD polyrotaxane showed high antitumor activity, compared to FA-M-b-CyD alone after the intravenous injections to tumor-bearing mice. Moreover, FA-M-b-CyD polyrotaxane negligibly changed blood chemistry values such as creatinine, blood urea nitrogen, aspartate aminotransferase, alanine aminotransferase and lactate dehydrogenase. Conclusion: These results suggest that FA-M-b-CyD has the potential for new antitumor agent.