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A smart pH-responsive nano-carrier as a drug delivery system for targeted delivery of ursolic acid: suppresses cancer growth and metastasis by modulating P53/MMP-9/PTEN/CD44 mediated multiple signaling pathways

Abstract

Ursolic acid (UA) has been recently used as a promising anti-tumor and cancer metastatic chemo-preventive agent due to its low toxicity and liver-protecting property. However, the low bioavailability and nonspecific tumor targeting restrict its further clinical application. To address the problem, a silica-based mesoporous nanosphere (MSN) controlled-release drug delivery system (denoted as UA@M-CS-FA) was designed and successfully synthesized, which was functionalized with folic acid (FA) and pH-sensitive chitosan (CS) for targeted delivery of UA to folate receptor (FR) positive tumor cells. UA@M-CS-FA were spherical with mean diameter below 150 nm, and showed about -20 mV potential. Meanwhile, UA@M-CS-FA exhibited a pH-sensitive release manner and high cellular uptake in FR over-expressing HeLa cancer cells. Also, in vitro cellular assays suggested that UA@M-CS-FA inhibited cancer cells growth, invasion and migration. Mechanistically, UA@M-CS-FA induced cancer cells apoptosis and inhibited migration via cell cycle arrest in G0/G1 stage, regulating the PARP/Bcl-2/MMP-9/CD44/PTEN/P53. Importantly, in vivo experiments further confirmed that UA@M-CS-FA significantly suppressed the tumor progression and lung metastasis in tumor-bearing nude mice. Immunohistochemical analysis revealed that UA@M-CS-FA treatment regulated CD44, a biomarker of cancer metastasis. Overall, our data demonstrated that CS and FA modified MSN controlled-release drug delivery system could help broaden the usage of UA and reflect the great application potential of the UA as an anticancer or cancer metastatic chempreventive agent.

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Publication details

The article was received on 10 Mar 2017, accepted on 04 Jun 2017 and first published on 07 Jun 2017


Article type: Paper
DOI: 10.1039/C7NR01677H
Citation: Nanoscale, 2017, Accepted Manuscript
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    A smart pH-responsive nano-carrier as a drug delivery system for targeted delivery of ursolic acid: suppresses cancer growth and metastasis by modulating P53/MMP-9/PTEN/CD44 mediated multiple signaling pathways

    K. Jiang, T. Chi, T. Li, G. Zheng, L. Fan, Y. Liu, X. Chen, S. Chen, L. Jia and J. Shao, Nanoscale, 2017, Accepted Manuscript , DOI: 10.1039/C7NR01677H

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