Covalent assembly of nanoparticles as a peptidase-degradable platform for molecular MRI

Francisco Perez-Balderas,Seung Seo Lee,Sandra J Campbell,Sander I Van Kasteren,Sébastien Serres,Alaa A A Aljabali,Andrew Jefferson,James R Larkin,Alexandre A Khrapitchev,Filippo De Simone,Manuel Sarmiento Soto,Claire Bristow,Robin P Choudhury,Benjamin G Davis,Kim Wals,Guillaume Bort,Nicola R Sibson,Daniel C Anthony

doi:10.1038/ncomms14254

Abstract

Ligand-conjugated microparticles of iron oxide (MPIO) have the potential to provide high sensitivity contrast for molecular magnetic resonance imaging (MRI). However, the accumulation and persistence of non-biodegradable micron-sized particles in liver and spleen precludes their clinical use and limits the translational potential of MPIO-based contrast agents. Here we show that ligand-targeted MPIO derived from multiple iron oxide nanoparticles may be coupled covalently through peptide linkers that are designed to be cleaved by intracellular macrophage proteases. The synthesized particles possess potential characteristics for targeted MRI contrast agents, including high relaxivity, unappreciable sedimentation, clearance from circulation and no overt toxicity. Importantly, we demonstrate that these particles are rapidly degraded both in vitro and in vivo, and that the targeted probes can be used for detection of inflammation in vivo using MRI. This approach provides a platform for molecular MRI contrast agents that is potentially more suitable for translation to humans.

Highlights

Ligand-conjugated microparticles of iron oxide (MPIO) have the potential to provide high sensitivity contrast for molecular magnetic resonance imaging (MRI)
We describe a microparticle system designed through covalent assembly of multiple iron oxide nanoparticles (NPs), which combines the advantages of the micron-size iron particle range with biodegradability via the endogenous clearance[23,24,25] and degradation systems of the body (Fig. 1, Supplementary Fig. 1)
We have previously shown that microparticles of 0.5–1 mm diameter combine favourable characteristics of high contrast effect and rapid blood phase clearance rate that are well suited to in vivo targeting studies[16], by delivering efficient particle binding to the site of interest and low background signal at the time of MRI

Summary

Introduction

Ligand-conjugated microparticles of iron oxide (MPIO) have the potential to provide high sensitivity contrast for molecular magnetic resonance imaging (MRI). We describe a microparticle system designed through covalent assembly of multiple iron oxide nanoparticles (NPs), which combines the advantages of the micron-size iron particle range with biodegradability via the endogenous clearance[23,24,25] and degradation systems of the body (Fig. 1, Supplementary Fig. 1) These microparticles are deserving of further research for their potentially enhanced utility as in vivo imaging agents and potential clinical application as iron-based molecular MRI contrast agents. By varying the reaction ratio of the two monomer types it was possible to change both the particle size and the nature of the surface reactive functional groups of the resulting mMPIO (Fig. 3a and Supplementary Table 4), which in turn would ensure that a broad range of targeting ligands could be conjugated This approach, allowed us to readily create mMPIO bearing either an excess of amine (mMPIO-NH2) or those bearing an excess of carboxylic acid (mMPIO-COOH)

Methods

Results

Conclusion