Basic Research - Cancer(구연) Oral Session 3 / Basic Research - Cancer (Ⅱ) (O-033) Rm.201 10월 30일(수) 14:00-15:00 Folate-conjugated liposomal carriers enhance the sensitivity to rapamycin in urothelial carcinoma (URCa) cells and orthotopic bladder cancer mouse model ¹중앙대학교 의과대학 비뇨기과학교실, ²약학대학 심재헌¹, 황영미¹, 황광용¹, 윤호엽², 최영욱², 장인호¹ Objective: Aberrant activation of the mammalian target of rapamycin (mTOR) signaling pathway is well-recognized in human cancers, including urothelial carcinoma (URCa). The mTOR inhibitors, such as rapamycin, have significant potential for application in the treatment of URCa of the bladder. However, it is unclear how to optimize the methods for delivering drugs selectively to URCa cells as the result of low tissue concentrations of rapamycin at clinically tolerable doses. Folate (FA) are essential to proliferating cancer rather than normal cells to carry out one carbon methylation reactions as well as de novo synthesis of nucleotide. Materials and methods: Therefore, we focused on enhancing the ability to take up rapamycin-conjugated with folate (RAFC) by receptor-mediated endocytosis, due to widely expressed the folate receptor-α (FRα) in URCa bladder. Results: Here, we observed that the FRα levels were highly expressed in URCa cells, then RAFC was constructed in modular form for the delivering rapamycin to URCa bladder. In comparison with unconjugated rapamycin, RAFC-treated URCa cells exhibited enhanced growth inhibition in vitro and in vivo that was associated with inhibition of mTOR activation and induction of apoptosis. Autophagy-related proteins were highly activated in URCa cells treated with RAFC through AMPK activation and mTOR inactivation, resulting in induction of apoptosis. Consistent with in vitro results, RAFC significantly retarded tumor growth and induced apoptosis in orthotopic bladder cancer mouse as compared with unconjugated rapamycin. Conclusions: These results suggest that folate-conjugation is a promising delivering design for increasing the tissue specificity and facilitating cellular endocytosis of rapamycin in bladder cancer. The National Research Foundation (NRF) of the Republic of Korea (NRF-2016R1D1A1B03933826 to Y.M.W., NRF-2018R1D1A1A02050248 to I.H.C.) and the Korea Health Technology R&D Project (HI17C0710 to I.H.C.). keywords : Urothelial carcinoma, Folate, Rapamycin