Hyaluronan oligomers-HPMA copolymer conjugates for targeting paclitaxel to CD44-overexpressing ovarian carcinoma

Gal Journo-Gershfeld, Dana Kapp, Yosi Shamay, Jindřich Kopeček, Ayelet David

Research output: Contribution to journalArticlepeer-review

58 Scopus citations

Abstract

Purpose: 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 (SKOV- 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.

Original languageEnglish
Pages (from-to)1121-1133
Number of pages13
JournalPharmaceutical Research
Volume29
Issue number4
DOIs
StatePublished - 1 Apr 2012

Keywords

  • CD44
  • HPMA copolymer-drug conjugates
  • Hyaluronan
  • Ovarian cancer
  • Paclitaxel

ASJC Scopus subject areas

  • Biotechnology
  • Molecular Medicine
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry
  • Pharmacology (medical)

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