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Please use this identifier to cite or link to this item: http://hdl.handle.net/1942/4879

Title: Camptothecin poly[N-(2-hydroxypropyl) methacrylamide] copolymers in antitopoisomerase-1 tumor therapy: Intratumor release and antitumor efficacy
Authors: Zamai, M.
VAN DE VEN, Martin
Farao, M.
Gratton, E.
Ghiglieri, A.
Castelli, M.G.
Fontana, E.
d' Argy, R.
Fiorino, A.
Pesenti, E.
Suarato, A.
Caiolfa, V.R.
Issue Date: 2003
Citation: Molecular cancer therapeutics, 2(1). p. 29-40
Abstract: Soluble copolymers of camptothecin (CPT), based on poly[N-(2-hydroxypropyl) methacrylamide] (pHPMA), were obtained by conjugation through the degradable spacers -Gly-Phe-Leu-Gly- or -Gly-6-aminohexanoyl-Gly-. We investigated to what extent passive accumulation and retention of hydroxypropyl methacrylamide copolymer of CPT (pHPMA-CPT) in tumors and modulation of the drug release influence efficacy. Release of CPT in vivo was detected by time-resolved phase-shift fluorescence imaging on tumor specimens, based on the evidence that free and bound drug had different fluorescence lifetimes in solution. HT-29 murine specimens, obtained at several times after treatment with 3 H-labeled free CPT, pHPMA-Gly-Phe-Leu-Gly-CPT, or pHPMA-Gly-6-aminohexanoyl-Gly-CPT, were either imaged for time-resolved phase-shift fluorescence or subjected to autoradiography. Phase shifts of CPT conjugates were equal or longer than those of free CPT, indicating the presence of both free and polymer-bound drug in the tumor, in agreement with autoradiograms. pHPMA-Gly-Phe-Leu-Gly-CPT underwent relevant intratumor hydrolysis during the first 24 h, whereas the hydrolysis of pHPMA-Gly-6-aminohexanoyl-Gly-CPT was slow. The latter showed antitumor activity at doses from 10 to 22.5 mg/kg/day against s.c. HT-29, A2780, M14, and A549 s.c. xenografts. Moreover, inhibition of tumor growth lasted for up to 73-88 days, and cures were observed on mice with orthotopic implanted HT-29; pHPMA-Gly-Phe-Leu-Gly-CPT was 2-fold more potent than pHPMAGly-6-aminohexanoyl-Gly-CPT but less tolerated. Our data suggest that the efficacy of pHPMA-CPT copolymers is related to their intratumor accumulation, and in vivo properties of releasing CPT by esterolytic and proteolytic degradation.
URI: http://hdl.handle.net/1942/4879
ISI #: 000180497700004
ISSN: 1535-7163
Category: A1
Type: Journal Contribution
Appears in Collections: Research publications

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