Systemic Delivery of Targeted Bi-Compartmental Nanoparticles for Glioblastoma Therapeutics
用于胶质母细胞瘤治疗的靶向双室纳米颗粒的系统递送
基本信息
- 批准号:10584553
- 负责人:
- 金额:$ 48.16万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-03-15 至 2027-02-28
- 项目状态:未结题
- 来源:
- 关键词:AccountingAdjuvant ChemotherapyAlbuminsAntibodiesArchitectureBiological AssayBloodBlood - brain barrier anatomyBrainBrain NeoplasmsCancer PatientCell DeathCellsCombined Modality TherapyDataDevelopmentDoseDoxorubicinDrug Delivery SystemsDrug KineticsEncapsulatedExcisionExhibitsFormulationGlioblastomaGliomaGoalsGrowthHeterogeneityHumanImmuneImmunityImmunologic MemoryIn VitroInfiltrationIntracranial NeoplasmsIonizing radiationKnowledgeMalignant - descriptorMalignant neoplasm of brainMedialMedicalMissionModalityModelingMolecularMusOperative Surgical ProceduresOrganPaclitaxelPatientsPatternPenetrationPeptidesPhagocytesPharmaceutical PreparationsPhase I Clinical TrialsPhenotypePolymersPrognosisProteinsRNARadiation therapyReportingSerum AlbuminSignal TransductionSignaling MoleculeSmall Interfering RNASurvival RateSystemT-LymphocyteTechniquesTechnologyTestingTherapeuticToxic effectTranscription Factor 3TransducersTranslatingTranslationsTreatment EfficacyUnited States National Institutes of HealthValidationWorkblood-brain barrier permeabilizationcell typechemotherapeutic agentclinically relevantcurative treatmentsdesigndocetaxeldrug actioneffective therapyefficacy evaluationexperimental studyimmunogenic cell deathimprovedinhibitorinnovationinnovative technologiesnanoparticlenanoparticle deliverynovelnovel strategiesnovel therapeuticspre-clinicalresponseside effectsmall moleculesmall molecule inhibitorstandard of caresynthetic proteintargeted deliverytemozolomidetherapeutic targettumortumor microenvironmentuptake
项目摘要
Abstract
Glioblastoma multiforme (GBM) is the prevalent primary malignant brain tumor accounting for 80% of all brain
cancer patients. It is typically associated with poor prognosis. The standard of care for GBM patients consists of
bulk surgical resection of the tumor mass in combination with focal radiotherapy and adjuvant chemotherapy,
using temozolomide (TMZ). Despite intense efforts, the prognosis of glioma patients remains dismal. Novel
approaches are greatly needed for this devastating form of brain cancer. Signal and Transducer of Activation 3
(STAT3) transcription factor has been proven to be a very attractive therapeutic target for malignant brain tumors,
as their growth is highly dependent of STAT3 signaling. Preliminary data from our team clearly suggest that
currently available small molecule STAT3 inhibitors are highly effective at eliciting regression of GBM tumors
growing in the periphery. In contrast, these same small molecule STAT3 inhibitors were ineffective in treating
GBM tumors located within the brain. We demonstrated that the lack of efficacy is due to limited BBB transport.
Similar difficulties are encountered for the delivery of other established chemotherapeutics, specifically paclitaxel
(PTX). Nanoparticle-based drug delivery systems offer potential solutions, but current delivery carriers have still
relatively low efficacy or require invasive intracranial delivery, to enable transport of therapeutics across the
blood-brain-barrier. In our preliminary studies, we were able to demonstrate that albumin-based drug delivery
carriers developed by our group significantly accumulate in intracranial tumors after systemic administration. In
this proposal, our interdisciplinary team will develop and evaluate a novel and scalable bi-compartmental human
serum albumin-based carrier system that allows controlled encapsulation of therapeutic ratios of STAT3 siRNA
and PTX within distinct compartments of the same albumin-based drug delivery carrier, while also incorporating
tumor-penetrating peptides, which have been previously shown to promote nanoparticle penetration into GBMs.
The experiments will test the hypothesis that the proposed bi-compartmental (bi-NP) STAT3i/PTX delivery
carriers in combination with standard of care, i.e., radiation therapy (IR) and TMZ, will significantly improve medial
survival of intracranial GBM bearing mice. We also hypothesize that the co-release of STAT3 siRNA and PTX,
when spatially and temporally orchestrated by an appropriately designed delivery carrier, will not exhibit
untoward adverse side effects in the host, neither within the brain, nor systemically. This work may result in a
new treatment modality for GBM, a tumor type, for which no effective treatments exist. New information on
accessing brain tumors with drugs will also ensue. Our ultimate goal is to translate this novel therapeutic modality
to patients with GBM by implementing Phase I clinical trials.
摘要
摘要多形性胶质母细胞瘤是最常见的脑部原发恶性肿瘤,占全脑的80%。
癌症患者。它通常与预后不良有关。GBM患者的护理标准包括
肿瘤大块切除联合局部放疗和辅助化疗,
使用替莫唑胺(TMZ)。尽管付出了巨大的努力,但胶质瘤患者的预后仍然令人沮丧。小说
对于这种毁灭性的脑癌,治疗方法是非常必要的。激活信号与转导蛋白3
(STAT3)转录因子已被证明是治疗恶性脑瘤的一个非常有吸引力的靶点,
因为它们的生长高度依赖于STAT3信号。我们团队的初步数据清楚地表明,
目前可用的小分子STAT3抑制剂在诱导GBM肿瘤消退方面非常有效
生长在外围。相反,这些小分子STAT3抑制剂在治疗中无效
基底膜肿瘤位于大脑内。我们证明,缺乏疗效是由于有限的血脑屏障转运。
其他已确定的化疗药物,特别是紫杉醇的输送也遇到了类似的困难。
(PTX)。基于纳米颗粒的药物输送系统提供了潜在的解决方案,但目前的输送载体仍然
相对较低的疗效或需要侵入性的颅内递送,以使治疗药物能够通过
血脑屏障。在我们的初步研究中,我们能够证明基于白蛋白的药物传递
我们团队开发的携带者在全身给药后显著积累在颅内肿瘤中。在……里面
这项提议,我们的跨学科团队将开发和评估一种新颖的、可扩展的两室人类
基于血清白蛋白的载体系统,允许可控地包裹STAT3 siRNA的治疗比率
和PTX在同一白蛋白为基础的药物输送载体的不同隔室内,同时还包括
肿瘤穿透性多肽,此前已被证明可促进纳米颗粒渗透到基底膜中。
实验将检验所提出的双隔室(bi-NP)STAT3i/PTX递送的假设
携带者与标准护理相结合,即放射治疗(IR)和TMZ,将显著改善医疗状况
脑内基底膜移植小鼠的存活。我们还假设STAT3 siRNA和PTX的共同释放,
当由适当设计的递送载体在空间和时间上协调时,将不会展示
对宿主的不良副作用,既不是大脑内部的,也不是全身的。这项工作可能会导致
GBM是一种肿瘤类型,目前还没有有效的治疗方法。关于以下方面的新信息
用药物接触脑瘤也会随之而来。我们的最终目标是将这种新颖的治疗方式
通过实施I期临床试验对GBM患者进行治疗。
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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Maria G Castro其他文献
Maria G Castro的其他文献
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{{ truncateString('Maria G Castro', 18)}}的其他基金
Uncover the role of H3.3-G343R mutation in shaping the DNA damage response, anti-tumor immunity and mechanisms of resistance in glioma.
揭示 H3.3-G343R 突变在塑造神经胶质瘤 DNA 损伤反应、抗肿瘤免疫和耐药机制中的作用。
- 批准号:
10384185 - 财政年份:2022
- 资助金额:
$ 48.16万 - 项目类别:
Uncover the role of H3.3-G343R mutation in shaping the DNA damage response, anti-tumor immunity and mechanisms of resistance in glioma.
揭示 H3.3-G343R 突变在塑造神经胶质瘤 DNA 损伤反应、抗肿瘤免疫和耐药机制中的作用。
- 批准号:
10550245 - 财政年份:2022
- 资助金额:
$ 48.16万 - 项目类别:
Systemic Delivery of Targeted Bi-Compartmental Nanoparticles for Glioblastoma Therapeutics
用于胶质母细胞瘤治疗的靶向双室纳米颗粒的系统递送
- 批准号:
10462033 - 财政年份:2022
- 资助金额:
$ 48.16万 - 项目类别:
Novel nano-vaccine technology for inducing immunity against gliomas
用于诱导神经胶质瘤免疫力的新型纳米疫苗技术
- 批准号:
10655464 - 财政年份:2021
- 资助金额:
$ 48.16万 - 项目类别:
Administrative Diversity Supplement- Novel Nano-Vaccine Technology for Inducing Immunity Against Gliomas
行政多样性补充-诱导神经胶质瘤免疫的新型纳米疫苗技术
- 批准号:
10622660 - 财政年份:2021
- 资助金额:
$ 48.16万 - 项目类别:
Novel nano-vaccine technology for inducing immunity against gliomas
用于诱导神经胶质瘤免疫力的新型纳米疫苗技术
- 批准号:
10443896 - 财政年份:2021
- 资助金额:
$ 48.16万 - 项目类别:
Chemo-immunotherapy strategy for pediatric high grade glioma
儿童高级别胶质瘤的化学免疫治疗策略
- 批准号:
10296214 - 财政年份:2021
- 资助金额:
$ 48.16万 - 项目类别:
Novel nano-vaccine technology for inducing immunity against gliomas
用于诱导神经胶质瘤免疫力的新型纳米疫苗技术
- 批准号:
10877283 - 财政年份:2021
- 资助金额:
$ 48.16万 - 项目类别:
Novel nano-vaccine technology for inducing immunity against gliomas
用于诱导神经胶质瘤免疫力的新型纳米疫苗技术
- 批准号:
10241830 - 财政年份:2021
- 资助金额:
$ 48.16万 - 项目类别:
Immune-suppressive Myeloid Cells in the Glioma Microenvironment: Signaling Mechanisms and Novel Therapeutic Strategies
胶质瘤微环境中的免疫抑制骨髓细胞:信号传导机制和新的治疗策略
- 批准号:
9981837 - 财政年份:2015
- 资助金额:
$ 48.16万 - 项目类别:
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