Advanced methods for radiolabelling nanomedicines for multi-modality nuclear/MR imaging

The advent of hybrid cameras that combine magnetic resonance imaging with either single-photon emission computed tomography (SPECT/MRI) or positron-emission tomography (PET/MRI) has stimulated growing interest in developing multi-modality imaging probes. Countless options are available for fusing magnetically active species with positron- or gamma-ray emitting radionuclides. The initial problem is one of choice: which chemical systems are a suitable basis for developing hybrid imaging agents? Any attempt to answer this question must also address how the physical, chemical, and biological properties of a unified imaging agent can be tailored to ensure that optimum specificity and contrast is achieved simultaneously for both imaging modalities. Nanoparticles have emerged as attractive platforms for building multi-modality SPECT/MRI and PET/MRI radiotracers. A wide variety of nanoparticle constructs have been utilised as radiotracers but irrespective of the particle class, radiolabelling remains a key step. Classical methods for radiolabelling nanoparticles involve functionalisation of the particle surface, core or coating. These modifications typically rely on using traditional metal ion chelate or prosthetic group chemistries. Though seemingly innocuous, appending nanoparticles with these radiolabelling handles can have dramatic effects on important properties such as particle size, charge and solubility. In turn, alterations in the chemical and physical properties of the nanoparticle often have a negative impact on their pharmacological profile. A central challenge in radiolabelling nanoparticles is to identify alternative chemical methods that facilitate the introduction of a radioactive nuclide without detrimental effects on the pharmacokinetic and toxicological properties of the construct. Efforts to solve this challenge have generated a range of innovative, ‘chelate-free’ radiolabelling methods that exploit intrinsic chemical features of nanoparticles. Here, the chemistry of nine mechanistically distinct methods for radiolabelling nanoparticles is presented. This discourse illustrates the evolution of nanoparticle radiochemistry from classical approaches through to modern chelate-free or intrinsic methods