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

• Published in: Chemical biology & drug design 2014-06, Vol.83 (6), p.741-752
• Main Authors: Goodarzi, Navid, Ghahremani, Mohammad H., Amini, Mohsen, Atyabi, Fatemeh, Ostad, Seyed N., Shabani Ravari, Nazanin, Nateghian, Navid, Dinarvand, Rassoul
• Format: Article
• Language: English
• Subjects: Breast Neoplasms - drug therapy; cancer stem cells; Cell Line, Tumor; conjugation; Drug Delivery Systems; Female; Humans; Hyaluronan Receptors - metabolism; Hyaluronic Acid - chemistry; macromolecular drug delivery; polysaccharides; prodrugs; Solubility; Taxoids - chemistry; Taxoids - therapeutic use; Water - chemistry
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.12288

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. Targeting the cancer stem cells (CSCs) is proposed as novel treatment modality in cancer chemotherapy to prohibit the risk of disease relapse. The study exploits novel docetaxel–macromolecular conjugates, which is prepared using hyaluronic acid and is targeted to breast cancer cells and breast CSCs via CD44 receptor. The conjugates enable preferential anticancer activity on CD44‐overexpressing cells in vitro and in vivo.