DEVELOPMENT OF THERAPEUTIC AGENTS FOR USE WITH CONTROLLED-RELEASE POLYMERS

与控释聚合物一起使用的治疗剂的开发

• 批准号: 6296007
• 负责人: MICHAEL E COLVIN
• 金额: --
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6296007
• 关键词: antineoplastics; antitumor antibody; athymic mouse; camptothecin; carmustine; clone cells; cooperative study; dextrans; diffusion; disease /disorder model; drug design /synthesis /production; drug screening /evaluation; exotoxins; glioma; ifosfamide; immunotoxicity; microcapsule; neoplasm /cancer chemotherapy; neoplasm /cancer immunotherapy; neurotoxins; nonhuman therapy evaluation; pharmacokinetics; polymers; slow release drug; xenotransplantation

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.

该计划的第一个目标是定义单个代理， 在体外对人具有高活性的药剂的组合 神经胶质瘤，并且其具有用于聚合物的适当性质， 释放系统待评价的药剂包括化疗药物， 分化剂、外毒素和抗神经胶质瘤抗体。 剂和 将评价在体外有活性的组合的活性 在从生物可降解材料释放后， 侧腹胶质瘤异种移植系统中的聚合物。 在这个系统中，代理人或 将结合到聚合物盘中的试剂的组合放置在 直接贴壁至已建立的胶质瘤异种移植物。 那些化合物 在体内有活性的组合将在程序1中研究， 脑中聚合物释放后的神经毒性，以及针对 在大鼠模型中颅内建立的大鼠和人神经胶质瘤。 该计划的第二个目标是与计划3合作， 增加药剂在脑中扩散距离的方法， 在颅内从聚合物释放后。 项目3中的前期工作 确定了大分子在大脑中的扩散比低分子扩散更远。 分子量化合物 因此，这项工作的一个主要组成部分将 是进一步发展，与方案3，代理人的概念， 通过不稳定的键连接到大分子上， 随着时间和空间的推移，大分子在大脑中扩散。 第三个目的是评估药物含有的潜力。 用于直接植入肿瘤的微球，用于从聚合物中释放 用于邻近肿瘤，以及用于鞘内给药以进行治疗 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， 药代动力学研究。