A supramolecular approach for liver radioembolization

Hepatic radioembolization therapies can suffer from discrepancies between diagnostic planning (scout-scan) and the therapeutic delivery itself, resulting in unwanted side-effects such as pulmonary shunting. We reasoned that a nanotechnology-based pre-targeting strategy could help overcome this shortcoming by directly linking pre-interventional diagnostics to the local delivery of therapy. Methods: The host-guest interaction between adamantane and cyclodextrin was employed in an in vivo pre-targeting set-up. Adamantane (guest)-functionalized macro albumin aggregates (MAA-Ad; d = 18 μm) and (radiolabeled) Cy5 and β-cyclodextrin (host)-containing PIBMA polymers (99mTc-Cy50.5CD10PIBMA39; MW ~ 18.8 kDa) functioned as the reactive pair. Following liver or lung embolization with (99mTc)-MAA-Ad or (99mTc)-MAA (controls), the utility of the pre-targeting concept was evaluated after intravenous administration of 99mTc-Cy50.5CD10PIBMA39. Results: Interactions between MAA-Ad and Cy50.5CD10PIBMA39 could be monitored in solution using confocal microscopy and were quantified by radioisotope-based binding experiments. In vivo the accumulation of the MAA-Ad particles in the liver or lungs yielded an approximate ten-fold increase in accumulation of 99mTc-Cy50.5CD10PIBMA39 in those organs (16.2 %ID/g and 10.5 %ID/g, respectively) compared to the control. Pre-targeting with MAA alone was shown to be only half as efficient. Uniquely, for the first time, this data demonstrates that the formation of supramolecular interactions between cyclodextrin and adamantane can be used to drive complex formation in the chemically challenging in vivo environment. Conclusion: The in vivo distribution pattern of the cyclodextrin host could be guided by the pre-administration of the adamantane guest, thereby creating a direct link between the scout-scan (MAA-Ad) and delivery of therapy.</p

Solvent extraction studies of different diastereomers of modified diglycolamide ligands for An(III) and Ln(III) extraction

BackgroundSolvent extraction is currently the preferred technique for the separation of actinides (An) from fission products (FP), and especially lanthanides (Ln), as constituents of Spent Nuclear Fuel (SNF) or PUREX raffinate. For this purpose, the separation of minor actinides (MA), especially Am(III) from Cm(III), Eu(III) and other Ln(III) is the current challenge of interest. Nowadays, extractants only made by carbon, hydrogen, oxygen, and nitrogen (CHON principle) are preferred for the extraction of MA, because they can be completely incinerated. Diglycolamides (DGA) showed promising results as extractants for trivalent Ln and An, such as N,N,N’,N’-tetra-n-octyl diglycolamide (TODGA), which usually have a higher affinity for Cm(III) over Am(III). Wilden et al. reported a variation of the Am(III) selectivity over Cm(III) with differently orientated methyl substitutions (syn and anti) in the ligand backbone of Me2-TODGA (Wilden et al., 2019). Here, we study the selectivity and affinity of derivative extractants of TODGA and N,N,N’,N’-tetra-n-decyl diglycolamide (TDDGA) with dipropyl and ethyl-methyl substitutions in the molecule backbone, and their respective diastereomers.MethodsThe experiments were carried out at different nitric acid concentrations (0.8 – 9.8 mol L-1) containing all Ln(III) (except Pm) and other fission products. 241Am, 244Cm, 152Eu and 239Pu(IV) were added as radioactive tracers. The new extractants were tested as 0.1 mol L-1 solution in n-dodecane. The extraction was carried out at 22°C for 30 min. After centrifugation for 5 min., phases were separated by hand using fine-tip pipets. Organic and aqueous phase samples were measured using gamma and alpha spectrometry and ICP-MS.ResultsThe steric hindrance from the alkyl side chains gave generally low distribution ratios (D 10). The syn-ethyl-methyl substitutions for both analogues showed the highest D values for Am(III) and all metals (except Ru) by all of the tested ligands giving promising molecules for further studies. No third phase formation was observed for any of the ligands. The results of the extraction studies will be presented and discussed in the poster.ConclusionsAmong the tested ligands, syn-ethyl-methyl substitution for both diglycolamides (octyl and decyl side chains) gave the highest D values for all Ln and An. Nevertheless, the D values were much lower than for their unsubstituted parent molecules. Pu(IV) was extracted much better rising the attention for extraction of tetravalent ions. Further studies aim at increasing the D values by e.g., increasing the ligand concentration.ReferencesWilden, A., Kowalski, P. M., Klaß, L., Kraus, B., Kreft, F., Modolo, G., . . . Verboom, W. (2019). Unprecedented Inversion of Selectivity and Extraordinary Difference in the Complexation of Trivalent f-Elements by Diastereomers of a Methylated Diglycolamide. Chem. Eur. J., 25(21), 5507-5513. https://doi.org/10.1002/chem.20180616

Solvent extraction studies of different diastereomers of modified diglycolamide ligands for An(III) and Ln(III) extraction

Solvent extraction is currently the preferred technique for the separation of actinides (An) from fission products(FP), and especially lanthanides (Ln), as constituents of Spent Nuclear Fuel (SNF) or PUREX raffinate. A specialinterest is on the separation of Am from Cm, Ln and other FP by testing various ligands to upgrade the currentmethods. Diglycolamide (DGA) derivatives have shown promising results as extractants for trivalent Ln and An,such as, N,N,N’,N’-tetra-n-octyl diglycolamide (TODGA), which usually have a higher affinity for Cm(III) overAm(III). Wilden et al. [1] reported a change on Am(III) selectivity over Cm(III) with methyl substitutions withdifferent orientation in the backbone of Me2-TODGA. Here, we study the selectivity and affinity of relatedextractants (TODGA and N,N,N’,N’-tetra-n-decyl diglycolamide, TDDGA) with dipropyl and ethyl-methylsubstitutions in the molecule backbone, and their respective diastereomers (syn or anti) in n-dodecane. Thechemical structures are shown in Figure 1 An inverse selectivity is observed for Am(III) over Cm(III) and otherLn(III) at high nitric acid concentration (7 - 10 mol L-1 HNO3). The steric hindrance gives low distribution ratios(D 10). This is unlike methyl anddimethyl-TODGA, which present similar distribution ratios between trivalent and tetravalent metal ions. The synethyl-methyl substitutions for both analogues showed the highest D values for Am(III) among the tested ligands,giving a promising molecule for further studies. The results of the extraction studies will be presented anddiscussed in the poster.References1. Wilden, A., et al., Unprecedented Inversion of Selectivity and Extraordinary Difference in theComplexation of Trivalent f-Elements by Diastereomers of a Methylated Diglycolamide. Chem. Eur. J.,2019. 25(21): p. 5507-5513

Underwater detection of tonal signals between 0.125 and 100 kHz by harbor seals (Phoca vitulina)

The underwater hearing sensitivities of two 1-year -old female harbor seals were quantified in a pool built for acoustic research, using a behavioral psychoacoustic technique. The animals were trained to respond when they detected an acoustic signal and not to respond when they did not (go/no-go response). Pure tones (0.125-0.25 kHz) and narrowband frequency modulated (tonal) signals (center frequencies 0.5-100 kHz) of 900 ms duration were tested. Thresholds at each frequency were measured using the up-down staircase method and defined as the stimulus level resulting in a 50% detection rate. The audiograms of the two seals did not differ statistically: both plots showed the typical mammalian U-shape, but with a wide and flat bottom. Maximum sensitivity (54 dB re 1 μPa, rms) occurred at 1 kHz. The frequency range of best hearing (within 10 dB of maximum sensitivity) was from 0.5 to 40 kHz (6 1 3 octaves). Higher hearing thresholds (indicating poorer sensitivity) were observed below 1 and above 40 kHz. Thresholds below 4 kHz were lower than those previously described for harbor seals, which demonstrates the importance of using quiet facilities, built specifically for acoustic research, for hearing studies in marine mammals. The results suggest that under unmasked conditions many anthropogenic noise sources and sounds from conspecifics are audible to harbor seals at greater ranges than formerly believed.</p

Effect of broadband-noise masking on the behavioral response of a harbor porpoise (Phocoena phocoena) to 1-s duration 6-7 kHz sonar up-sweeps

Naval sonar systems produce signals which may affect the behavior of harbor porpoises, though their effect may be reduced by ambient noise. To show how natural ambient noise influences the effect of sonar sweeps on porpoises, a porpoise in a pool was exposed to 1-s duration up-sweeps, similar in frequency range (6-7 kHz) to those of existing naval sonar systems. The sweep signals had randomly generated sweep intervals of 3-7 s (duty cycle: 19). Behavioral parameters during exposure to signals were compared to those during baseline periods. The sessions were conducted under five background noise conditions: the local normal ambient noise and four conditions mimicking the spectra for wind-generated noise at Sea States 2-8. In all conditions, the sweeps caused the porpoise to swim further away from the transducer, surface more often, swim faster, and breathe more forcefully than during the baseline periods. However, the higher the background noise level, the smaller the effects of the sweeps on the surfacing behavior of the porpoise. Therefore, the effects of naval sonar systems on harbor porpoises are determined not only by the received level of the signals and the hearing sensitivity of the animals but also by the background noise. © 2011 Acoustical Society of America