MicroPET imaging of brain tumor angiogenesis with 18F-labeled PEGylated RGD peptide.
We have previously labeled cyclic RGD peptide c(RGDyK) with fluorine-18 through conjugation labeling via a prosthetic 4-[18F]fluorobenzoyl moiety and applied this [18F]FB-RGD radiotracer for alphav-integrin expression imaging in different preclinical tumor models with good tumor-to-background contrast. However, the unfavorable hepatobiliary excretion and rapid tumor washout rate of this tracer limit its potential clinical applications. The aims of this study were to modify the [18F]FB-RGD tracer by inserting a heterobifunctional poly(ethylene glycol) (PEG, M.W. =3,400) between the 18F radiolabel and the RGD moiety and to test this [18F]FB-PEG-RGD tracer for brain tumor targeting and in vivo kinetics. [18F]FB-PEG-RGD was prepared by coupling the RGD-PEG conjugate with N-succinimidyl 4-[18F]fluorobenzoate ([18F]SFB) under slightly basic conditions (pH=8.5). The radiochemical yield was about 20-30% based on the active ester [18F]SFB, and specific activity was over 100 GBq/micromol. This tracer had fast blood clearance, rapid and high tumor uptake in the subcutaneous U87MG glioblastoma model (5.2+/-0.5%ID/g at 30 min p.i.). Moderately rapid tumor washout was observed, with the activity accumulation decreased to 2.2+/-0.4%ID/g at 4 h p.i. MicroPET and autoradiography imaging showed a very high tumor-to-background ratio and limited activity accumulation in the liver, kidneys and intestinal tracts. U87MG tumor implanted into the mouse forebrain was well visualized with [18F]FB-PEG-RGD. Although uptake in the orthotopic tumor was significantly lower (P<0.01) than in the subcutaneous tumor, the maximum tumor-to-brain ratio still reached 5.0+/-0.6 due to low normal brain background. The results of H&E staining post mortem agreed with the anatomical information obtained from non-invasive microPET imaging. In conclusion, PEGylation suitably modifies the physiological behavior of the RGD peptide. [18F]FB-PEG-RGD gave improved tumor retention and in vivo kinetics compared with [18F]FB-RGD.
Chen
Xiaoyuan
X
PET Imaging Science Center, Department of Radiology, University of Southern California Keck School of Medicine, 1510 San Pablo St., Suite 350, CA 90033, Los Angeles, USA.
Park
Ryan
R
Hou
Yingping
Y
Khankaldyyan
Vazgen
V
Gonzales-Gomez
Ignacio
I
Tohme
Michel
M
Bading
James R
JR
Laug
Walter E
WE
Conti
Peter S
PS
D000818:Animals; D001921:Brain / Q000098:blood supply / Q000000981:diagnostic imaging / Q000378:metabolism; D001932:Brain Neoplasms / Q000000981:diagnostic imaging* / Q000378:metabolism*; D005260:Female; D005909:Glioblastoma / Q000000981:diagnostic imaging* / Q000378:metabolism*; D008657:Metabolic Clearance Rate; D051379:Mice; D008819:Mice, Nude; D009389:Neovascularization, Pathologic / Q000000981:diagnostic imaging* / Q000378:metabolism*; D009928:Organ Specificity; D010456:Peptides, Cyclic / Q000493:pharmacokinetics*; D011092:Polyethylene Glycols / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D014018:Tissue Distribution; D014915:Whole-Body Counting
C496668:4-fluorobenzoyl-polyethylene glycol-cyclo(arginyl-glycyl-aspartyl-tyrosyl-lysyl); D010456:Peptides, Cyclic; D019275:Radiopharmaceuticals; D011092:Polyethylene Glycols