Intravesical delivery of rapamycin via folate-modified liposomes dispersed in thermo-reversible hydrogel

Ho Yub Yoon,1,* In Ho Chang,2,* Yoon Tae Goo,1 Chang Hyun Kim,1 Tae Hoon Kang,1 Soo-Yeon Kim,3 Sang Jin Lee,3 Seh Hyon Song,4 Young Mi Whang,2 Young Wook Choi1 1College of Pharmacy, Chung-ang University, Seoul, Korea; 2College of Medicine, Chung-ang University, Seoul, Korea; 3Research Insti...

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Autores principales:	Yoon HY, Chang IH, Goo YT, Kim CH, Kang TH, Kim SY, Lee SJ, Song SH, Whang YM, Choi YW
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2019
Materias:	bladder cancer prolonged retention enhanced uptake antitumor efficacy autophagy mTOR signaling Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/25e156383a6c4a59bd533d63e3940a86
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spelling	oai:doaj.org-article:25e156383a6c4a59bd533d63e3940a862021-12-02T08:57:16ZIntravesical delivery of rapamycin via folate-modified liposomes dispersed in thermo-reversible hydrogel1178-2013https://doaj.org/article/25e156383a6c4a59bd533d63e3940a862019-08-01T00:00:00Zhttps://www.dovepress.com/intravesical-delivery-of-rapamycin-via-folate-modified-liposomes-dispe-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Ho Yub Yoon,1,* In Ho Chang,2,* Yoon Tae Goo,1 Chang Hyun Kim,1 Tae Hoon Kang,1 Soo-Yeon Kim,3 Sang Jin Lee,3 Seh Hyon Song,4 Young Mi Whang,2 Young Wook Choi1 1College of Pharmacy, Chung-ang University, Seoul, Korea; 2College of Medicine, Chung-ang University, Seoul, Korea; 3Research Institute, National Cancer Center, Goyang, Korea; 4College of Pharmacy, Kyungsung University, Busan, Korea*These authors contributed equally to this workPurpose: To develop an intravesical instillation system for the treatment of bladder cancer, rapamycin (Rap) was encapsulated into liposomes and then homogeneously dispersed throughout a poloxamer 407 (P407)-based hydrogel.Methods: Rap-loaded conventional liposomes (R-CL) and folate-modified liposomes (R-FL) were prepared using a film hydration method and pre-loading technique, and characterized by particle size, drug entrapment efficiency, and drug loading. The cellular uptake behavior in folate receptor-expressing bladder cancer cells was observed by flow cytometry and confocal laser scanning microscopy using a fluorescent probe. In vitro cytotoxic effects were evaluated using MTT assay, colony forming assay, and Western blot. For in vivo intravesical instillation, Rap-loaded liposomes were dispersed in P407-gel, generating R-CL/P407 and R-FL/P407. Gel-forming capacities and drug release were evaluated. Using the MBT2/Luc orthotopic bladder cancer mouse model, in vivo antitumor efficacy was evaluated according to regions of interest (ROI) measurement.Results: R-CL and R-FL were successfully prepared, at approximately <160 nm, 42% entrapment efficiency, and 57 μg/mg drug loading. FL cellular uptake was enhanced over 2-fold than that of CL; folate receptor-mediated endocytosis was confirmed using a competitive assay with folic acid pretreatment. In vitro cytotoxic effects increased dose-dependently. Rap-loaded liposomes inhibited mTOR signaling and induced autophagy in urothelial carcinoma cells. With gelation time of <30 seconds and gel duration of >12 hrs, both R-CL/P407 and R-FL/P407 preparations transformed into gel immediately after instillation into the mouse bladder. Drug release from the liposomal gel was erosion controlled. In orthotopic bladder cancer mouse model, statistically significant differences in ROI values were found between R-CL/P407 and R-FL/P407 groups at day 11 (P=0.0273) and day 14 (P=0.0088), indicating the highest tumor growth inhibition by R-FL/P407.Conclusion: Intravesical instillation of R-FL/P407 might represent a good candidate for bladder cancer treatment, owing to its enhanced retention and FR-targeting.Keywords: bladder cancer, prolonged retention, enhanced uptake, antitumor efficacy, autophagy, mTOR signalingYoon HYChang IHGoo YTKim CHKang THKim SYLee SJSong SHWhang YMChoi YWDove Medical Pressarticlebladder cancerprolonged retentionenhanced uptakeantitumor efficacyautophagymTOR signalingMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 14, Pp 6249-6268 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	bladder cancer prolonged retention enhanced uptake antitumor efficacy autophagy mTOR signaling Medicine (General) R5-920
spellingShingle	bladder cancer prolonged retention enhanced uptake antitumor efficacy autophagy mTOR signaling Medicine (General) R5-920 Yoon HY Chang IH Goo YT Kim CH Kang TH Kim SY Lee SJ Song SH Whang YM Choi YW Intravesical delivery of rapamycin via folate-modified liposomes dispersed in thermo-reversible hydrogel
description	Ho Yub Yoon,1,* In Ho Chang,2,* Yoon Tae Goo,1 Chang Hyun Kim,1 Tae Hoon Kang,1 Soo-Yeon Kim,3 Sang Jin Lee,3 Seh Hyon Song,4 Young Mi Whang,2 Young Wook Choi1 1College of Pharmacy, Chung-ang University, Seoul, Korea; 2College of Medicine, Chung-ang University, Seoul, Korea; 3Research Institute, National Cancer Center, Goyang, Korea; 4College of Pharmacy, Kyungsung University, Busan, Korea*These authors contributed equally to this workPurpose: To develop an intravesical instillation system for the treatment of bladder cancer, rapamycin (Rap) was encapsulated into liposomes and then homogeneously dispersed throughout a poloxamer 407 (P407)-based hydrogel.Methods: Rap-loaded conventional liposomes (R-CL) and folate-modified liposomes (R-FL) were prepared using a film hydration method and pre-loading technique, and characterized by particle size, drug entrapment efficiency, and drug loading. The cellular uptake behavior in folate receptor-expressing bladder cancer cells was observed by flow cytometry and confocal laser scanning microscopy using a fluorescent probe. In vitro cytotoxic effects were evaluated using MTT assay, colony forming assay, and Western blot. For in vivo intravesical instillation, Rap-loaded liposomes were dispersed in P407-gel, generating R-CL/P407 and R-FL/P407. Gel-forming capacities and drug release were evaluated. Using the MBT2/Luc orthotopic bladder cancer mouse model, in vivo antitumor efficacy was evaluated according to regions of interest (ROI) measurement.Results: R-CL and R-FL were successfully prepared, at approximately <160 nm, 42% entrapment efficiency, and 57 μg/mg drug loading. FL cellular uptake was enhanced over 2-fold than that of CL; folate receptor-mediated endocytosis was confirmed using a competitive assay with folic acid pretreatment. In vitro cytotoxic effects increased dose-dependently. Rap-loaded liposomes inhibited mTOR signaling and induced autophagy in urothelial carcinoma cells. With gelation time of <30 seconds and gel duration of >12 hrs, both R-CL/P407 and R-FL/P407 preparations transformed into gel immediately after instillation into the mouse bladder. Drug release from the liposomal gel was erosion controlled. In orthotopic bladder cancer mouse model, statistically significant differences in ROI values were found between R-CL/P407 and R-FL/P407 groups at day 11 (P=0.0273) and day 14 (P=0.0088), indicating the highest tumor growth inhibition by R-FL/P407.Conclusion: Intravesical instillation of R-FL/P407 might represent a good candidate for bladder cancer treatment, owing to its enhanced retention and FR-targeting.Keywords: bladder cancer, prolonged retention, enhanced uptake, antitumor efficacy, autophagy, mTOR signaling
format	article
author	Yoon HY Chang IH Goo YT Kim CH Kang TH Kim SY Lee SJ Song SH Whang YM Choi YW
author_facet	Yoon HY Chang IH Goo YT Kim CH Kang TH Kim SY Lee SJ Song SH Whang YM Choi YW
author_sort	Yoon HY
title	Intravesical delivery of rapamycin via folate-modified liposomes dispersed in thermo-reversible hydrogel
title_short	Intravesical delivery of rapamycin via folate-modified liposomes dispersed in thermo-reversible hydrogel
title_full	Intravesical delivery of rapamycin via folate-modified liposomes dispersed in thermo-reversible hydrogel
title_fullStr	Intravesical delivery of rapamycin via folate-modified liposomes dispersed in thermo-reversible hydrogel
title_full_unstemmed	Intravesical delivery of rapamycin via folate-modified liposomes dispersed in thermo-reversible hydrogel
title_sort	intravesical delivery of rapamycin via folate-modified liposomes dispersed in thermo-reversible hydrogel
publisher	Dove Medical Press
publishDate	2019
url	https://doaj.org/article/25e156383a6c4a59bd533d63e3940a86
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_version_	1718398290831081472

Intravesical delivery of rapamycin via folate-modified liposomes dispersed in thermo-reversible hydrogel

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