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 (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.
journal_name
Pharm Resjournal_title
Pharmaceutical researchauthors
Journo-Gershfeld G,Kapp D,Shamay Y,Kopeček J,David Adoi
10.1007/s11095-012-0672-1subject
Has Abstractpub_date
2012-04-01 00:00:00pages
1121-33issue
4eissn
0724-8741issn
1573-904Xjournal_volume
29pub_type
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