Non-perturbative imaging of intracellular drug exposure and drug response of kinase inhibitors

激酶抑制剂细胞内药物暴露和药物反应的非微扰成像

基本信息

  • 批准号:
    10606525
  • 负责人:
  • 金额:
    $ 38.5万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-08-01 至 2025-04-30
  • 项目状态:
    未结题

项目摘要

Abstract: The past two decades have witnessed unparalleled success in the development of therapeutic kinase inhibitors targeting protein enzymes that are essential for cellular signaling cascades. The major challenges in kinase inhibitor drug treatment are interindividual variability, compromised drug efficacy, inevitable drug resistance, and toxicity. All of these properties depend strongly on intracellular drug concentration, which can be profoundly influenced by heterogeneous tissue penetration, drug transport, and lysosomal drug sequestration. However, currently there is no technology that can quantitatively examine intracellular concentration of kinase inhibitor drugs in living cells with subcellular spatial resolution. Stimulated Raman scattering (SRS) microscopy is an emerging chemical imaging technique that monitors molecule-specific vibrational signatures to provide quantitative, spatially resolved measurements of molecular concentration. We propose to develop novel SRS- based methods to enable non-perturbative, quantitative determination of single cell drug exposure for the first time. The first method uses the pH partition theory to derive cytosolic drug concentration based on lysosomal drug sequestration of weakly basic drugs. The second method uses an ultrasensitive Fourier-transform SRS technique and advanced chemometric analysis to directly determine cytosolic drug concentration. We will use these innovative methods to determine EGFR inhibitor penetration and drug sequestration in vitro using 3D tumor spheroids and in vivo using the dorsal skinfold chamber mouse model. In addition, we will systematically vary the physicochemical properties of drug compounds and determine their influence on drug transport, sequestration, and penetration. The second goal of this proposal is to elucidate the heterogeneity of cell response to kinase inhibitor drug treatment. Drug response of cancer cells depend on not only their genetic aberrations, but also their phenotypic states and microenvironments. Traditional proliferation assays measure the ensemble response of a cell population and are unable to resolve the highly heterogeneous drug response of cells in a 3D environment. We propose to develop a quantitative, high sensitivity single-cell growth-rate measurement technique based on deuterium pulse labeling. We will validate the use of growth rate change as an accurate predictor of drug response. By combining single cell drug exposure and drug response measurements in 3D tumor spheroids, we will further dissect the influence of drug penetration, intracellular drug exposure, and cell microenvironment on cell drug response. The proposed work builds on our strong expertise in label-free optical imaging and addresses key challenges in drug discovery and development by providing unprecedented measurement capabilities. The technologies and methods developed can be broadly applied to small molecule drugs, with great potentials to accelerate early stage drug discovery and empower personalized drug screening.
文摘:

项目成果

期刊论文数量(11)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Coherent Raman Microscopy: from instrumentation to applications.
相干拉曼显微镜:从仪器到应用。
Quantitative Chemical Imaging of Bone Tissue for Intraoperative and Diagnostic Applications.
  • DOI:
    10.1021/acs.analchem.1c04354
  • 发表时间:
    2022-03-08
  • 期刊:
  • 影响因子:
    7.4
  • 作者:
    Shin KS;Men S;Wong A;Cobb-Bruno C;Chen EY;Fu D
  • 通讯作者:
    Fu D
Real-Time, Two-Color Stimulated Raman Scattering Imaging of Mouse Brain for Tissue Diagnosis.
In vivo simultaneous nonlinear absorption Raman and fluorescence (SNARF) imaging of mouse brain cortical structures.
  • DOI:
    10.1038/s42003-022-03166-6
  • 发表时间:
    2022-03-10
  • 期刊:
  • 影响因子:
    5.9
  • 作者:
    Francis AT;Manifold B;Carlson EC;Hu R;Hill AH;Men S;Fu D
  • 通讯作者:
    Fu D
{{ 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 }}

Dan Fu其他文献

Dan Fu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('Dan Fu', 18)}}的其他基金

Fast volumetric imaging of oxygen delivery in the mouse brain at single red blood cell resolution
以单红细胞分辨率对小鼠大脑中的氧气输送进行快速体积成像
  • 批准号:
    10525881
  • 财政年份:
    2022
  • 资助金额:
    $ 38.5万
  • 项目类别:
Non-perturbative imaging of intracellular drug exposure and drug response of kinase inhibitors - Admin Supp
激酶抑制剂细胞内药物暴露和药物反应的非微扰成像 - Admin Supp
  • 批准号:
    10392656
  • 财政年份:
    2019
  • 资助金额:
    $ 38.5万
  • 项目类别:
Non-perturbative imaging of intracellular drug exposure and drug response of kinase inhibitors
激酶抑制剂细胞内药物暴露和药物反应的非微扰成像
  • 批准号:
    9980422
  • 财政年份:
    2019
  • 资助金额:
    $ 38.5万
  • 项目类别:
Non-perturbative imaging of intracellular drug exposure and drug response of kinase inhibitors
激酶抑制剂细胞内药物暴露和药物反应的非微扰成像
  • 批准号:
    10391453
  • 财政年份:
    2019
  • 资助金额:
    $ 38.5万
  • 项目类别:
Non-perturbative imaging of intracellular drug exposure and drug response of kinase inhibitors
激酶抑制剂细胞内药物暴露和药物反应的非微扰成像
  • 批准号:
    9796634
  • 财政年份:
    2019
  • 资助金额:
    $ 38.5万
  • 项目类别:

相似海外基金

EXCESS: The role of excess topography and peak ground acceleration on earthquake-preconditioning of landslides
过量:过量地形和峰值地面加速度对滑坡地震预处理的作用
  • 批准号:
    NE/Y000080/1
  • 财政年份:
    2024
  • 资助金额:
    $ 38.5万
  • 项目类别:
    Research Grant
Collaborative Research: FuSe: R3AP: Retunable, Reconfigurable, Racetrack-Memory Acceleration Platform
合作研究:FuSe:R3AP:可重调、可重新配置、赛道内存加速平台
  • 批准号:
    2328975
  • 财政年份:
    2024
  • 资助金额:
    $ 38.5万
  • 项目类别:
    Continuing Grant
SHINE: Origin and Evolution of Compressible Fluctuations in the Solar Wind and Their Role in Solar Wind Heating and Acceleration
SHINE:太阳风可压缩脉动的起源和演化及其在太阳风加热和加速中的作用
  • 批准号:
    2400967
  • 财政年份:
    2024
  • 资助金额:
    $ 38.5万
  • 项目类别:
    Standard Grant
Collaborative Research: FuSe: R3AP: Retunable, Reconfigurable, Racetrack-Memory Acceleration Platform
合作研究:FuSe:R3AP:可重调、可重新配置、赛道内存加速平台
  • 批准号:
    2328973
  • 财政年份:
    2024
  • 资助金额:
    $ 38.5万
  • 项目类别:
    Continuing Grant
Market Entry Acceleration of the Murb Wind Turbine into Remote Telecoms Power
默布风力涡轮机加速进入远程电信电力市场
  • 批准号:
    10112700
  • 财政年份:
    2024
  • 资助金额:
    $ 38.5万
  • 项目类别:
    Collaborative R&D
Collaborative Research: FuSe: R3AP: Retunable, Reconfigurable, Racetrack-Memory Acceleration Platform
合作研究:FuSe:R3AP:可重调、可重新配置、赛道内存加速平台
  • 批准号:
    2328972
  • 财政年份:
    2024
  • 资助金额:
    $ 38.5万
  • 项目类别:
    Continuing Grant
Collaborative Research: A new understanding of droplet breakup: hydrodynamic instability under complex acceleration
合作研究:对液滴破碎的新认识:复杂加速下的流体动力学不稳定性
  • 批准号:
    2332916
  • 财政年份:
    2024
  • 资助金额:
    $ 38.5万
  • 项目类别:
    Standard Grant
Collaborative Research: A new understanding of droplet breakup: hydrodynamic instability under complex acceleration
合作研究:对液滴破碎的新认识:复杂加速下的流体动力学不稳定性
  • 批准号:
    2332917
  • 财政年份:
    2024
  • 资助金额:
    $ 38.5万
  • 项目类别:
    Standard Grant
Collaborative Research: FuSe: R3AP: Retunable, Reconfigurable, Racetrack-Memory Acceleration Platform
合作研究:FuSe:R3AP:可重调、可重新配置、赛道内存加速平台
  • 批准号:
    2328974
  • 财政年份:
    2024
  • 资助金额:
    $ 38.5万
  • 项目类别:
    Continuing Grant
Study of the Particle Acceleration and Transport in PWN through X-ray Spectro-polarimetry and GeV Gamma-ray Observtions
通过 X 射线光谱偏振法和 GeV 伽马射线观测研究 PWN 中的粒子加速和输运
  • 批准号:
    23H01186
  • 财政年份:
    2023
  • 资助金额:
    $ 38.5万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了