Nanomaterials offer unique physical, chemical and biological properties of interest for medical imaging and therapy. Over the last two decades, there has been an increasing effort to translate nanomaterial-based medicinal products (so-called nanomedicines) into clinical practice and, although multiple nanoparticle-based formulations are clinically available, there is still a disparity between the number of pre-clinical products and those that reach clinical approval. To facilitate the efficient clinical translation of nanomedicinal-drugs, it is important to study their whole-body biodistribution and pharmacokinetics from the early stages of their development. Integrating this knowledge with that of their therapeutic profile and/or toxicity should provide a powerful combination to efficiently inform nanomedicine trials and allow early selection of the most promising candidates. In this context, radiolabelling nanomaterials allows whole-body and non-invasive in vivo tracking by the sensitive clinical imaging techniques positron emission tomography (PET), and single photon emission computed tomography (SPECT). Furthermore, certain radionuclides with specific nuclear emissions can elicit therapeutic effects by themselves, leading to radionuclide-based therapy. To ensure robust information during the development of nanomaterials for PET/SPECT imaging and/or radionuclide therapy, selection of the most appropriate radiolabelling method and knowledge of its limitations are critical. Different radiolabelling strategies are available depending on the type of material, the radionuclide and/or the final application. In this review we describe the different radiolabelling strategies currently available, with a critical vision over their advantages and disadvantages. The final aim is to review the most relevant and up-to-date knowledge available in this field, and support the efficient clinical translation of future nanomedicinal products for in vivo imaging and/or therapy.

/pdf/radiolabelling-of-nanomaterials-for-medical-imaging-and-1wnnia4i8w.pdf

Radiolabelling of nanomaterials for medical imaging and therapy.

Recombinant viruses are the workhorse of modern neuroscience. Whether one would like to understand a neuron's morphology, natural activity patterns, molecular composition, connectivity or behavioural and physiologic function, most studies begin with the injection of an engineered virus, often an adeno-associated virus or herpes simplex virus, among many other types. Recombinant viruses currently enable some combination of cell type-specific, circuit-selective, activity-dependent and spatiotemporally resolved transgene expression. Viruses are now used routinely to study the molecular and cellular functions of a gene within an identified cell type in the brain, and enable the application of optogenetics, chemogenetics, calcium imaging and related approaches. These advantageous properties of engineered viruses thus enable characterization of neuronal function at unprecedented resolution. However, each virus has specific advantages and disadvantages, which makes viral tool selection paramount for properly designing and executing experiments within the central nervous system. In the current Review, we discuss the key principles and uses of engineered viruses and highlight innovations that are needed moving forward.

Viral tools for neuroscience.

Fluorescence imaging of large-scale neural ensemble dynamics

https://pure.knaw.nl/ws/files/167702346/Klink2021.pdf

Combining brain perturbation and neuroimaging in non-human primates.

Current progress and limitations of AAV mediated delivery of protein therapeutic genes and the importance of developing quantitative pharmacokinetic/pharmacodynamic (PK/PD) models

Adeno-associated viruses (AAVs) are typically single-stranded deoxyribonucleic acid (ssDNA) encapsulated within 25-nm protein capsids. Recently, tissue-specific AAV capsids (e.g. PHP.eB) have been shown to enhance brain delivery in rodents via the LY6A receptor on brain endothelial cells. Here, we create a non-invasive positron emission tomography (PET) methodology to track viruses. To provide the sensitivity required to track AAVs injected at picomolar levels, a unique multichelator construct labeled with a positron emitter (Cu-64, t1/2 = 12.7 h) is coupled to the viral capsid. We find that brain accumulation of the PHP.eB capsid 1) exceeds that reported in any previous PET study of brain uptake of targeted therapies and 2) is correlated with optical reporter gene transduction of the brain. The PHP.eB capsid brain endothelial receptor affinity is nearly 20-fold greater than that of AAV9. The results suggest that novel PET imaging techniques can be applied to inform and optimize capsid design.

/pdf/positron-emission-tomography-imaging-of-novel-aav-capsids-5q0h9eeveo.pdf

Positron emission tomography imaging of novel AAV capsids maps rapid brain accumulation.

Genetic intervention is increasingly explored as a therapeutic option for debilitating disorders of the central nervous system. The safety and efficacy of gene therapies relies upon expressing a transgene in affected cells while minimizing off-target expression. To achieve organ/cell-type specific targeting after intravenous delivery of viral vectors, we employed a Cre-transgenic-based screening platform for fast and efficient capsid selection, paired with sequential engineering of multiple surface-exposed loops. We identified capsid variants that are enriched in the brain and detargeted from the liver in mice. The improved enrichment in the brain extends to non-human primates, enabling robust, non-invasive gene delivery to the marmoset brain following IV administration. Importantly, the capsids identified display non-overlapping cell-type tropisms within the brain, with one exhibiting high specificity to neurons. The ability to cross the blood–brain barrier with cell-type specificity in rodents and non-human primates enables new avenues for basic research and potential therapeutic interventions unattainable with naturally occurring serotypes.

/pdf/broad-gene-expression-throughout-the-mouse-and-marmoset-5d8h2rx52s.pdf

Broad gene expression throughout the mouse and marmoset brain after intravenous delivery of engineered AAV capsids

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Positron emission tomography imaging of novel AAV capsids maps rapid brain accumulation.

Broad gene expression throughout the mouse and marmoset brain after intravenous delivery of engineered AAV capsids