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: 6929007
• 负责人: ERIC E SIMANEK
• 金额: $ 25.46万
• 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/6929007
• 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(申请人提供)：建议的努力描述了对一类树枝状大分子的彻底调查，以确定这些单分散、可工程的大分子是否适合药物输送载体。它们的大小表明EPR效应可以被用来靶向肿瘤。用寻的肽装饰这些建筑的能力允许研究“神奇子弹”策略。该提案侧重于铂配位络合物，因为合作者对这种试剂非常感兴趣。生物学研究将由合作者与PI实验室的学生一起进行。这项建议涉及两个具体目标：1)树枝状大分子能否通过被动和/或主动策略靶向肿瘤？肿瘤对聚合物的渗透性和滞留能力的增强为破坏这些组织提供了一种被动的机制。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不同大小和组成的标记树枝状大分子的生物分布来进行。描述了有效筛选组合物和评价归巢多肽文库的策略。2)树枝状大分子能否负载细胞毒素并显示出合适的抗癌活性？铂将使用树枝状大分子通过侧链丙二酸基进行负载。丙二酸的释放是对pH变化的反应。其他细胞毒素将使用可逆或可生物降解的键进行偶联。还探索了这些树枝状大分子对抗癌药物进行非共价隔离的能力。