PUBLICATION
Delivery of mitochondriotropic doxorubicin derivatives using self-assembling hyaluronic acid nanocarriers in doxorubicin-resistant breast cancer
- Authors
- Liu, H.N., Guo, N.N., Guo, W.W., Huang-Fu, M.Y., Vakili, M.R., Chen, J.J., Xu, W.H., Wei, Q.C., Han, M., Lavasanifar, A., Gao, J.Q.
- ID
- ZDB-PUB-180601-4
- Date
- 2018
- Source
- Acta Pharmacologica Sinica 39(10): 1681-1692 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Antineoplastic Agents/chemistry
- Antineoplastic Agents/therapeutic use*
- Apoptosis/drug effects
- Breast Neoplasms/drug therapy*
- Doxorubicin/chemistry
- Doxorubicin/therapeutic use*
- Drug Carriers/chemistry*
- Drug Liberation
- Drug Resistance, Neoplasm/drug effects
- Female
- Humans
- Hyaluronic Acid/chemistry*
- MCF-7 Cells
- Membrane Potential, Mitochondrial/drug effects
- Mice, Inbred BALB C
- Mice, Nude
- Mitochondria/metabolism*
- Onium Compounds/chemistry
- Organophosphorus Compounds/chemistry
- Zebrafish
- PubMed
- 29849132 Full text @ Acta Pharmacol. Sin.
Citation
Liu, H.N., Guo, N.N., Guo, W.W., Huang-Fu, M.Y., Vakili, M.R., Chen, J.J., Xu, W.H., Wei, Q.C., Han, M., Lavasanifar, A., Gao, J.Q. (2018) Delivery of mitochondriotropic doxorubicin derivatives using self-assembling hyaluronic acid nanocarriers in doxorubicin-resistant breast cancer. Acta Pharmacologica Sinica. 39(10):1681-1692.
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.
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Human Disease / Model
Sequence Targeting Reagents
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Orthology
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