TY - JOUR
T1 - Hyaluronan oligomers-HPMA copolymer conjugates for targeting paclitaxel to CD44-overexpressing ovarian carcinoma
AU - Journo-Gershfeld, Gal
AU - Kapp, Dana
AU - Shamay, Yosi
AU - Kopeček, Jindřich
AU - David, Ayelet
N1 - Funding Information:
This study was supported by a research grant from the US−Israel Binational Science Foundation (BSF) (2007319). We thank Ms. Mazal Rubin for her valuable assistance during this project.
PY - 2012/4/1
Y1 - 2012/4/1
N2 - 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.
AB - 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.
KW - CD44
KW - HPMA copolymer-drug conjugates
KW - Hyaluronan
KW - Ovarian cancer
KW - Paclitaxel
UR - http://www.scopus.com/inward/record.url?scp=84862665043&partnerID=8YFLogxK
U2 - 10.1007/s11095-012-0672-1
DO - 10.1007/s11095-012-0672-1
M3 - Article
AN - SCOPUS:84862665043
SN - 0724-8741
VL - 29
SP - 1121
EP - 1133
JO - Pharmaceutical Research
JF - Pharmaceutical Research
IS - 4
ER -
