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：
8021832
负责人：
LALI K MEDINA-KAUWE
金额：
$ 33.21万
依托单位：
CEDARS-SINAI MEDICAL CENTER
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：
https://reporter.nih.gov/project-details/8021832
关键词：
Adenoviruses Affinity Alkanesulfonates Binding Biodistribution Biological Models Capsid Carrier Proteins Cell Communication Cell Death Cell Nucleus Cell Surface Receptors Cells Collaborations Complex Cytoplasm Cytoskeleton Cytosol Detection Development Dose Doxorubicin Drug Kinetics ERBB2 gene Epidermal Growth Factor Receptor Fluorescence Gallium Glioma Gray unit of radiation dose Heregulin Human Image Imagery Immune Immune Sera In Vitro Intervention Investigation Lead Ligands Macrocyclic Compounds Malignant Neoplasms Malignant neoplasm of prostate Mediating Membrane Membrane Proteins Metabolic Methodology Mitochondria Mitotic Modeling Modification Multimodal Imaging Mutation National Cancer Institute Ovarian Penetration Pilot Projects Post-Translational Protein Processing Property Proteins Public Health Publishing Regimen Research Research Project Grants Safety Screening procedure Serum System Technology Tertiary Protein Structure Testing Therapeutic Toxic effect Treatment Efficacy Variant Water alternative treatment base biological systems cancer cell cell killing cell type chemotherapy corrole cytotoxicity directed evolution dosage drug metabolism improved in vivo killings malignant breast neoplasm neoplastic cell new therapeutic target novel outcome forecast overexpression penton base prevent public health relevance receptor receptor mediated endocytosis targeted delivery tumor tumor growth uptake

项目摘要

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: This research project is relevant to public health because it will result in the development of a novel self-assembled therapeutic that can specifically target HER2+ tumors (which includes HER2+ breast cancer) at substantially lower, and thus safer doses compared to untargeted standard chemotherapy. Moreover, this therapeutic can be imaged during treatment so that tumor targeting can be detectable. Thus, this technology combines both detection and intervention in a single self-assembled targeted complex.

描述（由申请人提供）：该提案将检验以下假设：非共价牛rol组装同时介导了单个自组装复合物中肿瘤靶向检测和干预的介导。磺化的腐病是水溶性的大环化合物，可能是金属物质的，可以发出强烈的荧光。我们发现，腐病菌与载体蛋白自发地组装，这是促进CEL进入所需的载体蛋白，并且一旦进入CEL，就必须将其释放到细胞质中，以引起细胞毒性，同时将其留在细胞核中，从而将细胞质因子与柯洛（Corrole）介导的毒性的靶标有关。我们靶向的细胞渗透蛋白HERPBK10可在体外和体内摄取HER2+癌细胞的腐蚀性。 HERPBK10由源自此处的细胞蛋白蛋白的细胞靶向和内部化配体以及源自腺病毒（AD）Capsid Penton碱基的膜穿透域的组成。与化疗剂的直接肿瘤内疗法剂量的直接肿瘤内疗法相比，Corrole荧光可以在体外和体内可视化肿瘤细胞的靶向体外和靶向体内的肿瘤生长干预剂的剂量降低了近300倍。 HER2+癌症已成为测试我们实验室中新的靶向治疗剂的模型系统。随着HER2（或ERBB2）亚基的过表达增强了受体亲和力，HER2+细胞类型是测试配体指导疗法的理想模型。更重要的是，由于乳腺癌中的HER2过表达与侵袭性化学抗性肿瘤相关，并且预后不良，因此对标准方案的替代治疗方法可能在乳腺癌的这一子集中更为有效，尽管乳腺癌中不包括大多数病例，但乳腺癌中最致命的乳腺癌之一。然而，我们已经确定了我们这里指导的治疗剂的其他潜在靶标，包括卵巢，神经胶质瘤和前列腺癌细胞，这些癌细胞表达高水平的亚基。因此，此处介绍的靶向系统除了HER2+乳腺癌外，还可能对几种不同的肿瘤类型具有更广泛的应用。该提案结合了多个合作者的专业知识，以进一步将孔罗莱斯组件发展为可图像的肿瘤靶向剂。我们将评估靶细胞和与载体蛋白的免疫相互作用，以指导引入可能增强治疗功效和安全性的修饰的努力。我们将探索的一个令人兴奋的方向是应用定向的进化来选择载体蛋白结构域以改善靶细胞相互作用和免疫逃避。我们将在体外和体内测试这些修饰，以实现孔罗罗尔的递送，并利用孔洛尔的独特光发射特性来检测体内肿瘤靶向。公共卫生相关性：该研究项目与公共卫生有关，因为它将导致一种新型的自组装治疗性的发展，该治疗方法可以大大降低靶向HER2+肿瘤（包括HER2+乳腺癌），因此与未经预订的标准化疗相比，更安全的剂量。此外，可以在治疗过程中成像这种治疗性，以便可以检测到肿瘤靶向。因此，该技术结合了单个自组装的靶向复合物中的检测和干预。