Cholesterol-Based Nanovesicles Enhance the In Vitro Cytotoxicity, Ex Vivo Intestinal Absorption, and In Vivo Bioavailability of Flutamide

Critical adverse effects and frequent administration, three times per day, limit the use of flutamide (FLT) as a chemotherapeutic agent in the treatment of prostate cancer. Therefore, our research aimed to develop new cholesterol-based nanovesicles for delivering FLT to malignant cells in an endeavo...

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Autores principales:	Mohamed A. Ali, Magdy I. Mohamed, Mohamed A. Megahed, Tamer M. Abdelghany, Khalid M. El-Say
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	Draper–Lin small composite design ex vivo intestinal permeation flutamide in vitro cytotoxicity optimization in vivo pharmacokinetics Pharmacy and materia medica RS1-441
Acceso en línea:	https://doaj.org/article/621b646d5c7547c599b4375d12f03a30
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spelling	oai:doaj.org-article:621b646d5c7547c599b4375d12f03a302021-11-25T18:40:17ZCholesterol-Based Nanovesicles Enhance the In Vitro Cytotoxicity, Ex Vivo Intestinal Absorption, and In Vivo Bioavailability of Flutamide10.3390/pharmaceutics131117411999-4923https://doaj.org/article/621b646d5c7547c599b4375d12f03a302021-10-01T00:00:00Zhttps://www.mdpi.com/1999-4923/13/11/1741https://doaj.org/toc/1999-4923Critical adverse effects and frequent administration, three times per day, limit the use of flutamide (FLT) as a chemotherapeutic agent in the treatment of prostate cancer. Therefore, our research aimed to develop new cholesterol-based nanovesicles for delivering FLT to malignant cells in an endeavor to maximize its therapeutic efficacy and minimize undesired adverse effects. Draper–Lin small composite design was used to optimize the critical quality attributes of FLT-loaded niosomes and ensure the desired product quality. The influence of the selected four independent variables on mean particle size (Y<sub>1</sub>), zeta potential (Y<sub>2</sub>), drug entrapment efficiency (Y<sub>3</sub>), and the cumulative drug release after 24 h (Y<sub>4</sub>) was examined. The optimized nanovesicles were assessed for their in vitro cytotoxicity, ex-vivo absorption via freshly excised rabbit intestine as well as in vivo pharmacokinetics on male rats. TEM confirmed nanovescicles’ spherical shape with bilayer structure. Values of dependent variables were 748.6 nm, −48.60 mV, 72.8% and 72.2% for Y<sub>1</sub>, Y<sub>2</sub>, Y<sub>3</sub> and Y<sub>4</sub>, respectively. The optimized FLT-loaded niosomes exerted high cytotoxic efficacy against human prostate cancer cell line (PC-3) with an IC<sub>50</sub> value of 0.64 ± 0.04 µg/mL whilst, it was 1.88 ± 0.16 µg/mL for free FLT. Moreover, the IC<sub>50</sub> values on breast cancer cell line (MCF-7) were 0.27 ± 0.07 µg/mL and 4.07 ± 0.74 µg/mL for FLT-loaded niosomes and free FLT, respectively. The permeation of the optimized FLT-loaded niosomes through the rabbit intestine showed an enhancement ratio of about 1.5 times that of the free FLT suspension. In vivo pharmacokinetic study displayed an improvement in oral bioavailability of the optimized niosomal formulation with AUC and C<sub>max</sub> values of 741.583 ± 33.557 μg/mL × min and 6.950 ± 0.45 μg/mL compared to 364.536 ± 45.215 μg/mL × min and 2.650 ± 0.55 μg/mL for the oral FLT suspension. With these promising findings, we conclude that encapsulation of FLT in cholesterol-loaded nanovesicles enhanced its anticancer activity and oral bioavailability which endorse its use in the management of prostate cancer.Mohamed A. AliMagdy I. MohamedMohamed A. MegahedTamer M. AbdelghanyKhalid M. El-SayMDPI AGarticleDraper–Lin small composite designex vivo intestinal permeationflutamidein vitro cytotoxicityoptimizationin vivo pharmacokineticsPharmacy and materia medicaRS1-441ENPharmaceutics, Vol 13, Iss 1741, p 1741 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Draper–Lin small composite design ex vivo intestinal permeation flutamide in vitro cytotoxicity optimization in vivo pharmacokinetics Pharmacy and materia medica RS1-441
spellingShingle	Draper–Lin small composite design ex vivo intestinal permeation flutamide in vitro cytotoxicity optimization in vivo pharmacokinetics Pharmacy and materia medica RS1-441 Mohamed A. Ali Magdy I. Mohamed Mohamed A. Megahed Tamer M. Abdelghany Khalid M. El-Say Cholesterol-Based Nanovesicles Enhance the In Vitro Cytotoxicity, Ex Vivo Intestinal Absorption, and In Vivo Bioavailability of Flutamide
description	Critical adverse effects and frequent administration, three times per day, limit the use of flutamide (FLT) as a chemotherapeutic agent in the treatment of prostate cancer. Therefore, our research aimed to develop new cholesterol-based nanovesicles for delivering FLT to malignant cells in an endeavor to maximize its therapeutic efficacy and minimize undesired adverse effects. Draper–Lin small composite design was used to optimize the critical quality attributes of FLT-loaded niosomes and ensure the desired product quality. The influence of the selected four independent variables on mean particle size (Y<sub>1</sub>), zeta potential (Y<sub>2</sub>), drug entrapment efficiency (Y<sub>3</sub>), and the cumulative drug release after 24 h (Y<sub>4</sub>) was examined. The optimized nanovesicles were assessed for their in vitro cytotoxicity, ex-vivo absorption via freshly excised rabbit intestine as well as in vivo pharmacokinetics on male rats. TEM confirmed nanovescicles’ spherical shape with bilayer structure. Values of dependent variables were 748.6 nm, −48.60 mV, 72.8% and 72.2% for Y<sub>1</sub>, Y<sub>2</sub>, Y<sub>3</sub> and Y<sub>4</sub>, respectively. The optimized FLT-loaded niosomes exerted high cytotoxic efficacy against human prostate cancer cell line (PC-3) with an IC<sub>50</sub> value of 0.64 ± 0.04 µg/mL whilst, it was 1.88 ± 0.16 µg/mL for free FLT. Moreover, the IC<sub>50</sub> values on breast cancer cell line (MCF-7) were 0.27 ± 0.07 µg/mL and 4.07 ± 0.74 µg/mL for FLT-loaded niosomes and free FLT, respectively. The permeation of the optimized FLT-loaded niosomes through the rabbit intestine showed an enhancement ratio of about 1.5 times that of the free FLT suspension. In vivo pharmacokinetic study displayed an improvement in oral bioavailability of the optimized niosomal formulation with AUC and C<sub>max</sub> values of 741.583 ± 33.557 μg/mL × min and 6.950 ± 0.45 μg/mL compared to 364.536 ± 45.215 μg/mL × min and 2.650 ± 0.55 μg/mL for the oral FLT suspension. With these promising findings, we conclude that encapsulation of FLT in cholesterol-loaded nanovesicles enhanced its anticancer activity and oral bioavailability which endorse its use in the management of prostate cancer.
format	article
author	Mohamed A. Ali Magdy I. Mohamed Mohamed A. Megahed Tamer M. Abdelghany Khalid M. El-Say
author_facet	Mohamed A. Ali Magdy I. Mohamed Mohamed A. Megahed Tamer M. Abdelghany Khalid M. El-Say
author_sort	Mohamed A. Ali
title	Cholesterol-Based Nanovesicles Enhance the In Vitro Cytotoxicity, Ex Vivo Intestinal Absorption, and In Vivo Bioavailability of Flutamide
title_short	Cholesterol-Based Nanovesicles Enhance the In Vitro Cytotoxicity, Ex Vivo Intestinal Absorption, and In Vivo Bioavailability of Flutamide
title_full	Cholesterol-Based Nanovesicles Enhance the In Vitro Cytotoxicity, Ex Vivo Intestinal Absorption, and In Vivo Bioavailability of Flutamide
title_fullStr	Cholesterol-Based Nanovesicles Enhance the In Vitro Cytotoxicity, Ex Vivo Intestinal Absorption, and In Vivo Bioavailability of Flutamide
title_full_unstemmed	Cholesterol-Based Nanovesicles Enhance the In Vitro Cytotoxicity, Ex Vivo Intestinal Absorption, and In Vivo Bioavailability of Flutamide
title_sort	cholesterol-based nanovesicles enhance the in vitro cytotoxicity, ex vivo intestinal absorption, and in vivo bioavailability of flutamide
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/621b646d5c7547c599b4375d12f03a30
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Cholesterol-Based Nanovesicles Enhance the In Vitro Cytotoxicity, Ex Vivo Intestinal Absorption, and In Vivo Bioavailability of Flutamide

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