Camptothecin poly[N-(2-hydroxypropyl) methacrylamide] copolymers in antitopoisomerase-I tumor therapy: Intratumor release and antitumor efficacy

Moreno Zamai, Martin VandeVen, Mariella Farao, Enrico Gratton, Alberto Ghiglieri, Maria G. Castelli, Erminia Fontana, Roland D'Argy, Antonio Fiorino, Enrico Pesenti, Antonino Suarato, Valeria R. Caiolfa

Research output: Contribution to journalArticle

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 timeresolved 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 3H-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 pHPMA-Gly-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.

Original languageEnglish
Pages (from-to)29-40
Number of pages12
JournalMolecular Cancer Therapeutics
Volume2
Issue number1
Publication statusPublished - Jan 2003

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Drug Discovery
  • Pharmacology

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  • Cite this

    Zamai, M., VandeVen, M., Farao, M., Gratton, E., Ghiglieri, A., Castelli, M. G., Fontana, E., D'Argy, R., Fiorino, A., Pesenti, E., Suarato, A., & Caiolfa, V. R. (2003). Camptothecin poly[N-(2-hydroxypropyl) methacrylamide] copolymers in antitopoisomerase-I tumor therapy: Intratumor release and antitumor efficacy. Molecular Cancer Therapeutics, 2(1), 29-40.