Folate receptor-targeted liposomes enhanced the antitumor potency of imatinib through the combination of active targeting and molecular targeting

Peng Ye,1,2 Wendian Zhang,1 Tan Yang,1 Yao Lu,1 Miao Lu,1 Yongkang Gai,1 Xiang Ma,1 Guangya Xiang1 1School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Department of Pharmacy, Wuhan University, Renmin Hospital, Wuh...

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Autores principales:	Ye P, Zhang W, Yang T, Lu Y, Lu M, Gai Y, Ma X, Xiang G
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2014
Materias:	Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/cc2610dc1a0e4717902ed9de144b7dc7
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spelling	oai:doaj.org-article:cc2610dc1a0e4717902ed9de144b7dc72021-12-02T02:04:16ZFolate receptor-targeted liposomes enhanced the antitumor potency of imatinib through the combination of active targeting and molecular targeting1178-2013https://doaj.org/article/cc2610dc1a0e4717902ed9de144b7dc72014-05-01T00:00:00Zhttp://www.dovepress.com/folate-receptor-targeted-liposomes-enhanced-the-antitumor-potency-of-i-a16706https://doaj.org/toc/1178-2013 Peng Ye,1,2 Wendian Zhang,1 Tan Yang,1 Yao Lu,1 Miao Lu,1 Yongkang Gai,1 Xiang Ma,1 Guangya Xiang1 1School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Department of Pharmacy, Wuhan University, Renmin Hospital, Wuhan, People’s Republic of China Purpose: Imatinib inhibits platelet-derived growth factor receptor (PDGFR), and evidence shows that PDGFR participates in the development and progression of cervical cancer. Although imatinib has exhibited preclinical activity against cervical cancer, only minimal clinical therapeutic efficacy was observed. This poor therapeutic efficacy may be due to insufficient drug delivery to the tumor cells and plasma protein binding. Therefore, the purpose of this study was to explore a novel folate receptor (FR)-targeted delivery system via imatinib-loaded liposomes to enhance drug delivery to tumor cells and to reduce plasma protein binding. Methods: Imatinib was remote-loaded into FR-targeted liposomes which were prepared by thin film hydration followed by polycarbonate membrane extrusion. Encapsulation efficiency, mean size diameter, and drug retention were characterized and cellular uptake, cell cytotoxicity, and cell apoptosis on cervical cancer HeLa cells were evaluated. Comparative pharmacokinetic studies were also carried out with FR-targeted imatinib liposomes, simple imatinib liposomes, and free imatinib. Results: High encapsulation efficiency (>90%), appropriate mean particle size (143.5 nm), and zeta potential (–15.97 mV) were obtained for FR-targeted imatinib liposomes. The drug release profile showed minimal imatinib leakage (<5%) in phosphate-buffered saline (PBS) at pH =7.4 within 72 hours of incubation, while more leakage (>25%) was observed in PBS at pH =5.5. This indicates that these liposomes possess a certain degree of pH sensitivity. Cytotoxicity assays demonstrated that the FR-targeted imatinib liposomes promoted a six-fold IC50 reduction on the non-targeted imatinib liposomes from 910 to 150 µM. In addition, FR-targeted imatinib liposomes enhanced HeLa cell apoptosis in vitro compared to the non-targeted imatinib liposomes. Pharmacokinetic parameters indicated that both targeted and non-targeted liposomes exhibited long circulation properties in Kunming mice. Conclusion: These findings indicate that the nano-sized FR-targeted PDGFR antagonist imatinib liposomes may constitute a promising strategy in cervical cancer therapy through the combination of active targeting and molecular targeting. Keywords: liposomes, imatinib, folate receptor, tumor targeting, PDGFRYe PZhang WYang TLu YLu MGai YMa XXiang GDove Medical PressarticleMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol 2014, Iss Issue 1, Pp 2167-2178 (2014)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine (General) R5-920
spellingShingle	Medicine (General) R5-920 Ye P Zhang W Yang T Lu Y Lu M Gai Y Ma X Xiang G Folate receptor-targeted liposomes enhanced the antitumor potency of imatinib through the combination of active targeting and molecular targeting
description	Peng Ye,1,2 Wendian Zhang,1 Tan Yang,1 Yao Lu,1 Miao Lu,1 Yongkang Gai,1 Xiang Ma,1 Guangya Xiang1 1School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China; 2Department of Pharmacy, Wuhan University, Renmin Hospital, Wuhan, People’s Republic of China Purpose: Imatinib inhibits platelet-derived growth factor receptor (PDGFR), and evidence shows that PDGFR participates in the development and progression of cervical cancer. Although imatinib has exhibited preclinical activity against cervical cancer, only minimal clinical therapeutic efficacy was observed. This poor therapeutic efficacy may be due to insufficient drug delivery to the tumor cells and plasma protein binding. Therefore, the purpose of this study was to explore a novel folate receptor (FR)-targeted delivery system via imatinib-loaded liposomes to enhance drug delivery to tumor cells and to reduce plasma protein binding. Methods: Imatinib was remote-loaded into FR-targeted liposomes which were prepared by thin film hydration followed by polycarbonate membrane extrusion. Encapsulation efficiency, mean size diameter, and drug retention were characterized and cellular uptake, cell cytotoxicity, and cell apoptosis on cervical cancer HeLa cells were evaluated. Comparative pharmacokinetic studies were also carried out with FR-targeted imatinib liposomes, simple imatinib liposomes, and free imatinib. Results: High encapsulation efficiency (>90%), appropriate mean particle size (143.5 nm), and zeta potential (–15.97 mV) were obtained for FR-targeted imatinib liposomes. The drug release profile showed minimal imatinib leakage (<5%) in phosphate-buffered saline (PBS) at pH =7.4 within 72 hours of incubation, while more leakage (>25%) was observed in PBS at pH =5.5. This indicates that these liposomes possess a certain degree of pH sensitivity. Cytotoxicity assays demonstrated that the FR-targeted imatinib liposomes promoted a six-fold IC50 reduction on the non-targeted imatinib liposomes from 910 to 150 µM. In addition, FR-targeted imatinib liposomes enhanced HeLa cell apoptosis in vitro compared to the non-targeted imatinib liposomes. Pharmacokinetic parameters indicated that both targeted and non-targeted liposomes exhibited long circulation properties in Kunming mice. Conclusion: These findings indicate that the nano-sized FR-targeted PDGFR antagonist imatinib liposomes may constitute a promising strategy in cervical cancer therapy through the combination of active targeting and molecular targeting. Keywords: liposomes, imatinib, folate receptor, tumor targeting, PDGFR
format	article
author	Ye P Zhang W Yang T Lu Y Lu M Gai Y Ma X Xiang G
author_facet	Ye P Zhang W Yang T Lu Y Lu M Gai Y Ma X Xiang G
author_sort	Ye P
title	Folate receptor-targeted liposomes enhanced the antitumor potency of imatinib through the combination of active targeting and molecular targeting
title_short	Folate receptor-targeted liposomes enhanced the antitumor potency of imatinib through the combination of active targeting and molecular targeting
title_full	Folate receptor-targeted liposomes enhanced the antitumor potency of imatinib through the combination of active targeting and molecular targeting
title_fullStr	Folate receptor-targeted liposomes enhanced the antitumor potency of imatinib through the combination of active targeting and molecular targeting
title_full_unstemmed	Folate receptor-targeted liposomes enhanced the antitumor potency of imatinib through the combination of active targeting and molecular targeting
title_sort	folate receptor-targeted liposomes enhanced the antitumor potency of imatinib through the combination of active targeting and molecular targeting
publisher	Dove Medical Press
publishDate	2014
url	https://doaj.org/article/cc2610dc1a0e4717902ed9de144b7dc7
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Folate receptor-targeted liposomes enhanced the antitumor potency of imatinib through the combination of active targeting and molecular targeting

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