title: Hyaluronan oligomers-HPMA copolymer conjugates for targeting paclitaxel to CD44-overexpressing ovarian carcinoma.
abstract: OBJECTIVE
  To evaluate the effect of the size of low molecular weight hyaluronan (LMW-HA) oligomers on the targeting ability of the HA-containing copolymers to the CD44-overexpressing cells for delivering Paclitaxel (PTX) to ovarian cancer.
  
  
  METHODS
  LMW-HA oligosaccharides of 4, 6, 8, 10, 12 and 14 sugar residues were attained by digestion of HMW-HA using hyaluronate lyase at different incubation times and then attached to FITC-labeled HPMA copolymer precursor. The binding and uptake of the HA-modified HPMA-copolymer into CD44-expressing cells was studied by flow cytometry and confocal microscopy. PTX was further attached to HPMA-copolymer precursor bearing HA oligosaccharide at the size of 34 monosaccharides, through an acid-sensitive hydrazone linker. The cytotoxicity of the polymer was tested using cell viability assay.
  
  
  RESULTS
  Polymer conjugates bearing HA oligomers at the size of 10 oligosaccharides and above (HA(10-14)) bind actively and profoundly to CD44-overexpressing ovarian cancer cells (SK-OV-3) and internalize to the greatest extent relative to HA-polymer conjugates of 8 oligomers and below (HA(4-8)). The HA-modified HPMA-copolymer PTX conjugate (P-(HA)(34)-PTX) exhibited 50-times higher cytotoxicity towards CD44-overexpressing cells relative to the control, non-targeted, HPMA-copolymer PTX conjugate (P-PTX).
  
  
  CONCLUSIONS
  P-(HA)(34)-PTX was significantly more toxic than the non-targeted P-PTX in cells expressing high levels of CD44.
authors.affiliation: Department of Pharmacology, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, 84105, Israel.
authors.forename: Gal
authors.initials: G
authors.lastname: Journo-Gershfeld
authors.forename: Dana
authors.initials: D
authors.lastname: Kapp
authors.forename: Yosi
authors.initials: Y
authors.lastname: Shamay
authors.forename: Jindřich
authors.initials: J
authors.lastname: Kopeček
authors.forename: Ayelet
authors.initials: A
authors.lastname: David
mesh_terms: D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000096:biosynthesis* / Q000235:genetics; D006820:Hyaluronic Acid / Q000008:administration & dosage* / Q000737:chemistry*; D008297:Male; D009844:Oligosaccharides / Q000008:administration & dosage / Q000737:chemistry; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage* / Q000737:chemistry*; D011108:Polymers / Q000008:administration & dosage / Q000737:chemistry; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured
chemical_list: C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D009844:Oligosaccharides; D011108:Polymers; D006820:Hyaluronic Acid; D017239:Paclitaxel