The therapeutic potential of polymersomes loaded with 225Ac evaluated in 2D and 3D in vitro glioma models.

Alpha emitters have great potential in targeted tumour therapy, especially in destroying micrometastases, due to their high linear energy transfer (LET). To prevent toxicity caused by recoiled daughter atoms in healthy tissue, alpha emitters like 225Ac can be encapsulated in polymeric nanocarriers (polymersomes), which are capable of retaining the daughter atoms to a large degree. In the translation to a (pre-)clinical setting, it is essential to evaluate their therapeutic potential. As multicellular tumour spheroids mimic a tumour microenvironment more closely than a two-dimensional cellular monolayer, this study has focussed on the interaction of the polymersomes with U87 human glioma spheroids. We have found that polymersomes distribute themselves throughout the spheroid after 4 days which, considering the long half-life of 225Ac (9.9 d) (Vaidyanathan and Zalutsky, 1996), allows for irradiation of the entire spheroid. A decrease in spheroidal growth has been observed upon the addition of only 0.1 kBq 225Ac, an effect which was more pronounced for the 225Ac in polymersomes than when only coupled to DTPA. At higher activities (5 kBq), the spheroids have been found to be destroyed completely after two days. We have thus demonstrated that 225Ac containing polymersomes effectively inhibit tumour spheroid growth, making them very promising candidates for future in vivo testing.

Transport rate of arsenic, cadmium, copper and zinc in Potamogeton pectinatus L.: radiotracer experiments with 76As,109,115Cd,64Cu and 65,69mZn.

The present study was aimed at obtaining an insight into possible experimental approaches for providing numerical data on both the accumulation of sediment As, Cd, Cu and Zn in the submerged water plant Potamogeton pectinatus L., and the possible corresponding metal flows into the water phase. A hydroculture two-compartment system was used as the experimental set-up, and the selected metals were followed by measurements of their radioisotopes 76As, 109Cd, 115Cd, 64Cu, 65Zn and 69mZn. All experiments were performed in single plant mode. The results stress the extreme importance of leakage tests, which were performed using 99mTcO4-, and which resulted in approximately 30% of all experiments being discarded. Metal flows were shown as very near the metal limits of detection or obscured by and/or numerically very near the occurring leakage phenomena. Bio-concentration factors BCF (fresh wt. fine root basis) were calculated as 100, 10, 10 and 100-500 l/kg for Cu, Zn, Cd and As, respectively. The mobility, expressed as the shoot/root concentration ratio, CR, was obtained as < 10(-4), < 10(-5), 10(-3) and 10(-3) - 10(-2) for Cu, As, Cd and Zn, respectively. Double-labeling experiments showed that the CR values were due to the exclusive root-mediated transport in radiotracer experiments: results for simultaneous applications of 109Cd and 115Cd or 65Zn and 69mZn showed field-simulated CR values of approximately 0.04 and 14, respectively. Single-tracer experiments, using liquid scintillation counting (LSC) with 109Cd and 65Zn, were shown to strongly improve the sensitivities of flow determinations. Under the applied conditions, metal flows could be determined as <5 x 10(-8), <5 X 10(-8), 3.5+/-1.8 x 10(-10) and <8 x 10(-9) mol/h per kg root fresh wt. for Cu, As, Cd and Zn, respectively. Upscaling calculations, assuming plant steady state behavior, indicate that the metal accumulation in the plants may comprise up to 1% of the sediment metal occurrence, that the major part of an accumulated metal is retained in the plant roots, and that plant-mediated metal flow into the water phase (< 0.01% for Cd, Cu and Zn, < 0.1% for As within a growing season) may be regarded as not significantly contributing to the overall process of metal mobilization. It should be noted, however, that the above conclusions should be drawn with care, due to the pilot nature and the short-term duration of the presented experiments.