Periodic Reporting for period 4 - NanoSCAN (Developing multi-modality nanomedicines for targeted annotation of oncogenic signaling pathways)
Période du rapport: 2021-03-01 au 2022-01-31
Nanomedicine is the medical application of nanotechnology to diagnose or treat disease. With the advent of multi-modality diagnostic imaging tools, such as the fusion of functional nuclear imaging by Positron Emission Tomography (PET) with high-resolution anatomic soft-tissue imaging by Magnetic Resonance Imaging (MRI), there is a pressing need to develop new chemical probes that can maximise the information obtained from PET/MRI scans. The work outlined in this interdisciplinary ERC Project (NanoSCAN) was designed to advance new chemistry and imaging tools to measure changes that occur in cancer both during and after treatment.
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
Objective 2. Explore the potential of metal-halide bonds as a tool for rapid radiolabelling of nanomedicines
Objective 3. Evaluate the potential of radiolabelled nanoparticles and other biologically active tracers for multi-modality imaging of cancer signalling pathways
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
Objective 2. Explore the potential of metal-halide bonds as a tool for rapid radiolabelling of nanomedicines
Objective 3. Evaluate the potential of radiolabelled nanoparticles and other biologically active tracers for multi-modality imaging of cancer signalling pathways
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 used to introduce the radiolabel typically required extensive modifications to the nanoparticle structure. These included the addition of chemically reactive coatings or the use of organic (prosthetic) molecules for capturing the radioactive atoms. We reviewed the various methods for labelling nanoparticles (Lamb et al. J. Nucl. Med. 2017, DOI:10.2967/jnumed.116.187419) and created a set of ‘design criteria’ which were used as a guide during our experimental studies. 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. Our preliminary work indicated that chelate-free metal ion labelling was a viable method for introducing different radioactive metal ions (taken from across the periodic table, and including 64Cu, 68Ga, 89Zr, 111In, etc) on to the surface of magnetically-active nanoparticles based on iron oxides.
When radiolabelling molecules with very low (sub-nanomole) amounts of radioactive metal ions, chemical kinetics plays a major role in governing the success of the reaction (Holland, Chem. Eur. J. 2018, DOI: 10.1002/chem.201803261). The ability to synthesise particles that display multiple different chemical groups on the surface is also important in the design of cancer-targeted agents. To this end, we began a collaboration with the group of Prof. Christoph Salzmann (University College London, ERC Consolidator Grant No 725271) to access graphene nanoflakes (GNFs). Graphene-based materials are promising scaffolds for use in the design of tailored-made nanomedicines. GNFs consist of a graphene sheet approximately 30 nm in diameter with a pristine aromatic system and an edge terminated with carboxylic acid groups. In this work, we first developed relable methods to functionalise the edge of the GNF particles with mutliple different compounds, including radioactive metal ion compelxes for PET imaging, fluorophores for optical imaging and microscopy, and small-molecule drugs that target prostate cancer (Lamb et al. Chem. Sci. 2018, DOI: 10.1039/C9SC03736E). GNFs proved to be effective scaffolds for controlling multi-component drug-delivery, but we found that modification of their circulation half-life in vivo was required to make effective radiotracers because the particles were excreted rapidly through the renal pathway. Subsequent work led to the fucntionalisation of GNFs with gadolinium complexes for MRI, zirconium complexes for PET, and monoclonal antibodies to increase blood pool circulation times and to provide tumour-specific detection using PET/MRI. Detailed experimental studies, including 89Zr-radiolabelling, cellular binding assays, confocal microscopy in cells, spectroscopic analysis, and PET imaging combined with biodistirbution analysis in mice confirmed that GNF-antibody constructs are a promising and versatile new platform for developing multi-modality imaging agents (Lamb et al., Adv. Nanobiomed. Res. 2021, DOI: 10.1002/anbr.202100009).
Another key area of progress involved our work toward using radiotracer imaging to detect changes in receptor-driven oncogenic signalling pathways in prostate (and other) cancer models. In the early phase of the project, we developed and tested several different radiotracers for imaging and quantifying prostate-specific membrane antigen (PSMA) expression (Gourni et al. Mol. Imaging 2017, DOI: 10.1177/1536012117737010; Läppchen et al., Nucl. Med. Biol., 2018, DOI: 10.1016/j.nucmedbio.2018.03.002). Later, we also expanded our science by developing several different PET radiotracers to detect other biomarkers of cancer including the human epidermal growth-factor receptor 2 (HER2/neu) found in breast and ovarian cancers, and the human hepatocyte growth factor receptor (c-MET) which is commonly encountered in cancers of the gastrointestinal tract, and also the circulating biomarker prostate specific antigen (PSA) in prostate cancers. Work is ongoing to evaluate the tumour specificity and quantitative accuracy of imaging using these different radiotracers.
When radiolabelling molecules with very low (sub-nanomole) amounts of radioactive metal ions, chemical kinetics plays a major role in governing the success of the reaction (Holland, Chem. Eur. J. 2018, DOI: 10.1002/chem.201803261). The ability to synthesise particles that display multiple different chemical groups on the surface is also important in the design of cancer-targeted agents. To this end, we began a collaboration with the group of Prof. Christoph Salzmann (University College London, ERC Consolidator Grant No 725271) to access graphene nanoflakes (GNFs). Graphene-based materials are promising scaffolds for use in the design of tailored-made nanomedicines. GNFs consist of a graphene sheet approximately 30 nm in diameter with a pristine aromatic system and an edge terminated with carboxylic acid groups. In this work, we first developed relable methods to functionalise the edge of the GNF particles with mutliple different compounds, including radioactive metal ion compelxes for PET imaging, fluorophores for optical imaging and microscopy, and small-molecule drugs that target prostate cancer (Lamb et al. Chem. Sci. 2018, DOI: 10.1039/C9SC03736E). GNFs proved to be effective scaffolds for controlling multi-component drug-delivery, but we found that modification of their circulation half-life in vivo was required to make effective radiotracers because the particles were excreted rapidly through the renal pathway. Subsequent work led to the fucntionalisation of GNFs with gadolinium complexes for MRI, zirconium complexes for PET, and monoclonal antibodies to increase blood pool circulation times and to provide tumour-specific detection using PET/MRI. Detailed experimental studies, including 89Zr-radiolabelling, cellular binding assays, confocal microscopy in cells, spectroscopic analysis, and PET imaging combined with biodistirbution analysis in mice confirmed that GNF-antibody constructs are a promising and versatile new platform for developing multi-modality imaging agents (Lamb et al., Adv. Nanobiomed. Res. 2021, DOI: 10.1002/anbr.202100009).
Another key area of progress involved our work toward using radiotracer imaging to detect changes in receptor-driven oncogenic signalling pathways in prostate (and other) cancer models. In the early phase of the project, we developed and tested several different radiotracers for imaging and quantifying prostate-specific membrane antigen (PSMA) expression (Gourni et al. Mol. Imaging 2017, DOI: 10.1177/1536012117737010; Läppchen et al., Nucl. Med. Biol., 2018, DOI: 10.1016/j.nucmedbio.2018.03.002). Later, we also expanded our science by developing several different PET radiotracers to detect other biomarkers of cancer including the human epidermal growth-factor receptor 2 (HER2/neu) found in breast and ovarian cancers, and the human hepatocyte growth factor receptor (c-MET) which is commonly encountered in cancers of the gastrointestinal tract, and also the circulating biomarker prostate specific antigen (PSA) in prostate cancers. Work is ongoing to evaluate the tumour specificity and quantitative accuracy of imaging using these different radiotracers.
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 ‘photoradiosynthesis’ 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.
During the first half of the NanoSCAN project, our team has also developed a new method called ‘photoradiosynthesis’ 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.