Molecular Recognition in Dendrimers Based on Melamine

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、可工程化的大分子是否为药物递送的合适载体。它们的大小表明EPR效应可以用于靶向肿瘤。用归巢肽装饰这些结构的能力允许研究“魔术子弹”策略。该提案的重点是Pt-配位络合物，因为合作者对该试剂有很大的兴趣。生物学研究将由合作者与PI实验室的学生共同执行。该提案涉及两个具体目标：1）树枝状聚合物是否可以使用被动和/或主动策略靶向肿瘤？肿瘤对聚合物的增强的渗透性和保留提供了一种被动机制，用于靶向这些组织进行破坏。将归巢肽连接到聚合物药物递送载体提供了另外的主动策略以进一步区分患病组织与宿主组织。这些实验将通过观察不同大小和组成的标记树枝状聚合物的生物分布来执行。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显示出合适的抗癌活性？ 铂将使用树枝状聚合物通过丙二酸酯侧基负载。从丙二酸的释放是响应于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键结合。这些树枝状聚合物的能力，非共价螯合抗癌剂也进行了探讨。

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.