Imaging and treating tumor vasculature with targeted radiolabeled carbon nanotubes

Alessandro Ruggiero1*, Carlos H Villa1*, Jason P Holland1, Shanna R Sprinkle1, Chad May2, Jason S Lewis1, David A Scheinberg1, Michael R McDevitt11Departments of Medicine and Radiology, Pharmacology and Molecular Therapeutics, Memorial Sloan-Kettering Cancer Center, New York, USA; 2ImClone Systems,...

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Autores principales:	Alessandro Ruggiero, Carlos H Villa, Jason P Holland, et al
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2010
Materias:	Medicine (General) R5-920
Acceso en línea:	https://doaj.org/article/b8609bfd2f864313bc29dce036fe4838
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spelling	oai:doaj.org-article:b8609bfd2f864313bc29dce036fe48382021-12-02T02:46:49ZImaging and treating tumor vasculature with targeted radiolabeled carbon nanotubes1176-91141178-2013https://doaj.org/article/b8609bfd2f864313bc29dce036fe48382010-09-01T00:00:00Zhttp://www.dovepress.com/imaging-and-treating-tumor-vasculature-with-targeted-radiolabeled-carb-a5411https://doaj.org/toc/1176-9114https://doaj.org/toc/1178-2013Alessandro Ruggiero1, Carlos H Villa1, Jason P Holland1, Shanna R Sprinkle1, Chad May2, Jason S Lewis1, David A Scheinberg1, Michael R McDevitt11Departments of Medicine and Radiology, Pharmacology and Molecular Therapeutics, Memorial Sloan-Kettering Cancer Center, New York, USA; 2ImClone Systems, New York, USA; *Ruggiero and Villa contributed equally to this workAbstract: 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 antibody-alone 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 (&lt;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 endothelial-cadherin, radioimmunotherapy (RIT), radioimmunoPET Alessandro RuggieroCarlos H VillaJason P Hollandet alDove Medical PressarticleMedicine (General)R5-920ENInternational Journal of Nanomedicine, Vol 2010, Iss default, Pp 783-802 (2010)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine (General) R5-920
spellingShingle	Medicine (General) R5-920 Alessandro Ruggiero Carlos H Villa Jason P Holland et al Imaging and treating tumor vasculature with targeted radiolabeled carbon nanotubes
description	Alessandro Ruggiero1, Carlos H Villa1, Jason P Holland1, Shanna R Sprinkle1, Chad May2, Jason S Lewis1, David A Scheinberg1, Michael R McDevitt11Departments of Medicine and Radiology, Pharmacology and Molecular Therapeutics, Memorial Sloan-Kettering Cancer Center, New York, USA; 2ImClone Systems, New York, USA; *Ruggiero and Villa contributed equally to this workAbstract: 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 antibody-alone 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 (&lt;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 endothelial-cadherin, radioimmunotherapy (RIT), radioimmunoPET
format	article
author	Alessandro Ruggiero Carlos H Villa Jason P Holland et al
author_facet	Alessandro Ruggiero Carlos H Villa Jason P Holland et al
author_sort	Alessandro Ruggiero
title	Imaging and treating tumor vasculature with targeted radiolabeled carbon nanotubes
title_short	Imaging and treating tumor vasculature with targeted radiolabeled carbon nanotubes
title_full	Imaging and treating tumor vasculature with targeted radiolabeled carbon nanotubes
title_fullStr	Imaging and treating tumor vasculature with targeted radiolabeled carbon nanotubes
title_full_unstemmed	Imaging and treating tumor vasculature with targeted radiolabeled carbon nanotubes
title_sort	imaging and treating tumor vasculature with targeted radiolabeled carbon nanotubes
publisher	Dove Medical Press
publishDate	2010
url	https://doaj.org/article/b8609bfd2f864313bc29dce036fe4838
work_keys_str_mv	AT alessandroruggiero imagingandtreatingtumorvasculaturewithtargetedradiolabeledcarbonnanotubes AT carloshvilla imagingandtreatingtumorvasculaturewithtargetedradiolabeledcarbonnanotubes AT jasonpholland imagingandtreatingtumorvasculaturewithtargetedradiolabeledcarbonnanotubes AT etal imagingandtreatingtumorvasculaturewithtargetedradiolabeledcarbonnanotubes
_version_	1718402186307698688

Imaging and treating tumor vasculature with targeted radiolabeled carbon nanotubes

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