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Targeting large transmembrane molecules, including receptor tyrosine kinases, is a major pharmacological challenge. Specific oligonucleotide ligands (aptamers) can be generated for a variety of targets through the iterative evolution of a random pool of sequences (SELEX). Nuclease-resistant aptamers that recognize the human receptor tyrosine kinase RET were obtained using RET-expressing cells as targets in a modified SELEX procedure. Remarkably, one of these aptamers blocked RET-dependent intracellular signaling pathways by interfering with receptor dimerization when the latter was induced by the physiological ligand or by an activating mutation. This strategy is generally applicable to transmembrane receptors and opens the way to targeting other members of this class of proteins that are of major biomedical importance.

6-[18F]Fluoro-3,4-dihydroxy- L-phenylalanine (6-[18F]F- L-DOPA) is increasingly used for PET imaging of neuroendocrine tumours. In this study, we investigated the use of 6-[18F]F- L-DOPA to detect and to monitor the progression of medullary thyroid carcinoma (MTC) in a genetically engineered mouse model of multiple endocrine neoplasia type 2A (MEN2A). Dynamic [18F]FDG and 6-[18F]F- L-DOPA small animal PET scans were acquired during 60 or 90 min in 8- to 20-month-old MEN2A transgenic mice. The kinetics of 6-[18F]F- L-DOPA, standardized uptake values (SUV) at 60 min and tumour volumes were recorded. The detection of MTCs using PET was confirmed by autopsy and histological analysis. 6-[18F]F- L-DOPA performs better than [18F]FDG for MTC detection in this transgenic mouse model. Uptake kinetics of 6-[18F]F- L-DOPA in MTCs are very different between mice but, in all cases, high contrast could be observed. Furthermore, 6-[18F]F- L-DOPA can detect tumours with sizes (1.8 mm3) that are near the resolution limit of PET, whereas they were undetectable by autopsy at the macroscopic level. 6-[18F]F- L-DOPA PET imaging can monitor the progression of MTCs in a genetically engineered mouse model. [ABSTRACT FROM AUTHOR]

Because of the formation of specific antibodies to poly(ethylene glycol) (PEG) leading to life-threatening side effects, there is an increasing need to develop alternatives to treatments and diagnostic methods based on PEGylated copolymers. Block copolymers comprising a poly( N -vinyl-2-pyrrolidone) (PVP) segment can be used for the design of such vectors without any PEG block. As an example, a poly(acrylic acid)- block -poly( N -vinyl-2-pyrrolidone) (PAA- b -PVP) copolymer with controlled composition and molar mass is synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization. Mixing this copolymer with lanthanide cations (Gd 3+ , Eu 3+ , Y 3+ ) leads to the formation of hybrid polyion complexes with increased stability, preventing the lanthanide cytotoxicity and in vitro cell penetration. These new nanocarriers exhibit enhanced T 1 MRI contrast, when intravenously administered into mice. No leaching of gadolinium ions is detected from such hybrid complexes.

Anti-PDL1 is a monoclonal antibody targeting the programmed death-cell ligand (PD-L1) by blocking the programmed death-cell (PD-1)/PD-L1 axis. It restores the immune system response in several tumours, such as non-small cell lung cancer (NSCLC). Anti-PDL1 or anti-PD1 treatments rely on PD-L1 tumoural expression assessed by immunohistochemistry on biopsy tissue. However, depending on the biopsy extraction site, PD-L1 expression can vary greatly. Non-invasive imaging enables whole-body mapping of PD-L1 sites and could improve the assessment of tumoural PD-L1 expression., Methods: Pharmacokinetics (PK), biodistribution and dosimetry of a murine anti-PDL1 radiolabelled with zirconium-89, were evaluated in both healthy mice and immunocompetent mice with lung cancer. Preclinical PET (μPET) imaging was used to analyse [ 89 Zr]DFO-Anti-PDL1 distribution in both groups of mice. Non-compartmental (NCA) and compartmental (CA) PK analyses were performed in order to describe PK parameters and assess area under the concentration-time curve (AUC) for dosimetry evaluation in humans., Results: Organ distribution was correctly estimated using PK modelling in both healthy mice and mice with lung cancer. Tumoural uptake occurred within 24 h post-injection of [ 89 Zr]DFO-Anti-PDL1, and the best imaging time was at 48 h according to the signal-to-noise ratio (SNR) and image quality. An in vivo blocking study confirmed that [ 89 Zr]DFO-anti-PDL1 specifically targeted PD-L1 in CMT167 lung tumours in mice. AUC in organs was estimated using a 1-compartment PK model and extrapolated to human (using allometric scaling) in order to estimate the radiation exposure in human. Human-estimated effective dose was 131 μSv/MBq., Conclusion: The predicted dosimetry was similar or lower than other antibodies radiolabelled with zirconium-89 for immunoPET imaging., Competing Interests: Employment: CF and YB are employees of General Electric-Zionexa laboratory. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Krache, Fontan, Pestourie, Bardiès, Bouvet, Payoux, Chatelut, White-Koning and Salabert.)