Molecular Recognition in Dendrimers Based on Melamine

基于三聚氰胺的树枝状聚合物的分子识别

• 批准号: 7677851
• 负责人: ERIC E SIMANEK
• 金额: $ 19.69万
• 依托单位: TEXAS A&M UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-08-01 至 2010-08-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7677851
• 关键词: Acute; Antibodies; Architecture; Area; B-Lymphocytes; Biocompatible; Biodistribution; Biological Assay; Biological Availability; Bioluminescence; Breast; Chemicals; Chronic; Classification; Clinical Trials; Complex; Crowding; Cytotoxic agent; Dendrimers; Development; Diagnostic Imaging; Diamines; Drug Delivery Systems; Elements; Excretory function; Feedback; Generations; Goals; Immune system; Immunoglobulin Constant Region; Isotopes; Link; Malignant neoplasm of prostate; Measures; Melamine; Metabolism; Micelles; Molecular; Molecular Conformation; Organic Chemistry; Pharmaceutical Preparations; Phase; Polymers; Positron-Emission Tomography; Preparation; Property; Prostate; Prostatic Neoplasms; Proteins; Radio; Research; Research Personnel; Role; Route; Shapes; Solid Neoplasm; Structure; Synthetic Vaccines; System; T-Lymphocyte; Therapeutic; Time; Toxic effect; Transfection; Treatment Efficacy; Triazines; Vaccines; Variant; Water; absorption; antibody conjugate; base; design; macromolecule; molecular recognition; nanoscale; next generation; programs; success; tumor

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.

描述（由申请人提供）：树枝状聚合物是一类正在研究的纳米级球状聚合物，为下一代聚合物疗法提供了候选者。尺寸、形状和成分影响这些载体的各个方面，包括整体功效、生物利用度、毒性、代谢、吸收和排泄。使用树枝状大分子优化这些用于药物递送的参数需要（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-药物复合物的物理有机化学；最后，(3)疗效评估。迄今为止，由于合成路线缺乏系统改变尺寸、形状和组成以及结构-性能关系（物理有机化学的标志）的架构数量的方法，因此对设计标准知之甚少用于在药物输送中使用树枝状聚合物。拟议的研究有三个总体目标，重点是乳腺和前列腺肿瘤： 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 A) 生物相容性聚乙二醇化树枝状聚合物在水中包含的“相”数量及其对药物隔离的影响： 在单相树枝状聚合物中，封存量与MW成正比。 1B) 通过系统地切割显示出系链梯度和空间拥挤的结构中的生物活性连接体来定制药物释放速率的能力。 1C) 这些大分子的整体构象以及与之相关的客体。 具体目标#2：使用多功能树枝状聚合物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分子参数，使这些树枝状聚合物能够用作合成疫苗和抗体上的多功能接头单元。