EFFECTIVENESS AND SAFETY OF CONTROLLED-RELEASE DRUG DELIVERY FOR BRAIN TUMORS

我们正在提出一种新的方法来治疗脑肿瘤，利用局部 通过生物可降解聚合物有效药物的控制释放 直接到达肿瘤部位。在之前的授权期内，我们 测试了这样一种假设，即局部持续治疗通过提供这种 通过可生物降解的控制释放直接在肿瘤部位使用药物 聚合物将比全身治疗更有效。我们开发了 聚合物/药物复合体；以及，在动物身上进行了广泛的临床前研究 建立了其生物兼容性、安全性和有效性的模型， 我们进行了L-3期临床试验，植入的是一种氟尿嘧啶聚合物 通过NCDDG的合作努力制定的。我们有，在 与NCDDG的其他项目合作，开发了新的 并展示了它们的安全性和安全性 提高了治疗脑肿瘤的疗效。我们现在能够 在过去4年取得的成果的基础上，测试我们的假设 有效药物的最佳直接肿瘤输送将会改善 没有系统治疗及其组合副作用的结果 药剂和/或生物方法的组合将比单一的方法更有效 探员们。我们的具体目标是：目标L：检验新政策的有效性 通过(A)评估可生物降解聚合物在大脑中的安全性；以及 (B)评估其与既定药物一起使用时的有效性 对抗大鼠脑瘤。目标2：测试新方案的有效性 开发的抗肿瘤药物通过(A)测定它们的释放动力学。 各种聚合物及其体外药效；(B)新药评价 神经毒性的聚合物组合及其最大值的确定 耐受剂量；(C)对大鼠9L胶质瘤的疗效评价 (D)在裸鼠体内对人异种移植瘤的疗效。目标3： 探索药物和其他治疗方法的组合，包括(A) 研究放射增敏剂与外照射相结合；(B) 利用抗血管生成药物、免疫毒素和细胞因子， 化学药物和其他生物制剂。

We are proposing a new approach to treating brain tumors utilizing local controlled delivery via biodegradable polymers of effective agents directly to the site of the tumor. During the prior granting period we tested the hypothesis that local sustained treatment by delivery of such agents directly at the tumor site via biodegradable controlled release polymers would be more effective than systemic therapy. We developed polymer/drug complexes; and, after extensive preclinical studies in animal models that established their biocompatibility, safety, and effectiveness, we conducted Phase l - 3 clinical trials with a BCNU-polymer implant devised through the collaborative efforts of this NCDDG. We have, in collaboration with the other programs of this NCDDG, developed new polymers with new effective agents and demonstrated their safety and improved efficacy for treating brain tumors. We are now in a position to build on the gains made in the past 4 years to test our hypotheses that the optimal direct tumor delivery of an effective agent will improve outcome without the side effects of systemic therapy and that combinations of agents and/or biological approaches will be more effective than single agents. Our specific aims are: Aim l: To test the effectiveness of new biodegradable polymers by (a) evaluating their safety in the brain; and (b) assessing their effectiveness when utilized with established drugs against rat brain tumors. Aim 2: To test the effectiveness of newly developed antitumor drugs by (a) determining their release kinetics from various polymers and their efficacy in vitro; (b) evaluating the new drug polymer combination for neurotoxicity and establishing the maximum tolerated dose; (c) evaluating the effectiveness in the rat 9L glioma model; and (d) efficacy against human xenografts in the nude rat. Aim 3: To explore combinations of drugs and other treatments, including (a) investigating radiosensitizers in combination with external radiation; (b) utilizing antiangiogenic agents, immunotoxins, and cytokines, with chemotherapeutic and other biological agents.