Monitoring response to anticancer therapy by targeting microbubbles to tumor vasculature.
OBJECTIVE
New strategies to detect tumor angiogenesis and monitor response of tumor vasculature to therapy are needed. Contrast ultrasound imaging using microbubbles targeted to tumor endothelium offers a noninvasive method for monitoring and quantifying vascular effects of antitumor therapy. We investigated the use of targeted microbubbles to follow vascular response of therapy in a mouse model of pancreatic adenocarcinoma.


METHODS
Microbubbles conjugated to monoclonal antibodies were used to image and quantify vascular effects of two different antitumor therapies in s.c. and orthotopic pancreatic tumors in mice. Tumor-bearing mice were treated with anti-vascular endothelial growth factor (VEGF) monoclonal antibodies and/or gemcitabine, and the localization of microbubbles to endoglin (CD105), VEGF receptor 2 (VEGFR2), or VEGF-activated blood vessels (the VEGF-VEGFR complex) was monitored by contrast ultrasound.


RESULTS
Targeted microbubbles showed significant enhancement of tumor vasculature when compared with untargeted or control IgG-targeted microbubbles. Video intensity from targeted microbubbles correlated with the level of expression of the target (CD105, VEGFR2, or the VEGF-VEGFR complex) and with microvessel density in tumors under antiangiogenic or cytotoxic therapy.


CONCLUSIONS
We conclude that targeted microbubbles represent a novel and attractive tool for noninvasive, vascular-targeted molecular imaging of tumor angiogenesis and for monitoring vascular effects specific to antitumor therapy in vivo.
Korpanty
Grzegorz
G
Hamon Center for Therapeutic Oncology Research and Department of Surgery, University of Texas Southwestern Medical Center, Dallas 75390-8593, USA.
Carbon
Juliet G
JG
Grayburn
Paul A
PA
Fleming
Jason B
JB
Brekken
Rolf A
RA
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D000818:Animals; D015703:Antigens, CD / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D016903:Drug Monitoring; D000071063:Endoglin; D006801:Humans; D007074:Immunoglobulin G / Q000378:metabolism; D051379:Mice; D045423:Microbubbles; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000098:blood supply*; D009389:Neovascularization, Pathologic; D011956:Receptors, Cell Surface; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
D020533:Angiogenesis Inhibitors; D015703:Antigens, CD; D000970:Antineoplastic Agents; C064206:ENG protein, human; D000071063:Endoglin; D007074:Immunoglobulin G; D011956:Receptors, Cell Surface; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2