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.
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.
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|Ha, Sung Gil; Dileepan, Mythili; Ge, Xiao Na et al. (2018) Knob protein enhances epithelial barrier integrity and attenuates airway inflammation. J Allergy Clin Immunol 142:1808-1817.e3|
|Qu, Ying; Han, Bingchen; Gao, Bowen et al. (2017) Differentiation of Human Induced Pluripotent Stem Cells to Mammary-like Organoids. Stem Cell Reports 8:205-215|
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|Chung, Alice; Choi, Michael; Han, Bing-chen et al. (2015) Basal Protein Expression Is Associated With Worse Outcome and Trastuzamab Resistance in HER2+ Invasive Breast Cancer. Clin Breast Cancer 15:448-457.e2|
|Sims, Jessica D; Hwang, Jae Youn; Wagner, Shawn et al. (2015) A corrole nanobiologic elicits tissue-activated MRI contrast enhancement and tumor-targeted toxicity. J Control Release 217:92-101|
|Medina-Kauwe, Lali K (2013) Development of adenovirus capsid proteins for targeted therapeutic delivery. Ther Deliv 4:267-77|
|Hwang, Jae Youn; Farkas, Daniel L; Medina-Kauwe, Lali K (2013) Analysis of targeted viral protein nanoparticles delivered to HER2+ tumors. J Vis Exp :|
|Hwang, Jae Youn; Lee, Jungwoo; Lee, Changyang et al. (2012) Fluorescence response of human HER2+ cancer- and MCF-12F normal cells to 200MHz ultrasound microbeam stimulation: a preliminary study of membrane permeability variation. Ultrasonics 52:803-8|
|Hwang, Jae Youn; Lubow, David J; Sims, Jessica D et al. (2012) Investigating photoexcitation-induced mitochondrial damage by chemotherapeutic corroles using multimode optical imaging. J Biomed Opt 17:015003|
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