In-Vivo Monitoring of Therapeutic Drug Transport Across Biological Barriers
治疗药物跨生物屏障转运的体内监测
基本信息
- 批准号:10677650
- 负责人:
- 金额:$ 32.75万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-01 至 2026-08-31
- 项目状态:未结题
- 来源:
- 关键词:AcidityAffectAminoglycosidesAmoxicillinAmpicillinAntibiotic ProphylaxisAntibioticsBacteriaBehaviorBiologicalBiopsyBloodBlood capillariesBrainBrain InjuriesBrain regionCell LineCerebrospinal FluidCharacteristicsChemical StructureChemicalsChemoreceptorsClinicalComplexDangerousnessDataDetectionDevelopmentDoseDrug KineticsDrug TransportEndotheliumEnvironmentExposure toExtracellular SpaceFamilyFutureGentamicinsGlycopeptide AntibioticsGlycopeptidesGoalsHippocampusImplantIn VitroIndustryInfectionIrrigationKanamycinKineticsKnowledgeLibrariesLiverMapsMeasurementMeasuresMedicalMembraneMethodologyModelingMolecularMonitorNatureOperative Surgical ProceduresOrganPenetrating Brain InjuryPenetrationPenicillin GPerfusionPermeabilityPharmaceutical PreparationsPharmacotherapyPorosityPreparationProphylactic treatmentProstateProstaticRattusRegimenResearchResearch PersonnelResistance developmentResourcesSamplingStructureStructure of jugular veinTestingThalamic structureTherapeuticTherapeutic AgentsTimeTissuesTobramycinTransport ProcessTravelVancomycinWorkaptamerbasebeta-Lactamsblood cerebrospinal fluid barriercarrier mediated transportchemical propertycostdrug developmentimprovedin vivoin vivo evaluationin vivo monitoringnovel therapeuticspassive transportprecision drugspredictive modelingpreventprogramsreal time monitoringresponsesensorsensor technologyside effectstandard of caretemporal measurementtherapeutically effectivetumoruptakewound
项目摘要
Project Summary
The ability of therapeutic drugs to access specific organs strongly depends on the nature of the blood-tissue
barrier at said organs. The prostate and brain, for example, have tight barriers with no intercellular gaps, and
most drugs cannot permeate them at sufficiently high levels to be therapeutically effective. Thus, understanding
the relationships between drug chemical structure, dosing regimen, and organ penetration is crucial to
the development of new and effective drug therapies. Motivated by this, the long-term goal of this program
is to establish a measurement standard of molecular transport parameters affecting the passage of therapeutic
agents across biological barriers in vivo. Specifically, the objective of this proposal is to demonstrate that
electrochemical, aptamer-based (E-AB) sensors – an emerging sensing platform with the ability to continuously
measure the levels of specific molecules in the body – can support continuous monitoring of molecular transport
from blood to liver, prostate and brain. The proposed measurements will determine the transport parameters of
seven therapeutic agents (three aminoglycoside, three β-lactam and one glycopeptide antibiotics) across four
biological barriers (i.e., blood-liver, blood-prostate, blood-brain and blood-cerebrospinal fluid). These drugs were
chosen because, although effective at treating infections across organ barriers, they cause dangerous side
effects driven by their narrow therapeutic window, making their precise dosing an important medical challenge.
The central hypothesis of this work is that achieving spatially and temporally resolved drug measurements in
blood and target organs will produce unprecedented permeability data that will guide new therapeutic drug
development toward the creation of permeability-enhanced therapeutics and more effective dosing regimens.
This hypothesis will be tested by pursuing three specific aims: 1) Determine the kinetics of drug uptake in the
liver via continuous, seconds-resolved E-AB measurements; 2) Determine the transport kinetics of antibiotics
through the prostatic barrier; and 3) Determine the transport kinetics of prophylaxis antibiotics delivered from
blood to the brain. The proposed research is significant because it will define the structural and transport
characteristics necessary for therapeutic agents to penetrate targeted organs and propel the study of other
therapeutics beyond the families of antibiotics considered here. Thus, this work will develop foundational
knowledge and generate the necessary resources for other researchers and industries – working on drug
development, in-vivo testing and clinical dose scaling – to advance the field of therapeutics. The proposed
research will have an immediate positive impact as it will establish a better understanding of therapeutic drug
transport within compartments in the body. Longer term, this work will have established the groundwork
necessary for the in-vivo evaluation of molecular transport across tight biological barriers.
项目概要
治疗药物进入特定器官的能力很大程度上取决于血液组织的性质
例如,前列腺和大脑具有紧密的屏障,没有细胞间间隙,并且
大多数药物不能以足够高的水平渗透到它们中以达到治疗效果。
药物化学结构、给药方案和器官渗透之间的关系对于
以此为动力,开发新的有效药物疗法。
旨在建立影响治疗药物通过的分子转运参数的测量标准
具体来说,该提案的目的是证明:
基于适配体 (E-AB) 的电化学传感器——一种新兴的传感平台,能够连续
测量体内特定分子的水平——可以支持对分子运输的连续监测
所提出的测量将确定从血液到肝脏、前列腺和大脑的运输参数。
四种治疗药物(三种氨基糖苷类、三种β-内酰胺类和一种糖肽类抗生素)
生物(即血-肝、血-前列腺屏障、血-脑和血-脑脊液)。
选择它是因为,尽管它们可以有效治疗跨器官屏障的感染,但它们也会带来危险的一面
由于其狭窄的治疗窗口所驱动的效应,使其精确剂量成为一项重要的医学挑战。
这项工作的中心假设是实现空间和时间分辨率的药物测量
血液和靶器官将产生前所未有的渗透性数据,从而指导新的治疗药物
开发通透性增强疗法和更有效的给药方案。
该假设将通过追求三个具体目标来检验:1)确定药物摄取的动力学
通过连续、秒级分辨率的 E-AB 测量来检测肝脏;2) 确定抗生素的转运动力学;
通过前列腺屏障;和 3) 确定预防性抗生素的转运动力学
拟议的研究意义重大,因为它将定义血液的结构和运输。
治疗剂渗透目标器官并推动其他研究所需的特性
因此,这项工作将发展为基础性的。
知识并为其他研究人员和行业创造必要的资源——从事药物研究
开发、体内测试和临床剂量调整——以推进治疗领域。
研究将产生立竿见影的积极影响,因为它将加深对治疗药物的了解
从长远来看,这项工作将为体内的运输奠定基础。
对于跨越严格的生物屏障的分子运输的体内评估是必要的。
项目成果
期刊论文数量(9)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Optimization of Vancomycin Aptamer Sequence Length Increases the Sensitivity of Electrochemical, Aptamer-Based Sensors In Vivo.
万古霉素适体序列长度的优化提高了基于适体的电化学传感器的体内灵敏度。
- DOI:
- 发表时间:2022-12-23
- 期刊:
- 影响因子:8.9
- 作者:Shaver, Alexander;Mahlum, J D;Scida, Karen;Johnston, Melanie L;Aller Pellitero, Miguel;Wu, Yao;Carr, Gregory V;Arroyo
- 通讯作者:Arroyo
Expanding the Monolayer Scope for Nucleic Acid-Based Electrochemical Sensors Beyond Thiols on Gold: Alkylphosphonic Acids on ITO.
扩大基于核酸的电化学传感器的单层范围,超越金上的硫醇:ITO 上的烷基膦酸。
- DOI:
- 发表时间:2023-03-01
- 期刊:
- 影响因子:0
- 作者:Shaver, Alexander;Arroyo
- 通讯作者:Arroyo
Analytical Validation of Aptamer-Based Serum Vancomycin Monitoring Relative to Automated Immunoassays.
基于适体的血清万古霉素监测相对于自动免疫测定的分析验证。
- DOI:
- 发表时间:2024-01-26
- 期刊:
- 影响因子:8.9
- 作者:Liu, Yu;Mack, John O;Shojaee, Maryam;Shaver, Alexander;George, Ankitha;Clarke, William;Patel, Neel;Arroyo
- 通讯作者:Arroyo
Nucleic Acid-based Electrochemical Sensors Facilitate the Study of DNA Binding by Platinum (II)-based Antineoplastics.
基于核酸的电化学传感器促进基于铂 (II) 的抗肿瘤药物的 DNA 结合研究。
- DOI:
- 发表时间:2024-03-18
- 期刊:
- 影响因子:0
- 作者:Wu, Yao;Arroyo
- 通讯作者:Arroyo
Study of surface modification strategies to create glassy carbon-supported, aptamer-based sensors for continuous molecular monitoring.
研究表面修饰策略,以创建用于连续分子监测的玻璃碳支撑、基于适配体的传感器。
- DOI:
- 发表时间:2022-07
- 期刊:
- 影响因子:4.3
- 作者:Pellitero, Miguel Aller;Arroyo
- 通讯作者:Arroyo
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Netzahualcoyotl Arroyo Curras其他文献
Netzahualcoyotl Arroyo Curras的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Netzahualcoyotl Arroyo Curras', 18)}}的其他基金
In-Vivo Monitoring of Therapeutic Drug Transport Across Biological Barriers
治疗药物跨生物屏障转运的体内监测
- 批准号:
10094296 - 财政年份:2021
- 资助金额:
$ 32.75万 - 项目类别:
相似国自然基金
社会网络关系对公司现金持有决策影响——基于共御风险的作用机制研究
- 批准号:72302067
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
高尿酸调控TXNIP驱动糖代谢重编程影响巨噬细胞功能
- 批准号:82370895
- 批准年份:2023
- 资助金额:49 万元
- 项目类别:面上项目
倒装芯片超声键合微界面结构演变机理与影响规律
- 批准号:52305599
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
寒地城市学区建成环境对学龄儿童心理健康的影响机制与规划干预路径研究
- 批准号:52378051
- 批准年份:2023
- 资助金额:52 万元
- 项目类别:面上项目
原位研究聚变燃料纯化用Pd-Ag合金中Ag对辐照缺陷演化行为的影响及其相互作用机制
- 批准号:12305308
- 批准年份:2023
- 资助金额:30 万元
- 项目类别:青年科学基金项目
相似海外基金
Elucidating bacterial responses to the novel antimicrobial AGXX
阐明细菌对新型抗菌剂 AGXX 的反应
- 批准号:
10742217 - 财政年份:2023
- 资助金额:
$ 32.75万 - 项目类别:
Shaping Next Generation Aminoglycoside Antibiotics for Treatment of Multidrug-Resistant Diseases
打造下一代氨基糖苷类抗生素治疗多重耐药性疾病
- 批准号:
10585038 - 财政年份:2023
- 资助金额:
$ 32.75万 - 项目类别:
Molecular Mechanisms of Aminoglycoside Ototoxicity
氨基糖苷类耳毒性的分子机制
- 批准号:
10443277 - 财政年份:2022
- 资助金额:
$ 32.75万 - 项目类别: