title: Cellular uptake and internalization of hyaluronan-based doxorubicin and cisplatin conjugates.
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.
  
  
  OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.affiliation: Department of Pharmaceutical Chemistry, University of Kansas , Lawrence, KS , USA .
authors.forename: Shuang
authors.initials: S
authors.lastname: Cai
authors.forename: Adel Ali B
authors.initials: AA
authors.lastname: Alhowyan
authors.forename: Qiuhong
authors.initials: Q
authors.lastname: Yang
authors.forename: W C Melanie
authors.initials: WC
authors.lastname: Forrest
authors.forename: Yelizaveta
authors.initials: Y
authors.lastname: Shnayder
authors.forename: M Laird
authors.initials: ML
authors.lastname: Forrest
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D004317:Doxorubicin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D004337:Drug Carriers / Q000737:chemistry*; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000737:chemistry*; D008024:Ligands; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D015394:Molecular Structure; D058726:Nanoconjugates / Q000737:chemistry*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D018960:Hyaluronan Receptors; D008024:Ligands; D058726:Nanoconjugates; D004317:Doxorubicin; D006820:Hyaluronic Acid; D002945:Cisplatin
keywords: CD44 receptors; cisplatin; doxorubicin; hyaluronan; internalization mechanism