Bioreducible core-crosslinked hyaluronic acid micelle for targeted cancer therapy

• Published in: Journal of controlled release Vol. 200; pp. 158 - 166
• Main Authors: Han, Hwa Seung, Choi, Ki Young, Ko, Hyewon, Jeon, Jueun, Saravanakumar, G., Suh, Yung Doug, Lee, Doo Sung, Park, Jae Hyung
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 28.02.2015
• Subjects: Animals; Antibiotics, Antineoplastic - administration & dosage; Antibiotics, Antineoplastic - chemistry; Antibiotics, Antineoplastic - pharmacokinetics; Antibiotics, Antineoplastic - therapeutic use; blood; blood flow; Cell Line, Tumor; Crosslinked nanoparticle; Doxorubicin; Doxorubicin - administration & dosage; Doxorubicin - chemistry; Doxorubicin - pharmacokinetics; Doxorubicin - therapeutic use; Drug delivery; Drug Delivery Systems; Drug Liberation; Drug Stability; glutathione; Glutathione - metabolism; Hyaluronic acid; Hyaluronic Acid - chemistry; hydrophobicity; Mice, Nude; Micelles; nanocarriers; neoplasms; Neoplasms - drug therapy; Neoplasms - metabolism; Neoplasms - pathology; Oxidation-Reduction; pharmacokinetics; Stability; Tissue Distribution; Tumor Burden - drug effects; Crosslinked nanoparticle; Drug delivery; Stability; Hyaluronic acid; Doxorubicin
• ISSN: 0168-3659; 1873-4995; 1873-4995
• DOI: 10.1016/j.jconrel.2014.12.032

For drug delivery nanocarriers to be a safe and effective therapeutic option, blood stability, tumor-targetability, and intracellular drug release features should be considered. In this study, to develop a potent drug delivery carrier that can meet the multiple requirements, we engineered a bioreducible core-crosslinked polymeric micelle based on hyaluronic acid (CC-HAM) by a facile method using d,l-dithiothreitol in aqueous conditions. The CC-HAM exhibited enhanced structural stability under diluted conditions with PBS containing FBS or sodium dodecyl sulfates. We also successfully encapsulated doxorubicin (DOX), chosen as a hydrophobic anti-cancer drug, in CC-HAMs with high loading efficiency (>80%). The drug release rate of CC-HAMs was rapidly accelerated in the presence of glutathione, whereas the drug release was significantly retarded in physiological buffer (pH7.4). An in vivo biodistribution study demonstrated the superior tumor targetability of CC-HAMs to that of non-crosslinked HAMs, primarily ascribed to robust stability of CC-HAMs in the bloodstream. Notably, these results correspond with the improved pharmacokinetics and tumor accumulation of DOX-loaded CC-HAMs as well as their excellent therapeutic efficacy. Overall, these results suggest that the robust, bioreducible CC-HAM can be applied as a potent doxorubicin delivery carrier for targeted cancer therapy. Core-crosslinked hyaluronic acid micelles can securely deliver doxorubicin into tumor cells after intravenous administration given their (i) robust blood stability, (ii) systemic accumulation, (iii) CD44-mediated cell permeation, and (iv) intracellular drug release by cleavage of the disulfide crosslinks in the micelle core. [Display omitted]