CXCR4-Targeted and MMP-Responsive Iron Oxide Nanoparticles for Enhanced Magnetic Resonance Imaging

• Published in: Angewandte Chemie International Edition 2014-09, Vol.53 (36), p.9550-9554
• Main Authors: Gallo, Juan, Kamaly, Nazila, Lavdas, Ioannis, Stevens, Elizabeth, Nguyen, Quang-De, Wylezinska-Arridge, Marzena, Aboagye, Eric O., Long, Nicholas J.
• Format: Article
• Language: English
• Subjects: Alkynes; Alkynes - chemistry; Animals; Azides - chemistry; click chemistry; Clusters; Communication; Contrast agents; Contrast Media - chemistry; Enzymes; imaging agents; Iron oxides; Magnetic resonance imaging; Magnetic Resonance Imaging - methods; Magnetite Nanoparticles - chemistry; Matrix metalloproteinases; Matrix Metalloproteinases - drug effects; Mice; Mice, Inbred BALB C; Mice, Nude; Nanoparticles; Neoplasms, Experimental - pathology; NMR; Nuclear magnetic resonance; Peptides; Polyethylene glycol; Receptors, CXCR4 - drug effects; self-assembly; tumor targeting
• ISSN: 1433-7851; 1521-3773
• DOI: 10.1002/anie.201405442

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. Cleave and cluster: Iron oxide nanoparticles were produced that display azide (red) or alkyne (blue) groups masked by PEG‐linked tumor‐targeting peptides (green) that bind to the CXCR4 receptor. Matrix metalloproteinases (MMPs) in the tumor microenvironment specifically cleave the peptide linker at the base of the PEG moiety to expose the cross‐reactive azide and alkyne groups. This leads to the assembly of clusters and thus to an enhancement of the MRI signal.