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: 7475688
• 负责人: ERIC E SIMANEK
• 金额: $ 24.52万
• 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 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7475688
• 关键词: Acute; Antibodies; Architecture; Area; B-Lymphocytes; Biocompatible; Biodistribution; Biological Assay; Biological Availability; Bioluminescence; Breast; Chemicals; Chronic; Class; Classification; Clinical Trials; Complex; Crowding; Cytotoxic agent; Dendrimers; Development; Diagnostic Imaging; Diamines; Disease regression; Drug Delivery Systems; Elements; Excretory function; Feedback; Generations; Goals; Immune system; Immunoglobulin Constant Region; Isotopes; Link; Localized; Malignant neoplasm of prostate; Measures; Melamine; Metabolism; Micelles; Molecular; Molecular Conformation; Numbers; Organic Chemistry; Pharmaceutical Preparations; Phase; Polymers; Positron-Emission Tomography; Preparation; Property; Prostate; Prostate Cancer Vaccine; Prostatic Neoplasms; Proteins; Radio; Rate; 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; concept; design; macromolecule; molecular recognition; nanoscale; next generation; programs; size; 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未充分研究的纳米级球形聚合物，为下一代聚合物治疗提供候选物。尺寸、形状和组成影响这些媒介物的所有方面，包括总体功效、生物利用度、毒性、代谢、吸收和排泄。使用树枝状聚合物的药物递送的这些参数的优化需要（1）对树枝状聚合物候选物的合成的精细控制;（2）对这些大分子和大分子-药物复合物的物理有机化学的理解;以及最后，（3）对治疗功效的评估。到目前为止，由于合成路线缺乏系统的变化的大小，形状和组成以及结构-性质关系（物理有机化学的标志）的体系结构的数量的方法，很少有基本的理解的设计标准使用的树枝状聚合物在药物输送。有三个总体目标的拟议研究，重点是乳腺癌和前列腺肿瘤： 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：1A）生物相容性聚乙二醇化树枝状聚合物在水中包含的“相”的数量以及这对药物螯合的影响：在单相树枝状聚合物中，螯合与MW成比例。1B）通过在显示系链梯度和空间拥挤的结构中系统性裂解生物不稳定接头来定制药物释放速率的能力。1C）这些大分子和与它们缔合的客体的全局构象。 具体目标#2：使用多功能树枝状聚合物鉴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聚合物作为合成疫苗和抗体上的多功能接头单元的分子参数。