PET/MRI dual-modality tumor imaging using arginine-glycine-aspartic (RGD)-conjugated radiolabeled iron oxide nanoparticles.
The purpose of this study was to develop a bifunctional iron oxide (IO) nanoparticle probe for PET and MRI scans of tumor integrin alphavbeta3 expression.


METHODS
Polyaspartic acid (PASP)-coated IO (PASP-IO) nanoparticles were synthesized using a coprecipitation method, and particle size and magnetic properties were measured. A phantom study was used to assess the efficacy of PASP-IO as a T2-weighted MRI contrast agent. PASP-IO nanoparticles with surface amino groups were coupled to cyclic arginine-glycine-aspartic (RGD) peptides for integrin alphavbeta3 targeting and macrocyclic 1,4,7,10-tetraazacyclododecane-N,N',N'',N''',-tetraacetic acid (DOTA) chelators for PET after labeling with 64Cu. IO nanoparticle conjugates were further tested in vitro and in vivo to determine receptor targeting efficacy and feasibility for dual PET/MRI.


RESULTS
PASP-IO nanoparticles made by single-step reaction have a core size of 5 nm with a hydrodynamic diameter of 45 +/- 10 nm. The saturation magnetization of PASP-IO nanoparticles is about 117 emu/g of iron, and the measured r2 and r2* are 105.5 and 165.5 (s.mM)(-1), respectively. A displacement competitive binding assay indicates that DOTA-IO-RGD conjugates bound specifically to integrin alphavbeta3 in vitro. Both small-animal PET and T2-weighted MRI show integrin-specific delivery of conjugated RGD-PASP-IO nanoparticles and prominent reticuloendothelial system uptake.


CONCLUSIONS
We have successfully developed an IO-based nanoprobe for simultaneous dual PET and MRI of tumor integrin expression. The success of this bifunctional imaging approach may allow for earlier tumor detection with a high degree of accuracy and provide further insight into the molecular mechanisms of cancer.
Lee
Ha-Young
HY
Molecular Imaging Program at Stanford (MIPS), Department of Radiology and Bio-X Program, Stanford University School of Medicine, Stanford, California 94305-5484, USA.
Li
Zibo
Z
Chen
Kai
K
Hsu
Andrew R
AR
Xu
Chenjie
C
Xie
Jin
J
Sun
Shouheng
S
Chen
Xiaoyuan
X
D000818:Animals; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000737:chemistry; D003301:Copper Radioisotopes; D005260:Female; D005290:Ferric Compounds / Q000737:chemistry*; D005909:Glioblastoma / Q000000981:diagnostic imaging; D006573:Heterocyclic Compounds, 1-Ring / Q000737:chemistry; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D051379:Mice; D008819:Mice, Nude; D053758:Nanoparticles; D009368:Neoplasm Transplantation; D009842:Oligopeptides / Q000737:chemistry*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D014183:Transplantation, Heterologous
D002614:Chelating Agents; D003301:Copper Radioisotopes; D005290:Ferric Compounds; D006573:Heterocyclic Compounds, 1-Ring; D039302:Integrin alphaVbeta3; D009842:Oligopeptides; D019275:Radiopharmaceuticals; C071349:1,4,7,10-tetraazacyclododecane- 1,4,7,10-tetraacetic acid; C000499:ferric oxide; C047981:arginyl-glycyl-aspartic acid