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In vivo evaluation of riboflavin receptor targeted fluorescent USPIO in mice with prostate cancer xenografts

Nano Research 2016年第5期9卷 1319-1333页

作者： Jabadurai Jayapaul Susanne Ares Matt Bunker Marek Weiler Sandra Rutherford Peter Comba Fabian Kiessling Institute for Experimental Molecular Imaging RWTH Aachen University Pauwelsstrasse 30 Aachen 52074 Germany Anorganisch-Chemisches Institut Universit#t Heidelberg Im Neuenheimer Feld 270 Heidelberg 59120 Germany Molecular Imaging Group Department of Structural Biology Leibniz Institut fur Molekulare Pharmakologie (FMP) Robert-Rossle-Str. 10 Berlin 13125 Germany AstraZeneca Pharmaceutical Development Charter Way Macclesfield Cheshire SK10 2NA UK Molecular Profiles Ltd. 8 Orchard Place Nottingham Business Park Nottingham NG8 6PX UK

riboflavin （Rf） receptors bind and translocate Rf and its phosphorylated forms （e.g. flavin mononucleotide, FMN） into cells where they mediate various cellular metabolic pathways. Previously, we showed that FMN-coated ultrasmall superparamagnetic iron oxide （FLUSPIO） nanoparticles are suitable for labeling metabolically active cancer and endothelial cells in vitro. In this study, we focused on the in vivo application of FLUSPIO using prostate cancer xenografts. Size, charge, and chemical composition of FLUSPIO were evaluated. We explored the in vitro specificity of FLUSPIO for its cellular receptors using magnetic resonance imaging （MRI） and Prussian blue staining. Competitive binding experiments were performed in vivo by injecting free FMN in excess. Bio-distribution of FLUSPIO was determined by estimating iron content in organs and tumors using a colorimetric assay. AFM analysis and zeta potential measurements revealed a particulate morphology approximately 20-40 nm in size and a negative zeta potential （-24.23±0.15 mV） in water. X-ray photoelectron spectroscopy and time-of-flight secondary ion mass spectrometry data confirmed FMN present on the USPIO nanoparticle surface. FLUSPIO uptake in prostate cancer cells and human umbilical vein endothelial cells was significantly higher than that of control USPIO, while addition of excess of free FMN reduced accumulation. Similarly, in vivo MRI and histology showed specific FLUSPIO uptake by prostate cancer cells, tumor endothelial cells, and tumor-associated macrophages. Besides prominent tumor accumulation, FLUSPIO accumulated in the liver, spleen, lung, and skin. Hence, our data strengthen our hypothesis that targeting riboflavin receptors is an efficient approach to accumulate nanomedicines in tumors opening perspectives for the development of diagnostic and therapeutic systems.

关键词： flavin mononucleotide iron oxide nanoparticles magnetic resonance imaging molecular imaging riboflavin carrier protein riboflavin transporters

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