Molecular Recognition in Dendrimers Based on Melamine

描述（由申请人提供）：提议的努力描述了对一类树状大分子的彻底研究，以确定这些单分散的、可工程的大分子是否适合用于药物递送。它们的大小表明EPR效应可以被用来靶向肿瘤。用归巢肽修饰这些架构的能力允许研究“魔弹”策略。由于合作者对pt -配位配合物非常感兴趣，本提案的重点是pt -配位配合物。生物学研究将由合作者与PI实验室的学生一起进行。这一建议解决了两个具体的目标：1)树突状分子能否使用被动和/或主动策略靶向肿瘤？肿瘤增强了聚合物的渗透性和滞留性，为靶向这些组织进行破坏提供了一种被动机制。将归巢肽附着在高分子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状大分子的生物分布来执行。描述了有效筛选组合物和评估归巢肽库的策略。2)树状大分子能否装载细胞毒素并表现出适当的抗癌活性？铂将通过垂坠的丙二酸基团用树状大分子装载。丙二酸盐的释放是由于ph值的变化而触发的。其他细胞毒素将通过可逆或生物稳定的键结合。这些树状大分子的能力，以非共价隔离抗癌药物也进行了探讨。

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.