Disrupting the endothelial vascular architecture associated with tumor can impact tumor growth. Conventionally designed drugs have been investigated which inhibit angiogenesis or are cytotoxic to tumor vascular endothelial cells, but have limited potency and specificity, impeding their clinical utility. We hypothesize that nano-scale carbon nanotube constructs can be designed which amplify the intrinsic targeting, binding, and therapeutic attributes of a conventional radiolabled drug construct and thereby improve the therapeutic index. These novel synthetic nanostructures will be designed as hybrid molecules consisting of biologics, radionuclides and carbon nanotubes and should have emergent anti-cancer properties. The carbon nanotube provides a platform to amplify these moieties and deliver to vascular endothelial cells. The stoichiometric amplification of targeting, binding, and therapeutic moieties should therefore improve potency, specificity, and efficacy relative to current therapeutics. The goal of this project is to target and selectively irradiate angiogenic endothelium in tumor, disrupt angiogenesis, and potently inhibit further tumor growth or eradicate tumor. Drugs have been investigated which inhibit angiogenesis or are cytotoxic to tumor vascular endothelial cells, but despite rapid accessibility they suffer from low potency and minimal specificity, weak binding interaction, rapid clearance, and a limited number of target molecules per cell. In order to overcome those issues related to low specificity and/or weak binding, a strategy will be investigated to synthetically amplify the avidity and potency of drug constructs directed against tumor neovascular endothelium. Constructs will be synthesized which have both multiple targeting moieties to increase avidity and multiple therapeutic alpha particle emitting radionuclides to increase the specific activity. In the proposed model systems, RGD peptide targeting molecules directed against tumor vasculature integrin epitopes will be examined and potent alpha emitting radionuclides are proposed as the therapeutic modality.
The specific aims are: 1. To synthesize and characterize the radiolabled, targeting carbon nanotube constructs and 2. To investigate the pharmacokinetics and biodistribution of constructs in appropriate vascular models in mice and explore the therapeutic efficacy of specific constructs versus control constructs in tumored mice. Angiogenesis encompasses the proliferation of new blood vessels from existing vasculature and is a highly regulated process. Angiogenesis has a crucial role in normal physiological events such as wound healing, embryonic development and trophoblast implantation. However, it also has a role in aberrant physiological processes such as diabetic retinopathy, rheumatoid arthritis, and the growth of many aggressive solid tumors and metastatic disease. A variety of cellular processes and their respective regulatory molecules work in concert to modulate extracellular matrix remodeling, invasion, migration, and proliferation events. Interfering with aberrant angiogenesis may lessen the symptoms of retinopathy, arthritis and tumorogenesis. We hypothesize that novel nanodevices based on hybrid molecules consisting of biologics, radionuclides and carbon nanotubes will have emergent anti-cancer properties and the amplification of the intrinsic targeting, binding, and therapeutic attributes of this nanodevice should therefore improve potency, specificity, and efficacy relative to conventional anti-angiogenic agents. ? ? ?
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| Behling, Katja; Maguire, William F; Di Gialleonardo, Valentina et al. (2016) Remodeling the Vascular Microenvironment of Glioblastoma with ?-Particles. J Nucl Med 57:1771-1777 |
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| Alidori, Simone; Bowman, Robert L; Yarilin, Dmitry et al. (2016) Deconvoluting hepatic processing of carbon nanotubes. Nat Commun 7:12343 |
| Maguire, William F; McDevitt, Michael R; Smith-Jones, Peter M et al. (2014) Efficient 1-step radiolabeling of monoclonal antibodies to high specific activity with 225Ac for ?-particle radioimmunotherapy of cancer. J Nucl Med 55:1492-8 |
| McDevitt, Michael R; Scheinberg, David A (2014) Fibrillous carbon nanotube: an unexpected journey. Crit Rev Oncog 19:261-8 |
| Mallikaratchy, Prabodhika; Gardner, Jeffery; Nordstrøm, Lars Ulrik R et al. (2013) A self-assembling short oligonucleotide duplex suitable for pretargeting. Nucleic Acid Ther 23:289-99 |
| Mulvey, J Justin; Villa, Carlos H; McDevitt, Michael R et al. (2013) Self-assembly of carbon nanotubes and antibodies on tumours for targeted amplified delivery. Nat Nanotechnol 8:763-71 |
| Alidori, Simone; Asqiriba, Karim; Londero, Pablo et al. (2013) Deploying RNA and DNA with Functionalized Carbon Nanotubes. J Phys Chem C Nanomater Interfaces 117:5982-5992 |
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