Chemically produced neural progenitors loaded with ferumoxide-protamine sulfate complex for visualization of gliomas
化学生产的神经祖细胞负载有氧化铁-硫酸鱼精蛋白复合物,用于神经胶质瘤的可视化
基本信息
- 批准号:9621033
- 负责人:
- 金额:$ 30万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-01 至 2021-11-30
- 项目状态:已结题
- 来源:
- 关键词:Adipose tissueAdultAnimalsApoptosisAreaBiological AssayBone MarrowBrainBrain NeoplasmsCellsCerebral hemisphereChemical ExposureChemicalsClinicalComplexConditioned Culture MediaContralateralContrast MediaDataDetectionDiagnosisDiagnosticDisadvantagedDistantDrug Delivery SystemsExcisionExhibitsExposure toExtracellular Matrix ProteinsFailureFibronectinsGenerationsGlioblastomaGliomaGoalsHistologicHumanImageryImaging technologyImplantIn VitroInfiltrationInjectionsIntracranial NeoplasmsInvestigational TherapiesIronLabelLeftMagnetic Resonance ImagingMagnetismMalignant GliomaMalignant NeoplasmsManufacturer NameMesenchymal Stem CellsMethodsMicrosatellite RepeatsModificationMonitorNude MicePatientsPhasePositioning AttributeProductionProtamine SulfateProtocols documentationPrussian blueRecurrenceReportingReproducibilityResearchRiskRouteSmall Business Innovation Research GrantSourceStainsStem cellsSystemTechnologyTestingTherapeuticTreatment EfficacyTropismTumor Cell InvasionVisualization softwareWorkXenograft procedurebrain parenchymabrain tissuecancer cellcell typecost effectivecytotoxicityferumoxidesimage visualizationimaging modalityimplantationimprovedin vivoinduced pluripotent stem celllaminin-9migrationneoplastic cellnerve stem celloutcome forecastparticlephase 1 studyphase 2 studyrelating to nervous systemsmall moleculestemstem cell technologystem cell therapytooltumortumor growth
项目摘要
Glioblastoma is a highly invasive tumor with a recurrence rate of 98%, which is in most cases rapidly fatal. The
failure of current clinical and experimental therapies to eradicate disseminated glioma cells results in tumor
recurrence and a median survival of 3–6 months. Furthermore, currently available imaging technologies are
not sufficiently sensitive for detection of small tumor satellites, which are responsible for recurrence. Recent
research advances have established mesenchymal stem cells (MSCs), neural stem cells (NSCs), and neural
progenitor cells (NPCs) as promising therapeutic delivery vehicles for gliomas. These stem cells track down
cancer cells in the tumor mass as well as migratory cancer cells into the brain parenchyma. Because of this
unique ability, the use of MSCs and NSCs/NPCs as therapeutic and imaging modalities has been explored.
Several recent studies demonstrated many advantages of NSCs over MSCs. Specifically, NSCs have a unique
ability to suppress tumor growth in vivo, and exhibit greater and more specific tropism to gliomas. The
disadvantage of NSCs is the lack of an adequate NSC source. Current alternative approaches to produce
NSCs by induced pluripotent stem cell (iPSC) technologies are fraught with incalculable risks. Recently, we
have been able to generate neural stem/progenitor cells from human bone marrow and adipose derived MSCs
using a purely chemical approach (or small molecule approach) that has several advantages over currently
known technologies. Our recent studies demonstrated that these chemically induced neural progenitors
(CiNPCs) exhibited higher migratory capacity to malignant glioma D54-GM cells compared to hMSCs which
was further increased by pre-exposure of these cells to D54-MG conditioned medium (GCM). Thus, CiNPCs
produced by our recently developed safe, fast, reproducible, and cost-effective reprogramming approach can
be efficiently used as a drug delivery vehicle for the treatment of brain tumors and/or as carriers for magnetic
resonance imaging (MRI) contrast agents for visualization of gliomas. The goal of this SBIR phase I proposal is
to investigate whether GCM pre-exposed and magnetically labeled CiNPCs could be utilized for visualization of
intracranial D54-MG glioma cells by MRI. Phase II studies will investigate the potential use of these cells for
MRI visualization of different types of gliomas. Commercial and clinically compatible research products
emerging from Phase I/II work includes technology for large-scale clinical grade production of magnetically
loaded CiNPCs that can be used for visualization of different gliomas by MRI. To achieve these goals the
following Specific Aims are proposed for Phase I studies. Specific Aim 1 will test the hypothesis that GCM pre-
exposed CiNPCs loaded with ferumoxide-protamine sulfate complex (FE-Pro) will retain their viability and
tropism to D54-MG cells in vitro. Specific Aim 2 will test the hypothesis that GCM pre-exposed and FE-Pro-
loaded CiNPCs will exhibit tropism to D54-MG glioma xenografts in vivo, which can be monitored by MRI.
胶质母细胞瘤是一种高度侵袭性肿瘤,复发率为98%,在大多数情况下迅速致命。的
目前的临床和实验治疗不能根除播散的神经胶质瘤细胞,
复发和中位生存期为3-6个月。此外,目前可用的成像技术
对于检测导致复发的小肿瘤卫星不够敏感。最近
研究进展已经建立了间充质干细胞(MSC)、神经干细胞(NSC)和神经干细胞(NSC)。
祖细胞(NPC)作为神经胶质瘤有前途的治疗载体。这些干细胞追踪
肿瘤块中的癌细胞以及迁移到脑实质中的癌细胞。因为如此
由于其独特的能力,已经探索了MSC和NSC/NPC作为治疗和成像方式的用途。
最近的几项研究表明,NSC比MSC具有许多优势。具体来说,NSC具有独特的
抑制体内肿瘤生长的能力,并表现出对神经胶质瘤更大和更特异的向性。的
NSC的缺点是缺乏足够的NSC来源。目前的替代生产方法
通过诱导多能干细胞(iPSC)技术的NSC充满了不可估量的风险。最近我们
已经能够从人骨髓和脂肪来源的MSC产生神经干/祖细胞
使用纯化学方法(或小分子方法),
已知的技术。我们最近的研究表明,这些化学诱导的神经祖细胞
与hMSC相比,CiNPCs表现出更高的向恶性胶质瘤D54-GM细胞的迁移能力,
通过将这些细胞预暴露于D54-MG条件培养基(GCM)进一步增加。因此,CiNPC
通过我们最近开发的安全、快速、可重复和具有成本效益的重编程方法,
有效地用作治疗脑肿瘤的药物递送载体和/或用作磁性药物的载体。
用于神经胶质瘤可视化的磁共振成像(MRI)造影剂。SBIR第一阶段提案的目标是
研究GCM预暴露和磁性标记的CiNPC是否可用于可视化
颅内D54-MG胶质瘤细胞。II期研究将调查这些细胞用于
不同类型胶质瘤的MRI可视化。商业和临床兼容的研究产品
从I/II期工作中出现的技术包括大规模临床级磁性药物生产技术,
这些细胞可以用于通过MRI可视化不同的神经胶质瘤。为了实现这些目标,
I期研究提出了以下具体目标。具体目标1将检验假设,即大气环流模型前-
负载有阿魏酸去铁蛋白-硫酸鱼精蛋白复合物(FE-Pro)的暴露的CiNPC将保持它们的活力,
对D54-MG细胞的体外嗜性。具体目标2将检验GCM预暴露和FE-Pro-
负载的CiNPC将在体内表现出对D54-MG神经胶质瘤异种移植物的向性,这可以通过MRI监测。
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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Arshak R Alexanian其他文献
Arshak R Alexanian的其他文献
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{{ truncateString('Arshak R Alexanian', 18)}}的其他基金
Hypoxic chamber system for cost-effective and efficient screening of the effect of different oxygen levels on cellular growth and function
低氧室系统可经济有效地筛选不同氧气水平对细胞生长和功能的影响
- 批准号:
10324537 - 财政年份:2021
- 资助金额:
$ 30万 - 项目类别:
New Cell Reprogramming Technology to Produce Dopaminergic Neurons
产生多巴胺能神经元的新细胞重编程技术
- 批准号:
8904832 - 财政年份:2015
- 资助金额:
$ 30万 - 项目类别:
New Cell Reprogramming Technology to Produce Dopaminergic Neurons
产生多巴胺能神经元的新细胞重编程技术
- 批准号:
9444809 - 财政年份:2015
- 资助金额:
$ 30万 - 项目类别:
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