Targeted Systemic Radiotherapy with scVEGF/177Lu Leads to Sustained Disruption of the Tumor Vasculature and Intratumoral Apoptosis
| Autor: | Michael G. Goris, Joseph M. Backer, Marina V. Backer, Francis G. Blankenberg, Zoia Levashova, Carl V. Hamby |
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| Rok vydání: | 2011 |
| Předmět: |
Vascular Endothelial Growth Factor A
Biodistribution Pathology medicine.medical_specialty Indoles Cell Survival Angiogenesis Inhibitors Apoptosis Breast Neoplasms Mice SCID Lutetium Antibodies Monoclonal Humanized Mice Cell Line Tumor Sunitinib Animals Humans Medicine Pyrroles Radiology Nuclear Medicine and imaging Radioisotopes Mice Inbred BALB C Mice Inbred ICR Reporter gene Neovascularization Pathologic business.industry Mesenchymal stem cell Endothelial Cells Transfection Combined Modality Therapy Bevacizumab Receptors Vascular Endothelial Growth Factor Cell culture Monoclonal Female Radiopharmaceuticals Stem cell business Ex vivo |
| Zdroj: | Journal of Nuclear Medicine. 52:1630-1637 |
| ISSN: | 2159-662X 0161-5505 |
| DOI: | 10.2967/jnumed.111.091629 |
| Popis: | Tumor vessels abundantly express receptors for vascular endothelial growth factor (VEGF), despite treatment with conventional or antiangiogenic drugs. We wished to determine whether the high levels of VEGF receptor (VEGFR) within the tumor vasculature could be leveraged for intracellular delivery of therapeutically significant doses of scVEGF/(177)Lu, a novel radiopharmaceutical based on a recombinant single-chain (sc) derivative of VEGF, in orthotopic breast cancer models.scVEGF-PEG (polyethylene gycol)-DOTA conjugates containing 2.0-, 3.4-, or 5.0-kDa PEG linkers site-specifically conjugated to a cysteine-containing tag (Cys-tag) in scVEGF were radiolabeled with (177)Lu (scVEGF/(177)Lu) for in vivo studies. Human MDA231luc and mouse 4T1luc cell lines were injected orthotopically to establish breast carcinoma tumors in immunodeficient and immunocompetent hosts, respectively. The effects of scVEGF/(177)Lu were defined by analysis of changes in tumor growth and immunohistochemical staining for the endothelial markers CD31 and VEGFR-2 and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) staining for intratumoral apoptosis.Biodistribution assays and dosimetric calculations established that scVEGF/(177)Lu with a 3.4-kDa PEG linker delivered the highest dose of radiation to tumors (69.9 cGy/MBq/g of tissue) and the lowest dose to the kidneys (33.3 cGy/MBq/organ). Total doses below 40 MBq/mouse of scVEGF/(177)Lu did not affect renal function, and 3 divided doses of 6.3 MBq/mouse or a bolus dose of 18.9 MBq/mouse induced only transient lymphopenia and weight loss (10% baseline weight). In mice with orthotopic mammary breast carcinoma, intravenous injections of well-tolerated bolus and fractionated doses of scVEGF/(177)Lu in the range from 6.3 to 18.9 MBq/mouse (25-76 MBq/m(2)) resulted in dose-dependent tumor growth inhibition. Immunohistochemical analysis of tumors at 4-5 wk after single injections of scVEGF/(177)Lu indicated dose-dependent regression of tumor vasculature and widespread intratumoral apoptosis. A single dose of 7.4 MBq/mouse of scVEGF/(177)Lu given before a course of bevacizumab or sunitinib treatment enhanced the antiangiogenic effects of both drugs.Selective targeting of VEGFR in tumor vasculature with well-tolerated doses of scVEGF/(177)Lu is effective in orthotopic breast cancer models. As high levels of VEGFR expression in the tumor vasculature are a common feature in a variety of cancers, targeting tumor angiogenesis with scVEGF/(177)Lu warrants further exploration. |
| Databáze: | OpenAIRE |
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