Ahlem Bouhlel

Early and accurate tumor detection is key to successful cancer management. Nanotechnology‐based biomedical imaging offers strong potential to enhance tumor detection through improved sensitivity and specificity, particularly via the enhanced permeability and retention (EPR) effect. However, suboptimal biodistribution of imaging agents is often associated with a pronounced liver retention. Fluorinated compounds, though rare in nature, provide unique physicochemical properties thanks to the high electronegativity of fluorine, its strong inductive effect, and the low polarizability of the C‐F bond, conferring exceptional chemical stability and biological inertness. Here, we report a fluorinated supramolecular dendrimer nanosystem for tumor imaging using positron emission tomography (PET). This system was constructed via the self‐assembly of an amphiphilic fluorinated dendrimer radiolabeled with gallium‐68, a positron‐emitting radionuclide commonly used for PET. This fluorinated radiotracer exhibited a nanoscale size and had high radiochemical purity and stability. Compared to its non‐fluorinated analogue, the fluorinated system showed reduced liver accumulation, improved pharmacokinetics, and significantly enhanced tumor uptake in orthotopic and ectopic mouse xenograft models of glioblastoma and pancreatic adenocarcinoma. These results demonstrate that fluorination is a powerful strategy to optimize pharmacokinetics and biodistribution of imaging agents, enabling more accurate and effective tumor detection.

Microvesicles, so-called endothelial large extracellular vesicles (LEVs), are of great interest as biological markers and cell-free biotherapies in cardiovascular and oncologic diseases. However, their therapeutic perspectives remain limited due to the lack of reliable data regarding their systemic biodistribution after intravenous administration. Methods: Applied to a mouse model of peripheral ischemia, radiolabeled endothelial LEVs were tracked and their in vivo whole-body distribution was quantified by microSPECT/CT imaging. Hindlimb perfusion was followed by LASER Doppler and motility impairment function was evaluated up to day 28 post-ischemia. Results: Early and specific homing of LEVs to ischemic hind limbs was quantified on the day of ischemia and positively correlated with reperfusion intensity at a later stage on day 28 after ischemia, associated with an improved motility function. Conclusions: This concept is a major asset for investigating the biodistribution of LEVs issued from other cell types, including cancer, thus partly contributing to better knowledge and understanding of their fate after injection.

Succinate influences angiogenesis and neovascularization via a hormonelike effect on G-protein-coupled receptor 91 (GPR91). This effect has been demonstrated in the pathophysiology of diabetic retinopathy and rheumatoid arthritis. To evaluate whether succinate can play a role in acute peripheral ischemia, a preclinical study was conducted with ischemic mice treated with succinate or PBS and evaluated by imaging. Acute ischemia was followed by an increased in GPR91 expression in the ischemic muscle. As assessed with LASER-Doppler, succinate treatment resulted in an earlier and more intense reperfusion of the ischemic hindlimb compared to the control group (* p = 0.0189). A microPET study using a radiolabeled integrin ligand ([⁶⁸Ga]Ga-RGD₂) showed an earlier angiogenic activation in the succinate arm compared to control mice (* p = 0.020) with a prolonged effect. Additionally, clinical recovery following ischemia was better in the succinate group. In conclusion, succinate injection promotes earlier angiogenesis after ischemia, resulting in a more effective revascularization and subsequently a better functional recovery.

Due to its ideal physical properties, fluorine-18 turns out to be a key radionuclide for positron emission tomography (PET) imaging, for both preclinical and clinical applications. However, usual biomolecules radiofluorination procedures require the formation of covalent bonds with fluorinated prosthetic groups. This drawback makes radiofluorination impractical for routine radiolabeling, gallium-68 appearing to be much more convenient for the labeling of chelator-bearing PET probes. In response to this limitation, a recent expansion of the ¹⁸F chemical toolbox gave aluminum [¹⁸F]fluoride chemistry a real prominence since the late 2000s. This approach is based on the formation of an [¹⁸F][AlF]²⁺ cation, complexed with a 9-membered cyclic chelator such as NOTA, NODA or their analogs. Allowing a one-step radiofluorination in an aqueous medium, this technique combines fluorine-18 and non-covalent radiolabeling with the advantage of being very easy to implement. Since its first reports, [¹⁸F]AlF radiolabeling approach has been applied to a wide variety of potential PET imaging vectors, whether of peptidic, proteic, or small molecule structure. Most of these [¹⁸F]AlF-labeled tracers showed promising preclinical results and have reached the clinical evaluation stage for some of them. The aim of this report is to provide a comprehensive overview of [¹⁸F]AlF labeling applications through a description of the various [¹⁸F]AlF-labeled conjugates, from their radiosynthesis to their evaluation as PET imaging agents.