Molecular Recognition in Dendrimers Based on Melamine

描述(申请人提供)：树枝状大分子是一类未被充分研究的纳米级球形聚合物，为下一代聚合物疗法提供了候选。大小、形状和组成影响这些载体的方方面面，包括总体疗效、生物利用度、毒性、新陈代谢、吸收和排泄。使用树枝状大分子优化药物输送参数需要：(1)对候选树枝状大分子的合成进行精确控制；(2)了解这些大分子和大分子-药物复合体的物理有机化学；以及(3)治疗效果的评估。到目前为止，由于合成路线缺乏一种方法来系统地改变大小、形状和组成以及结构-性质关系的结构数量(物理有机化学的标志)，因此对树枝状大分子在药物输送中使用的设计标准几乎没有基本的了解。针对乳腺癌和前列腺癌的拟议研究有三个总体目标： 具体目标#1：检查这些大分子的基本物理有机化学，因为它涉及：1)生物相容的聚乙二醇化树枝状大分子在水中包含的“相”的数量以及这对药物固定的影响：在单相树枝状大分子中，固定与相对分子质量成正比。1b)通过在显示系绳梯度和空间拥挤的体系中系统地切割可生物降解的连接物来定制药物释放速率的能力。1c)这些大分子和与它们相关的客体的全局构象。 具体目标#2：使用多功能树枝状大分子确定生物分布和肿瘤靶向的分子决定因素。 具体目标#3：探索大分子识别，以确定允许这些树枝状大分子用作合成疫苗和抗体上多功能适配器单元的分子参数。

DESCRIPTION (provided by applicant): Dendrimers are an understudied class of nanometer-scale, globular polymers that offer candidates for the next-generation of polymer therapeutics. Size, shape, and composition impact all aspects of these vehicles including overall efficacy, bioavailability, toxicity, metabolism, absorption and excretion. Optimization of these parameters for drug delivery using dendrimers requires (1) exquisite control over the synthesis of dendrimer candidates; (2) an understanding of the physical organic chemistry of these macromolecules and macromolecule-drug complexes; and finally, (3) assessment of therapeutic efficacy. To date, owing to synthetic routes that lack an approach for systematic variation of size, shape, and composition as well as number of architectures for structure-property relationships (the hallmark of physical organic chemistry), there is little fundamental understanding of the design criteria for the use of dendrimers in drug delivery. There are three overall aims of proposed research which focuses on breast and prostate tumors: Specific Aim #1: Examine the fundamental physical organic chemistry of these macromolecules as it pertains to: 1 A) The number of "phases" a biocompatible PEGylated dendrimer comprises in water and the impact that this has on the sequestration of drugs: In monophasic dendrimers, sequestration is proportional to MW. 1B) The ability to tailor release rates of drugs through systematic cleavage of bioloabile linkers in architectures showing a gradient of tethers and steric crowding. 1C) The global conformation of these macromolecules and the guests associated with them. Specific Aim #2: Identify the molecular determinants for biodistribution and tumor targeting using multifuctional dendrimers. Specific Aim #3: Explore macromolecular recognition to determine the molecular parameters that allow these dendrimers to serve as synthetic vaccines and as multi-functional adaptor units on antibodies.