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

    54 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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