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Report

Teaser, summary, work performed and final results

Periodic Reporting for period 2 - NanoSCAN (Developing multi-modality nanomedicines for targeted annotation of oncogenic signaling pathways)

Teaser

Summary

Nanomedicine is the medical application of nanotechnology to diagnose or treat disease. In light of the recent introduction of tools like Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) scanners, there is now an opportunity to develop hybrid imaging agents that can take advantage of the simultaneously functional and anatomic information available from PET and MRI. The work outlined in this interdisciplinary ERC Project (NanoSCAN) is designed to advance new chemistry and imaging tools to measure changes that occur in cancer both during and after treatment.

A wide range of nanoparticles have been radiolabelled with different nuclides including 18F, 64Cu, 68Ga and 89Zr for PET. However, at the start of this ERC project, existing technologies typically required extensive modifications to the nanoparticle structure such as the addition of chemically reactive coatings and organic molecules for capturing the radioactive atoms. These chemical modifications often compromise the biological viability of nanoparticles leading to suboptimal targeting and distribution in vivo. From the outset, the main problem to be addressed was that no general method was available for rapid, facile and versatile radiolabelling of nanoparticles using a variety of different radionuclides.

Development of new radiolabelling methods is vital to advancing both nanomedicine and new hybrid imaging modalities like PET/MRI. If new chemistry can be developed that makes the production of radiolabelled nanomedicines easier, faster and more reproducible, it would facilitate the translation of this technology from the research setting into clinical practice. With an aging population, and with incidence rates for many cancers on the rise globally, there is a pressing need to develop new methods for detecting cancer, treating the disease, and for monitoring patient outcomes. In this context, PET/MRI, and the potential use of imaging tools based on nanomedicines offer much promise to society by changing the way in which we diagnose cancer patients and facilitating a more personalised treatment plan.

The overall objectives of the NanoSCAN project are to expand the tool-box of chemical methods that are available for radiolabelling different nanomedicines ranging from nanoparticles through to antibodies, proteins, peptides and small-molecules. To this end, we are exploring the use of several high-risk, high-gain strategies that combine radiochemistry with other areas of chemistry that have not traditionally been used in the production of imaging agents. Specifically, our main experimental goals were to explore the use of surface-chemistry as a means for radiolabelling nanoparticles and producing radiotracers that target different cancer biomarkers.

Objective 1. Develop new radiochemical methods for chelate-free labelling of nanoparticles containing metal-based cores

Objective 2. Explore the potential of metal-fluoride bond formation as a tool for rapid fluorine-18 radiolabelling of nanomedicines

Objective 3. Evaluate the potential of radiolabelled nanoparticles and M-18F tracers for multi-modality imaging of AR-mediated signalling in prostate cancer

Work performed

During the first half of this NanoSCAN project we have made strong progress in the experimental goals. Specifically, after establishing our new laboratory and team, we focused efforts on the synthesis and characterisation of metal-based nanoparticles using iron oxide as a core material. While we are also working with other nanomaterials such as graphene-based particles, iron oxides were our primary choice because of their inherent magnetic properties which make them suitable for use as MRI contrast agents. In our pilot experiments we discovered (and patented) a new approach for radiolabelling clinical grade iron oxide nanoparticles using a â€˜heat-induced chelate-freeâ€™ radiolabelling method that eliminated the need to perform complex chemistry on the nanoparticle core or coatings. We are exploring the chemical scope of this new radiolabelling process by using different radioactive metal ions including 64Cu, 68Ga and 89Zr for PET imaging. In addition, we are also making nanoparticles that target particular proteins found in high abundance on cancer cells such as a prostate-specific membrane antigen (PSMA). By attaching small organic drugs to our nanoparticles, we have been able to show that radiolabelled nanoparticles can be taken up specifically by certain prostate cancers. The mammalian body is an extremely challenging environment. Therefore, after making sure that the particles remain stable under appropriate conditions on the bench and in cells, we have begun to explore the distribution, excretion, stability and metabolism using PET imaging in animal models of human disease.

Final results

Chelate-free radiolabelling methods remain state-of the-art in the field of radiolabelled nanomedicines. After starting the NanoSCAN project, and in light of our initial publications, many groups around the world have adapted this approach for radiolabelling different nanoparticle systems. In addition, we and other groups throughout the EU and the world are investigating the mechanism of chelate-free radiolabelling. Understanding how different radiometal ions interact with nanomaterials is vital to the successful development of PET/MRI imaging agents but also has implications in other areas such as understanding the role of nanoparticle and metal ion toxicity in hospitals, in the food chain, in aquatic systems and in complex environmental biomes.

During the first half of the NanoSCAN project, our team has also developed a new method called â€˜photoradiosynthesisâ€™ that uses light to radiolabel nanomedicines, including antibodies. The work is related to initial goals of the project but is a new spin-off topic that was not part of the original proposal. Our chemistry and methods have recently been reported in several high-impact scientific articles and in international press releases issued by the university and various news agencies.