DEVELOPMENT OF THERAPEUTIC AGENTS FOR USE WITH CONTROLLED-RELEASE POLYMERS

该计划的第一个目标是定义单一代理和 体外高活性抗人类药物的组合 胶质瘤，并且具有用于该聚合物的适当性质 释放系统。被评估的药物包括化疗药物， 分化因子、外毒素和抗胶质瘤抗体。代理和 在体外有效的组合将被评估活性。 从可生物降解的药物中释放后在体内对抗已建立的肿瘤 侧翼胶质瘤异种移植系统中的聚合物。在此系统中，代理或 合并到聚合物圆盘中的药剂组合将放置在 直接与已建立的胶质瘤异种移植瘤结合。那些化合物 活体内活跃的组合将在L计划中进行研究 聚合物在大脑中释放后的神经毒性，以及针对 在大鼠脑内建立大鼠和人脑胶质瘤模型。 该计划的第二个目标是与计划3合作开发 增加药物在大脑中扩散距离的方法， 在颅内从聚合物中释放后。计划3中的先前工作 证实了大分子在大脑中的扩散比低分子要远得多 分子量化合物。因此，工作的一个主要组成部分将是 是方案3对受约束代理概念的进一步发展 通过不稳定的键连接到大分子，这样试剂就会被释放 随着时间和空间的推移，大分子在大脑中扩散。 第三个目标是评估包含药物的潜力 直接植入肿瘤的微球，用于从聚合物中释放 邻近肿瘤，用于鞘内给药治疗 鞘内肿瘤。 最后，该计划将为其他计划提供化学支持 通过合成用于扩散的放射性标记剂和 药代动力学研究。

The first objective of this program is to define single agents and combinations of agents which are highly active in vitro against human gliomas, and which have appropriate properties for use in the polymer release system. Agents to be evaluated include chemotherapeutic drugs, differentiating agents, exotoxins, and anti-glioma antibodies. Agents and combinations which are active in vitro will be evaluated for activity against an established tumor in vivo after release from biodegradable polymers in a flank glioma xenograft system. in this system the agent or combination of agents, incorporated into a polymer disk, will be place in direct apposition to the established glioma xenograft. Those compounds and combinations which are active in vivo will be studied in Program l for neurotoxicity after polymer release in the brain, and for activity against intracranially established rat and human gliomas in a rat model. The second objective of this program is to work with Program 3 to develop approaches to increasing the diffusion distance of agents in the brain, after intracranial release from polymers. Previous work in Program 3 established that macromolecules diffuse much further in the brain than low molecular weight compounds. Therefore, a major component of the work will be the further development, with Program 3, of the concept of agents bound to macromolecules through labile bonds, such that the agents are released over time and space as the macromolecules diffuse through the brain. A third objective is to evaluate the potential of drug containing microspheres for direct implantation in tumors, for release from polymers adjacent to tumors, and for intrathecal administration for the treatment of intrathecal tumor. Finally, this program will provide chemical support to the other programs of this NCDDC by synthesizing radiolabeled agents for diffusion and pharmacokinetic studies.