Nitroxide-Based Macromolecular Contrast Agents with Unprecedented Transverse Relaxivity and Stability for Magnetic Resonance Imaging of Tumors

Applications

This technology is a nitroxide-based MRI negative-contrast agent with applications in tumor imaging.

Problem Addressed

Magnetic resonance imaging (MRI) is among the most popular and useful diagnostic imaging tools due to its ability to generate high resolution three dimensional images without the use of ionizing radiation. The usefulness of MRI as a diagnostic relies on the ability to distinguish healthy and diseased tissue, however, this can often be challenging, particularly in small tumors. Therefore, contrast agents are commonly used to enhance tissue imaging. Currently approved contrast agents are metal-based, and often have significant toxicity concerns. Additionally, lower toxicity metal-free contrast agents have thus far proven to suffer from low sensitivity, short in vivo half-lives, and the need for very high concentrations of contrast agent. Due to these shortcomings non-metal based contrast agents have not been clinically adopted. These inventors have built nitroxide nanoparticles that overcome many of the current challenges in metal-free contrast agents.

Technology

This technology is a nitroxide-based brush-arm star polymer organic radial contrast agent (BASP-ORCA). Nitroxide ORCAs have previously been suggested to have potential as a contrast agent. However, nitroxide ORCAs in monomer form are very rapidly reduced to non-functional derivatives in vivo, and they suffer from low proton relaxivity as they possess only one unpaired electron. BASP-ORCAs are polymeric macromolecules that consist of a polyacetal core, many polyethylene glycol (PEG) arms extending from the central core, and a nitroxide group attached at the interface between the core and the PEG arms creating a dense nitroxide layer. This design both protects the nitroxide groups from reduction, and overcomes the low relaxivity of nitroxide monomers by including many nitroxide units, thereby increasing the number of unpaired electrons. Nanoparticles between 10nm and 200nm have been previously demonstrated to accumulate in tumors. BASP-ORCA particles are of an ideal size for tumor accumulation, and indeed BASP-ORCA particles build up in tumors in in vivo mouse tumor transplant models (both subcutaneous and orthotopic models). BASP-ORCA injected intravenously into mice additionally displays clinically relevant circulation half-life, has very low toxicity, and provides negative-contrast enhancement on par with metal-based contrast agents. Finally, other imaging agents and/or drug molecules can be concurrently incorporated into the BASP-ORCA alongside of nitroxides, which provides an additional imaging modality such as IR fluorescence imaging of tumors or combined imaging and therapy strategies. 

Advantages

  • Metal-free T2 negative-contrast agent for MRI imaging of tumors
  • Tumor homing BASP-ORCA particles allow specific tumor contrast enhancement
  • Increases in vivo half-life of nitroxide by protecting from rapid reduction reaction
  • High relaxivity and effective contrast enhancement through incorporation of many nitroxide groups into each BASP-ORCA nanoparticle
  • Multimodal imaging through addition of IR fluorescence functional groups