Intracellular Self-Assembly of Theranostic Nanoparticles for Enhanced Imaging and Tumor Therapy
用于增强成像和肿瘤治疗的治疗诊断纳米颗粒的细胞内自组装
基本信息
- 批准号:10207626
- 负责人:
- 金额:$ 51.64万
- 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:2020-07-10 至 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAnti-Inflammatory AgentsAntineoplastic AgentsArginineAspirinBiodistributionBloodCaspaseCell divisionCell membraneCellsCellular MembraneChemical AgentsChemicalsCleaved cellColon CarcinomaContrast MediaDNA MethylationDNA Methylation InhibitionDU145DataDetectionDrug EffluxDrug ExposureEnzymesFDA approvedFailureFormulationGlutathioneGoalsHourHumanHydroxyl RadicalImageImage EnhancementIn VitroInjectableIntravenousKidneyLNCaPLabelLengthLiverMRI ScansMagnetic Resonance ImagingMalignant - descriptorMalignant NeoplasmsMalignant neoplasm of prostateMeasurementMeasuresMediatingMembrane ProteinsModelingModificationMulti-Drug ResistanceMusNanostructuresNear-infrared optical imagingOpticsOrganPenetrationPeptidesPermeabilityPharmaceutical PreparationsPharmacologyPhysical condensationPrediction of Response to TherapyPropertyProprotein ConvertasesProstateProstate Cancer therapyProtonsReactionSalicylic AcidsSignal TransductionSpleenTestingTherapeuticTimeToxic effectTransgenic MiceTreatment EfficacyValidationXenograft Modelasparaginylendopeptidasebasebiomaterial compatibilitycancer cellcancer imagingchemical reactionclinical translationclinically relevantcontrast enhancedefflux pumpimaging biomarkerimaging platformin vivoinhibitor/antagonistmouse modelnanoparticlenanotheranosticsnear infrared dyeneoplastic cellnovelnovel anticancer drugoverexpressionprognosticprostate cancer cellprostate cancer cell lineprostate cancer modelprotein aminoacid sequenceself assemblysingle moleculesmall moleculesubcutaneoussuccesstheranosticstransgenic adenocarcinoma of mouse prostatetreatment responsetumortumor growthuptake
项目摘要
Our overall aim is to develop a precision-based nanotheranostic platform where the imaging signal may
serve as an early predictive imaging biomarker for intracellular nanoparticle accumulation and therapeutic
response. New anti-cancer agents continue to be developed, but many fail due to the tumor developing (multi-)
drug resistance. Cellular membrane proteins acting as a drug efflux pump have been identified, and while
some promising agents enter tumor cells, they cannot always be retained long enough to be effective. We aim
to exploit the enzyme legumain (an asparaginyl endopeptidase) that is overexpressed in prostate cancer cells
for specific cleavage of an olsalazine (Olsa)-conjugated peptide substrate, following which the substrate self-
assembles into intracellular nanoparticles. This enzyme-driven self-assembly serves several purposes: 1)
intracellular entrapment with minimal drug efflux; 2) prolonged tumor drug exposure; and 3) minimal toxicity to
normal organs due to rapid blood clearance of non-assembled single molecules. We have preliminary data
demonstrating this concept to be feasible in vivo. Since it does not only serve as an anti-cancer drug through
inhibition of DNA methylation, but also as a non-metallic, label-free contrast agent for chemical exchange
saturation transfer magnetic resonance imaging (CEST MRI), olsalazine is a unique theranostic agent. The
drug can be visualized without modification, allowing direct imaging without pharmacological alterations that
may affect self-assembly and/or biodistribution. Following in vitro selection of an optimal Olsa-CBT-800CW-Rn-
AAN substrate with maximum tumor cell penetration and retention in legumain-overexpressing DU145 cells
(Aim 1), we will test this compound for its in vivo nanotheranostic properties in an orthotopic mouse prostate
tumor model (Aim 2) and a transgenic mouse model (TRAMP mouse) where normal prostate cells undergo a
malignant transformation over time (Aim 3). If successful, this approach may be extended to other enzyme-
targeted CEST MRI-detectable theranostic platforms for imaging tumor aggressiveness, drug accumulation,
and predicting therapeutic response.
我们的总体目标是开发一个基于精密的纳米治疗平台,其中成像信号可以
作为细胞内纳米颗粒积累和治疗的早期预测成像生物标志物
回复。新的抗癌药物不断被开发,但许多都因肿瘤的发展而失败(多)
耐药性。已鉴定出充当药物流出泵的细胞膜蛋白,同时
一些有前途的药物进入肿瘤细胞,但它们不能总是保留足够长的时间以发挥作用。我们的目标
利用在前列腺癌细胞中过度表达的 Legumain 酶(一种天冬酰胺酰内肽酶)
用于奥沙拉嗪 (Olsa) 缀合肽底物的特异性裂解,随后底物自
组装成细胞内纳米颗粒。这种酶驱动的自组装有几个目的:1)
细胞内包埋,药物流出最少; 2)肿瘤药物暴露时间延长; 3) 毒性最小
由于非组装单分子的快速血液清除而导致正常器官。我们有初步数据
证明这个概念在体内是可行的。因为它不仅可以作为抗癌药物
抑制 DNA 甲基化,还可作为非金属、无标记造影剂进行化学交换
饱和转移磁共振成像(CEST MRI),奥沙拉嗪是一种独特的治疗诊断剂。这
药物无需修改即可可视化,无需药理学改变即可直接成像
可能会影响自组装和/或生物分布。在体外选择最佳 Olsa-CBT-800CW-Rn- 后
AAN 底物在过表达 legumain 的 DU145 细胞中具有最大的肿瘤细胞渗透和保留能力
(目标 1),我们将在原位小鼠前列腺中测试该化合物的体内纳米治疗特性
肿瘤模型(目标 2)和转基因小鼠模型(TRAMP 小鼠),其中正常前列腺细胞经历
随着时间的推移发生恶性转变(目标 3)。如果成功的话,这种方法可能会扩展到其他酶
靶向 CEST MRI 可检测治疗诊断平台,用于对肿瘤侵袭性、药物积累、
并预测治疗反应。
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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Jeff W. Bulte其他文献
Jeff W. Bulte的其他文献
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{{ truncateString('Jeff W. Bulte', 18)}}的其他基金
Precision magnetic hyperthermia by integrating magnetic particle imaging
通过集成磁粒子成像实现精确磁热疗
- 批准号:
10296182 - 财政年份:2021
- 资助金额:
$ 51.64万 - 项目类别:
Precision magnetic hyperthermia by integrating magnetic particle imaging
通过集成磁粒子成像实现精确磁热疗
- 批准号:
10667448 - 财政年份:2021
- 资助金额:
$ 51.64万 - 项目类别:
Precision magnetic hyperthermia by integrating magnetic particle imaging
通过集成磁粒子成像实现精确磁热疗
- 批准号:
10415219 - 财政年份:2021
- 资助金额:
$ 51.64万 - 项目类别:
Intracellular Self-Assembly of Theranostic Nanoparticles for Enhanced Imaging and Tumor Therapy
用于增强成像和肿瘤治疗的治疗诊断纳米颗粒的细胞内自组装
- 批准号:
10400220 - 财政年份:2020
- 资助金额:
$ 51.64万 - 项目类别:
Intracellular Self-Assembly of Theranostic Nanoparticles for Enhanced Imaging and Tumor Therapy
用于增强成像和肿瘤治疗的治疗诊断纳米颗粒的细胞内自组装
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10063659 - 财政年份:2020
- 资助金额:
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Non-Invasive Tracking of Genome-Corrected iPS cells in ALS
对 ALS 中基因组校正的 iPS 细胞进行无创追踪
- 批准号:
10472760 - 财政年份:2019
- 资助金额:
$ 51.64万 - 项目类别:
Non-Invasive Tracking of Genome-Corrected iPS cells in ALS
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10447292 - 财政年份:2019
- 资助金额:
$ 51.64万 - 项目类别:
Non-Invasive Tracking of Genome-Corrected iPS cells in ALS
对 ALS 中基因组校正的 iPS 细胞进行无创追踪
- 批准号:
9810637 - 财政年份:2019
- 资助金额:
$ 51.64万 - 项目类别:
Non-Invasive Tracking of Genome-Corrected iPS cells in ALS
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再生医学中复合透明质酸水凝胶的无标记成像
- 批准号:
9389085 - 财政年份:2017
- 资助金额:
$ 51.64万 - 项目类别:
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