Harnessing nanoparticles and bioorthogonal chemistries for improving precision of nuclear medicine

The convergence of nanotechnology, radiopharmaceutical development and molecular imaging has unveiled exciting opportunities for the progress of innovative diagnostic and therapeutic strategies, paving the way for significant advancements in biomedical research, especially in relation to cancer. For example, the use of highly sensitive and quantitative nuclear imaging techniques including PET and SPECT, together with nanoparticles for tumour imaging and therapy has recently expanded rapidly. While the long circulating properties of many nanomaterials are beneficial for prodrug chemotherapy formulations, due to the constant decay processes involved in nuclear medicines, directly labelled materials result in prolonged systemic radiation exposure and reduced therapeutic indices due to the unfavourable target-to-background ratios. This is due to the tendency for long circulating nanomaterials to distribute within the blood to other organs, such as the liver and spleen. The recent integration of bioorthogonal chemistry with nanotechnology and molecular imaging/radiotherapy has revolutionized the field by allowing the decoupling of the targeting molecule (i.e. nanomaterial with a bioorthogonal tag) and the imaging/therapeutic radioisotope. In this way, the detection/therapeutic element can be administered as a secondary "chase" molecule that contains the bioorthogonal partner, thereby creating an avenue to improve therapeutic index and provide imaging and treatments with reduced risk. This review will provide an overview of the progress made thus far in the field of nuclear imaging and radiotherapy for cancer using the combination of nanomaterials and bioorthogonal chemistry. We also provide a critical evaluation of the challenges and opportunities for using these approaches to better understand disease and treatment mechanisms, with the potential for downstream clinical translation.