Optimization and Pharmacokinetic Evaluation of Synergistic Fenbendazole and Rapamycin Co-Encapsulated in Methoxy Poly(Ethylene Glycol)-b-Poly(Caprolactone) Polymeric Micelles

Hee Ji Shin,1,* Min Jeong Jo,1,* Ik Sup Jin,1 Chun-Woong Park,1 Jin-Seok Kim,2 Dae Hwan Shin1 1College of Pharmacy, Chungbuk National University, Cheongju, 28160, Republic of Korea; 2Drug Information Research Institute (DIRI), College of Pharmacy, Sookmyung Women’s University, Seoul,...

Descripción completa

Guardado en:
Detalles Bibliográficos
Autores principales: Shin HJ, Jo MJ, Jin IS, Park CW, Kim JS, Shin DH
Formato: article
Lenguaje:EN
Publicado: Dove Medical Press 2021
Materias:
Acceso en línea:https://doaj.org/article/251ed3a1e0e447fbb8885ae764207a40
Etiquetas: Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
id oai:doaj.org-article:251ed3a1e0e447fbb8885ae764207a40
record_format dspace
spelling oai:doaj.org-article:251ed3a1e0e447fbb8885ae764207a402021-12-02T16:11:38ZOptimization and Pharmacokinetic Evaluation of Synergistic Fenbendazole and Rapamycin Co-Encapsulated in Methoxy Poly(Ethylene Glycol)-b-Poly(Caprolactone) Polymeric Micelles1178-2013https://doaj.org/article/251ed3a1e0e447fbb8885ae764207a402021-07-01T00:00:00Zhttps://www.dovepress.com/optimization-and-pharmacokinetic-evaluation-of-synergistic-fenbendazol-peer-reviewed-fulltext-article-IJNhttps://doaj.org/toc/1178-2013Hee Ji Shin,1,* Min Jeong Jo,1,* Ik Sup Jin,1 Chun-Woong Park,1 Jin-Seok Kim,2 Dae Hwan Shin1 1College of Pharmacy, Chungbuk National University, Cheongju, 28160, Republic of Korea; 2Drug Information Research Institute (DIRI), College of Pharmacy, Sookmyung Women’s University, Seoul, 04310, Republic of Korea*These authors contributed equally to this workCorrespondence: Dae Hwan ShinCollege of Pharmacy, Chungbuk National University, Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju, 28160, Republic of KoreaTel +82 43 261 2820Fax +82 43 268 2732Email dshin@chungbuk.ac.krPurpose: We aimed to develop a nanocarrier formulation incorporating fenbendazole (FEN) and rapamycin (RAPA) with strong efficacy against A549 cancer cells. As FEN and RAPA are poorly soluble in water, it is difficult to apply them clinically in vivo. Therefore, we attempted to resolve this problem by encapsulating these drugs in polymeric micelles.Methods: We evaluated drug synergy using the combination index (CI) values of various molar ratios of FEN and RAPA. We formed and tested micelles composed of different polymers. Moreover, we conducted cytotoxicity, stability, release, pharmacokinetic, and biodistribution studies to investigate the antitumor effects of FEN/RAPA-loaded mPEG-b-PCL micelles.Results: We selected mPEG-b-PCL-containing FEN and RAPA at a molar ratio of 1:2 because these particles were consistent in size and had high encapsulation efficiency (EE, %) and drug loading (DL, %) capacity. The in vitro cytotoxicity was assessed for various FEN, RAPA, and combined FEN/RAPA formulations. After long-term exposures, both the solutions and the micelles had similar efficacy against A549 cancer cells. The in vivo pharmacokinetic study revealed that FEN/RAPA-loaded mPEG-b-PCL micelles had a relatively higher area under the plasma concentration–time curve from 0 to 2 h (AUC0– 2 h) and 0 to 8 h (AUC0– 8 h) and plasma concentration at time zero (Co) than that of the FEN/RAPA solution. The in vivo biodistribution assay revealed that the IV injection of FEN/RAPA-loaded mPEG-b-PCL micelles resulted in lower pulmonary FEN concentration than the IV injection of the FEN/RAPA solution.Conclusion: When FEN and RAPA had a 1:2 molar ratio, they showed synergism. Additionally, using data from in vitro cytotoxicity, synergism between a 1:2 molar ratio of FEN and RAPA was observed in the micelle formulation. The FEN/RAPA-loaded mPEG-b-PCL micelle had enhanced bioavailability than the FEN/RAPA solution.Keywords: combination therapy, drug interaction, cytotoxicity, biodistribution, bioavailabilityShin HJJo MJJin ISPark CWKim JSShin DHDove Medical Pressarticlecombination therapydrug interactioncytotoxicitybiodistributionbioavailabilityMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 16, Pp 4873-4889 (2021)
institution DOAJ
collection DOAJ
language EN
topic combination therapy
drug interaction
cytotoxicity
biodistribution
bioavailability
Medicine (General)
R5-920
spellingShingle combination therapy
drug interaction
cytotoxicity
biodistribution
bioavailability
Medicine (General)
R5-920
Shin HJ
Jo MJ
Jin IS
Park CW
Kim JS
Shin DH
Optimization and Pharmacokinetic Evaluation of Synergistic Fenbendazole and Rapamycin Co-Encapsulated in Methoxy Poly(Ethylene Glycol)-b-Poly(Caprolactone) Polymeric Micelles
description Hee Ji Shin,1,* Min Jeong Jo,1,* Ik Sup Jin,1 Chun-Woong Park,1 Jin-Seok Kim,2 Dae Hwan Shin1 1College of Pharmacy, Chungbuk National University, Cheongju, 28160, Republic of Korea; 2Drug Information Research Institute (DIRI), College of Pharmacy, Sookmyung Women’s University, Seoul, 04310, Republic of Korea*These authors contributed equally to this workCorrespondence: Dae Hwan ShinCollege of Pharmacy, Chungbuk National University, Osongsaengmyeong 1-ro, Osong-eup, Heungdeok-gu, Cheongju, 28160, Republic of KoreaTel +82 43 261 2820Fax +82 43 268 2732Email dshin@chungbuk.ac.krPurpose: We aimed to develop a nanocarrier formulation incorporating fenbendazole (FEN) and rapamycin (RAPA) with strong efficacy against A549 cancer cells. As FEN and RAPA are poorly soluble in water, it is difficult to apply them clinically in vivo. Therefore, we attempted to resolve this problem by encapsulating these drugs in polymeric micelles.Methods: We evaluated drug synergy using the combination index (CI) values of various molar ratios of FEN and RAPA. We formed and tested micelles composed of different polymers. Moreover, we conducted cytotoxicity, stability, release, pharmacokinetic, and biodistribution studies to investigate the antitumor effects of FEN/RAPA-loaded mPEG-b-PCL micelles.Results: We selected mPEG-b-PCL-containing FEN and RAPA at a molar ratio of 1:2 because these particles were consistent in size and had high encapsulation efficiency (EE, %) and drug loading (DL, %) capacity. The in vitro cytotoxicity was assessed for various FEN, RAPA, and combined FEN/RAPA formulations. After long-term exposures, both the solutions and the micelles had similar efficacy against A549 cancer cells. The in vivo pharmacokinetic study revealed that FEN/RAPA-loaded mPEG-b-PCL micelles had a relatively higher area under the plasma concentration–time curve from 0 to 2 h (AUC0– 2 h) and 0 to 8 h (AUC0– 8 h) and plasma concentration at time zero (Co) than that of the FEN/RAPA solution. The in vivo biodistribution assay revealed that the IV injection of FEN/RAPA-loaded mPEG-b-PCL micelles resulted in lower pulmonary FEN concentration than the IV injection of the FEN/RAPA solution.Conclusion: When FEN and RAPA had a 1:2 molar ratio, they showed synergism. Additionally, using data from in vitro cytotoxicity, synergism between a 1:2 molar ratio of FEN and RAPA was observed in the micelle formulation. The FEN/RAPA-loaded mPEG-b-PCL micelle had enhanced bioavailability than the FEN/RAPA solution.Keywords: combination therapy, drug interaction, cytotoxicity, biodistribution, bioavailability
format article
author Shin HJ
Jo MJ
Jin IS
Park CW
Kim JS
Shin DH
author_facet Shin HJ
Jo MJ
Jin IS
Park CW
Kim JS
Shin DH
author_sort Shin HJ
title Optimization and Pharmacokinetic Evaluation of Synergistic Fenbendazole and Rapamycin Co-Encapsulated in Methoxy Poly(Ethylene Glycol)-b-Poly(Caprolactone) Polymeric Micelles
title_short Optimization and Pharmacokinetic Evaluation of Synergistic Fenbendazole and Rapamycin Co-Encapsulated in Methoxy Poly(Ethylene Glycol)-b-Poly(Caprolactone) Polymeric Micelles
title_full Optimization and Pharmacokinetic Evaluation of Synergistic Fenbendazole and Rapamycin Co-Encapsulated in Methoxy Poly(Ethylene Glycol)-b-Poly(Caprolactone) Polymeric Micelles
title_fullStr Optimization and Pharmacokinetic Evaluation of Synergistic Fenbendazole and Rapamycin Co-Encapsulated in Methoxy Poly(Ethylene Glycol)-b-Poly(Caprolactone) Polymeric Micelles
title_full_unstemmed Optimization and Pharmacokinetic Evaluation of Synergistic Fenbendazole and Rapamycin Co-Encapsulated in Methoxy Poly(Ethylene Glycol)-b-Poly(Caprolactone) Polymeric Micelles
title_sort optimization and pharmacokinetic evaluation of synergistic fenbendazole and rapamycin co-encapsulated in methoxy poly(ethylene glycol)-b-poly(caprolactone) polymeric micelles
publisher Dove Medical Press
publishDate 2021
url https://doaj.org/article/251ed3a1e0e447fbb8885ae764207a40
work_keys_str_mv AT shinhj optimizationandpharmacokineticevaluationofsynergisticfenbendazoleandrapamycincoencapsulatedinmethoxypolyethyleneglycolbpolycaprolactonepolymericmicelles
AT jomj optimizationandpharmacokineticevaluationofsynergisticfenbendazoleandrapamycincoencapsulatedinmethoxypolyethyleneglycolbpolycaprolactonepolymericmicelles
AT jinis optimizationandpharmacokineticevaluationofsynergisticfenbendazoleandrapamycincoencapsulatedinmethoxypolyethyleneglycolbpolycaprolactonepolymericmicelles
AT parkcw optimizationandpharmacokineticevaluationofsynergisticfenbendazoleandrapamycincoencapsulatedinmethoxypolyethyleneglycolbpolycaprolactonepolymericmicelles
AT kimjs optimizationandpharmacokineticevaluationofsynergisticfenbendazoleandrapamycincoencapsulatedinmethoxypolyethyleneglycolbpolycaprolactonepolymericmicelles
AT shindh optimizationandpharmacokineticevaluationofsynergisticfenbendazoleandrapamycincoencapsulatedinmethoxypolyethyleneglycolbpolycaprolactonepolymericmicelles
_version_ 1718384397249413120