Phosphatidylserine-Targeted Molecular Imaging of Tumor Vasculature by Magnetic Resonance Imaging

Journal of Biomedical Nanotechnology (Impact Factor: 5.34). 05/2014; 10(5):846-55. DOI: 10.1166/jbn.2014.1851
Source: PubMed


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.

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    • "Interestingly, another study has shown that anti-PS antibodies can elicit immune antitumor responses by converting myeloid-derived suppressive cells into tumoricidal M1 macrophages or dendritic cells capable of engaging cytotoxic T cell– dependent cytotoxicity [81]. Preclinical studies showed good targeting efficacy of PS-directed antibodies in several tumor models [82] [83] [84] [85] [86]. In orthotopic mouse models of pancreatic cancer, Beck et al. showed that gemcitabine plus the PS-targeting antibody 3G4 had additive antitumor activity and significantly reduced metastases [87]. "
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