): Malignant gliomas (MG) are refractory to intensive treatments including surgery, radiation, and chemotherapy. In vitro, 5-iodo-2'-deoxyuridine (IUdR) markedly sensitizes MG to radiation. Systemic administration, however, causes high toxicity, low incorporation and resultant failure of radiosensitization. Synthetic, implantable biodegradable polymers (p-carboxyphenoxypropane (PCPP) : sebacic acid (SA) (PCPP:SA) offer sustained, controlled, local delivery of drugs to human MG. The goal of this project is to measure the release of IUdR from polymers, the delivery of the IUdR to U251 MG xenografts and the polymer-mediated radiosensitization and radionuclide therapy using unlabeled and 125-I radiolabeled IUdR, respectively.
The specific aims are:
Aim #1.) To measure the release of IUdR from the PCPP:SA polymers in vitro and the incorporation in vivo when implanted in U251 MG xenografts. The investigators will test the hypotheses that the ratios of PCPP to SA and the percentages of loading with IUdR or of co-loading with the hydrophilic D-glucose modulate the rates of release of IUdR in vitro. They will test the hypothesis that local diffusion from polymers causes high uptake of IUdR in U251 xenografts.
Aim #2.) To measure the radiosensitization of U251 MG xenografts after IUdR polymer and fractionated external beam radiotherapy. The investigators will test the hypothesis that the complementarity of the rate and uniformity of the release of IUdR from polymers and the cellular growth kinetics determine incorporation and radiosensitivity.
Aim #3.) To quantitate local 125-IUdR delivery, dosimetry, and therapy of U251 MG xenografts in vivo using biodegradable polymers. They will test the hypothesis that local diffusion of 125-IUdR will cause high dose deposition in the treated xenografts. They will achieve Aim #1 by loading PCPP:SA polymers having increasing (20, 40, 60, or 80%) proportions of SA with increasing (5, 10, 20, 40, 60, 80%) proportions of IUdR, incubating polymers in phosphate-buffered saline, and measuring release using high performance liquid chromatography. To quantify uptake of IUdR as functions of the regional S, G2/M and G1 durations they will use anti-IUdR monoclonal antibodies and fluorescence-activated cell sorting. The investigators will achieve Aim #2 using fractionated external beam irradiation of xenografts bearing the IUdR polymers developed in Aim #1. They will optimize the radiation schedules using the kinetic data obtained in Aim #1. They will achieve Aim #3 using PCPP:SA polymers bearing increasing activities (uCi) of 125-I radiolabeled IUdR. Based upon the specific release kinetic and cellular uptake data learned in Aims #1 and #2, they will optimize 125-IUdR radionuclide therapy of both intracerebral and flank U251 xenografts. If successful, these studies will lead to an important new method of treatment for human MG. The results could provide the rationales for the selective radiosensitization and radionuclide therapy of human MG using implantable, biodegradable polymers.
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