Imaging and treating tumor vasculature with targeted radiolabeled carbon nanotubes

Abstract

Single wall carbon nanotube (SWCNT) constructs were covalently appended with radiometal-ion chelates (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid [DOTA] or desferrioxamine B [DFO]) and the tumor neovascular-targeting antibody E4G10. The E4G10 antibody specifically targeted the monomeric vascular endothelial-cadherin (VE-cad) epitope expressed in the tumor angiogenic vessels. The construct specific activity and blood compartment clearance kinetics were significantly improved relative to corresponding antibodyalone constructs. We performed targeted radioimmunotherapy with a SWCNT-([²²⁵Ac]DOTA) (E4G10) construct directed at the tumor vasculature in a murine xenograft model of human colon adenocarcinoma (LS174T). The specific construct reduced tumor volume and improved median survival relative to controls. We also performed positron emission tomographic (PET) radioimmunoimaging of the tumor vessels with a SWCNT-([⁸⁹Zr]DFO)(E4G10) construct in the same murine LS174T xenograft model and compared the results to appropriate controls. Dynamic and longitudinal PET imaging of LS174T tumor-bearing mice demonstrated rapid blood clearance (<1 hour) and specific tumor accumulation of the specific construct. Incorporation of the SWCNT scaffold into the construct design permitted us to amplify the specific activity to improve the signal-to-noise ratio without detrimentally impacting the immunoreactivity of the targeting antibody moiety. Furthermore, we were able to exploit the SWCNT pharmacokinetic (PK) profile to favorably alter the blood clearance and provide an advantage for rapid imaging. Near-infrared three-dimensional fluorescent-mediated tomography was used to image the LS174T tumor model, collect antibody-alone PK data, and calculate the number of copies of VE-cad epitope per cell. All of these studies were performed as a single administration of construct and were found to be safe and well tolerated by the murine model. These data have implications that support further imaging and radiotherapy studies using a SWCNT-based platform and focusing on the tumor vessels as the target.

Keywords:

• actinium-225 (²²⁵Ac)
• zirconium-89 (⁸⁹Zr)
• angiogenesis
• vascular endothelialcadherin
• radioimmunotherapy (RIT)
• radioimmunoPET

Acknowledgments

/disclosure

Funded in part by the National Institutes of Health grants R21 CA128406, R01 CA55349, R25T CA096945, R24 CA83084, P30 CA08748, P01 CA33049; the Memorial Sloan-Kettering Brain Tumor Center; the Memorial Sloan- Kettering Experimental Therapeutics Center; the Geoffrey Beene Cancer Research Center of Memorial Sloan-Kettering Cancer Center; and the Office of Science (BER), US Department of Energy (Award DE-SC0002456). We would also like to thank Medactinium, Inc for the ²²⁵Ac; ImClone Systems (a wholly-owned subsidiary of Eli Lilly and Company) for the E4G10 antibody; and Amy Carol McDevitt for the graphic illustration and figure. Conflict of interest statement: David A Scheinberg is a consultant for Enscyce; Michael R McDevitt was a consultant for Medactinium; and Chad May was employed by ImClone Systems at the time of this study.