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Acta Pharmacol Sin. 2018 Oct;39(10):1681-1692. doi: 10.1038/aps.2018.9. Epub 2018 May 31.

Delivery of mitochondriotropic doxorubicin derivatives using self-assembling hyaluronic acid nanocarriers in doxorubicin-resistant breast cancer.

Author information

1
Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
2
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, T6G 2E1, Alberta, Canada.
3
Department of Radiation Oncology, Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, the Second Affiliated Hospital, Zhejiang University, College of Medicine, Hangzhou, 310058, China.
4
Institute of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China. hanmin@zju.edu.cn.
5
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, T6G 2E1, Alberta, Canada. afsaneh@ualberta.ca.

Abstract

Breast cancer is the leading cause of cancer-related death for women, and multidrug resistance (MDR) is the major obstacle faced by chemotherapy for breast cancer. We have previously synthesized a doxorubicin (DOX) derivative by conjugating DOX with triphenylphosphonium (TPP) to achieve mitochondrial delivery, which induced higher cytotoxicity in drug-resistant breast cancer cells than DOX itself. Due to its amphiphilicity, TPP-DOX is difficult to physically entrap in nanocarriers. Thus, we linked it to hyaluronic acid (HA) by a novel ionic bond utilizing the specific bromide ion of TPP to form supra-molecular self-assembled structures (HA-ionic-TPP-DOX). The product was analyzed uisng 1H-NMR, 13C-NMR and mass spectrometry. The HA nanocarriers (HA-ionic-TPP-DOX) were shown to self-assemble into spherical nanoparticles, and sensitive to acidic pH in terms of morphology and drug release. Compared with free DOX, HA-ionic-TPP-DOX produced much greater intracellular DOX accumulation and mitochondrial localization, leading to increased ROS production, slightly decreased mitochondrial membrane potential, increased cytotoxicity in MCF-7/ADR cells and enhanced tumor targeting in vivo. In xenotransplant zebrafish model with the MCF-7/ADR cell line, both TPP-DOX and HA-ionic-TPP-DOX inhibited tumor cell proliferation without inducing significant side effects compared with free DOX. In addition, we observed a better anti-tumor effect of HA-ionic-TPP-DOX on MCF-7/ADR cells in zebrafish than that of TPP-DOX treatment. Furthermore, HA-ionic-DOX-TPP exhibited favorable biocompatibility and anti-tumor effects in MCF-7/ADR tumor-bearing nude mice in comparison with the effects of TPP-DOX and DOX, suggesting the potential of HA-ionic-TPP-DOX for the targeted delivery and controlled release of TPP-DOX, which can lead to the sensitization of resistant breast tumors.

KEYWORDS:

TPP-DOX; breast cancer; doxorubicin; drug resistance; hyaluronic acid; ionic bond; mitochondrial target; nanocarriersl zebrafish

PMID:
29849132
PMCID:
PMC6289358
[Available on 2019-10-01]
DOI:
10.1038/aps.2018.9
[Indexed for MEDLINE]

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