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:10210648
- 负责人:
- 金额:$ 60.62万
- 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 TrialsConvectionCouplesDevelopmentDiagnosisDiffusionDoseDrug Delivery SystemsDrug FormulationsDrug KineticsEngineeringEnvironmentExcisionExposure toFeedbackFocused UltrasoundFormulationFoundationsGenerationsGlioblastomaGliomaGrowthHistologyHumanImmunocompetentImmunohistochemistryImplantInfiltrationInfrastructureInvestigational TherapiesLeadLibrariesLife ExpectancyMagnetic Resonance ImagingMalignant - descriptorMaximum Tolerated DoseMeasuresMediatingMicrobubblesModelingModificationMusNatureOperative Surgical ProceduresPaperPatient RecruitmentsPatientsPenetrationPharmaceutical PreparationsPharmacologic SubstancePhysiologic pulsePhysiologicalPositioning AttributePrimary Brain NeoplasmsPropertyProtocols documentationPublishingRadiationRadiation therapyRattusReproducibilitySafetySchemeSiteSystemTestingTherapeuticTherapeutic AgentsTissuesTranslatingTranslationsTreatment EfficacyTumor TissueUltrasonographyVisionastrogliosisbasebrain tissuecancer cellchemotherapyclinical translationcontrast enhancedcontrolled releasedesignexperienceimage guidedimage-guided drug deliveryimprovedin vivoinnovationinterstitialnanoparticlenanoparticle deliverynext generationnovelpreconditioningpressurequantumscreeningstability testingstem cellssuccesstargeted deliverytemozolomidetumortumor growthtumor microenvironment
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。即使在接受手术治疗的时候,
放疗和化疗,患者最常被诊断为胶质瘤,IV级胶质母细胞瘤
(GB),预期寿命只有14个月。治疗银屑病的主要挑战是其高度侵袭性,
由于浸润性癌细胞受到保护,不会受到全身化疗的影响,
血脑屏障(BBB)。在这里,我们建议开发一种针对GB夫妇的治疗方法
MRI引导聚焦通过激活血管内微泡(MBS)无创开放血脑屏障
超声(FUS)和可生物降解的[聚天冬氨酸-聚乙二醇(PAA-PEG)],顺铂(CDDP)-
装满的“脑穿透纳米颗粒”。我们之前已经证明了“第一代”的功效。
CDDP-BPN代理,FUS能够精确地将BPN通过BBB传递到MR图像-
大脑中的选定靶点,以及CDDP-BPN对胶质瘤的传递。
在此,我们提出了四个具体目标,旨在显著提高
接近并将其推进到临床试验。在目标1中,我们将为以下目标设计下一代CDDP-BPN
专门用于系统性给药和FUS靶向递送的配方。同时,目标2和目标3将
通过对FUS的新的、临床可操作的改进显著增加BPN对侵袭性胶质瘤的输送
应用程序协议。这些措施将包括根据MRI指导扩大治疗量,测试
BBB开启期间“现场选择性”声发射反馈的概念,以及对新识别的评估
FUS“预调节”脉冲序列以提高BPN穿透的能力。值得注意的是,一种创新的新
在AIMS 2和AIMS 3中,将使用MR图像引导的肿瘤间质流动和扩散分析
直接确定FUS如何调节肿瘤微环境以促进CDDP-BPN通过
治疗体积。然后,目标4将通过建立CDDP-BPN的最大耐受剂量(MTD)和
使用优化的FUS方案评估CDDP-BPN给药后脑胶质瘤的顺铂水平。接下来,我们将测试
将下一代CDDP-BPN与用于增强BPN交付的新型FUS协议相结合是否将
控制肿瘤生长,阻断侵袭,提高存活率。重要的是,我们即将在
UVA,其中MR图像引导的FUS(InSightec ExAblate Neuro System)将与MBS一起使用以打开BBB
并在接受手术切除后每周向GB患者提供化疗
辐射。此外,MPI Hanes在推进药物控释制剂方面拥有丰富的经验
交付给临床试验。因此,翻译开了一个明确的先例。鉴于我们的基础设施和
凭借专业知识,我们非常有能力将成功的研究成果转化为临床应用。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Justin S. Hanes其他文献
Justin S. Hanes的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
$ 60.62万 - 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:
10541232 - 财政年份:2021
- 资助金额:
$ 60.62万 - 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:
$ 60.62万 - 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:
$ 60.62万 - 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:
$ 60.62万 - 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:
$ 60.62万 - 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:
$ 60.62万 - 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:
$ 60.62万 - 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:
$ 60.62万 - 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:
$ 60.62万 - 项目类别:
相似海外基金
Unraveling the Dynamics of International Accounting: Exploring the Impact of IFRS Adoption on Firms' Financial Reporting and Business Strategies
揭示国际会计的动态:探索采用 IFRS 对公司财务报告和业务战略的影响
- 批准号:
24K16488 - 财政年份:2024
- 资助金额:
$ 60.62万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Mighty Accounting - Accountancy Automation for 1-person limited companies.
Mighty Accounting - 1 人有限公司的会计自动化。
- 批准号:
10100360 - 财政年份:2024
- 资助金额:
$ 60.62万 - 项目类别:
Collaborative R&D
Accounting for the Fall of Silver? Western exchange banking practice, 1870-1910
白银下跌的原因是什么?
- 批准号:
24K04974 - 财政年份:2024
- 资助金额:
$ 60.62万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
CPS: Medium: Making Every Drop Count: Accounting for Spatiotemporal Variability of Water Needs for Proactive Scheduling of Variable Rate Irrigation Systems
CPS:中:让每一滴水都发挥作用:考虑用水需求的时空变化,主动调度可变速率灌溉系统
- 批准号:
2312319 - 财政年份:2023
- 资助金额:
$ 60.62万 - 项目类别:
Standard Grant
A New Direction in Accounting Education for IT Human Resources
IT人力资源会计教育的新方向
- 批准号:
23K01686 - 财政年份:2023
- 资助金额:
$ 60.62万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
An empirical and theoretical study of the double-accounting system in 19th-century American and British public utility companies
19世纪美国和英国公用事业公司双重会计制度的实证和理论研究
- 批准号:
23K01692 - 财政年份:2023
- 资助金额:
$ 60.62万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
An Empirical Analysis of the Value Effect: An Accounting Viewpoint
价值效应的实证分析:会计观点
- 批准号:
23K01695 - 财政年份:2023
- 资助金额:
$ 60.62万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Accounting model for improving performance on the health and productivity management
提高健康和生产力管理绩效的会计模型
- 批准号:
23K01713 - 财政年份:2023
- 资助金额:
$ 60.62万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
New Role of Not-for-Profit Entities and Their Accounting Standards to Be Unified
非营利实体的新角色及其会计准则将统一
- 批准号:
23K01715 - 财政年份:2023
- 资助金额:
$ 60.62万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Improving Age- and Cause-Specific Under-Five Mortality Rates (ACSU5MR) by Systematically Accounting Measurement Errors to Inform Child Survival Decision Making in Low Income Countries
通过系统地核算测量误差来改善特定年龄和特定原因的五岁以下死亡率 (ACSU5MR),为低收入国家的儿童生存决策提供信息
- 批准号:
10585388 - 财政年份:2023
- 资助金额:
$ 60.62万 - 项目类别: