Molecular Recognition in Dendrimers Based on Melamine

树枝状大分子是一类未被研究的纳米级球形聚合物，为 下一代聚合物疗法。大小、形状和组成影响这些方面的各个方面 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的这些参数需要(1)精确控制 候选树枝状大分子的合成；(2)对这些化合物的物理有机化学的理解 最后，(3)疗效评价。 到目前为止，由于合成路线缺乏系统地改变大小、形状和 结构-属性关系的架构组成和数量(物理 有机化学)，对于使用树枝状大分子的设计标准几乎没有基本的理解 在药物输送方面。拟议中的研究有三个总体目标，重点是乳房和前列腺癌 肿瘤： 具体目标#1：检查这些大分子的基本物理有机化学 涉及：1a)生物相容的聚乙二醇化树枝状大分子在水中的“相数” 这对药物封存的影响：在单相树状大分子中，封存是成比例的 致MW。1b)通过系统地切割可生物降解的连接物来调整药物释放速率的能力 呈现系绳梯度和立体拥挤的建筑。1C)它们的全球构象 大分子和与之相关的客体。 具体目标#2：确定生物分布和肿瘤靶向的分子决定因素 多功能树枝状大分子。 具体目标#3：探索大分子识别以确定允许 这些树枝状大分子可用作合成疫苗和抗体上的多功能适配器单元。

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.