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 drugs. 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.
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 drugs. 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.
Authors: C Mouta Carreira; S M Nasser; E di Tomaso; T P Padera; Y Boucher; S I Tomarev; R K Jain Journal: Cancer Res Date: 2001-11-15 Impact factor: 12.701
Authors: Ti Zhang; Shuang Cai; Chad Groer; Wai Chee Forrest; Qiuhong Yang; Eva Mohr; Justin Douglas; Daniel Aires; Sandra M Axiak-Bechtel; Kimberly A Selting; Jeffrey A Swarz; Deborah J Tate; Jeffrey N Bryan; M Laird Forrest Journal: J Pharm Sci Date: 2016-05-04 Impact factor: 3.534
Authors: Shuang Cai; Ti Zhang; W C Forrest; Qiuhong Yang; Chad Groer; Eva Mohr; Daniel J Aires; Sandra M Axiak-Bechtel; Brian K Flesner; Carolyn J Henry; Kimberly A Selting; Deborah Tate; Jeffrey A Swarz; Jeffrey N Bryan; M Laird Forrest Journal: Am J Vet Res Date: 2016-09 Impact factor: 1.156