POLYMERS FOR IUDR RADIOSENSITIZATION OF GLIOMA

用于神经胶质瘤 IUDR 放射增敏的聚合物

• 批准号: 2429901
• 负责人: JEFFERY A WILLIAMS
• 金额: $ 8.06万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-06-05 至 1999-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2429901
• 关键词: athymic mouse; autoradiography; biotransformation; flow cytometry; glioma; high performance liquid chromatography; human tissue; idoxuridine; iodine; monoclonal antibody; neoplasm /cancer radionuclide therapy; neoplasm /cancer transplantation; polymers; radiation therapy dosage; radionuclide implant; radionuclides; radiopharmacology; radiosensitizer; slow release drug; xenotransplantation

DESCRIPTION (Applicant's Description): 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.

描述（申请人的描述）：恶性神经胶质瘤（mg）是 对包括手术，辐射和 化学疗法。 体外，5- iodo-2'-脱氧尿苷（IUDR）显着敏感 毫克辐射。 但是，全身给药会引起高毒性， 放射敏化的低掺入和结果失败。 合成的， 可植入的可生物降解聚合物（P-羧基氧基丙烷（PCPP）：皮脂 酸（SA）（PCPP：SA）提供持续的，受控的局部药物的药物 人毫克。 该项目的目的是衡量IUDR从 聚合物，将IUDR递送到U251 mg异种移植物和 使用未标记的聚合物介导的放射敏化和放射性核素治疗 和125-i放射性标记的IUDR。 具体目的是：目标＃1。） 测量IUDR从PCPP中释放：体外和 植入U251 mg异种移植物中时，将体内掺入体内。 这 调查人员将检验PCPP与SA和SA的比率和 与IUDR的负载百分比或与亲水性共同载荷的百分比 D-葡萄糖调节体外IUDR的释放速率。 他们将测试 从聚合物中局部扩散引起IUDR的高吸收的假设 在U251异种移植物中。 目标＃2。）测量U251 mg的放射敏化 IUDR聚合物后的异种移植物和分离外束放射疗法。 研究人员将检验以下假设 IUDR从聚合物和细胞释放的速率和均匀性 生长动力学决定了掺入和放射敏感性。 目标＃3。）到 定量局部125-IUDR递送，剂量法和U251 mg的治疗 使用可生物降解的聚合物在体内的异种移植物。 他们将测试 假设125-IUDR的局部扩散将导致高剂量沉积 在处理的异种移植物中。 他们将通过加载PCPP来达到AIM＃1 与SA相比的聚合物增加（20％，40％，60％或80％） 增加（5、10、20、40、60、80％）IUDR的比例，孵育聚合物 在磷酸盐缓冲盐水中，并使用高性能测量释放 液相色谱。 量化IUDR的摄取作为 区域S，G2/M和G1持续时间它们将使用抗IUDR单克隆 抗体和荧光激活的细胞分选。 调查人员会 使用异种移植物的分离外梁照射达到目标＃2 轴承IUDR聚合物在AIM＃1中开发。 他们将优化 使用AIM＃1中获得的动力学数据的辐射时间表。 他们会的 使用PCPP实现AIM＃3：SA聚合物的活动增加活动（UCI） 125-I放射性标记的IUDR。 基于特定版本动力学和 在AIMS＃1和2中学习的蜂窝摄取数据，它们将优化125-IUDR 脑内和侧面U251异种移植物的放射性核素治疗。 如果 成功，这些研究将导致一种重要的新治疗方法 对于人类MG。 结果可以为选择性提供理由 使用可植入的人类MG的放射敏化和放射性核素治疗， 可生物降解的聚合物。