MMP-14 Chimeric Ligands for Targeted Imaging of Metastatic Tumors
用于转移性肿瘤靶向成像的 MMP-14 嵌合配体
基本信息
- 批准号:9035372
- 负责人:
- 金额:$ 19.63万
- 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:2015-04-01 至 2019-03-31
- 项目状态:已结题
- 来源:
- 关键词:AchievementActive SitesAffinityAftercareAttentionBindingBinding SitesBiological MarkersBreastBreast Cancer CellBreast Cancer PatientCatalytic DomainCause of DeathCell membraneCellsCharacteristicsClinicalCollagenConfocal MicroscopyDetectionDevelopmentDiagnosisDiagnosticDiseaseDisseminated Malignant NeoplasmDyesEarly DiagnosisElementsEnsureExocytosisExtracellular MatrixFamilyFluorescent DyesFoundationsGoalsHealthHemopexinHomodimerizationHydrolysisImageIn VitroIndividualInhibition of Matrix Metalloproteinases PathwayIntegral Membrane ProteinLabelLengthLigandsMMP14 geneMalignant NeoplasmsMatrix MetalloproteinasesMembraneNeoplasm Circulating CellsNeoplasm MetastasisNormal tissue morphologyOpticsOutcomePatient-Focused OutcomesPatientsPeptidesPlayPositron-Emission TomographyPrimary NeoplasmProcessProliferatingQuality of lifeRadiolabeledResearchScreening for cancerSolventsSpecificityStagingTechnologyTestingTherapeuticTherapeutic AgentsTranslatingWorkangiogenesisbasecancer cellclinically relevantexpectationimaging agentimaging modalityimaging platformimaging probein vivoin vivo imaginginhibitor/antagonistinnovationmalignant breast neoplasmmicroscopic imagingmigrationmolecular imagingnoveloptical imagingoutcome forecastoverexpressionradiotracerscaffoldsmall moleculestatisticstargeted agenttargeted imagingtargeted treatmenttumortumor growthtumor progressiontumorigenic
项目摘要
DESCRIPTION (provided by applicant): The proposed work is aimed at developing a selective MMP-14 probe for detecting metastatic and pro-tumorigenic cancer cells characterized by the over-expression of MMP-14. This will be achieved by optimizing a chimeric heterobivalent platform targeted simultaneously to two separate domains of MMP-14. Ligands to both the active site of the catalytic domain and the hemopexin domain will be tethered through a modular linker unit that can be varied in length to match the distance between the two domains. In a solvent exposed region of the linker, a near-IR dye will be installed to allow the heterobivalent platform to selectively label MMP-14- positive cells for detection by confocal microscopy and in vivo optical imaging. This achievement is important because it will ensure the feasibility of advancing this technology to PET imaging applications. In all likelihood, this general strategy can be applied to the selective targeting of other MMPs that serve as disease biomarkers. Our central hypothesis is that a high-affinity MMP-14-specific heterobivalent platform can be developed by optimizing the linker length between a MMP catalytic domain inhibitor and hemopexin domain ligand. When outfitted with a fluorescent dye, this chimeric platform will selectively label MMP-14-positive cells for in vitro and in vivo detection by confocal microscopy and optical imaging, respectively. The rationale for undertaking the proposed research is that the MMP-14-specific imaging platform will serve as the foundation for developing a clinically-relevant imaging modality for the diagnosis and post-treatment assessment of breast and other tumors characterized by over-expression of MMP-14. The approach is innovative in that it aims to selectively target the membrane-bound MMP-14 with a heterobivalent platform tailored to the distance between two of MMP-14's targetable domains rather than optimizing the affinity of scaffolds targeted to a single binding site. In Aim #1, we will test the working hypothesis that optimizing the linker length between a MMP catalytic domain inhibitor and hemopexin domain ligand will result in greater and selective affinity for MMP-14 than monovalent ligands or inhibitors. It is our expectation that the distance between the two domains will provide a unique and additional specificity element to the proposed chimeric heterobivalent platform, which can be tailored to individual MMPs, including MMP-14. Aim 2 is focused on proving-the-concept that enhanced binding to MMP-14 can be accomplished with heterobivalent platform and that fluorescently-labeling this platform with a near-IR fluorescent dye will enable optical in vivo imaging of MMP-14-positive tumors. At the conclusion of these studies, it is our expectation that a working probe for targeting MMP-14-positive tumors will be available for subsequent radiolabeling and the development of a clinically-relevant PET imaging agent for pro-metastatic tumors.
描述(由申请人提供):所提出的工作旨在开发用于检测以MMP-14过表达为特征的转移性和促肿瘤发生性癌细胞的选择性MMP-14探针。这将通过优化同时靶向MMP-14的两个单独结构域的嵌合异二价平台来实现。与催化结构域的活性位点和血红素结合蛋白结构域两者的配体将通过模块化接头单元拴系,所述模块化接头单元的长度可以变化以匹配两个结构域之间的距离。在接头的溶剂暴露区域中,将安装近IR染料以允许异二价平台选择性地标记MMP-14阳性细胞,用于通过共聚焦显微镜和体内光学成像进行检测。这一成就非常重要,因为它将确保将该技术推进到PET成像应用的可行性。在所有的可能性中,这种一般策略可以应用于作为疾病生物标志物的其他MMPs的选择性靶向。 我们的中心假设是,可以通过优化MMP催化结构域抑制剂和血液结合蛋白结构域配体之间的接头长度来开发高亲和力的MMP-14特异性异二价平台。当配备荧光染料时,这种嵌合平台将选择性地标记MMP-14阳性细胞,分别通过共聚焦显微镜和光学成像进行体外和体内检测。开展拟议研究的基本原理是MMP-14特异性成像平台将作为开发临床相关成像模式的基础,用于乳腺和其他以MMP-14过度表达为特征的肿瘤的诊断和治疗后评估。该方法是创新的,因为它旨在用针对MMP-14的两个可靶向结构域之间的距离定制的异二价平台选择性地靶向膜结合的MMP-14,而不是优化靶向单个结合位点的支架的亲和力。 在目标#1中,我们将测试工作假设,即优化MMP催化结构域抑制剂和血红素结合蛋白结构域配体之间的接头长度将导致对MMP-14的亲和力比单价配体或抑制剂更大且具有选择性。我们期望两个结构域之间的距离将为所提出的嵌合异二价平台提供独特和额外的特异性元件,其可以针对个体MMP(包括MMP-14)进行定制。目的2集中于证明可以用异二价平台实现与MMP-14的增强结合的概念,并且用近IR荧光染料荧光标记该平台将使得能够对MMP-14阳性肿瘤进行光学体内成像。在这些研究的结论中,我们期望用于靶向MMP-14阳性肿瘤的工作探针将可用于随后的放射性标记和用于促转移肿瘤的临床相关PET成像剂的开发。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Phosphorus containing analogues of SAHA as inhibitors of HDACs.
- DOI:10.1080/14756366.2022.2063281
- 发表时间:2022-12
- 期刊:
- 影响因子:5.6
- 作者:Pun MD;Wu HH;Olatunji FP;Kesic BN;Peters JW;Berkman CE
- 通讯作者:Berkman CE
{{
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 }}
Clifford Berkman其他文献
Clifford Berkman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('Clifford Berkman', 18)}}的其他基金
Near-IR Ratiometric Fluorescence Probes for Assessing Cargo Delivery to Prostate Tumors
用于评估前列腺肿瘤的货物输送的近红外比率荧光探针
- 批准号:
10328982 - 财政年份:2021
- 资助金额:
$ 19.63万 - 项目类别:
Near-IR Ratiometric Fluorescence Probes for Assessing Cargo Delivery to Prostate Tumors
用于评估前列腺肿瘤的货物输送的近红外比率荧光探针
- 批准号:
10112677 - 财政年份:2021
- 资助金额:
$ 19.63万 - 项目类别:
Development of a Malarial Kinase-on-Phage Screening Platform
疟疾激酶噬菌体筛选平台的开发
- 批准号:
8240362 - 财政年份:2012
- 资助金额:
$ 19.63万 - 项目类别:
Development of a Malarial Kinase-on-Phage Screening Platform
疟疾激酶噬菌体筛选平台的开发
- 批准号:
8517570 - 财政年份:2012
- 资助金额:
$ 19.63万 - 项目类别:
Chemoaffinity Agents For Capturing Prostate Cancer Cells
用于捕获前列腺癌细胞的化学亲和剂
- 批准号:
7512105 - 财政年份:2008
- 资助金额:
$ 19.63万 - 项目类别:
Chemoaffinity Agents For Capturing Prostate Cancer Cells
用于捕获前列腺癌细胞的化学亲和剂
- 批准号:
7666023 - 财政年份:2008
- 资助金额:
$ 19.63万 - 项目类别:
相似海外基金
Collaborative Research: Beyond the Single-Atom Paradigm: A Priori Design of Dual-Atom Alloy Active Sites for Efficient and Selective Chemical Conversions
合作研究:超越单原子范式:双原子合金活性位点的先验设计,用于高效和选择性化学转化
- 批准号:
2334970 - 财政年份:2024
- 资助金额:
$ 19.63万 - 项目类别:
Standard Grant
NSF-BSF: Towards a Molecular Understanding of Dynamic Active Sites in Advanced Alkaline Water Oxidation Catalysts
NSF-BSF:高级碱性水氧化催化剂动态活性位点的分子理解
- 批准号:
2400195 - 财政年份:2024
- 资助金额:
$ 19.63万 - 项目类别:
Standard Grant
Collaborative Research: Beyond the Single-Atom Paradigm: A Priori Design of Dual-Atom Alloy Active Sites for Efficient and Selective Chemical Conversions
合作研究:超越单原子范式:双原子合金活性位点的先验设计,用于高效和选择性化学转化
- 批准号:
2334969 - 财政年份:2024
- 资助金额:
$ 19.63万 - 项目类别:
Standard Grant
Mechanochemical synthesis of nanocarbon and design of active sites for oxygen reducton/evolution reactions
纳米碳的机械化学合成和氧还原/演化反应活性位点的设计
- 批准号:
23K04919 - 财政年份:2023
- 资助金额:
$ 19.63万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Creation of porous inorganic frameworks with controlled structure of metal active sites by the building block method.
通过积木法创建具有金属活性位点受控结构的多孔无机框架。
- 批准号:
22KJ2957 - 财政年份:2023
- 资助金额:
$ 19.63万 - 项目类别:
Grant-in-Aid for JSPS Fellows
Catalysis of Juxaposed Active Sites Created in Nanospaces and Their Applications
纳米空间中并置活性位点的催化及其应用
- 批准号:
23K04494 - 财政年份:2023
- 资助金额:
$ 19.63万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Generation of carbon active sites by modifying the oxygen containing functional groups and structures of carbons for utilizing to various catalytic reactions.
通过修饰碳的含氧官能团和结构来产生碳活性位点,用于各种催化反应。
- 批准号:
23K13831 - 财政年份:2023
- 资助金额:
$ 19.63万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
CAREER: CAS: Understanding the Chemistry of Palladium and Silyl Compounds to Design Catalyst Active Sites
职业:CAS:了解钯和甲硅烷基化合物的化学性质以设计催化剂活性位点
- 批准号:
2238379 - 财政年份:2023
- 资助金额:
$ 19.63万 - 项目类别:
Continuing Grant
CAS: Collaborative Research: Tailoring the Distribution of Transient vs. Dynamic Active Sites in Solid-Acid Catalysts and Their Impacts on Chemical Conversions
CAS:合作研究:定制固体酸催化剂中瞬时活性位点与动态活性位点的分布及其对化学转化的影响
- 批准号:
2154399 - 财政年份:2022
- 资助金额:
$ 19.63万 - 项目类别:
Standard Grant
Engineering of Active Sites in Heterogeneous Catalysts for Sustainable Chemical and Fuel Production.
用于可持续化学和燃料生产的多相催化剂活性位点工程。
- 批准号:
RGPIN-2019-06633 - 财政年份:2022
- 资助金额:
$ 19.63万 - 项目类别:
Discovery Grants Program - Individual