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...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Dove Medical Press
2019-08-01
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| Series: | International Journal of Nanomedicine |
| Subjects: | |
| Online Access: | https://www.dovepress.com/intravesical-delivery-of-rapamycin-via-folate-modified-liposomes-dispe-peer-reviewed-article-IJN |
| _version_ | 1818993345144291328 |
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| 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 |
| collection | DOAJ |
| 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 |
| first_indexed | 2024-12-20T20:40:34Z |
| format | Article |
| id | doaj.art-25e156383a6c4a59bd533d63e3940a86 |
| institution | Directory Open Access Journal |
| issn | 1178-2013 |
| language | English |
| last_indexed | 2024-12-20T20:40:34Z |
| publishDate | 2019-08-01 |
| publisher | Dove Medical Press |
| record_format | Article |
| series | International Journal of Nanomedicine |
| spelling | doaj.art-25e156383a6c4a59bd533d63e3940a862022-12-21T19:27:07ZengDove Medical PressInternational Journal of Nanomedicine1178-20132019-08-01Volume 146249626847635Intravesical delivery of rapamycin via folate-modified liposomes dispersed in thermo-reversible hydrogelYoon HYChang IHGoo YTKim CHKang THKim SYLee SJSong SHWhang YMChoi YWHo 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 signalinghttps://www.dovepress.com/intravesical-delivery-of-rapamycin-via-folate-modified-liposomes-dispe-peer-reviewed-article-IJNbladder cancerprolonged retentionenhanced uptakeantitumor efficacyautophagymTOR signaling |
| spellingShingle | 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 International Journal of Nanomedicine bladder cancer prolonged retention enhanced uptake antitumor efficacy autophagy mTOR signaling |
| title | 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_short | 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 |
| topic | bladder cancer prolonged retention enhanced uptake antitumor efficacy autophagy mTOR signaling |
| url | https://www.dovepress.com/intravesical-delivery-of-rapamycin-via-folate-modified-liposomes-dispe-peer-reviewed-article-IJN |
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