Molecular Recognition in Dendrimers Based on Melamine

描述（由申请人提供）：树状大分子是一种未被充分研究的纳米级球状聚合物，为下一代聚合物治疗提供了候选物。大小、形状和成分影响这些载体的各个方面，包括总体功效、生物利用度、毒性、代谢、吸收和排泄。利用树状大分子优化这些给药参数需要：(1)精细控制候选树状大分子的合成；(2)了解这些大分子和大分子-药物复合物的物理有机化学；最后，(3)疗效评价。迄今为止，由于合成路线缺乏对大小、形状和组成的系统变化以及结构-性质关系（物理有机化学的标志）的结构数量的方法，对在药物递送中使用树状大分子的设计标准的基本理解很少。针对乳腺和前列腺肿瘤的拟议研究有三个总体目标：

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.