RELEASABLE LINKERS FOR POLYETHYLENE GLYCOL- AND DENDRIMER-DRUG CONJUGATES

聚乙二醇和树枝状聚合物药物缀合物的可释放连接体

• 批准号: 8363839
• 负责人: DANIEL V. SANTI
• 金额: $ 0.5万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8363839
• 关键词: Cleaved cell; Collaborations; Dendrimers; Drug Kinetics; Environment; Enzymes; Funding; Future; Grant; Mass Spectrum Analysis; National Center for Research Resources; Peptides; Pharmaceutical Preparations; Physiological; Polyethylene Glycols; Principal Investigator; Research; Research Infrastructure; Resources; Site; Solutions; Source; Staging; Structure; Technology; Therapeutic; Time; United States National Institutes of Health; controlled release; cost; macromolecule; novel

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Many potent and specific peptides suffer problems of short or sub-optimal duration. A possible solution to such problems involves conjugation to macromolecules such as polyethylene glycol (PEG) that are slowly eliminated from the body, and thus prolong the action of the attached peptide. For peptide therapeutics, it is usually essential that the unchanged drug be released from the macromolecule with timing appropriate to satisfy the need. Current approaches often use cleavable linkers to attach the peptide to the macromolecule by a linker that cleaves because of the effect of an enzyme, or physiological environment. Although such approaches are often successful, they usually do not allow prediction or control of the rate of drug release and hence the duration of action. The objective of this project is a) to develop a novel platform technology that allows site-specific attachment of a macromolecule -- PEG or pegylated dendrimers  to peptides, and b) to develop technology for predictable, chemically-controlled release of such peptides. If successful, a) we will have developed general technology for controlled release of peptides from macromolecules that could be broadly applied and set the stage for future applications of such technology to therapeutic peptides. The UCSF mass spectrometry facility collaboration will allow us to confirm the structures of linker-drug, PEG-linker drug and dendrimer-linker-drug conjugates. It may also enable determination of the latter two in pharmacokinetic studies.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 许多有效的和特异性的肽遭受短的或次优的持续时间的问题。这些问题的一个可能的解决方案涉及与大分子如聚乙二醇（PEG）缀合，所述大分子从体内缓慢消除，从而延长所连接的肽的作用。对于肽治疗剂，通常重要的是以适当的时间从大分子释放未改变的药物以满足需要。目前的方法通常使用可裂解的接头来通过由于酶或生理环境的作用而裂解的接头将肽连接到大分子。虽然这些方法通常是成功的，但它们通常不允许预测或控制药物释放的速率，因此不能预测或控制作用的持续时间。 本项目的目标是a）开发一种新的平台技术，允许大分子- PEG或聚乙二醇化树枝状聚合物的位点特异性附着  和B）开发用于可预测的、化学控制释放的 这样的肽。如果成功，a）我们将开发出从大分子中控制释放肽的通用技术，该技术可以广泛应用，并为将来将这种技术应用于治疗肽奠定基础。 UCSF质谱设施的合作将使我们能够确认接头-药物，PEG-接头药物和树枝状聚合物-接头-药物缀合物的结构。它还可以在药代动力学研究中确定后两者。