Tumor Targeted Corroles for Detection and Intervention
用于检测和干预的肿瘤靶向作用
基本信息
- 批准号:8206856
- 负责人:
- 金额:$ 33.21万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-02-05 至 2014-12-31
- 项目状态:已结题
- 来源:
- 关键词:AdenovirusesAffinityAlkanesulfonatesBindingBiodistributionBiological ModelsCapsidCarrier ProteinsCell CommunicationCell DeathCell NucleusCell Surface ReceptorsCellsCollaborationsComplexCytoplasmCytoskeletonCytosolDetectionDevelopmentDoseDoxorubicinDrug KineticsERBB2 geneEpidermal Growth Factor ReceptorFluorescenceGalliumGliomaGray unit of radiation doseHeregulinHumanImageImageryImmuneImmune SeraIn VitroInterventionInvestigationLeadLigandsMacrocyclic CompoundsMalignant NeoplasmsMalignant neoplasm of prostateMediatingMembraneMembrane ProteinsMetabolicMethodologyMitochondriaMitoticModelingModificationMultimodal ImagingMutationNational Cancer InstituteOvarianPenetrationPilot ProjectsPost-Translational Protein ProcessingPropertyProteinsPublic HealthPublishingRegimenResearchResearch Project GrantsSafetyScreening procedureSerumSystemTechnologyTertiary Protein StructureTestingTherapeuticToxic effectTreatment EfficacyVariantWateralternative treatmentbasebiological systemscancer cellcell killingcell typechemotherapycorrolecytotoxicitydirected evolutiondosagedrug metabolismimprovedin vivokillingsmalignant breast neoplasmneoplastic cellnew therapeutic targetnoveloutcome forecastoverexpressionpenton basepreventreceptorreceptor mediated endocytosistargeted deliverytumortumor growthuptake
项目摘要
ABSTRACT
This proposal will test the hypothesis that noncovalent corrole assemblies simultaneously mediate both
tumor targeted detection and intervention in a single self-assembled complex.
Sulfonated corroles are water soluble, macrocyclic compounds that may be metallated and can emit an
intense fluorescence. We have found that corroles spontaneously assemble with carrier proteins, which are
required to facilitate cel entry, and once entering cels, must be released into the cytoplasm to elicit
cytotoxicity while remaining excluded from the nucleus, thus implicating cytosolic factors as the targets of
corrole-mediated toxicity. Our targeted cell penetration protein, HerPBK10, enables corrole uptake into
HER2+ cancer cells in vitro and in vivo. HerPBK10 is comprised of a cell-targeting and internalizing ligand
derived from the heregulin protein, and membrane penetration domain derived from the adenovirus (Ad)
capsid penton base. Corrole fluorescence enables visualization of tumor cell targeting in vitro and in vivo,
and tumor targeting in vivo results in tumor growth intervention at nearly 300x less dosage in
comparison to direct intratumoral delivery of the chemotherapy agent, doxorubicin.
HER2+ cancer has served as a model system for testing new targeted therapeutics in our lab. As the
overexpression of the HER2 (or ErbB2) subunit enhances receptor affinity, the HER2+ cell type is an ideal
model for testing ligand-directed therapies. More importantly, as HER2 overexpression in breast cancer
correlates with aggressive chemoresistant tumors and predicts a poor prognosis, alternative treatments to
standard regimens may prove more effective on this subset of breast cancers that, while not comprising a
majority of cases, are among the most deadly of breast cancers. Nevertheless, we have identified additional
potential targets of our heregulin-directed therapeutics, including ovarian, glioma, and prostate cancer cells
that express high levels of different HER subunits. Thus, the HER-targeted system presented here may have
a broader application to several different tumor types in addition to HER2+ breast cancer.
This proposal combines the expertise of multiple collaborators to further develop corrole assemblies into
image-able tumor targeting agents. We will assess target cell and immune interactions with the carrier
protein to direct efforts in introducing modifications that may enhance therapeutic efficacy and safety. One
exciting direction we will explore is to apply directed evolution to select carrier protein domains to improve
target cell interactions and immune evasion. We will test these modifications for corrole delivery in vitro
and in vivo, and utilize the unique photoemission properties of corroles to detect in vivo tumor targeting.
抽象的
该提案将检验非共价咔咯组装体同时介导两者的假设
单个自组装复合物中的肿瘤靶向检测和干预。
磺化咔咯是水溶性大环化合物,可以金属化并能释放出
强烈的荧光。我们发现咔咯自发地与载体蛋白组装,载体蛋白是
促进细胞进入所必需的,一旦进入细胞,必须释放到细胞质中以引起
细胞毒性,同时仍被排除在细胞核之外,因此暗示细胞质因子是细胞毒性的目标
咯咯介导的毒性。我们的靶向细胞渗透蛋白 HerPBK10 能够使 Corrole 摄取到
体外和体内 HER2+ 癌细胞。 HerPBK10 由细胞靶向和内化配体组成
源自调蛋白,以及源自腺病毒(Ad)的膜穿透结构域
衣壳五邻体碱基。 Corrole 荧光能够实现体外和体内肿瘤细胞靶向的可视化,
体内肿瘤靶向导致肿瘤生长干预的剂量减少了近 300 倍
与直接瘤内递送化疗药物阿霉素的比较。
HER2+ 癌症已成为我们实验室测试新靶向疗法的模型系统。作为
HER2(或 ErbB2)亚基的过度表达可增强受体亲和力,HER2+ 细胞类型是理想的
用于测试配体定向疗法的模型。更重要的是,乳腺癌中 HER2 过度表达
与侵袭性化疗耐药肿瘤相关并预测不良预后,替代治疗
标准治疗方案可能被证明对这部分乳腺癌更有效,尽管不包含
大多数病例属于最致命的乳腺癌之一。尽管如此,我们还是确定了额外的
我们的调蛋白导向疗法的潜在靶标,包括卵巢癌细胞、神经胶质瘤细胞和前列腺癌细胞
表达高水平的不同 HER 亚基。因此,这里提出的 HER 靶向系统可能具有
除 HER2+ 乳腺癌外,还可更广泛地应用于多种不同的肿瘤类型。
该提案结合了多个合作者的专业知识,将 corrole 组件进一步开发为
可成像的肿瘤靶向剂。我们将评估靶细胞和免疫与载体的相互作用
蛋白质来指导引入可能增强治疗功效和安全性的修饰的努力。一
我们将探索的令人兴奋的方向是应用定向进化来选择载体蛋白结构域以改进
靶细胞相互作用和免疫逃避。我们将测试这些修饰在体外的可罗传递
并利用corroles独特的光电发射特性来检测体内肿瘤靶向。
项目成果
期刊论文数量(0)
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{{ truncateString('LALI K MEDINA-KAUWE', 18)}}的其他基金
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10367490 - 财政年份:2022
- 资助金额:
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Nucleocapsid bioparticles eliciting multi-pronged attack on tumor metastases
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- 批准号:
10610443 - 财政年份:2022
- 资助金额:
$ 33.21万 - 项目类别:
Targeting inhibitor-resistant breast tumors with HER3-homing nano-capsids
使用 HER3 归巢纳米衣壳靶向抑制剂耐药性乳腺肿瘤
- 批准号:
10619565 - 财政年份:2022
- 资助金额:
$ 33.21万 - 项目类别:
Tumor Targeted Corroles for Detection and Intervention
用于检测和干预的肿瘤靶向作用
- 批准号:
8599443 - 财政年份:2010
- 资助金额:
$ 33.21万 - 项目类别:
Tumor Targeted Corroles for Detection and Intervention
用于检测和干预的肿瘤靶向作用
- 批准号:
8021832 - 财政年份:2010
- 资助金额:
$ 33.21万 - 项目类别:
Tumor Targeted Corroles for Detection and Intervention
用于检测和干预的肿瘤靶向作用
- 批准号:
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- 资助金额:
$ 33.21万 - 项目类别:
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用于肿瘤靶向的蛋白质-DNA 药物载体
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8254429 - 财政年份:2009
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$ 33.21万 - 项目类别:
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用于肿瘤靶向的蛋白质-DNA 药物载体
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8192951 - 财政年份:2009
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$ 33.21万 - 项目类别:
Protein-DNA Drug Carriers for Tumor Targeting
用于肿瘤靶向的蛋白质-DNA 药物载体
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7816792 - 财政年份:2009
- 资助金额:
$ 33.21万 - 项目类别:
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