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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：
8403815
负责人：
LALI K MEDINA-KAUWE
金额：
$ 31.22万
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/8403815
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 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 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 prostate cancer cell receptor receptor mediated endocytosis screening targeted delivery tumor tumor growth uptake

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.

摘要