SYNTHETIC, IMPLANTABLE POLYMERS FOR LOCAL-DELIVERY OF IUDR TO EXPERIMENTAL HUMAN-MALIGNANT GLIOMA

Purpose: Recently, polymeric controlled delivery of chemotherapy has b een shown to improve survival of patients with malignant glioma. We ev aluated whether we could similarly deliver halogenated pyrimidines to experimental intracranial human malignant glioma. To address this issu e we studied the irt vitro release from polymers and the in vivo drug delivery of IUdR to experimental human U251 glioblastoma xenografts. M ethods and Materials: In vitro: To measure release, increasing (10%, 3 0%, 50%) proportions of IUdR in synthetic [(poly(bis(p-carboxyphenoxy) -propane) (PCPP):sebacic acid (SA) polymer discs were serially incubat ed in buffered saline and the supernatant fractions were assayed. In v ivo: To compare local versus systemic delivery, mice bearing flank xen ografts had intratumoral or contralateral flank IUdR polymer (50% load ing) treatments. Mice bearing intracranial (i.c.) xenografts had i.c. versus flank IUdR polymer treatments. Four or 8 days after implantatio n of polymers, mice were sacrificed and the percentage tumor cells tha t were labeled with IUdR was measured using quantitative microscopic i mmunohistochemistry. Results: In vitro: Increasing percentage loadings of IUdR resulted in higher percentages of release: 43.7 + 0.1, 70.0 0.2, and 90.2 + 0.2 (p < 0.001 ANOVA) for the 10%, 30%, and 50% loadi ngs, respectively. In vivo: For the flank tumors, both the ipsilateral and contralateral IUdR polymers resulted in similarly high percentage s labeling of the tumors versus time. For the ipsilateral IUdR polymer s, the percentage of tumor cellular labeling after 4 days versus 8 day s was 45.8 +/- 7.0 versus 40.6 +/- 3.9 (p = NS). For the contralateral polymer implants, the percentage of tumor cellular labeling were 43.9 +/- 10.1 versus 35.9 +/- 5.2 (p = NS) measured 4 days versus 8 days a fter implantation. For the i.c. tumors treated with extracranial IUdR polymers, the percentage of tumor cellular labeling was low: 13.9 +/- 8.8 and 11.2 +/- 5.7 measured 4 and 8 days after implantation. For the i.c. tumors having the i.c. IUdR polymers, however, the percentage la beling was comparatively much higher: 34.3 +/- 4.9 and 35.3 +/- 4.0 on days 4 and 8, respectively. For the i.c. tumors, examination of the p ercentage cellular labeling versus distance from the implanted IUdR po lymer showed that labeling was highest closest to the polymer disc. Co nclusion: Synthetic, implantable biodegradable polymers provide the lo cal, controlled release of IUdR and result in the high, local delivery of IUdR to experimental intracranial human malignant glioma. This tec hnique holds promise for the local delivery of IUdR for radiosensitiza tion of human brain tumors. (C) 1998 Elsevier Science Inc.