Dual-pronged nano-drug delivery using plant virus-like particles
使用植物病毒样颗粒的双管齐下纳米药物输送
基本信息
- 批准号:9372245
- 负责人:
- 金额:$ 47.01万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-08-01 至 2018-06-30
- 项目状态:已结题
- 来源:
- 关键词:4T1AddressAnatomyAnimalsAntibodiesApplications GrantsArtificial nanoparticlesBiologicalBreast Cancer PatientCapsid ProteinsCellsClinicalColon CarcinomaCowpea Mosaic VirusesDataDevelopmentDiseaseDistant MetastasisDoxorubicinDrug Delivery SystemsERBB2 geneEstrogen ReceptorsFlow CytometryHistocytochemistryImageImmuneImmune responseImmunofluorescence ImmunologicImmunologic MemoryImmunotherapyKnockout MiceLeadLibrariesLifeLigandsLocationMalignant NeoplasmsMalignant neoplasm of ovaryMediatingMemoryMolecularMosaic VirusesMouse StrainsMusNanotechnologyNatureNeoplasm MetastasisNucleic AcidsOncolyticParticulatePathway interactionsPatientsPharmaceutical PreparationsPlant VirusesPlantsPlayPrimary NeoplasmProgesterone ReceptorsRecurrenceResearchRoleShapesSignal PathwaySignal TransductionTLR7 geneTestingTherapeuticTimeToll-like receptorsTranslatingTreatment EfficacyTumor DebulkingTumor ImmunityVirusVirus-like particleWomanantitumor effectarmbasechemotherapyengineering designimmune activationimmunogenicimprovedin vivo imaginginsightmelanomamortalitymouse modelnanocarriernanodrugnanoparticlenanotherapyoutcome forecastparticleresponsesuccesstargeted treatmenttherapy outcometriple-negative invasive breast carcinomatumortumor microenvironment
项目摘要
Summary
Triple negative breast cancer (TNBC) is an aggressive life-threatening disease with poor prognosis and
limited treatment options. To address this clinical need, we propose a dual-pronged drug delivery approach
that combines chemo- and immune-drugs with a highly potent drug delivery platform, that itself has anti-tumor
efficacy. This grant application is based on our recent demonstration that virus-like particles (VLP) from the
plant virus cowpea mosaic virus (CPMV), when introduced into the tumor microenvironment, elicit potent local
and systemic anti-tumor immunity and protects animals from outgrowth of metastatic disease or recurrence of
the disease [Nature Nanotechnology 2016]. We have demonstrated efficacy in multiple mouse models treating
primary and metastatic tumors in multiple anatomic locations and multiple mouse strains, including mouse
models of TNBC. The nanoparticle engineering design space and pathway of immune-activation is not yet un-
derstood, and one arm of this R01 grant application will decipher the underlying mechanism. Second, we will
develop and test dual-pronged therapeutic approaches through combination of the nanoparticle platform with
chemotherapies and immune-drugs to potentiate the therapy and enable treatment of late-stage disease. We
will fulfill the following specific aims: 1) We will address whether the anti-tumor effect is CPMV-specific, wheth-
er the particulate, multivalent nature is a requirement, and whether nanoparticle shape and size plays a role. A
library of plant-derived VLPs of distinct molecular composition, size, and shape will be studied and efficacy will
be assessed using the 4T1 mouse model of TNBC. 2) We will determine the cells and signaling pathways in-
volved in the VLP-induced anti-tumor immune response. Longitudinal imaging in combination with histochemis-
try and flow cytometry will provide comprehensive insight into the biological response. To identify the potential
signaling pathways involved, studies will be performed in knockout mouse models that lack ASC, Myd88 or Trif
adaptor molecules. 3) Immunotherapy as monotherapy is generally effective only against small tumors, and
most patients do not respond to single approach immunotherapy. The combination of therapeutic regimes, i.e.
the combination of multiple immunotherapies or combination with chemotherapy, however, could form the ba-
sis for success. First, we will combine VLPs with doxorubicin (an immunogenic chemotherapy) through co-
administration (unconjugated) or co-delivery (conjugated to the VLP). Second, we will combine VLPs with
known `immunogenic danger signals' and co-deliver ssRNA or CpGs to activate signaling through Toll-like re-
ceptors. We hypothesize that the combination of the immune-stimulatory VLP and chemo- or immune-drugs
will potentiate efficacy while mounting a systemic anti-tumor immune response and memory, and this will be
tested through treatment of mice bearing 4T1 primary and metastatic tumors. The recent approval of the onco-
lytic immunotherapy T-VEC highlights the potential of virus-based therapeutics. Our application is distinct, be-
cause we use a plant VLP for dual-pronged tumor treatment and priming of anti-tumor immune memory.
总结
三阴性乳腺癌(TNBC)是一种侵袭性的危及生命的疾病,预后不良,
有限的治疗选择。为了满足这种临床需求,我们提出了一种双管齐下的药物递送方法
它将化疗和免疫药物与一个高效的药物输送平台相结合,
功效这项拨款申请是基于我们最近的证明,即病毒样颗粒(VLP)从
植物病毒豇豆花叶病毒(CPMV),当被引入肿瘤微环境中时,
和全身抗肿瘤免疫,并保护动物免受转移性疾病的生长或肿瘤复发。
[Nature Nanotechnology 2016]。我们已经在多种小鼠模型中证明了治疗
多个解剖位置和多个小鼠品系中的原发性和转移性肿瘤,包括小鼠
TNBC的模式。免疫激活的纳米粒子工程设计空间和途径尚未确定,
理解,和这个R 01赠款申请的一个手臂将破译潜在的机制。二是
开发和测试双管齐下的治疗方法,通过纳米颗粒平台与
化学疗法和免疫药物,以加强治疗并能够治疗晚期疾病。我们
将实现以下具体目标:1)我们将解决抗肿瘤作用是否是CPMV特异性的,
对于微粒,要求多价性质,以及纳米颗粒的形状和大小是否起作用。一
将研究具有不同分子组成、大小和形状的植物来源的VLP文库,
使用TNBC的4 T1小鼠模型进行评估。2)我们将确定细胞和信号通路-
参与VLP诱导的抗肿瘤免疫应答。纵向成像结合组织化学-
尝试和流式细胞术将提供对生物反应的全面了解。识别潜在
涉及的信号通路,将在缺乏ASC、Myd 88或Trif的敲除小鼠模型中进行研究
衔接分子3)免疫疗法作为单一疗法通常仅对小肿瘤有效,
大多数患者对单一途径免疫疗法没有反应。治疗方案,即
然而,多种免疫疗法的组合或与化疗的组合可以形成基础,
妹妹成功。首先,我们将联合收割机VLP与阿霉素(一种免疫原性化疗药物)联合,
施用(未缀合)或共递送(缀合至VLP)。其次,我们将联合收割机与
已知的“免疫原性危险信号”和共同递送ssRNA或CpG以通过Toll样重链激活信号传导,
感受器我们假设免疫刺激性VLP和化疗或免疫药物的组合
将增强疗效,同时建立系统性抗肿瘤免疫应答和记忆,这将是
通过治疗携带4 T1原发性和转移性肿瘤的小鼠进行测试。最近,关于《关于...
裂解性免疫疗法T-VEC突出了基于病毒的疗法的潜力。我们的应用程序是不同的,是-
因为我们使用植物VLP进行双管齐下的肿瘤治疗和启动抗肿瘤免疫记忆。
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 }}
Nicole Franziska Steinmetz其他文献
Nicole Franziska Steinmetz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('Nicole Franziska Steinmetz', 18)}}的其他基金
Dual-pronged nano-drug delivery using plant virus-like particles
使用植物病毒样颗粒的双管齐下纳米药物输送
- 批准号:
10700990 - 财政年份:2022
- 资助金额:
$ 47.01万 - 项目类别:
Dual-pronged nano-drug delivery using plant virus-like particles.
使用植物病毒样颗粒进行双管齐下的纳米药物输送。
- 批准号:
9982275 - 财政年份:2018
- 资助金额:
$ 47.01万 - 项目类别:
Dual-pronged nano-drug delivery using plant virus-like particles.
使用植物病毒样颗粒进行双管齐下的纳米药物输送。
- 批准号:
10224677 - 财政年份:2018
- 资助金额:
$ 47.01万 - 项目类别:
A theranostic approach for risk stratification and intervention of deep vein thrombosis.
深静脉血栓形成风险分层和干预的治疗诊断方法。
- 批准号:
9767271 - 财政年份:2017
- 资助金额:
$ 47.01万 - 项目类别:
Diagnosis and longitudinal monitoring of metastatic prostate cancer through molecular MR imaging
通过分子磁共振成像诊断和纵向监测转移性前列腺癌
- 批准号:
9208751 - 财政年份:2016
- 资助金额:
$ 47.01万 - 项目类别:
Diagnosis and longitudinal monitoring of metastatic prostate cancer through molecular MR imaging.
通过分子磁共振成像诊断和纵向监测转移性前列腺癌。
- 批准号:
9755062 - 财政年份:2016
- 资助金额:
$ 47.01万 - 项目类别:
Diagnosis and longitudinal monitoring of metastatic prostate cancer through molecular MR imaging.
通过分子磁共振成像诊断和纵向监测转移性前列腺癌。
- 批准号:
9629935 - 财政年份:2016
- 资助金额:
$ 47.01万 - 项目类别:
Engineering 'Grapevine Virus A' filaments for nanomedical applications
工程“葡萄病毒 A”细丝用于纳米医学应用
- 批准号:
9144385 - 财政年份:2015
- 资助金额:
$ 47.01万 - 项目类别:
Detection of lethal prostate cancer with macromolecule-based, EGFL-7 targeted MR imaging approach
使用基于大分子的 EGFL-7 靶向 MR 成像方法检测致命性前列腺癌
- 批准号:
8954282 - 财政年份:2015
- 资助金额:
$ 47.01万 - 项目类别:
Detection of lethal prostate cancer with macromolecule-based, EGFL-7 targeted MR imaging approach
使用基于大分子的 EGFL-7 靶向 MR 成像方法检测致命性前列腺癌
- 批准号:
9094573 - 财政年份:2015
- 资助金额:
$ 47.01万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 47.01万 - 项目类别:
Fellowship
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 47.01万 - 项目类别:
Continuing Grant
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 47.01万 - 项目类别:
Research Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 47.01万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 47.01万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 47.01万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 47.01万 - 项目类别:
EU-Funded
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 47.01万 - 项目类别:
Standard Grant
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 47.01万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 47.01万 - 项目类别:
Research Grant














{{item.name}}会员




