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Discovery Research Oncology [M. Z., M. F., A. F., E. P., A. S.] and Global Drug Metabolism Research [A. G., M. G. C., E. F., R. d.], Pharmacia Corporation, 20014 Nerviano (MI), Italy; ISS, Champaign, Illinois 61822 [M. v.]; Laboratory for Fluorescence Dynamics, University of Illinois, Urbana-Champaign, Illinois 61801 [E. G.]; and Fondazione Centro San Raffaele, Scientific Institute, 20132 Milan, Italy [V. R. C.]

2 To whom requests for reprints should be addressed, at Discovery Research Oncology, Pharmacia Corp., V.le Pasteur 10, 20014 Nerviano (MI), Italy. Phone: 39-0248385318; Fax: 3-0248383750; E-mail: moreno.zamai{at}Pharmacia.com (to M. Z.) and Fondazione Centro San Raffaele, DIBIT Scientific Institute, Via Olgettina 58, 4A1 20132 Milan, Italy. Phone: 39-0226434780; Fax: 39-0226434861; E-mail: valeria.caiolfa{at}hsr.it (to V. R. C.)

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 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.

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