A Carrier-Free Folate Receptor-Targeted Ursolic Acid/Methotrexate Nanodelivery System for Synergetic Anticancer Therapy

Jin-Shuai Lan,1,2,* Yan-Hong Qin,2,* Li Liu,2 Rui-Feng Zeng,2 Yang Yang,3 Kai Wang,3 Yue Ding,1,2 Tong Zhang,1,2 Rodney JY Ho4 1Experiment Center of Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 2School of Pharmacy...

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Autores principales: Lan JS, Qin YH, Liu L, Zeng RF, Yang Y, Wang K, Ding Y, Zhang T, Ho RJY
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Publicado: Dove Medical Press 2021
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spelling oai:doaj.org-article:ed6dec3bdcab443696fd69fb0fc9b8ed2021-12-02T14:41:27ZA Carrier-Free Folate Receptor-Targeted Ursolic Acid/Methotrexate Nanodelivery System for Synergetic Anticancer Therapy1178-2013https://doaj.org/article/ed6dec3bdcab443696fd69fb0fc9b8ed2021-03-01T00:00:00Zhttps://www.dovepress.com/a-carrier-free-folate-receptor-targeted-ursolic-acidmethotrexate-nanod-peer-reviewed-article-IJNhttps://doaj.org/toc/1178-2013Jin-Shuai Lan,1,2,* Yan-Hong Qin,2,* Li Liu,2 Rui-Feng Zeng,2 Yang Yang,3 Kai Wang,3 Yue Ding,1,2 Tong Zhang,1,2 Rodney JY Ho4 1Experiment Center of Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 2School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 3Science and Technology Experimental Center, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 4Department of Pharmaceutics, University of Washington, Seattle, WA, 98195, USA*These authors contributed equally to this workCorrespondence: Tong Zhang; Yue DingExperiment Centre of Teaching and Learning, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Pudong New District, Shanghai, 201203, People’s Republic of ChinaTel +86 21 5132 2318; Tel +86 21 5132 2325Email zhangtongshutcm@hotmail.com; dingyue1640@shutcm.edu.cnPurpose: To avoid undefined metabolic mechanisms and to eliminate potential side effects of traditional nanocarriers, new green carriers are urgently needed in cancer treatment. Carrier-free nanoparticles (NPs) based on ursolic acid (UA) have attracted significant attention, but the UA NPs targeting the folate receptor have never been explored. We designed a novel self-assembled UA-Methotrexate (MTX) NPs targeting the folate-receptor and its synergetic anticancer activity was studied in vitro and in vivo.Methods: UA-MTX NPs were prepared using the solvent precipitation method. Characterization of the UA-MTX NPs preparation was performed using a size analyzer, transmission electron microscopy, and UV-vis spectrophotometry. The in vitro pH-responsive drug release capability of UA-MTX NPs was tested at different pH values. The UA-MTX NPs targeting of folates was determined by comparing the endocytosis rates of cell lines with low or overexpression of the folate receptor (A549 and MCF-7 cells). The cytotoxicity and cell apoptosis of UA-MTX NPs were also studied to determine the in vitro synergistic effects. Combination chemotherapy of UA-MTX NPs in vivo was evaluated using MCF-7 xenografted tumor models.Results: Compared with free UA or MTX, the water solubility of UA-MTX NPs improved significantly. Drug-release from the UA-MTX NPs was faster at pH 5.0 than pH 7.4, suggesting MTX-UA NPs could rapidly release MTX in the acidic conditions of the tumor microenvironment. Confocal laser scanning microscopy revealed the excellent folate receptor targeting of UA-MTX NPs in MCF-7 cells. Cytotoxicity and cell apoptosis results demonstrated greater antiproliferative capacity of UA-MTX NPs than that of free drug in folate receptor overexpressing MCF-7 cells. Anticancer effects in vivo suggested MTX-UA NPs exhibited good biological safety and could enhance antitumor efficacy due to the combination therapy.Conclusion: Our findings indicate that the UA-MTX NPs targeting folate-receptors is an efficient strategy for combination chemotherapy.Keywords: ursolic acid, methotrexate, anticancer, carrier free, targeted drug deliveryLan JSQin YHLiu LZeng RFYang YWang KDing YZhang THo RJYDove Medical Pressarticleursolic acidmethotrexateanticancercarrier freetargeted drug deliveryMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol Volume 16, Pp 1775-1787 (2021)
institution DOAJ
collection DOAJ
language EN
topic ursolic acid
methotrexate
anticancer
carrier free
targeted drug delivery
Medicine (General)
R5-920
spellingShingle ursolic acid
methotrexate
anticancer
carrier free
targeted drug delivery
Medicine (General)
R5-920
Lan JS
Qin YH
Liu L
Zeng RF
Yang Y
Wang K
Ding Y
Zhang T
Ho RJY
A Carrier-Free Folate Receptor-Targeted Ursolic Acid/Methotrexate Nanodelivery System for Synergetic Anticancer Therapy
description Jin-Shuai Lan,1,2,* Yan-Hong Qin,2,* Li Liu,2 Rui-Feng Zeng,2 Yang Yang,3 Kai Wang,3 Yue Ding,1,2 Tong Zhang,1,2 Rodney JY Ho4 1Experiment Center of Teaching and Learning, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 2School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 3Science and Technology Experimental Center, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China; 4Department of Pharmaceutics, University of Washington, Seattle, WA, 98195, USA*These authors contributed equally to this workCorrespondence: Tong Zhang; Yue DingExperiment Centre of Teaching and Learning, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Pudong New District, Shanghai, 201203, People’s Republic of ChinaTel +86 21 5132 2318; Tel +86 21 5132 2325Email zhangtongshutcm@hotmail.com; dingyue1640@shutcm.edu.cnPurpose: To avoid undefined metabolic mechanisms and to eliminate potential side effects of traditional nanocarriers, new green carriers are urgently needed in cancer treatment. Carrier-free nanoparticles (NPs) based on ursolic acid (UA) have attracted significant attention, but the UA NPs targeting the folate receptor have never been explored. We designed a novel self-assembled UA-Methotrexate (MTX) NPs targeting the folate-receptor and its synergetic anticancer activity was studied in vitro and in vivo.Methods: UA-MTX NPs were prepared using the solvent precipitation method. Characterization of the UA-MTX NPs preparation was performed using a size analyzer, transmission electron microscopy, and UV-vis spectrophotometry. The in vitro pH-responsive drug release capability of UA-MTX NPs was tested at different pH values. The UA-MTX NPs targeting of folates was determined by comparing the endocytosis rates of cell lines with low or overexpression of the folate receptor (A549 and MCF-7 cells). The cytotoxicity and cell apoptosis of UA-MTX NPs were also studied to determine the in vitro synergistic effects. Combination chemotherapy of UA-MTX NPs in vivo was evaluated using MCF-7 xenografted tumor models.Results: Compared with free UA or MTX, the water solubility of UA-MTX NPs improved significantly. Drug-release from the UA-MTX NPs was faster at pH 5.0 than pH 7.4, suggesting MTX-UA NPs could rapidly release MTX in the acidic conditions of the tumor microenvironment. Confocal laser scanning microscopy revealed the excellent folate receptor targeting of UA-MTX NPs in MCF-7 cells. Cytotoxicity and cell apoptosis results demonstrated greater antiproliferative capacity of UA-MTX NPs than that of free drug in folate receptor overexpressing MCF-7 cells. Anticancer effects in vivo suggested MTX-UA NPs exhibited good biological safety and could enhance antitumor efficacy due to the combination therapy.Conclusion: Our findings indicate that the UA-MTX NPs targeting folate-receptors is an efficient strategy for combination chemotherapy.Keywords: ursolic acid, methotrexate, anticancer, carrier free, targeted drug delivery
format article
author Lan JS
Qin YH
Liu L
Zeng RF
Yang Y
Wang K
Ding Y
Zhang T
Ho RJY
author_facet Lan JS
Qin YH
Liu L
Zeng RF
Yang Y
Wang K
Ding Y
Zhang T
Ho RJY
author_sort Lan JS
title A Carrier-Free Folate Receptor-Targeted Ursolic Acid/Methotrexate Nanodelivery System for Synergetic Anticancer Therapy
title_short A Carrier-Free Folate Receptor-Targeted Ursolic Acid/Methotrexate Nanodelivery System for Synergetic Anticancer Therapy
title_full A Carrier-Free Folate Receptor-Targeted Ursolic Acid/Methotrexate Nanodelivery System for Synergetic Anticancer Therapy
title_fullStr A Carrier-Free Folate Receptor-Targeted Ursolic Acid/Methotrexate Nanodelivery System for Synergetic Anticancer Therapy
title_full_unstemmed A Carrier-Free Folate Receptor-Targeted Ursolic Acid/Methotrexate Nanodelivery System for Synergetic Anticancer Therapy
title_sort carrier-free folate receptor-targeted ursolic acid/methotrexate nanodelivery system for synergetic anticancer therapy
publisher Dove Medical Press
publishDate 2021
url https://doaj.org/article/ed6dec3bdcab443696fd69fb0fc9b8ed
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