Molecular Recognition in Dendrimers Based on Melamine

基于三聚氰胺的树枝状聚合物的分子识别

• 批准号: 6646987
• 负责人: ERIC E SIMANEK
• 金额: $ 6万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6646987
• 关键词: antineoplastics; chemical conjugate; chemical structure function; chemical synthesis; combinatorial chemistry; drug screening /evaluation; drug vehicle; pharmacokinetics; polymers; resin; solubility; triazines

DESCRIPTION (provided by applicant): The efforts proposed describe the thorough investigation of a class of dendrimers to determine whether these monodisperse, engineerable macromolecules are suitable vehicles for drug delivery. Their size suggests that the EPR effect can be exploited to target tumors. The ability to decorate these architectures with homing peptides allows for the investigation of "magic bullet" stategies. The proposal focuses on Pt-coordination complexes, as the collaborator has great interest in this agent. The biological studies will be executed by the collaborator in conjunction with students from the PI's laboratory.This proposal addresses two specific aims:1) Can the dendrimers be targeted to tumors using passive and/or active strategies? The enhanced permeability and retention of polymers by tumors offers a passive mechanism for targeting these tissues for destruction. Attaching homing peptides to the polymeric drug delivery vehicle offers an additional active strategy to further discriminate the diseased tissue from host tissue. These experiments will be executed by looking at the biodistribution of labeled dendrimers that differ in size and composition. Strategies for screening compositions efficiently, and evaluating libraries of homing peptides are described.2) Can the dendrimers be loaded with cytotoxins and display suitable anticancer activity? Platinum will be loaded using dendrimers through pendant malonate groups. Release from the malonate is triggered in response to a change in pH. Other cytotoxins will be conjugated using reversible or biolabile linkages. The ability of these dendrimers to noncovalently sequester anticancer agents is also explored.

描述（由申请人提供）：所提出的努力描述了对一类树枝状聚合物的彻底研究，以确定这些单分散的、可工程化的大分子是否是适合药物输送的载体。它们的大小表明 EPR 效应可用于靶向肿瘤。用归巢肽装饰这些结构的能力允许研究“神奇子弹”策略。该提案重点关注 Pt 配位配合物，因为合作者对此药物非常感兴趣。生物学研究将由合作者与 PI 实验室的学生一起执行。该提案涉及两个具体目标：1) 树枝状大分子能否使用被动和/或主动策略靶向肿瘤？肿瘤增强的聚合物渗透性和保留能力提供了一种针对这些组织进行破坏的被动机制。将归巢肽附着到聚合物药物递送载体上提供了一种额外的主动策略，以进一步区分病变组织和宿主组织。这些实验将通过观察大小和组成不同的标记树枝状聚合物的生物分布来进行。描述了有效筛选组合物和评估归巢肽文库的策略。2)树枝状聚合物能否负载细胞毒素并表现出适当的抗癌活性？将使用树枝状聚合物通过侧链丙二酸基团负载铂。丙二酸的释放是响应 pH 值的变化而触发的。其他细胞毒素将使用可逆或生物不稳定的连接进行缀合。还探索了这些树枝状聚合物非共价螯合抗癌剂的能力。