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Cellular Uptake and Internalization of Hyaluronan-based Doxorubicin and Cisplatin Conjugates
Cai, Shuang Alhowyan, Adel Ali B. Yang, Qiuhong Forrest, W. C. Melanie Shnayder, Yelizaveta Forrest, M. Laird
Cai, Shuang
Alhowyan, Adel Ali B.
Yang, Qiuhong
Forrest, W. C. Melanie
Shnayder, Yelizaveta
Forrest, M. Laird
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Abstract
Background
Hyaluronan (HA) is a ligand for the CD44 receptor which is crucial to cancer cell proliferation and metastasis. High levels of CD44 expression in many cancers have encouraged the development of HA-based carriers for anti-cancer therapeutics.
Purpose
The objective of this study was to determine whether HA conjugation of anticancer drugs impacts CD44-specific HA-drug uptake and disposition by human head and neck cancer cells.
Methods
The internalization and cellular disposition of hyaluronan-doxorubicin (HA-DOX), hyaluronan-cisplatin (HA-Pt), and hyaluronan-cyanine7 (HA-Cy7) conjugates were investigated by inhibiting endocytosis pathways, and by inhibiting the CD44–mediated internalization pathways that are known to mediate hyaluronan uptake in vitro.
Results
Cellular internalization of HA was regulated by CD44 receptors. In mouse xenografts, HA conjugation significantly enhanced tumor cell uptake compared to unconjugated drug.
Discussion
The results suggested that the main mechanism of HA-based conjugate uptake may be active transport via CD44 in conjunction with a clathrin–dependent endocytic pathway. Other HA receptors, hyaluronan–mediated motility receptor (RHAMM) and lymphatic vessel endothelial hyaluronan receptor (LYVE-1), did not play a significant role in conjugate uptake.
Conclusions
HA conjugation significantly increased CD44 mediated drug uptake and extended the residence time of drugs in tumor cells.
Description
Date
2014-06-03
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Publisher
Informa Healthcare
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Keywords
Hyaluronan, Doxorubicin, Cisplatin, Internalization mechanism, CD44 receptors
Citation
Cai, Shuang, Adel Ali B. Alhowyan, Qiuhong Yang, W. C. Melanie Forrest, Yelizaveta Shnayder, and M. Laird Forrest. "Cellular Uptake and Internalization of Hyaluronan-based Doxorubicin and Cisplatin Conjugates." Journal of Drug Targeting 22.7 (2014): 648-57.