CXCR4-targeted and MMP-responsive iron oxide nanoparticles for enhanced magnetic resonance imaging.

Juan Gallo,Elizabeth Stevens,Nazila Kamaly,Marzena Wylezinska-Arridge,Quang-De Nguyen,Ioannis Lavdas,Eric O Aboagye,Nicholas J Long

doi:10.1002/anie.201405442

Abstract

MRI offers high spatial resolution with excellent tissue penetration but it has limited sensitivity and the commonly administered contrast agents lack specificity. In this study, two sets of iron oxide nanoparticles (IONPs) were synthesized that were designed to selectively undergo copper-free click conjugation upon sensing of matrix metalloproteinase (MMP) enzymes, thereby leading to a self-assembled superparamagnetic nanocluster network with T2 signal enhancement properties. For this purpose, IONPs with bioorthogonal azide and alkyne surfaces masked by polyethylene glycol (PEG) layers tethered to CXCR4-targeted peptide ligands were synthesized and characterized. The IONPs were tested in vitro and T2 signal enhancements of around 160 % were measured when the IONPs were incubated with cells expressing MMP2/9 and CXCR4. Simultaneous systemic administration of the bioorthogonal IONPs in tumor-bearing mice demonstrated the signal-enhancing ability of these ‘smart’ self-assembling nanomaterials.

Highlights

MRI offers high spatial resolution with excellent tissue penetration but it has limited sensitivity and the commonly administered contrast agents lack specificity
The matrix metalloproteinase (MMP) enzymes MMP2 and MMP9 have been shown to play an important role in tumor development and metastasis.[1,2]
MRI suffers from limited sensitivity[5] and the use of contrast agents is necessary to increase sensitivity and image contrast in MR scans.[5a,6] Superparamagnetic iron oxide nanoparticles (IONPs) are widely used in MRI owing to their biocompatible nature and strong effects on T2 and T2* relaxation.[7]

Summary

Introduction

MRI offers high spatial resolution with excellent tissue penetration but it has limited sensitivity and the commonly administered contrast agents lack specificity. We have designed two sets of novel IONPs that only form aggregates within the tumor environment, where self-assembly into larger particles is triggered by cancer-specific MMP biomarkers.

Results

Conclusion