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 copperfree click conjugation upon sensing of matrix metalloproteinase (MMP) enzymes, thereby leading to a self-assembled superparamagnetic nanocluster network with T 2 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 T 2 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.The early detection of primary tumors and metastases is a major clinical challenge, and an emerging approach for targeting imaging agents to tumors is to exploit the changes that occur within the local tumor microenvironment. The matrix metalloproteinase (MMP) enzymes MMP2 and MMP9 have been shown to play an important role in tumor development and metastasis. [1,2] These MMPs are thus excellent biomarkers for the development of tumor-targeted contrast agents.[3]In biomedical imaging, MRI is a noninvasive imaging technique that has high spatial resolution and does not require ionizing radiation.[4] However, 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 IONPs are widely used in MRI owing to their biocompatible nature and strong effects on T 2 and T 2 * relaxation. [7] To increase the sensitivity of T 2 -weighted MRI, several strategies with NPs have been adopted, [8] however, fewer examples exist that utilize changes in NP size to achieve signal amplification in MR scans.[9] Larger iron oxide nanoparticles (IONPs) and magnetic nanoparticle aggregates have pronounced magnetic properties, [7, 9c] but are cleared faster from the blood pool by the mononuclear phagocyte system. [10] 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. The sensitivity of MRI can thus be enhanced through both specific tumor targeting and tumor-associated proteolytic enzyme activity. It is known that magnetic susceptibility increases when NP aggregates are formed and this process also increases the r 2 relaxivity.[11] The issue of low sensitivity is being tackled, [9a,c, 12] however, the work has either not progressed to in vitro or in vivo stages, or the aggregation process has relied upon electrostatic and non-covalent interactions.In this work, we utilized copper-free "click" chemistry...

Polyphenol‐Inspired Facile Construction of Smart Assemblies for ATP‐ and pH‐Responsive Tumor MR/Optical Imaging and Photothermal Therapy

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Multiplexed imaging for diagnosis and therapy

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Promise of chemokine network‐targeted nanoparticles in combination nucleic acid therapies of metastatic cancer

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