CD44-Targeted Docetaxel Conjugate for Cancer Cells and Cancer Stem-Like Cells: A Novel Hyaluronic Acid-Based Drug Delivery System

Authors

  • Navid Goodarzi,

    1. Nanomedicine and Biomaterial Lab, Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
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  • Mohammad H. Ghahremani,

    1. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
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  • Mohsen Amini,

    1. Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
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  • Fatemeh Atyabi,

    1. Nanomedicine and Biomaterial Lab, Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
    2. Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
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  • Seyed N. Ostad,

    1. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
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  • Nazanin Shabani Ravari,

    1. Nanomedicine and Biomaterial Lab, Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
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  • Navid Nateghian,

    1. Nanomedicine and Biomaterial Lab, Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
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  • Rassoul Dinarvand

    Corresponding author
    1. Nanomedicine and Biomaterial Lab, Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
    2. Nanotechnology Research Centre, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
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Abstract

A CD44-targeted macromolecular conjugate of docetaxel was prepared via a pH-sensitive linkage to hyaluronic acid and was characterized using NMR, gel permeation chromatography, and differential scanning calorimetry. The conjugated species were further evaluated in terms of drug release, cytotoxicity, cellular uptake, cell cycle inhibition, and subacute toxicity in mice. Cellular microscopic studies revealed that CD44-expressing cells including MCF-7 cancer stem cells and MDA-MB-231 metastatic breast cancer cells had internalized the conjugates via a selective receptor-mediated mechanism, leading to cell cycle arrest in the G2/M phase. Hyaluronic acid–docetaxel conjugates showed specific toxicity only in CD44-expressing cells in vitro, along with a decreased risk of neutropenia and dose-dependent mortality in vivo. Hyaluronic acid–drug conjugates represent a promising and efficient platform for solubilization of sparingly soluble molecules as well as active and selective targeted delivery to cancer cells and cancer stem cells.

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