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.
小儿脑肿瘤的治疗
胶质母细胞瘤(GBM)是儿童中最常见的原发性恶性脑肿瘤,
生存时间不到一年。疾病复发是常见的,并且是由神经胶质瘤启动的肿瘤细胞的存在引起的。
细胞(GIC)不接受传统疗法,强调迫切需要新的治疗方法。
选项.我们的目标是开发一种新的策略,专门破坏GIC的生命线,而不会导致有毒的
对正常大脑的影响GBM的高度血管化性质和血管周围的关键功能
GIC的营养供应的利基已经激发了对新型血管破坏剂(VDA)的极大兴趣。
血管内给药的VDA容易到达GBM血管,并且不依赖于增强的渗透性,
保留效应,其可以限制大分子向肿瘤组织的递送。VDA介导的血管
破坏导致有效的药物递送到GIC小生境和许多肿瘤细胞的饥饿。相比
经典的抗血管生成药物VDA不仅破坏肿瘤血管,而且引起显著的GIC,
细胞凋亡通过直接的细胞毒性作用。虽然对癌症治疗非常有效,但最初的VDA
制剂也对正常脑产生显著的毒性。这对儿童尤其重要,因为
与成人大脑相比,发育中的大脑更容易受到毒副作用的影响。为了解决这个问题,
我们开发了新型的VDA负载治疗诊断(联合治疗和诊断)纳米颗粒,
在脑肿瘤中被基质金属蛋白酶14(MMP-14)特异性激活。正常的大脑不会
表达MMP-14,因此不会激活治疗诊断药物,从而产生高效的癌症
无副作用的治疗。本课题的主要目标是开发MMP-14激活的治疗诊断剂,
纳米颗粒(TNP)用于GBM的治愈性治疗,而不会对正常大脑造成毒性。的
方法依赖于MMP-14在GBM中的高流行率,这是一种经证实的MMP-14可激活的前药策略,
基于FDA批准的氧化铁纳米颗粒的纳米载体平台。我们假设我们的TNP将是
仅在表达MMP-14的肿瘤中转化为活性治疗剂,释放治疗药物
azademethylcolchicine并引起显著的抗肿瘤作用。此外,我们假设氧化铁
纳米颗粒部分将允许实时监测药物在肿瘤处的积聚和定位,
磁共振成像(MRI)。在目的1中,我们将评估TNP剂量和VDA有效载荷是否影响VDA介导的细胞凋亡。
血管破坏、血脑屏障(BBB)破坏和癌症特异性毒性。在目标2中,我们将研究
VDA介导的肿瘤微血管破坏、微血管内皮细胞死亡和GIC之间的联系
死亡TNP具有显著提高治疗效果的潜力,同时减少
剂量限制性毒性。实现我们的目标将揭示成功GBM治疗的新靶点和机制,
消除或大大减少脱靶毒性,并为患有脑癌的儿童提供急需的
新的治疗方案
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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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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