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

Acta Pharmacologica Sinica
Hui-Na LiuJian-Qing Gao

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...Continue Reading

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Citations

Mar 5, 2020·Angewandte Chemie·Si Si LiewShao Q Yao
Mar 1, 2019·International Journal of Molecular Sciences·Safia NazJinghua Chen
Oct 23, 2019·Pharmaceutics·Okhil K Nag, James B Delehanty
Jan 15, 2021·Journal of Materials Chemistry. B, Materials for Biology and Medicine·Jiatao YangZhou Zhou
May 21, 2020·Current Drug Metabolism·Abu BakerMohd Sajid Khan
Jul 1, 2021·Life Sciences·Shalini ManiKeshav K Singh
Jan 31, 2019·Molecular Pharmaceutics·Fakhrossadat EmamiSimmyung Yook
Sep 7, 2021·International Journal of Pharmaceutics·Jiatao YangZhou Zhou

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Methods Mentioned

BETA
xenograft
nuclear magnetic resonance
NMR
transmission electron microscopy
confocal microscopy
Assay
flow cytometry
fluorescence microscopy
transgenic
nuclear magnetic

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