Over 10 million magnetic resonance imaging (MRI) procedures are performed each year;a significant fraction require the use of a paramagnetic Gd (III) contrast enhancement agent. Gd (III) agents are not suitable for patients with impaired kidney function, newborn children, or for patients that require liver transplants. Paramagnetic organic radical contrast agents (ORCAs) could provide suitable alternatives to Gd (III) agents, but several technological hurdles inhibit their development. We propose the synthesis of a novel class of nanostructured ORCAs that will be suitable for translation to clinical imaging applications. These materials will be constructed from branched macromonomers that carry poly (ethylene glycol) (PEG) and reduction resistant spirocyclohexyl nitroxide domains. Parallel ring opening metathesis polymerization (ROMP) of these macromonomers will yield a library of novel nanostructured branched-brush ORCAs with controlled sizes, high water solubility, fluorescent labels, and homogeneous structures. These materials represent a synergistic intersection between nanostructures developed by the Johnson lab and the current state-of-the-art dendritic ORCAs developed by Rajca. We will characterize the nitroxide quenching kinetics for all ORCAs in the presence of biologically relevant reducing agents;the MRI relaxivities will be measured for all new agents. The results will allow for correlation of relaxivity with nanostructure, and will guide the development of next generation ORCAs. In this study, the top ORCA candidates based on low high solubility, high relaxivity, high resistance to reduction, and low in vitro toxicity will be studied in vivo using mouse models. We will study the toxicity, biodistribution, and MRI contrast enhancement. Ex vivo biodistribution will be quantified by whole animal fluorescence imaging and EPR spectral analysis of organ homogenates. We will explore passive targeting to tumors with leaky vasculature using a mouse xenograft model. The key innovations of this proposal are the synthetic approach and the new nanostructures, which work synergistically to allow for rapid synthesis of ORCAs with ideal architectures for MRI applications. Specifically, the placement of nitroxides near the nanostructure core will provide adequate steric shielding for imaging at long times, but sufficient access to water for high relaxivity. Importantly, the method is versatile;it can be extended to dual-modal imaging, and ultimately development of combined drug delivery and imaging platforms (theranostics). Taken as a whole, the results of this proposal will lead to a new class of ORCAs for MR imaging, and new synthetic concepts for the preparation of nanostructures for biomedical applications.
This proposal describes the synthesis of novel nanostructured organic contrast agents (ORCAs) for magnetic resonance imaging (MRI). The results will lead to clinically applicable contrast agents for patients with poor renal function. The proposed strategy represents a key advance in the field of nanoparticle synthesis that will enable the synthesis of contrast agent libraries for correlation of structure/function relationships in vivo.
|Sowers, Molly A; McCombs, Jessica R; Wang, Ying et al. (2014) Redox-responsive branched-bottlebrush polymers for in vivo MRI and fluorescence imaging. Nat Commun 5:5460|
|Gao, Angela X; Liao, Longyan; Johnson, Jeremiah A (2014) Synthesis of Acid-Labile PEG and PEG-Doxorubicin-Conjugate Nanoparticles via Brush-First ROMP. ACS Macro Lett 3:854-857|