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

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.

Engineering of inorganic nanoparticles as magnetic resonance imaging contrast agents

“…For example, such a self-assembly strategy allows for small NPs to circulate in the blood pool over a prolonged time duration, which can then be triggered in the tumor to self-assemble into a large structure for enhanced MRI. The trigger may include many physiological characteristics, such as molecular interactions, 195 enzymes, 196 receptors, 197 and redox status. 198 On the other hand, the disassembly strategy utilizes the different tumor microenvironments to release CAs preconfined in NPs, also achieving amplified MRI contrast.…”

“…Mao and co-workers reported that ultrafine iron oxide NPs (~3.5 nm) with high T 1 relaxivity exhibited prolonged in vivo circulation life time and could be self-assembled or clustered into larger ones in the tumor, thereby switching from bright T 1 contrast to dark T 2 contrast in MRI. 205 In another report, two complementary iron oxide NPs that were linked to a peptide substrate for enzymatic cleavage and a functional group (azide or alkyne) for click reaction 196 were able to self-assemble into a larger nanocluster network in the presence of matrix metalloproteinase enzymes, leading to approximately 160% enhancement of T 2 signal intensity.…”

Click Chemistry in the Development of Contrast Agents for Magnetic Resonance Imaging

“…29 In their study, two types of IONPs-based, CXCR4 receptor targeted nanoparticles were conjugated with either azide or alkyne functional groups. Both IONPs were conjugated with protease-specific peptide sequence, which was cleavable by MMP enzymes in MMP2/6 overexpressing tumors.…”

Furin‐Controlled Fe3O4 Nanoparticle Aggregation and 19F Signal “Turn‐On” for Precise MR Imaging of Tumors

“…[1] Of these, magnetic resonance imaging (MRI) has attracted much attention because of its noninvasive and nonradiative properties and high contrast and resolution in soft tissues. [11,12] It has been proved that magnetization and size of SPIO NPs significantly contributed to the transverse relaxation rate (R 2 ) of proximal water protons, and higher magnetic fields generally lead to larger R 2 values. [6][7][8] Conventional CAs are roughly divided into two categories, longitudinal (T 1 ) CAs and transverse (T 2 ) CAs.…”