Phosphatidylserine-Targeted Molecular Imaging of Tumor Vasculature by Magnetic Resonance Imaging
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.
Available from: Victor Blanco
- "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 . Preclinical studies showed good targeting efficacy of PS-directed antibodies in several tumor models     . 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 . "
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ABSTRACT: Pancreatic cancer remains one of the most intractable cancers, with a dismal prognosis reflected by a 5-year survival of ~6%. Since early disease symptoms are undefined and specific biomarkers are lacking, about 80% of patients present with advanced, inoperable tumors that represent a daunting challenge. Despite many clinical trials, no single chemotherapy agent has been reliably associated with objective response rates above 10% or median survival longer than 5 to 7 months. Although combination chemotherapy regimens have in recent years provided some improvement, overall survival (8-11 months) remains very poor. There is therefore a critical need for novel therapies that can improve outcomes for pancreatic cancer patients. Here, we present a summary of the current therapies used in the management of advanced pancreatic cancer and review novel therapeutic strategies that target tumor biomarkers. We also describe our recent research using phosphatidylserine-targeted saposin C-coupled dioleoylphosphatidylserine nanovesicles for imaging and therapy of pancreatic cancer.
Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.
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ABSTRACT: The efficient delivery of therapeutic molecule agents into target cells of interest is a critical challenge to broad application of non-viral vector systems. In this research, maytansine-loaded star-shaped folate-core polylactide-D-α-tocopheryl polyethylene glycol 1000 succinate (FA-PLA-TPGS) block copolymer was applied to be a vector of maytansine for folate receptor positive (FR(+)) breast cancer therapy. The uptake of maytansine nanoparticles by SKBR3 cells were observed by fluorescence microscopy and confocal laser scanning microscopy. The cell viability of maytansine-NPs in SKBR3 cells was assessed according to the changed level of intracellular microtubules and apoptosis-associated proteins. The cytotoxicity of the SKBR3 cells was significantly increased by maytansine-NPs when compared with control groups. In conclusion, the maytansine-NPs offer a considerable potential formulation for FR-expressing tumor targeting biotherapy.
Available from: Sebastian B. Riese
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ABSTRACT: Monodisperse small iron oxide nanoparticles functionalized with dendritic polyglycerol (dPG) or dendritic polyglycerol sulfate (dPGS) are prepared. They are highly stable in aqueous solutions as well as physiological media. In particular, oleic acid capped iron oxide particles (core diameter = 11 ± 1 nm) were modified by a ligand exchange process in a one pot synthesis with dPG and dPGS bearing phosphonate as anchor groups. Dynamic light scattering measurements performed in water and different biological media demonstrate that the hydrodynamic diameter of the particles is only slightly increased by the ligand exchange process resulting in a final diameter of less than 30 nm and that the particles are stable in these media. It is also revealed by magnetic resonance studies that their magnetic relaxivity is reduced by the surface modification but it is still sufficient for high contrast magnetic resonance imaging (MRI). Additionally, incubation of dPGS functionalized iron oxide nanoparticles with human umbilical vein endothelial cells showed a 50% survival at 85 nM (concentration of nanoparticles). Surface plasmon resonance (SPR) studies demonstrate that the dPGS functionalized iron oxide nanoparticles inhibit L-selectin ligand binding whereas the particles containing only dPG do not show this effect. Experiments in a flow chamber with human myelogenous leukemia cells confirmed L-selectin inhibition of the dPGS functionalized iron oxide nanoparticles and with that the L-selectin mediated leukocyte adhesion. These results indicate that dPGS functionalized iron oxide nanoparticles are a promising contrast agent for inflamed tissue probed by MRI.
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