Supramolecular Bioorthogonal Nanozymes for Targeted Activation of Therapeutics In our proposed research we will create nanozymes?nanoparticles featuring protein-like size and surface properties that catalyze bioorthogonal processes using transition metal centers. These nanozymes will be used to activate prodrugs at tumor sites, using the bioorthogonal capabilities of the nanozyme to target tumors, generating therapeutics at the targeted tissue. We will assess these particles using in vitro models to determine intracellular therapeutic/imaging efficacy, targeting efficiency, and hemolytic properties. The particles will then be tested in vivo, assessing their efficacy in both imaging and therapeutic contexts. In our proposed studies, we will Aim 1: Fabricate nanozymes featuring different monolayer designs for optimizing particle loading and catalyst stability. We will quantify catalytic efficiency of these nanozymes for activating prodrugs, and determine their stability.
Aim 2 : Test the intracellular activity of nanozymes in cells through activation of pro- fluorophores and prodrugs. We will attach Her-2 targeting elements to the nanozymes and EGFR-targeting peptides to the polymeric prodrug delivery particles, and determine the ability to use dual AND targeting of nanozyme and carrier to target only cells that overexpress both receptors.
Aim 3 : Use targeted nanozymes to activate profluorophores and prodrugs at tumor sites using orthotopic breast carcinoma models.
Aim 4 : Differently targeted nanozymes and PEG/PLGA nanoparticles carrying prodrug will be used to provide therapeutic efficacy only at tumors overexpressing both targeted receptors, providing highly specific AND gate targeting. The goal of this research is to create therapeutic systems capable of high specificity through bioorthogonal chemistry. This research will build upon the supramolecular and nanomaterials strength of Rotello coupled with the cancer biology and animal model strengths of D. Joseph Jerry (UMass Vet. and Ani. Sci).
Significance: This research is focused on the development of a new strategy for activation of therapeutics at tumor sites. This approach presents the possibility of generating active drugs only at tumor sites, reducing off-target effects and minimizing health consequences for chemotherapy.
| Gupta, Akash; Das, Riddha; Yesilbag Tonga, Gulen et al. (2018) Charge-Switchable Nanozymes for Bioorthogonal Imaging of Biofilm-Associated Infections. ACS Nano 12:89-94 |
| Jeong, Youngdo; Tonga, Gulen Yesilbag; Duncan, Bradley et al. (2018) Solubilization of Hydrophobic Catalysts Using Nanoparticle Hosts. Small 14: |
| Ray, Moumita; Lee, Yi-Wei; Hardie, Joseph et al. (2018) CRISPRed Macrophages for Cell-Based Cancer Immunotherapy. Bioconjug Chem 29:445-450 |
| Luther, D C; Lee, Y W; Nagaraj, H et al. (2018) Delivery approaches for CRISPR/Cas9 therapeutics in vivo: advances and challenges. Expert Opin Drug Deliv 15:905-913 |
| Scaletti, Federica; Hardie, Joseph; Lee, Yi-Wei et al. (2018) Protein delivery into cells using inorganic nanoparticle-protein supramolecular assemblies. Chem Soc Rev 47:3421-3432 |
| Cao-Milán, Roberto; He, Luke D; Shorkey, Spencer et al. (2017) Modulating the Catalytic Activity of Enzyme-like Nanoparticles Through their Surface Functionalization. Mol Syst Des Eng 2:624-628 |
| Mout, Rubul; Ray, Moumita; Tay, Tristan et al. (2017) General Strategy for Direct Cytosolic Protein Delivery via Protein-Nanoparticle Co-engineering. ACS Nano 11:6416-6421 |
| Tang, Rui; Wang, Ming; Ray, Moumita et al. (2017) Active Targeting of the Nucleus Using Nonpeptidic Boronate Tags. J Am Chem Soc 139:8547-8551 |
| Elci, S Gokhan; Yesilbag Tonga, Gulen; Yan, Bo et al. (2017) Dual-Mode Mass Spectrometric Imaging for Determination of in Vivo Stability of Nanoparticle Monolayers. ACS Nano 11:7424-7430 |
| Mumtaz, Shazia; Wang, Li-Sheng; Hussain, Syed Zajif et al. (2017) Dopamine coated Fe3O4 nanoparticles as enzyme mimics for the sensitive detection of bacteria. Chem Commun (Camb) 53:12306-12308 |
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