title: Phosphatidylserine-targeted molecular imaging of tumor vasculature by magnetic resonance imaging.
abstract: Phosphatidylserine (PS), normally restricted to the inner leaflet of the plasma membrane, becomes exposed on the outer surface of viable endothelial cells in tumor vasculature, but not in normal blood vessels. In the present study, we report the use of PGN635, a novel human monoclonal antibody that specifically targets PS, for in vivo molecular MRI of tumor vasculature. The F(ab')2 fragments of PGN635 were conjugated to polyethylene glycol (PEG) coated iron oxide nanoparticles (IO). Targeting specificity of the PS-targeted Nanoprobe, IO-PGN635F(ab')2 was first confirmed by in vitro MRI and histological staining. In vivo longitudinal MRI was then performed before and after i.v. injection of IO-PGN635F(ab')2 into mice bearing 4T1 breast tumors. T2-weighted MR images at 9.4 T revealed inhomogeneous signal loss in tumor as early as 2 h post injection. Furthermore, ionizing radiation induced a significant increase in PS exposure on tumor vascular endothelial cells, resulting in significantly enhanced and sustained tumor contrast (p < 0.05). Spatially heterogeneous MRI contrast correlated well with histological staining of tumor vascular endothelium. Our studies suggest that PS exposed within the lumen of tumor vasculature is a highly specific and useful biomarker for targeted MRI contrast agents.
authors.forename: Heling
authors.initials: H
authors.lastname: Zhou
authors.forename: Jason H
authors.initials: JH
authors.lastname: Stafford
authors.forename: Rami R
authors.initials: RR
authors.lastname: Hallac
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
authors.forename: Gang
authors.initials: G
authors.lastname: Huang
authors.forename: Ralph P
authors.initials: RP
authors.lastname: Mason
authors.forename: Jinming
authors.initials: J
authors.lastname: Gao
authors.forename: Philip E
authors.initials: PE
authors.lastname: Thorpe
authors.forename: Dawen
authors.initials: D
authors.lastname: Zhao
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D008279:Magnetic Resonance Imaging / Q000379:methods*; D058185:Magnetite Nanoparticles; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D057054:Molecular Imaging / Q000379:methods*; D009374:Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology / Q000532:radiotherapy; D009389:Neovascularization, Pathologic / Q000378:metabolism* / Q000473:pathology* / Q000532:radiotherapy; D010718:Phosphatidylserines / Q000493:pharmacokinetics*; D020266:Radiotherapy, Conformal; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D016896:Treatment Outcome
chemical_list: D058185:Magnetite Nanoparticles; D010718:Phosphatidylserines