In vivo 212Pb/212Bi generator using indium-DTPA-tagged liposomes

International audienceIndium-DTPA-tagged liposomes were studied in the present work as carriers of in vivo 212Pb / 212Bi generator to be used in targeted alpha therapy. The liposomal uptake of 212Pb, into preformed liposomes, was investigated using different lipophilic chelate (DCP, 2,3-dimercapto-1-propanol (BAL), sodium acetate, and A23187), as a function of various parameters (temperature, concentrations of lipids, Pb, DTPA,...) with 212Pb as a tracer. Different formulations of liposomes were tested to evaluate the radiolabeling efficiency. No complexing agent was necessary for the passage of Pb2+ through the membrane. It occurs naturally via a partial permeability of the lipid bilayer which increases with the temperature. A complexing agent (DTPA) appears necessary to concentrate Pb in the internal compartment of the liposomes. Conditions were found (T = 65°C, internal DTPA concentration of 0.025 M, pH 7.4, ...) yielding a high and rapid uptake of 212Pb in liposomes. The protocol established provides a novel method for the efficient entrapment of about 2-3 Pb atoms per liposome with a yield of 75% in conditions relevant for nuclear medicine

Mise en évidence de la mutation Y250X du gène de TFR2 par PCR

BREST-BU Médecine-Odontologie (290192102) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Coupling a gamma-ray detector with asymmetrical flow field flow fractionation (AF4): Application to a drug-delivery system for alpha-therapy

International audienceAlpha-particle-emitting radionuclides have been the subject of considerable investigation as cancer ther-apeutics, sincethey have the advantages of highpotency and specificity. Among ␣-emitting radionuclides that are medically relevant and currently available, the lead-212/bismuth-212 radionuclide pair could constitute an in vivo generator. Considering its short half-life (T 1/2 = 60.6min), 212 Bi can only be delivered using labelled carrier molecules that would rapidly accumulate in the target tumor. To expand the range of applications, an interesting method is to use its longer half-life parent 212 Pb (T 1/2 = 10.6 h) that decays to 212 Bi. The challenge consists in keeping 212 Bi bound to the vector after the 212 Pb decay. Preclinical and clinical studies have shown that a variety of vectors may be used to target alpha-emitting radionu-clidesto cancer cells. Nanoparticles, notably liposomes,allow combinedtargeting options, achieving high specific activities, easier combination of imaging and therapy and development of multimodality therapeutic agents (e.g., radionuclide therapy plus chemotherapy). The aim of thiswork consists in assessing the in vitro stabilityof 212 Pb/ 212 Bi encapsulation in the liposomes. Indeed, the release of the radionuclide from the carrier molecules might causes toxicity to normal tissues. To reach this goal,Asymmetrical Flow Field-Flow Fractionation(AF4) coupled with a Multi-Angle Light Scattering detector (MALS) was used and coupling with a gamma () ␥ ray detector was developed. AF4-MALS-␥ was shown to be a powerful tool for monitoring the liposome size together with the incorporation of the high energy alpha emitter. This was successfully extended to assess thestability of 212 Bi-radiolabelled liposomes in serum showing that more than 85% of 212 Pb/ 212 Bi is retained after 24 h of incubation at 37 • C

Phenotypic Differences Between Polygenic and Monogenic Hypobetalipoproteinemia

International audienceObjective: Primary hypobetalipoproteinemia is characterized by LDL-C (low-density lipoprotein cholesterol) concentrations below the fifth percentile. Primary hypobetalipoproteinemia mostly results from heterozygous mutations in the APOB (apolipoprotein B) and PCSK9 genes, and a polygenic origin is hypothesized in the remaining cases. Hypobetalipoproteinemia patients present an increased risk of nonalcoholic fatty liver disease and steatohepatitis. Here, we compared hepatic alterations between monogenic, polygenic, and primary hypobetalipoproteinemia of unknown cause. Approach and Results: Targeted next-generation sequencing was performed in a cohort of 111 patients with hypobetalipoproteinemia to assess monogenic and polygenic origins using an LDL-C-dedicated polygenic risk score. Forty patients (36%) had monogenic hypobetalipoproteinemia, 38 (34%) had polygenic hypobetalipoproteinemia, and 33 subjects (30%) had hypobetalipoproteinemia from an unknown cause. Patients with monogenic hypobetalipoproteinemia had lower LDL-C and apolipoprotein B plasma levels compared with those with polygenic hypobetalipoproteinemia. Liver function was assessed by hepatic ultrasonography and liver enzymes levels. Fifty-nine percent of patients with primary hypobetalipoproteinemia presented with liver steatosis, whereas 21% had increased alanine aminotransferase suggestive of liver injury. Monogenic hypobetalipoproteinemia was also associated with an increased prevalence of liver steatosis (81% versus 29%, P<0.001) and liver injury (47% versus 0%) compared with polygenic hypobetalipoproteinemia.Conclusions: This study highlights the importance of genetic diagnosis in the clinical care of primary hypobetalipoproteinemia patients. It shows for the first time that a polygenic origin of hypobetalipoproteinemia is associated with a lower risk of liver steatosis and liver injury versus monogenic hypobetalipoproteinemia. Thus, polygenic risk score is a useful tool to establish a more personalized follow-up of primary hypobetalipoproteinemia patients