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
- 来源:
- 关键词:AddressAffectAffinityAmericanAssessment toolBeta CellBindingBiochemicalBiologicalBiological AssayBiophysicsCRISPR/Cas technologyCell ProliferationCell physiologyCellsCellular biologyChelating AgentsChemicalsClustered Regularly Interspaced Short Palindromic RepeatsDevelopmentDiabetes MellitusDiabetic mouseDiseaseDisease modelDoseDrug Delivery SystemsDrug ExposureDrug KineticsDrug TargetingFunctional disorderGenesGeneticHospitalizationHumanImmuneIn VitroInsulinIslets of Langerhans TransplantationMeasurementMeasuresMethodologyMethodsModelingMolecularMorbidity - disease rateMusNatural regenerationOrganPathologicPathway interactionsPermeabilityPharmaceutical ChemistryPharmaceutical PreparationsPositioning AttributeProductionPropertyRodentSeriesSolubilitySpectrometry, Mass, Electrospray IonizationStreptozocinStructure-Activity RelationshipSystemTechnologyTherapeuticTissuesTransplantationWorkZincbiophysical propertiesblood glucose regulationcell regenerationchelationclinical developmentdiabeticdrug metabolismefficacy validationexperienceexperimental studygrowth promoting activityimprovedin vivoinsightinterestisletmass spectrometric imagingmortalitynext generationnovelpharmacologicpre-clinicalpreservationpreventregenerativeregenerative therapytargeted deliverytargeted treatmenttechnology platformtherapeutic targettool
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.
项目总结
糖尿病是一种葡萄糖稳态紊乱,会导致过度住院、发病率和早期死亡。
在超过3420万受疾病影响的美国人中。因此,发展药理学
保存β细胞功能和/或刺激β细胞大量扩增的方法是人们非常感兴趣的。目前,
由于缺乏安全的治疗靶点,改进的糖尿病药物的创造受到阻碍。事实上,在目标上
但组织外药物效应正在减缓包括β细胞在内的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-
生产β细胞可用于恢复或提高内源性胰岛素的生产能力。最近,我们
开发了几种新的高效化学诱导剂--人类β细胞增殖。然而,非选择性的
这些分子的促生长活性阻止了临床的进一步发展。因此,一种“模块化”
实现下一代糖尿病需要β细胞靶向给药系统(易于转移)
治疗学。为了应对这一挑战,我们正在开发一种β细胞靶向药物输送模块,该模块基于
β电池独一无二的高锌含量。在这个体系中,锌螯合部分被共价结合到一个
复制促进(CARAD)化合物,以产生选择性地
增强β细胞的药物积累和复制促进活性。这里,我们结合了一种药物化学
通过系统的体外和体内试验促进我们的β细胞靶向药物平台技术的发展
送货。在目标1中,我们将定义管理锌依赖的β细胞靶向的化学“规则”。我们会
合成和测定多种βRepZCs,其中货物/螯合剂组成,锌结合亲和力和
物理化学性质是系统变化的。在目标2中,我们将检查体内β细胞的选择性
(蓄积和复制促进活性)系统递送的βRepZCs。我们将使用解吸
电喷雾电离质谱仪(DESI-MSI)测量组织特异性药物蓄积和预测
组织特异性生物活性。本工作将展示新型β修复锌C疗法的体内疗效。
多种糖尿病小鼠模型,并提供经过验证的方法学;克服开发的主要障碍
细胞靶向治疗:缺乏一种简便的体内测量组织特异性药物释放的方法。
在目标3中,我们将使用CRISPR技术从基因上剖析控制β的途径-细胞锌和锌-
约束性药物积聚。作为这项努力的一部分,我们将从基因上增强β-细胞βRepZCs的积累和
β-细胞选择性复制诱导。总体而言,我们的研究将推进β的模块化技术-以细胞为目标
药物传递,优化βRepZCs,验证了评估体内细胞靶向药物传递的迫切需要的工具
并提供了对β细胞生物学的基本(有针对性的)见解。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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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:
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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