Implantable biodegradable polymers for IUdR radiosensitization of experimental human malignant glioma

Purpose: The potential of halogenated pyrimidines for the radiosensitization of human malignant gliomas remains unrealized. To assess the role of local delivery for radiosensitization, we tested a synthetic, implantablebiodegradable polymer for the controlled release of 5-iodo-2-deoxyuridine (IUdR) both in vitro and in vivo and the resultant radiosensitizationof human malignant glioma xenografts in vivo.Materials and methods: In vitro: To measure release, increasing (10%, 30%, 50%) proportions (weight/weight) of IUdR in the polyanhydride (poly(bis(p-carboxyphenoxy)-propane) (PCPP) :sebacic acid (SA) (PCPP : SA ratio 20 : 80)] polymer discs were incubated (1 ml phosphate-buffered saline, 37° C). The supernatant fractions were serially assayed using high performance liquid chromatography. To measure modulation of release,polymer discs were co-loaded with 20 Ci 5-125-iodo-2-deoxyuridine (125-IUdR) and increasing (10%, 30%, or 50%) proportions of D-glucose. To test radiosensitization, cells (U251 human malignant glioma) were sequentially exposed to increasing (0 or 10 M) concentrations of IUdR and increasing (0, 2.5, 5.0, or 10 Gy) doses of acute radiation. In vivo: To measure release, PCPP : SA polymerdiscs having 200 Ci 125-IUdR were surgically placed in U251 xenografts (0.1—0.2 cc) growing in the flanksof nude mice. The flanks were reproducibly positioned over a collimated scintillation detector and counted. To measure radiosensitization, PCPP : SApolymer discs having 0% (empty) or 50% IUdR wereplaced in the tumor or contralateral flank. After five days, the tumors were acutely irradiated (500 cGy × 2 daily fractions).Results: In vitro: Intact IUdR was released from the PCPP : SA polymer discs in proportion to the percentage loading. After 4 days the cumulative percentages of loaded IUdR that were released were 43.7 $plusmn; 0.1, 70.0 ± 0.2, and 90.2 ± 0.2 (p < 0.001 ANOVA) for the 10, 30, and 50% loadings. With 0, 10, 30,or 50% D-glucose co-loading, the cumulative release of 125-IUdR from PCPP : SA polymers was 21, 70, 92, or 97%(p < 0.001), respectively, measured 26 days after incubation.IUdR radiosensitized U251 cells in vitro. Cell survival (log₁₀) was – 2.02 ± 0.02 and – 3.68± 0.11 (p < 0.001) after the 10 Gy treatment and no (control) or 10 M IUdR exposures, respectively. In vivo: 125-IUdR Release: The average counts (log₁₀ cpm ± SEM) (hours after implant) were 5.2 ± 0.05 (0.5), 4.3 ± 0.07 (17), 3.9 ± 0.08 (64), and 2.8 ± 0.06 (284). Radiosensitization: Afterintratumoral implantation of empty polymer or intratumoral 50%IUdR polymer, or implantation of 50% IUdR polymers contralateral to tumors, the average growth delays of tumors to4 times the initial volumes were 15.4 ± 1.8, 20.1 + 0.1,and 20.3 + 3.6 (mean + SEM) days, respectively (p = 0.488one-way ANOVA). After empty polymer and radiation treatments,no tumors regressed and the growth delay was 31.1 + 2.1 (p = 0.046 vs. empty polymer alone) days. After implantation of50% IUdR polymers either contralateral to the tumors orinside the tumors, followed by radiation, tumors regressed; growth delays to return to the initial average volumes of 14.0+ 3.6 or 24.2 + 0.2 (p < 0.01) days, respectively.Conclusions: Synthetic, implantable biodegradable polymers hold promise for the controlled release and local delivery ofIUdR for radiosensitization of gliomas.