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种基于精确的纳米治疗诊断平台,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性成像生物标志物
反应新的抗癌药物继续开发,但许多失败,由于肿瘤的发展(多)
耐药性细胞膜蛋白作为药物外排泵已被确定,而
一些有希望的药剂进入肿瘤细胞后,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豆荚蛋白酶(一种天冬酰胺酰内肽酶)
用于特异性切割奥沙拉嗪(Olsa)缀合的肽底物,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:
具有最小药物流出的细胞内包埋; 2)延长的肿瘤药物暴露;和3)对
由于非组装单分子的快速血液清除,正常器官。我们有初步数据
证明了该概念在体内是可行的。因为它不仅是一种抗癌药物,
抑制DNA甲基化,也可作为非金属、无标记的化学交换造影剂
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。的
药物可以可视化而无需修改,允许直接成像而无需药理学改变,
可能影响自组装和/或生物分布。在体外选择最佳的Olsa-CBT-800 CW-Rn-1后,
AAN底物在豆类蛋白过表达的DU 145细胞中具有最大的肿瘤细胞渗透和保留
(Aim 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诊断特性
肿瘤模型(Aim 2)和转基因小鼠模型(TRAMP小鼠),其中正常前列腺细胞经历了
随着时间的推移发生恶性转化(目标3)。如果成功,这种方法可以扩展到其他酶-
靶向CEST MRI可检测的治疗诊断平台,用于成像肿瘤侵袭性,药物积聚,
和预测治疗反应。
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
- 批准号:
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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- 批准号:
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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10006002 - 财政年份:2019
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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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