Iron oxide nanoparticles have been extensively utilised as negative (T₂) contrast agents in magnetic resonance imaging. In the past few years, researchers have also exploited their application as positive (T₁) contrast agents to overcome the limitation of traditional Gd³⁺ contrast agents. To provide T₁ contrast, these particles must present certain physicochemical properties with control over the size, morphology and surface of the particles. In this review, we summarise the reported T₁ iron oxide nanoparticles and critically revise their properties, synthetic protocols and application, not only in MRI but also in multimodal imaging. In addition, we briefly summarise the most important nanoparticulate Gd and Mn agents to evaluate whether T₁ iron oxide nanoparticles can reach Gd/Mn contrast capabilities.

Here, we present a comprehensive review on the use of microwave chemistry for the synthesis of iron-oxide nanoparticles focused on molecular imaging. We provide a brief introduction on molecular imaging, the applications of iron oxide in biomedicine, and traditional methods for the synthesis of these nanoparticles. The review then focuses on the different examples published where the use of microwaves is key for the production of nanoparticles. We study how the different parameters modulate nanoparticle properties, particularly for imaging applications. Finally, we explore principal applications in imaging of microwave-produced iron-oxide nanoparticles.

The combination of radioisotopes and nanomaterials is creating a new library of tracers for molecular imaging, exploiting the sensitivity of nuclear imaging techniques and the size-dependent properties of nanomaterials. This new approach is expanding the range of applications, including the possibility of theranostics. Among the many different combinations, the use of ⁶⁸Ga as the radioisotope in the radio-nanomaterial is particularly convenient. The physicochemical properties of this isotope allow incorporating it into many materials with great chemical flexibility. Furthermore, its production from a benchtop generator eases the preparation of the tracer. Here, we review main results from the last years in which a nanomaterial has been radiolabeled with ⁶⁸Ga. In thus process, we pay attention to the use of nanomaterials for biomedical imaging in general and main properties of this radioisotope. We study the main methods to carry out such radiolabeling and the most important applications for molecular imaging.

Proton therapy allows the treatment of specific areas and avoids the surrounding tissues. However, this technique has uncertainties in terms of the distal dose fall-off. A promising approach to studying the proton range is the use of nanoparticles as proton-activatable agents that produce detectable signals. For this, we developed an iron oxide nanoparticle doped with Zn (IONP@Zn-cit) with a hydrodynamic size of 10 nm and stability in serum. Cytotoxicity, defined as half of the surveillance, was 100 μg Zn/mL in the U251 cell line. The effect on clonogenic cell death was tested after X-ray irradiation, which suggested a radioprotective effect of these nanoparticles at low concentrations (1–10 μg Zn/mL). To evaluate the production of positron emitters and prompt-gamma signals, IONP@Zn-cit was irradiated with protons, obtaining prompt-gamma signals at the lowest measured concentration (10 mg Zn/mL). Finally, ⁶⁷Ga-IONP@Zn-cit showed accumulation in the liver and spleen and an accumulation in the tumor tissue of 0.95% ID/g in a mouse model of U251 cells. These results suggest the possibility of using Zn nanoparticles as proton-activatable agents to verify the range by prompt gamma detection and face the challenges of prompt gamma detection in a specific biological situation, opening different avenues to go forward in this field.

INTRODUCTION: A subset of Alzheimer's disease (AD) patients exhibits a procoagulant state that remains undiagnosed despite available treatments. We developed positron emission tomography (PET) strategies to in vivo detect cerebral microthrombi in TgCRND8 mice. METHODS: PET was performed with a fibrin‐binding probe (FBP) in TgCRND8 and wild‐type mice using a zirconium‐89–radiolabeled and a click‐chemistry pre‐targeted gallium‐68 radiotracer. Platelet content was assessed in post mortem brain tissue from AD patients and TgCRND8 mice, and evaluated by PET using a CD41 pre‐targeted gallium‐68 nanoradiotracer. RESULTS: Cerebral FBP uptake differentiated TgCRND8 from wild‐type mice, particularly ex vivo and with advancing age. Cerebral fibrin burden correlated with platelet content in AD patients, and elevated cerebral platelet burden in TgCRND8 mice was confirmed in post mortem tissue and in vivo by PET. DISCUSSION: Our findings support PET‐based detection of AD‐associated cerebral microthrombi and the development of imaging biomarkers to stratify AD patients by procoagulant status and inform personalized therapies.

Background: Alzheimer’s disease (AD) is the most common cause of dementia (1). It is a multifactorial degenerative disease pathologically characterized by intracellular neurofibrillary tangles and extracellular deposition of amyloid. An early haemostatic dysregulation is also present and contributes to an increment in clot formation, leading to hypoperfusion, blood brain barrier disruption and neuronal loss (2). The detection of this prothrombotic state is of the upmost importance in diagnostic approaches to identify AD patients who would benefit from anticoagulation.Aim: Using the in vivo nanotracer Thrombo‐tag (3) for the detection of brain thrombi in an AD mouse model by fast pre‐targeted positron emission tomography (PET) imaging.Method: AD animals and their wild‐type (WT) littermates were intravenously injected with the antiplatelet antibody against CD41 conjugated with transcyclooctene (TCO‐antiCD41). Twenty‐four hours later, [⁶⁸Ga]core‐doped iron oxide nanoparticles (NP) functionalized with tetrazine (TZ) were intravenously administered. TCO and TZ produce a rapid in vivo reaction by means of bioorthogonal chemistry, allowing to non‐invasively evaluate platelets’ levels by PET. Two hours after [⁶⁸Ga]NP‐TZ injection, a static PET study of each mouse was acquired with a scanner for small animals (nanoScan® PET/CT, Mediso, USA). Finally, biodistribution assays of different organs after the PET study were performed. All PET images were analyze by regions of interest (ROI) and voxel‐wise analyses.Result: Thrombo‐tag has proven to be an effective and efficient method for neuroimaging in vivo. This PET probe allows us to accurately identify the presence and accumulation of platelets within the brain of animal models of Alzheimer’s disease. Additionally, Thrombo‐tag enables us to determine the distribution of platelets’ accumulations within various regions of the brain in comparison to WT controls.Conclusion: Thrombo‐tag provides a neuroimaging biomarker that could allow us to diagnose the prothrombotic state towards the personalization of anticoagulation treatment in AD patients.Funding: Carlos is the recipient of a Predoctoral Fellowship from the Fundación Española de Trombosis y Hemostasia.Bibliography: 1. Alzheimers Dement, 17, 327‐406, (2021), doi.org/10.1002/alz.123282. Cortes‐Canteli & Iadecola, Journal of the American College of Cardiology, 75, 942‐951, (2020)3. Adrover, Pellico et al., Nanoscale, 12, 22978‐22987, (2020)