Theranostics for Pediatric Brain Cancer
小儿脑癌的治疗诊断学
基本信息
- 批准号:10393485
- 负责人:
- 金额:$ 66.86万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-04-15 至 2026-01-31
- 项目状态:未结题
- 来源:
- 关键词:AdultAffectAnimalsApoptosisBinding SitesBiosensorBlood - brain barrier anatomyBlood VesselsBrainBrain NeoplasmsCell DeathCellsChildChildhoodChildhood Malignant Brain TumorColchicineDataDevelopmentDiagnosisDiagnosticDiseaseDisease remissionDoseDose-LimitingDrug Delivery SystemsDrug MonitoringEndothelial CellsEndotheliumEnzymesFDA approvedFluorescein-5-isothiocyanateFluorescence MicroscopyFormulationGenerationsGlioblastomaGliomaGoalsHigh PrevalenceHorseradish PeroxidaseIntravenousLabelLeadLinkLocationMMP14 geneMagnetic Resonance ImagingMalignant NeoplasmsMalignant neoplasm of brainMean Survival TimesMeasuresMediatingMicrotubulesMitosisModelingMusNatureNutritionalOrganOutcomePediatric NeoplasmPeptide HydrolasesPerivascular NeoplasmPermeabilityPharmaceutical PreparationsPharmacotherapyPlacebosPositioning AttributeProblem SolvingProdrugsPrognosisProteinsRadiationRattusRecurrenceResearchSiteStarvationSystemTherapeuticTherapeutic AgentsTherapeutic EffectToxic effectTreatment EfficacyTubulinTumor SuppressionTumor TissueVisceralantiangiogenesis therapyantitumor effectbasecancer therapycell killingclinical translationclinically translatableconventional therapycurative treatmentscytotoxicdensitydesignimprovedimproved outcomein vivointerestintravital microscopyiron oxide nanoparticlemacromoleculenanocarriernanoparticleneoplastic cellneuro-oncologynovelnovel drug classnovel strategiesnovel therapeuticsoverexpressionreal time monitoringside effectsuccesstheranosticstherapy resistanttumortumor growth
项目摘要
THERANOSTICS FOR PEDIATRIC BRAIN CANCER
Glioblastoma (GBM) is the most frequently diagnosed primary malignant brain tumor in children with median
survival of less than one year. Disease recurrence is common and is caused by the presence of glioma-initiating
cells (GICs) that are unreceptive to conventional therapies, underscoring the urgent need for new therapeutic
options. We aim to develop a novel strategy to specifically disrupt the lifeline of GICs, without causing toxic
effects to the normal brain. The highly vascularized nature of GBMs and the critical function of the perivascular
niche for nutritional supply of GICs have spurred much interest in novel vascular-disruptive agents (VDAs).
Intravenously administered VDAs easily reach GBM vessels and do not rely on the enhanced permeability and
retention effect, which can limit the delivery of macromolecules to the tumor tissue. VDA-mediated blood vessel
disruption causes efficient drug delivery to the GIC niche and starvation of many tumor cells. In contrast to
classical anti-angiogenesis drugs, VDAs not only disrupt the tumor vasculature, but also cause significant GIC
apoptosis through direct cytotoxic effects. While being highly effective for cancer treatment, initial VDA
formulations also caused significant toxicity to the normal brain. This is particularly concerning for children, as
the developing brain is more vulnerable to toxic side effects compared to the adult brain. To solve this problem,
we developed novel VDA-loaded theranostic (combined therapeutic and diagnostic) nanoparticles, which are
specifically activated in brain tumors by matrix metalloproteinases 14 (MMP-14). The normal brain does not
express MMP-14 and therefore, does not activate the theranostic drug, thereby creating highly effective cancer
therapy without side effects. The major goal of our project is to develop MMP-14-activatable theranostic
nanoparticles (TNPs) for curative treatment of GBM, without causing toxicity to the normal brain. The
approach relies on the high prevalence of MMP-14 in GBM, a proven MMP-14-activatable prodrug strategy, and
a nanocarrier platform based on FDA-approved iron oxide nanoparticles. We hypothesize that our TNPs will be
converted to an active therapeutic agent only within MMP-14-expressing tumors, releasing the therapeutic drug
azademethylcolchicine and causing significant antitumor effects. In addition, we postulate that the iron oxide
nanoparticle moiety will allow real-time monitoring of drug accumulation and localization at tumors with magnetic
resonance imaging (MRI). In aim 1, we will evaluate whether TNP dose and VDA payload affect VDA mediated
vascular disruption, blood brain barrier (BBB) breakdown and cancer-specific toxicity. In aim 2, we will investigate
the link between VDA-mediated tumor microvessel disruption, microvascular endothelial cell death and GIC
death. TNPs hold the potential to substantially improving therapeutic efficacy whilst simultaneously reducing
dose-limiting toxicities. Realizing our goal will uncover new targets and mechanisms for successful GBM therapy,
eliminate or substantially reduce off-target toxicities and provide children with brain cancers with a much needed
new treatment option.
小儿脑癌的治疗
项目成果
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Heike Elizabeth Daldrup-Link其他文献
Heike Elizabeth Daldrup-Link的其他文献
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{{ truncateString('Heike Elizabeth Daldrup-Link', 18)}}的其他基金
Advanced Imaging Tools to Assess Cancer Therapeutics in Pediatric
用于评估儿科癌症治疗的先进成像工具
- 批准号:
10360372 - 财政年份:2022
- 资助金额:
$ 66.86万 - 项目类别:
Advanced Imaging Tools to Assess Cancer Therapeutics in Pediatric
用于评估儿科癌症治疗的先进成像工具
- 批准号:
10570915 - 财政年份:2022
- 资助金额:
$ 66.86万 - 项目类别:
Cellular Senescence Network: New Imaging Tools for Arthritis Imaging
细胞衰老网络:关节炎成像的新成像工具
- 批准号:
10907051 - 财政年份:2021
- 资助金额:
$ 66.86万 - 项目类别:
Cellular Senescence Network: New Imaging Tools for Arthritis Imaging
细胞衰老网络:关节炎成像的新成像工具
- 批准号:
10493340 - 财政年份:2021
- 资助金额:
$ 66.86万 - 项目类别:
Cellular Senescence Network: New Imaging Tools for Arthritis Imaging
细胞衰老网络:关节炎成像的新成像工具
- 批准号:
10376536 - 财政年份:2021
- 资助金额:
$ 66.86万 - 项目类别:
Co-Clinical Research Resource for Imaging Tumor Associated Macrophages
肿瘤相关巨噬细胞成像联合临床研究资源
- 批准号:
10304651 - 财政年份:2021
- 资助金额:
$ 66.86万 - 项目类别:
Co-Clinical Research Resource for Imaging Tumor Associated Macrophages
肿瘤相关巨噬细胞成像联合临床研究资源
- 批准号:
10688045 - 财政年份:2021
- 资助金额:
$ 66.86万 - 项目类别:
Imaging Chemotherapy-Induced Brain Damage in Pediatric Cancer Survivors
对小儿癌症幸存者化疗引起的脑损伤进行成像
- 批准号:
10054003 - 财政年份:2020
- 资助金额:
$ 66.86万 - 项目类别:
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