Focused ultrasound pre-conditioning for augmented nanoparticle penetration in infiltrative gliomas
聚焦超声预处理增强纳米颗粒在浸润性神经胶质瘤中的渗透
基本信息
- 批准号:10541232
- 负责人:
- 金额:$ 58.34万
- 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:2021-04-01 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:Absorbable ImplantsAccountingAcidsAcousticsAddressBloodBlood - brain barrier anatomyBlood CirculationBrainBrain NeoplasmsBypassCessation of lifeCisplatinClinicClinicalClinical TrialsConvectionCouplesCytoprotectionDevelopmentDiagnosisDiffusionDoseDrug Delivery SystemsDrug FormulationsDrug KineticsEngineeringEnvironmentExcisionExposure toFeedbackFocused UltrasoundFormulationFoundationsGenerationsGlioblastomaGliomaGliosisGrowthHistologyHumanImmunocompetentImmunohistochemistryImplantInfiltrationInfrastructureInvestigational TherapiesLeadLibrariesLife ExpectancyMagnetic Resonance ImagingMalignant - descriptorMaximum Tolerated DoseMeasuresMediatingMicrobubblesModelingModificationMusNatureOperative Surgical ProceduresPaperPatient RecruitmentsPatientsPenetrationPharmaceutical PreparationsPharmacologic SubstancePhysiologic pulsePhysiologicalPolyethylene GlycolsPositioning AttributePrimary Brain NeoplasmsPropertyProtocols documentationPublishingRadiationRadiation therapyRattusReproducibilitySafetySchemeSiteSystemTestingTherapeuticTherapeutic AgentsTissuesTranslatingTranslationsTreatment EfficacyTumor TissueVisionastrogliosisbrain tissuecancer cellchemotherapyclinical translationcontrast enhancedcontrolled releasedesignexperienceimage guidedimage-guided drug deliveryimprovedin vivoinnovationinterstitialnanoparticlenanoparticle deliverynext generationnovelpreconditioningpressurequantumscreeningstability testingstem cellssuccesstargeted deliverytemozolomidetissue preparationtumortumor growthtumor microenvironmentultrasound
项目摘要
Gliomas are the most common malignant human brain tumors. Even when treated with surgery,
radiotherapy, and chemotherapy, patients with the most commonly diagnosed glioma, grade IV glioblastoma
(GB), have a life expectancy of only 14 months. The primary challenge to treating GB is its highly invasive nature,
as infiltrating cancer cells are “protected” from exposure to systemically administered chemotherapies by the
blood brain barrier (BBB). Here, we propose the development of a therapeutic approach for GB that couples
non-invasive BBB opening via the activation of intravascular microbubbles (MBs) with MRI-guided focused
ultrasound (FUS) and biodegradable [polyaspartic acid-polyethyleneglycol (PAA-PEG)], cisplatin (CDDP)-
loaded, “brain-penetrating nanoparticles”. We have previously demonstrated the efficacy of “first-generation”
CDDP-BPN agents, the ability of FUS to precisely target the delivery of BPN across the BBB to MR image-
selected targets in the brain, and the delivery of CDDP-BPN to gliomas.
Here, we propose four specific aims designed to markedly improve the therapeutic efficacy of the
approach and advance it to clinical trials. In Aim 1, we will engineer a “next-generation” CDDP-BPN for
formulation specifically for systemic administration and FUS-targeted delivery. In parallel, Aims 2 and 3 will be
to markedly augment BPN delivery to invasive gliomas via novel, clinically-operable, modifications to FUS
application protocols. These will include extending treatment volumes based on MRI guidance, testing the
concept of “site-selective” acoustic emissions feedback during BBB opening, and evaluating newly identified
FUS “pre-conditioning” pulse sequences for their ability to increase BPN penetration. Of note, an innovative new
MR image-guided transport analysis of tumor interstitial flow and diffusion will be employed in Aims 2 and 3 to
directly ascertain how FUS modulates the tumor microenvironment to facilitate CDDP-BPN spread though the
treatment volume. Aim 4 will then start by establishing the maximum tolerated dose (MTD) of CDDP-BPN and
assessing cisplatin levels in gliomas after CDDP-BPN delivery using optimized FUS protocols. Next, we will test
whether combining next-generation CDDP-BPN with novel FUS protocols for augmented BPN delivery will
control tumor growth, block infiltration, and improve survival. Importantly, we are about to open a clinical trial at
UVA wherein MR image-guided FUS (Insightec Exablate Neuro System) will be used with MBs to open the BBB
and deliver chemotherapy on a weekly basis to GB patients after they have undergone surgical resection and
radiation. Moreover, MPI Hanes has deep experience with advancing controlled-release formulations for drug
delivery to clinical trials. Thus, a clear precedent has been set for translation. Given our infrastructure and
expertise, we are exceptionally well-positioned to translate successful findings to the clinic.
胶质瘤是人类最常见的恶性脑肿瘤。即使接受手术治疗,
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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Justin S. Hanes其他文献
Justin S. Hanes的其他文献
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{{ truncateString('Justin S. Hanes', 18)}}的其他基金
Focused ultrasound pre-conditioning for augmented nanoparticle penetration in infiltrative gliomas
聚焦超声预处理增强纳米颗粒在浸润性神经胶质瘤中的渗透
- 批准号:
10375573 - 财政年份:2021
- 资助金额:
$ 58.34万 - 项目类别:
Focused ultrasound pre-conditioning for augmented nanoparticle penetration in infiltrative gliomas
聚焦超声预处理增强纳米颗粒在浸润性神经胶质瘤中的渗透
- 批准号:
10210648 - 财政年份:2021
- 资助金额:
$ 58.34万 - 项目类别:
Targeted Delivery of Brain Penetrating DNA Nanoparticles to Brain Tumors
脑部穿透性 DNA 纳米颗粒靶向递送至脑肿瘤
- 批准号:
9083426 - 财政年份:2016
- 资助金额:
$ 58.34万 - 项目类别:
Targeted Delivery of Brain Penetrating DNA Nanoparticles to Brain Tumors
脑部穿透性 DNA 纳米颗粒靶向递送至脑肿瘤
- 批准号:
9260870 - 财政年份:2016
- 资助金额:
$ 58.34万 - 项目类别:
Targeted Delivery of Brain Penetrating DNA Nanoparticles to Brain Tumors
脑部穿透性 DNA 纳米颗粒靶向递送至脑肿瘤
- 批准号:
9891031 - 财政年份:2016
- 资助金额:
$ 58.34万 - 项目类别:
Biodegradable Mucus Penetrating DNA Nanoparticle for Gene Therapy of CF
用于 CF 基因治疗的可生物降解粘液穿透 DNA 纳米颗粒
- 批准号:
8863900 - 财政年份:2015
- 资助金额:
$ 58.34万 - 项目类别:
Mucus Microstructure and Osmotic Pressure: Biomarkers for CB in COPD
粘液微观结构和渗透压:COPD 中 CB 的生物标志物
- 批准号:
8852864 - 财政年份:2015
- 资助金额:
$ 58.34万 - 项目类别:
Glutaminase Inhibitor Drug Discovery and Nanoparticle-Based Delivery for Pancreatic Cancer Therapy
谷氨酰胺酶抑制剂药物的发现和基于纳米颗粒的胰腺癌治疗递送
- 批准号:
9188044 - 财政年份:2015
- 资助金额:
$ 58.34万 - 项目类别:
Glutaminase Inhibitor Drug Discovery and Nanoparticle-Based Delivery for Pancreatic Cancer Therapy
谷氨酰胺酶抑制剂药物的发现和基于纳米颗粒的胰腺癌治疗递送
- 批准号:
9028315 - 财政年份:2015
- 资助金额:
$ 58.34万 - 项目类别:
Biodegradable Mucus Penetrating DNA Nanoparticle for Gene Therapy of CF
用于 CF 基因治疗的可生物降解粘液穿透 DNA 纳米颗粒
- 批准号:
9229059 - 财政年份:2015
- 资助金额:
$ 58.34万 - 项目类别:
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