Synthetic, Implantable Polymers for IUdR Radiosensitization of Experimental Human Malignant Glioma

Abstract

Recently, polymeric controlled delivery of chemotherapy has been shown to improve survival of patients with malignant glioma. We tested the delivery of IUdR via polymers for radiosensitization of experimental intracranial human malignant glioma. To assess efficacy, we measured the in vitro release, the in vivo delivery of IUdR and the resultant radiosensitization of experimental human U251 glioblastoma xenografts. In vitro: To measure release, increasing (10%, 30%, 50%) proportions of IUdR in synthetic [(poly(bis(p-carboxyphenoxy)-propane) (PCPP):sebacic acid (SA) polymer discs were serially incubated in buffered saline and the supernatant fractions were assayed. In vivo: To compare local vs. systemic delivery, mice bearing flank xenografts had intratumoral or contralateral flank IUdR polymer (50% loading) treatments. Mice bearing intracranial (i.c.) xenografts had i.c. vs. flank IUdR polymer treatments. Four or 8 days after implantation of polymers, mice were sacrificed and the percentage tumor cells that were labeled with IUdR was measured using quantitative microscopic immunohistochemistry. For comparisons of radiosensitization, mice bearing i.c. xenografts had i.c. vs. flank IUdR polymers and cranial fractionated external beam irradiation (2 Gy BID x 4 days). 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% loadings, respectively. In vivo: For the flank tumors, both the ipsilateral and contralateral IUdR polymers resulted in similarly high percentages labeling of the tumors vs. time. For the ipsilateral IUdR polymers, the percentages of tumor cellular labeling after 4 vs. 8 days were 45.8 +/- 7.0 vs. 40.6 +/- 3.9 (p = NS. For the contralateral polymer implants, the percentages tumor cellular labeling were 43.9 +/- 10.1 vs. 35.9 +/- 5.2 (p = NS) measured 4 vs. 8 days after implantation. For the i.c. tumors treated with extracranial IUdR polymers, the percentages of tumor cellular labeling were 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 percentages labeling were 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 percentage cellular labeling vs. distance from the implanted IUdR polymer showed labeling was highest closest to the polymer disc. Radiosensitization: For mice bearing i.c. tumors and receiving flank vs. intracranial IUdR polymer treatments, the survival after external beam irradiation was significantly higher for the intracranial treatments: 49 + 8.9 vs. 80 + 4.1 (p = 0.03) days, respectively. Implantable biodegradable polymers provide the local, controlled release of IUdR and result in the high, local delivery of IUdR to experimental intracranial human malignant glioma. The local delivery and labeling result in improved survival following radiotherapy. This technique holds promise for the local delivery of IUdR for radiosensitization of human brain tumors.