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.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。 列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 许多有效和特定的肽遭受短期或最佳持续时间的问题。解决此类问题的一种可能解决方案涉及与大分子（例如聚乙烯乙二醇（PEG））的共轭，这些乙二醇（PEG）被缓慢地从体内消除，从而延长了附着的肽的作用。对于肽疗法，通常必须从大分子中释放出未改变的药物，并适合满足需求的时间。当前的方法通常使用可切合的接头将肽通过裂解的接头将肽连接到大分子上，因为酶的作用或生理环境的作用。尽管这种方法通常是成功的，但它们通常不允许预测或控制药物释放速率，从而使作用持续时间。 该项目的目的是a）开发一种新颖的平台技术，该技术允许大分子的特定地点依恋 - 钉或peggy的树枝状聚合物对肽，而b）开发技术，以可预测的，化学的化学释放 这样的肽。如果成功，a）我们将开发一般技术，以控制大分子从大分子中释放肽，这些肽可以广泛应用，并为这种技术在治疗性肽中的未来应用奠定了基础。 UCSF质谱设施的协作将使我们能够确认接头 - 毒品，钉链药物和树枝状聚合物 - 链接剂 - 毒品偶联物的结构。它还可以在药代动力学研究中确定后两种。