Leveraging the Uniquely High Beta-Cell Zinc Content for Targeted Drug Delivery

利用独特的高β细胞锌含量进行靶向药物输送

基本信息

  • 批准号:
    10576401
  • 负责人:
  • 金额:
    $ 48.14万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-09-01 至 2025-03-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Diabetes is a disorder of glucose homeostasis that causes excess hospitalization, morbidity and early mortality among the more than 34.2 million disease-affected Americans. Consequently, developing pharmacologic methods to preserve β-cell function and/or stimulate β-cell mass expansion is of intense interest. Presently, the creation of improved diabetes medications is stymied by a dearth of safe therapeutic targets. In fact, on-target but off-tissue drug effects are slowing progress across multiple diabetes therapeutic domains including β-cell regeneration, β-cell preservation, and immune-protection. In principle, stimulating the regeneration of insulin- producing β-cells could be used to restore or enhance endogenous insulin production capacity. Recently, we developed several new highly potent chemical inducers of human β-cell proliferation. However, the non-selective growth-promoting activity of these molecules prevents further clinical development. Consequently, a “modular” (readily transferable) system for β-cell-targeted drug delivery is needed to realize the next generation of diabetes therapeutics. To address this challenge, we are developing a β-cell-targeted drug delivery module based upon the uniquely high zinc content of β-cells. In this system, a zinc-chelating moiety is covalently integrated into a replication-promoting (cargo) compound to generate a bi-functional compound (βRepZnC) that selectively enhances β-cell drug accumulation and replication-promoting activity. Here, we combine a medicinal chemistry effort with systematic in vitro and in vivo interrogation to advance our platform technology for β-cell-targeted drug delivery. In Aim 1, we will define the chemical “rules” that govern zinc-dependent β-cell targeting. We will synthesize and assay diverse βRepZnCs where cargo/chelator composition, zinc-binding affinity and physicochemical properties are systematically varied. In Aim 2, we will examine the in vivo β-cell selectivity (accumulation and replication-promoting activity) of systemically-delivered βRepZnCs. We will use desorption electrospray ionization mass spectrometry (DESI-MSI) to measure tissue-specific drug accumulation and predict tissue-specific bioactivity. This work will demonstrate the in vivo efficacy of novel βRepZnC therapeutics in multiple diabetes mouse models and deliver a validated methodology; overcoming a major barrier to developing cell-targeted therapeutics: the lack of a facile method for in vivo measurement of tissue-specific drug delivery. In Aim 3, we will use CRISPR technology to genetically dissect the pathways that control β-cell zinc and zinc- binding drug accumulation. As part of this effort, we will genetically enhance β-cell βRepZnCs accumulation and β-cell selective replication induction. Overall, our studies will advance a modular technology for β-cell-targeted drug delivery, optimize βRepZnCs, validate a greatly needed tool for assessing cell-targeted drug delivery in vivo and provide fundamental (targetable) insights into β-cell biology.
项目摘要 糖尿病是一种葡萄糖稳态失调,会导致过度住院、发病和早期死亡 在超过3420万受疾病影响的美国人中。因此,开发药理学 保持β-细胞功能和/或刺激β-细胞团扩增的方法受到强烈关注。如今 由于缺乏安全的治疗靶点,改进的糖尿病药物的产生受到阻碍。事实上, 但组织外药物效应正在减缓多个糖尿病治疗领域的进展, 再生、β细胞保存和免疫保护。原则上,刺激胰岛素的再生- 产生β-细胞可用于恢复或增强内源性胰岛素产生能力。最近我们 开发了几种新的人类β细胞增殖的高效化学诱导剂。然而,非选择性 这些分子的促生长活性阻止了进一步的临床发展。因此,“模块化” 为实现下一代糖尿病,需要用于β细胞靶向药物递送的(易转移的)系统 治疗学为了应对这一挑战,我们正在开发一种β细胞靶向药物递送模块, β细胞中独特的高锌含量。在该系统中,锌螯合部分共价整合到 复制促进(货物)化合物,以产生选择性地 增强β细胞药物积累和复制促进活性。在这里,我们将联合收割机 通过系统的体外和体内研究,努力推进我们的β细胞靶向药物平台技术 交付.在目标1中,我们将定义控制锌依赖性β细胞靶向的化学“规则”。我们将 合成和测定不同β RepZnC,其中货物/螯合剂组成、锌结合亲和力和 物理化学性质系统地变化。在目标2中,我们将检查体内β细胞选择性 (积累和复制促进活性)。我们将使用解吸 电喷雾离子化质谱法(ESI-MSI)测量组织特异性药物蓄积并预测 组织特异性生物活性。这项工作将证明新的βRepZnC治疗剂在体内的功效, 多种糖尿病小鼠模型,并提供经过验证的方法;克服开发的主要障碍 细胞靶向治疗:缺乏一种简便的方法,在体内测量组织特异性药物输送。 在目标3中,我们将使用CRISPR技术从遗传学上剖析控制β细胞锌和锌的途径。 结合药物蓄积。作为这项工作的一部分,我们将在遗传上增强β细胞βRepZnCs的积累, β细胞选择性复制诱导。总的来说,我们的研究将推进β细胞靶向的模块化技术, 药物递送,优化βRepZnCs,验证用于评估体内细胞靶向药物递送的急需工具 并提供对β细胞生物学的基本(可靶向)见解。

项目成果

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Justin Pierce Annes其他文献

Justin Pierce Annes的其他文献

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{{ truncateString('Justin Pierce Annes', 18)}}的其他基金

Developing A Platform Technology For β-Cell-Targeted Drug Delivery
开发β细胞靶向药物输送的平台技术
  • 批准号:
    10729390
  • 财政年份:
    2023
  • 资助金额:
    $ 48.14万
  • 项目类别:
Development of Beta-Cell-Targeted Regenerative Therapeutics Using A Novel Prodrug Strategy
使用新型前药策略开发β细胞靶向再生疗法
  • 批准号:
    10215497
  • 财政年份:
    2019
  • 资助金额:
    $ 48.14万
  • 项目类别:
Development of Beta-Cell-Targeted Regenerative Therapeutics Using A Novel Prodrug Strategy
使用新型前药策略开发β细胞靶向再生疗法
  • 批准号:
    10661006
  • 财政年份:
    2019
  • 资助金额:
    $ 48.14万
  • 项目类别:
Development of Beta-Cell-Targeted Regenerative Therapeutics Using A Novel Prodrug Strategy
使用新型前药策略开发β细胞靶向再生疗法
  • 批准号:
    10453575
  • 财政年份:
    2019
  • 资助金额:
    $ 48.14万
  • 项目类别:
Enrichment Program
强化计划
  • 批准号:
    10197909
  • 财政年份:
    2017
  • 资助金额:
    $ 48.14万
  • 项目类别:
Leveraging the Uniquely High Beta-Cell Zinc Content for Targeted Drug Delivery
利用独特的高β细胞锌含量进行靶向药物输送
  • 批准号:
    10207073
  • 财政年份:
    2015
  • 资助金额:
    $ 48.14万
  • 项目类别:
Leveraging the Uniquely High Beta-Cell Zinc Content for Targeted Drug Delivery
利用独特的高β细胞锌含量进行靶向药物输送
  • 批准号:
    10366072
  • 财政年份:
    2015
  • 资助金额:
    $ 48.14万
  • 项目类别:
The Role of Adenosine Kinase in Controlling Beta-Cell Regeneration
腺苷激酶在控制 β 细胞再生中的作用
  • 批准号:
    8888112
  • 财政年份:
    2015
  • 资助金额:
    $ 48.14万
  • 项目类别:
Interrogating the Role of Adenosine Kinase in Islet Beta-Cells
探讨腺苷激酶在胰岛β细胞中的作用
  • 批准号:
    8480250
  • 财政年份:
    2013
  • 资助金额:
    $ 48.14万
  • 项目类别:
Interrogating the Role of Adenosine Kinase in Islet Beta-Cells
探讨腺苷激酶在胰岛β细胞中的作用
  • 批准号:
    8643226
  • 财政年份:
    2013
  • 资助金额:
    $ 48.14万
  • 项目类别:

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