Pharmacokinetic and pharmaco-technological approaches of actinides decorporation by an in vivo sequestering agent. Application to the development of new treatments

After internal contamination by transuranic actinides, diethylene-triamine-pentaacetic acid (DTPA) is the only treatment available to haste the decorporation i.e. the excretion from the body of these radio-contaminants by the natural pathways (urinary and faecal excretion). However, the effectiveness of DTPA is variable and seems to be limited to mobilize efficiently the radionuclides from their sites of deposit and retention which are mainly the liver and the skeleton. Indeed, this molecule displays unfavourable pharmacokinetics (a low tissue distribution and a high urinary excretion) which do not match with the distribution of the actinides in vivo. Moreover, because of its physicochemical properties, DTPA is not able to pass through the plasmic membranes and to penetrate in the cells. Consequently, the use of colloidal vectors such as liposomes could make it possible to modulate DTPA pharmacokinetics as well as to promote the access of the chelating agent to the intracellular compartment of the macrophages of the reticulo-endothelial system which also uptake the radionuclides. The objective of this thesis thus was to improve the treatment of decorporation treatments of transuranic actinides, in particular of plutonium (Pu) by the sequestering agent DTPA by a double approach. The strategy consisted in developing liposomes in order to encapsulate and to modify the distribution of DTPA in vivo. The encapsulation of the DTPA in large multi-lamellar (MLV) and conventional liposomes (composed of DOPC:CH:PG) and in stealth MLV liposomes (composed of DOPC:CH:DSPE-PEG) could modify DTPA pharmacokinetics by prolonging its circulation time and by increasing its distribution especially in the liver (conventional MLV) and in the skeleton (stealth MLV). These modifications of the distribution of DTPA were well correlated with an increased de-corporating effect on Pu in the rats. The reduction of the diameter of liposomes to approximately 100 nm made it possible to further modulate the pharmacokinetic parameters by prolonging their circulation time. Stealth liposomes of diameters reduced to around 100 nm (SL-100 nm) displayed a more convenient distribution which may improve the pharmacological effect of DTPA. Indeed, the administration of a single dose of approximately 3 μmol.kg-1 of DTPA encapsulated in SL-100 nm induced an excretion of more than 90% of the Pu injected activity after 16 days while one free DTPA dose of 30 μmol.kg-1 induced only less than 50% of excretion of Pu under the same conditions. Moreover, one weekly administration of the SL-100 nm makes it possible to reduce significantly the retention of plutonium in the liver to less than 2% of Pu injected activity and that in the skeleton to less than 0.2%, only 30 days after Pu contamination. All these improvements may be attributed to the increase in the aria under the curve of the DTPA concentrations (AUC) and to an increased distribution of DTPA to the liver and the skeleton by the SL-100 nm. Contrary to the injection of free DTPA, SL-100 nm liposomes seem to be able to interact with the macrophages and the hepatocytes in the liver, then to intercept plutonium and to prevent the deposition of the actinide in the skeleton in the rats. Liposomal formulations of DTPA and their pharmacokinetic studies thus make it possible to optimize the treatment of decorporation of Pu. (author)