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

Authors Lan JS, Qin YH, Liu L, Zeng RF, Yang Y, Wang K, Ding Y, Zhang T, Ho RJY

Received 29 October 2020

Accepted for publication 22 January 2021

Published 3 March 2021 Volume 2021:16 Pages 1775—1787

DOI https://doi.org/10.2147/IJN.S287806

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3

Editor who approved publication: Prof. Dr. Thomas J. Webster


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 work

Correspondence: Tong Zhang; Yue Ding
Experiment Centre of Teaching and Learning, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Pudong New District, Shanghai, 201203, People’s Republic of China
Tel +86 21 5132 2318
; Tel +86 21 5132 2325
Email [email protected]; [email protected]

Purpose: 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

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