Synthetic, Implantable, Biodegradable Polymers for Controlled Release of Radiosensitizers

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Abstract
Synthetic, implantable, biodegradable polymers offer the sustained local release of disparate therapeutic agents for the treatment of human malignant brain tumors. The role of polymeric devices for the local delivery of radiosensitizers remains unexplored, however. We therefore quantified the release of the representative radiosensitizers IUdR (5-iodo-2'-deoxyuridine), tirapazamine (3-amino-1,2,4-benzotriazine-1,4-dioxide) and etanidazole [N-(2-hydroxyethyl)-2-nitro-1-imidazole-1-acetamide] from the [(poly(bis(p-carboxyphenoxy)-propane) (PCPP):sebacic acid (SA) (PCPP:SA ratio 20:80)] polymer.For measurements of controlled release, triplicate polymer discs were incubated for known intervals in 2 ml 0.1 phosphate-buffered saline, pH 7.4, 37 degrees C. Using a predefined schedule, the supernatant fractions were systematically removed and replaced with fresh solution. The supernatant fractions were measured. The cumulative percentage of the loaded drug that appeared in these serial supernatant fractions was plotted vs. time. The percentage of the drug that was loaded into each polymer and that was released vs. time was fit to the power function of the form y = (a) x tb, where y is the cumulative released agent, a and b are constants and t is time (days).The IUdR was released over an interval of approximately one week, while the release of the tirapazimine persisted for over 100 days. The etanidazole was released most rapidly, over a period of hours. Modeling of release showed that regardless of percentage loading of the drug, the monoexponential function showed high correlation of the fit of the plot of the release vs. time.These results suggest that the hydrophilicity and percentage loading of the drug predominantly determine the rate of release. Based upon these results, IUdR and tirapazamine warrant preclinical testing for radiosensitization of human malignant brain tumors via the synthetic, implantable, biodegradable polymeric devices.