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.
抽象的
多形性胶质母细胞瘤(GBM)是常见的原发性恶性脑肿瘤,占所有脑肿瘤的80%
癌症患者。它通常与不良预后相关。 GBM 患者的护理标准包括
肿瘤块的整体手术切除结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,神经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,我们非常需要一些方法。激活信号和传感器3
(STAT3)转录因子已被证明是恶性脑肿瘤非常有吸引力的治疗靶点,
因为它们的生长高度依赖于 STAT3 信号传导。我们团队的初步数据清楚地表明
目前可用的小分子 STAT3 抑制剂在引发 GBM 肿瘤消退方面非常有效
生长在外围。相比之下,这些相同的小分子 STAT3 抑制剂在治疗方面无效
GBM 肿瘤位于大脑内。我们证明缺乏功效是由于 BBB 运输有限。
其他已建立的化疗药物(特别是紫杉醇)的递送也遇到类似的困难
(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
疗效相对较低或需要侵入性颅内输送,以实现治疗药物的跨部位运输
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递送
本课题组开发的载体在全身给药后在颅内肿瘤中显着富集。在
根据这项提议,我们的跨学科团队将开发和评估一种新颖且可扩展的双室人类
基于血清白蛋白的载体系统,可控制 STAT3 siRNA 治疗比例的封装
和 PTX 位于同一基于白蛋白的药物递送载体的不同隔室中,同时还包含
肿瘤穿透肽,之前已被证明可以促进纳米颗粒渗透到 GBM 中。
实验将检验所提出的双室 (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,将显着改善内侧
颅内携带 GBM 的小鼠的存活率。我们还假设 STAT3 siRNA 和 PTX 的共同释放,
当由适当设计的交付载体在空间和时间上精心安排时,不会表现出
对宿主产生不良副作用,既不在大脑内,也不在全身。这项工作可能会导致
GBM(一种尚无有效治疗方法的肿瘤类型)的新治疗方式。新信息关于
用药物治疗脑肿瘤也将随之而来。我们的最终目标是转化这种新颖的治疗方式
通过实施 I 期临床试验来治疗 GBM 患者。
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 }}
Maria G Castro其他文献
Maria G Castro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('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:
相似海外基金
3D Engineered Model of Microscopic Colorectal Cancer Liver Metastasis for Adjuvant Chemotherapy Screens
用于辅助化疗筛选的显微结直肠癌肝转移 3D 工程模型
- 批准号:
10556192 - 财政年份:2023
- 资助金额:
$ 48.16万 - 项目类别:
Developing Digital Pathology Biomarkers for Response to Neoadjuvant and Adjuvant Chemotherapy in Breast Cancer
开发数字病理学生物标志物以应对乳腺癌新辅助和辅助化疗
- 批准号:
10315227 - 财政年份:2021
- 资助金额:
$ 48.16万 - 项目类别:
Circulating Tumour DNA Analysis Informing Adjuvant Chemotherapy in Stage III Colorectal Cancer: A Multicentre Phase II/III Randomised Controlled Trial (DYNAMIC-III)
循环肿瘤 DNA 分析为 III 期结直肠癌辅助化疗提供信息:多中心 II/III 期随机对照试验 (DYNAMIC-III)
- 批准号:
443988 - 财政年份:2021
- 资助金额:
$ 48.16万 - 项目类别:
Operating Grants
Establishment of new selection system for adjuvant chemotherapy of colorectal cancer
结直肠癌辅助化疗新选择体系的建立
- 批准号:
20K09011 - 财政年份:2020
- 资助金额:
$ 48.16万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Improved survival by Helicobacter pylori-modulated immunity in gastric cancer patients with adjuvant chemotherapy
幽门螺杆菌调节免疫力可改善接受辅助化疗的胃癌患者的生存率
- 批准号:
19K09130 - 财政年份:2019
- 资助金额:
$ 48.16万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
A new strategy of adjuvant chemotherapy for lung cancer based on the expression of anti-aging gene Klotho
基于抗衰老基因Klotho表达的肺癌辅助化疗新策略
- 批准号:
19K18225 - 财政年份:2019
- 资助金额:
$ 48.16万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Novel candidate factors predicting the effect of S-1 adjuvant chemotherapy of pancreatic cancer
预测胰腺癌S-1辅助化疗效果的新候选因素
- 批准号:
18K16337 - 财政年份:2018
- 资助金额:
$ 48.16万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Project 2-Metabolic Modulation of Myeloid-Derived Suppressor Cells to Increase Efficacy of Neo adjuvant Chemotherapy and Immunotherapy
项目2-骨髓源性抑制细胞的代谢调节以提高新辅助化疗和免疫疗法的疗效
- 批准号:
10005254 - 财政年份:2018
- 资助金额:
$ 48.16万 - 项目类别:
Radiogenomic tools for prediction of breast cancer neo-adjuvant chemotherapy response from pre-treatment MRI
通过治疗前 MRI 预测乳腺癌新辅助化疗反应的放射基因组学工具
- 批准号:
9763320 - 财政年份:2018
- 资助金额:
$ 48.16万 - 项目类别:
Analysis of the molecular mechanism for the prognostic biomarker of adjuvant chemotherapy
辅助化疗预后生物标志物的分子机制分析
- 批准号:
18K07341 - 财政年份:2018
- 资助金额:
$ 48.16万 - 项目类别:
Grant-in-Aid for Scientific Research (C)














{{item.name}}会员




