Three-dimensional MR mapping of angiogenesis with alpha5beta1(alpha nu beta3)-targeted theranostic nanoparticles in the MDA-MB-435 xenograft mouse model.
Our objectives were 1) to characterize angiogenesis in the MDA-MB-435 xenograft mouse model with three-dimensional (3D) MR molecular imaging using alpha(5)beta(1)(RGD)- or irrelevant RGS-targeted paramagnetic nanoparticles and 2) to use MR molecular imaging to assess the antiangiogenic effectiveness of alpha(5)beta(1)(alpha(nu)beta(3))- vs. alpha(nu)beta(3)-targeted fumagillin (50 mug/kg) nanoparticles. Tumor-bearing mice were imaged with MR before and after administration of either alpha(5)beta(1)(RGD) or irrelevant RGS-paramagnetic nanoparticles. In experiment 2, mice received saline or alpha(5)beta(1)(alpha(nu)beta(3))- or alpha(nu)beta(3)-targeted fumagillin nanoparticles on days 7, 11, 15, and 19 posttumor implant. On day 22, MRI was performed using alpha(5)beta(1)(alpha(nu)beta(3))-targeted paramagnetic nanoparticles to monitor the antiangiogenic response. 3D reconstructions of alpha(5)beta(1)(RGD)-signal enhancement revealed a sparse, asymmetrical pattern of angiogenesis along the tumor periphery, which occupied <2.0% tumor surface area. alpha(5)beta(1)-targeted rhodamine nanoparticles colocalized with FITC-lectin corroborated the peripheral neovascular signal. alpha(5)beta(1)(alpha(nu)beta(3))-fumagillin nanoparticles decreased neovasculature to negligible levels relative to control; alpha(nu)beta(3)-targeted fumagillin nanoparticles were less effective (P>0.05). Reduction of angiogenesis in MDA-MB-435 tumors from low to negligible levels did not decrease tumor volume. MR molecular imaging may be useful for characterizing tumors with sparse neovasculature that are unlikely to have a reduced growth response to targeted antiangiogenic therapy.
Schmieder
Anne H
AH
Washington University Medical School, Campus Box 8215, 4320 Forest Park Ave., St. Louis, MO 63108, USA.
Caruthers
Shelton D
SD
Zhang
Huiying
H
Williams
Todd A
TA
Robertson
J David
JD
Wickline
Samuel A
SA
Lanza
Gregory M
GM
D020533:Angiogenesis Inhibitors / Q000008:administration & dosage; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology*; D002448:Cell Adhesion; D003287:Contrast Media; D003510:Cyclohexanes / Q000627:therapeutic use; D005231:Fatty Acids, Unsaturated / Q000627:therapeutic use; D005353:Fibronectins / Q000378:metabolism; D005434:Flow Cytometry; D039302:Integrin alphaVbeta3 / Q000008:administration & dosage*; D018810:Magnetic Resonance Angiography; D051379:Mice; D018613:Microscopy, Confocal; D053758:Nanoparticles; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000175:diagnosis / Q000473:pathology*; D009842:Oligopeptides; D010316:Particle Size; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D012717:Sesquiterpenes / Q000627:therapeutic use
D020533:Angiogenesis Inhibitors; D003287:Contrast Media; D003510:Cyclohexanes; D005231:Fatty Acids, Unsaturated; D005353:Fibronectins; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D019030:Receptors, Vitronectin; D012717:Sesquiterpenes; C094340:integrin alphavbeta1; C047981:arginyl-glycyl-aspartic acid; C026211:fumagillin