Targeting of diethylene triamine pentaacetic acid encapsulated in liposomes to rat liver: an effective strategy to prevent bone deposition and increase urine elimination of plutonium in rats.

PURPOSE: To modify the distribution of the chelating agent diethylene triamine pentaacetic acid (DTPA) by using a formulation approach with liposomes in order to match the in vivo distribution of plutonium (Pu) and, as a consequence, to improve actinide decorporation. MATERIALS AND METHODS: DTPA was encapsulated in conventional and stealth liposomes. Their pharmacokinetics and ability to remove Pu were evaluated in rats 2 and 16 days after a single intravenous treatment given 2 h after contamination with colloidal Pu (239Pu phytate) or with soluble Pu (238Pu citrate). RESULTS: Both formulations induced major pharmacokinetic modifications in rats, allowing an accumulation of [14C]-DTPA mainly in the liver and secondarily (for stealth liposomes) in bone and spleen. These modifications were associated with major increases in urine elimination and with a decrease in skeletal Pu deposition, depending of the nature of the Pu contaminant. After contamination by Pu phytate, conventional liposomes of DTPA (6 micromol kg(-1)) were as efficient as free DTPA (30 micromol kg(-1)) in maintaining the Pu content in the femur below 4.3% of the injected dose after 16 days, a 3.6-fold reduction compared with free DTPA (4 micromol kg(-1)) treatment or without treatment. CONCLUSIONS: A formulation approach with liposomes appears to be a powerful tool to improve the efficiency of Pu chelating agents in vivo.

In vivo measurement of Pu dissolution parameters of MOX aerosols and related uncertainties in the values of the dose per unit intake.

The aim of this study was to compare dissolution parameter values for Pu from industrial MOX with different Pu contents. For this purpose, preliminary results obtained after inhalation exposure of rats to MOX containing 2.5% Pu are reported and compared to those obtained previously with MOX containing 5% Pu. Dissolution parameter values appear to increase when the amount of Pu decreases. Rapid fractions, f(r), of 4 x 10(-3) (s.d. = 2 x 10(-3)) and 1 x 10(-3) (s.d. = 6 x 10(-4)) and slow dissolution rates, s(s) of 2 x 10(-4) d(-1) (standard deviation, sigma = 5 x 10(-5)) and 5 x 10(-5) d(-1) (sigma = 1 x 10(-5)) were derived for MOX containing 2.5 and 5% of Pu, respectively. Simulations were performed to assess uncertainties on dose due to experimental errors. The relative standard deviations of the dose per unit intake (DPUI) due to f(r) (4-8%), are far less than those due to s(s) (about 20%), which is the main parameter altering the dose. Although quite different dissolution parameter values were derived, similar DPUIs were obtained for MOX aerosols containing 2.5 and 5% Pu which appear close to that for default Type S values.

Comparative decorporation efficacy of 3,4,3-LIHOPO, 4,4,4-LIHOPO and DTPA after contamination of rats with soluble forms of 238Pu and 233U.

The aim of this study was to compare the efficacies of DTPA, 3,4,3-LIHOPO and a newly synthesised molecule, 4,4,4-LIHOPO, in removing 233U and 238Pu after internal contamination by soluble forms of those nuclides. For this purpose, intravenous injections of DTPA (30 micromol kg(-1)) or 3,4,3-LIHOPO or 4,4,4-LIHOPO at dosages of 0.3 or 30 micromol kg(-1) were performed 1, 6 and 24 h after contamination of rats by intravenously injected 238Pu citrate and 1 h after intravenous injection of 233U nitrate. Actinide content in the main retention organs and cumulated excretion were measured 48 h after contamination. These experiments show similar decorporation efficacies of 4,4,4-LIHOPO and 3,4,3-LIHOPO for Pu, which are much higher than that of DTPA. At a dosage of 0.3 micromol kg(-1), the two LIHOPO analogues were as efficient as DTPA at a dosage of 30 micromol kg(-1). After U contamination, a 20% decorporation efficacy was obtained for either 3,4,3-LIHOPO or 4,4,4-LIHOPO at a dosage of 30 micromol kg(-1).

[Specific parameters for the calculation of dose after aerosol inhalation of transuranium elements]. / Mesure de paramètres spécifiques pour le calcul de dose après inhalation d'aérosols renfermant des éléments transuraniens.

A review on specific parameter measurements to calculate doses per unit of incorporation according to recommendations of the International Commission of Radiological Protection has been performed for inhaled actinide oxides. Alpha activity distribution of the particles can be obtained by autoradiography analysis using aerosol sampling filters at the work places. This allows us to characterize granulometric parameters of "pure" actinide oxides, but complementary analysis by scanning electron microscopy is needed for complex aerosols. Dissolution parameters with their standard deviation are obtained after rat inhalation exposure, taking into account both mechanical lung clearance and actinide transfer to the blood estimated from bone retention. In vitro experiments suggest that the slow dissolution rate might decrease as a function of time following exposure. Dose calculation software packages have been developed to take into account granulometry and dissolution parameters as well as specific physiological parameters of exposed individuals. In the case of poorly soluble actinide oxides, granulometry and physiology appear as the main parameters controlling dose value, whereas dissolution only alters dose distribution. Validation of these software packages are in progress.