The Tumor Microenvironment in Nanoparticle Delivery and Function
纳米颗粒递送和功能中的肿瘤微环境
基本信息
- 批准号:10059035
- 负责人:
- 金额:$ 37.46万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-06-01 至 2025-05-31
- 项目状态:未结题
- 来源:
- 关键词:AreaBlood VesselsCharacteristicsChemicalsCholineCholine KinaseCollaborationsCollagenCollagen FiberComplexDataDextransDown-RegulationEffectivenessEnvironmentEvolutionExtracellular MatrixFiberFormulationFunctional ImagingFutureGene SilencingGenerationsGenetic EngineeringGoalsGrowth Factor OverexpressionHumanHypoxiaImageImaging TechniquesImaging technologyImmunohistochemistryLinkLymphaticMDA MB 231Magnetic Resonance ImagingMalignant NeoplasmsMass Spectrum AnalysisMediatingMicroscopyModelingOutcomePermeabilityPhysiologicalPlayPorosityPositron-Emission TomographyProteomeProteomicsRNA deliveryReagentReporterReportingResourcesResponse ElementsRoleSliceSmall Interfering RNASpecificityTestingTissuesTranslationsVascular Endothelial Growth FactorsXenograft procedurebasebiomaterial compatibilitycancer cellcancer imagingclinically translatabledruggable targetex vivo imagingexperienceextracellularimaging studyimprovedin vivointerestmagnetic resonance spectroscopic imagingmetabolomemetabolomicsmolecular imagingmultimodalitynanoparticlenanoparticle deliveryoptical imagingoverexpressionprecision medicineprecision oncologyprotein expressionresponsesecond harmonicspectroscopic imagingtheranosticstherapeutic nanoparticlestriple-negative invasive breast carcinomatumortumor hypoxiatumor microenvironmentuptake
项目摘要
In response to this IRCN FOA, in this application we have combined our experience of two decades in
understanding the tumor microenvironment (TME) with molecular and functional imaging, and our experience
of a decade in developing theranostic nanoparticles (NPs) that deliver small interfering RNA (siRNA), to
understand the role of TME in siRNA NP delivery and function.
siRNA have emerged as promising candidates for precision medicine in cancer that becomes significantly
important for cancers such as triple negative breast cancer (TNBC) that lack targeted treatments. Here we will
perform combined in vivo PET-MR imaging studies to relate siRNA NP delivery, as detected by PET imaging,
to vascular parameters, acidic extracellular pH (pHe), and extracellular matrix (ECM) porosity as detected by
MRI to understand the role of the TME in siRNA NP delivery and function. The dextran NP we selected is
biocompatible making it an excellent translational candidate; the siRNA we selected for delivery downregulates
choline kinase (Chk), an important target in cancer cells. Downregulation of Chk results in a decrease of total
choline that can be imaged with MR spectroscopic imaging (MRSI), allowing us to relate siRNA delivery to
function noninvasively. Both PET and MR are also easily translatable to humans.
We will integrate ex vivo mass spectrometry imaging (MSI), second harmonic generation (SHG) microscopy,
and immunohistochemistry (IHC) of co-localized tumor sections to expand our understanding of the changes
mediated by the Chk siRNA on the proteome, lipidome and metabolome with MSI, and of the characteristics of
the ECM that play a role in NP delivery and distribution with SHG microscopy and IHC. These studies will be
performed with human TNBC xenografts genetically engineered to overexpress vascular endothelial growth
factor (VEGF) or to report on hypoxia. The reagents, resources, tumor models and imaging technologies
developed through this application will be available to the Alliance awardees and for collaborations outside of
the current Alliance network to establish mutually beneficial collaborations. These studies have the potential to
provide future clinically translatable applications in achieving precision medicine of cancer.
为了响应IRCN FOA,在此应用中,我们结合了二十年的经验,
通过分子和功能成像了解肿瘤微环境(TME),以及我们的经验
在开发治疗诊断纳米颗粒(NP),提供小干扰RNA(siRNA),
了解TME在siRNA NP递送和功能中的作用。
siRNA已经成为癌症精确医学的有希望的候选者,
对于缺乏靶向治疗的三阴性乳腺癌(TNBC)等癌症非常重要。这里我们将
进行组合的体内PET-MR成像研究以关联siRNA NP递送,如通过PET成像检测的,
血管参数,酸性细胞外pH值(pHe)和细胞外基质(ECM)孔隙率,如通过
MRI以了解TME在siRNA NP递送和功能中的作用。我们选择的右旋糖酐NP是
生物相容性使其成为一个优秀的翻译候选者;我们选择用于递送的siRNA下调
胆碱激酶(Chk)是癌细胞中的重要靶点。Chk的下调导致总的
胆碱,可以用MR光谱成像(MRSI)成像,使我们能够将siRNA递送与
非侵入性功能。PET和MR也很容易翻译成人类。
我们将整合离体质谱成像(MSI),二次谐波发生(SHG)显微镜,
和免疫组化(IHC)的共定位肿瘤切片,以扩大我们的理解的变化,
Chk siRNA介导的蛋白质组、脂质组和代谢组MSI,以及
用SHG显微镜和IHC观察在NP递送和分布中起作用ECM。这些研究报告将
用基因工程改造的人TNBC异种移植物进行,
因子(VEGF)或报告缺氧。试剂、资源、肿瘤模型和成像技术
通过此应用程序开发的应用程序将提供给联盟获奖者,并用于
目前的联盟网络,以建立互利的合作。这些研究有可能
为实现癌症的精确医疗提供未来的临床可转化应用。
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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Zaver M. Bhujwalla其他文献
Low-dose temozolomide selectively increases glioblastoma’s vascular permeability, tumor microenvironment penetration and the killing potential of systemic actinium-225 α-particle dendrimer-radioconjugates improving treatment efficacy
- DOI:
10.1007/s00259-025-07332-w - 发表时间:
2025-05-14 - 期刊:
- 影响因子:7.600
- 作者:
Rajiv Ranjit Nair;Aira Sarkar;Pooja Hariharan;Kathleen L. Gabrielson;Tony Wu;Chang Liu;Anjali Sharma;Wathsala Liyanage;Zaver M. Bhujwalla;Marie-France Penet Vidaver;Rangaramanujam M. Kannan;Stavroula Sofou - 通讯作者:
Stavroula Sofou
Artificial neural network detection of pancreatic cancer from proton (1H) magnetic resonance spectroscopy patterns of plasma metabolites
基于血浆代谢物质子(1H)磁共振波谱模式的胰腺癌人工神经网络检测
- DOI:
10.1038/s43856-024-00727-0 - 发表时间:
2025-01-21 - 期刊:
- 影响因子:6.300
- 作者:
Meiyappan Solaiyappan;Santosh Kumar Bharti;Raj Kumar Sharma;Mohamad Dbouk;Wasay Nizam;Malcolm V. Brock;Michael G. Goggins;Zaver M. Bhujwalla - 通讯作者:
Zaver M. Bhujwalla
Molecular and functional imaging insights into the role of hypoxia in cancer aggression
- DOI:
10.1007/s10555-019-09788-3 - 发表时间:
2019-03-06 - 期刊:
- 影响因子:8.700
- 作者:
Samata Kakkad;Balaji Krishnamachary;Desmond Jacob;Jesus Pacheco-Torres;Eibhlin Goggins;Santosh Kumar Bharti;Marie-France Penet;Zaver M. Bhujwalla - 通讯作者:
Zaver M. Bhujwalla
Zaver M. Bhujwalla的其他文献
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{{ truncateString('Zaver M. Bhujwalla', 18)}}的其他基金
The Tumor Microenvironment in Nanoparticle Delivery and Function
纳米颗粒递送和功能中的肿瘤微环境
- 批准号:
10405098 - 财政年份:2020
- 资助金额:
$ 37.46万 - 项目类别:
The Tumor Microenvironment in Nanoparticle Delivery and Function
纳米颗粒递送和功能中的肿瘤微环境
- 批准号:
10170305 - 财政年份:2020
- 资助金额:
$ 37.46万 - 项目类别:
The Tumor Microenvironment in Nanoparticle Delivery and Function
纳米颗粒递送和功能中的肿瘤微环境
- 批准号:
10617333 - 财政年份:2020
- 资助金额:
$ 37.46万 - 项目类别:
Molecular Imaging Reagents for Prostate Cancer Theranostics
用于前列腺癌治疗诊断的分子成像试剂
- 批准号:
10226208 - 财政年份:2017
- 资助金额:
$ 37.46万 - 项目类别:
Molecular Imaging of Cachexia in Pancreatic Cancer
胰腺癌恶病质的分子影像
- 批准号:
9026680 - 财政年份:2015
- 资助金额:
$ 37.46万 - 项目类别:
Decoy nanoparticles to disrupt cancer cell-stromal cell networks
诱饵纳米颗粒破坏癌细胞-基质细胞网络
- 批准号:
9102034 - 财政年份:2015
- 资助金额:
$ 37.46万 - 项目类别:
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