Cellular uptake and internalization of hyaluronan-based doxorubicin and cisplatin conjugates. (August 2014)

• Record Type: Journal Article
• Authors: Cai, Shuang; Alhowyan, Adel Ali B.; Yang, Qiuhong; Forrest, W. C. Melanie; Shnayder, Yelizaveta; Forrest, M. Laird
• Is Part Of: Journal of drug targeting. Volume 22:Number 7(2014)
• Page Start: 648
• Page End: 657
• Publication Date: 2014-08
• Subjects: Drug delivery systems -- Periodicals; Drug Delivery Systems; Vehicles; Drug Administration Routes; Drug Evaluation; 615.7
• DOI: 10.3109/1061186X.2014.921924
• Languages: English
• ISSNs: 1061-186X

Abstract

<abstract> <title>Abstract</title> <p> <italic>Background</italic>: 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.</p> <p> <italic>Purpose</italic>: 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.</p> <p> <italic>Methods</italic>: 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 <italic>in vitro</italic>.</p> <p> <italic>Results</italic>: Cellular internalization of HA was regulated by CD44 receptors. In mouse xenografts, HA conjugation significantly enhanced tumor cell uptake compared to unconjugated drugs.</p> <p> <italic>Discussion</italic>: 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.</p> <p> <italic>Conclusions</italic>: HA conjugation significantly increased CD44-mediated drug uptake and extended the residence time of drugs in tumor cells.</p> </abstract>