Spontaneous association of different forms of non-conjugated astatine-211 to serum albumin.

AIM/INTRODUCTION Astatine-211 is one of the alpha-particle emitting nuclides investigated for use within Targeted Alpha Therapy (TAT) of disseminated cancer. In previous studies, a difference in blood clearance has been observed when comparing astatinated compounds with their iodinated counterparts. This has been explained by a potentially prolonged retention in the blood by present free astatine. This study examined the spontaneous binding of non-conjugated astatine to albumin under physiological conditions in vitro and compared it to that of iodine. Additionally, the in vivo blood circulation patterns of free astatine were assessed and contrasted with those of iodine.

MATERIALS AND METHODS Astatine solutions were formulated following dry distillation and evaporation to dryness of astatine solvated in CHCl3. In vitro evaluation of astatine and iodine association to albumin was mainly performed using size exclusion chromatography applying both disposable columns (PD10 and NAP10) as well as an FPLC system (ÄKTA) with online UV detection and activity fraction collection. Also methanol precipitation and radio-TLC methods were used for analysis. In vivo evaluation was performed using furry BALB/C mice (3/group) with both i.v. and i.p. injection of astatine, followed by sequential blood sampling from the tail vein and biodistribution.

RESULTS Oxidized and unmodified forms of free astatine display a significantly higher and more rapid association to albumin in vitro compared to reduced forms, with >97% compared to <25% associated after 10 min. Both the corresponding oxidized and reduced forms of iodine display a very low and slow association to albumin with <5% associated after 40 min. Oxidized, unmodified and reduced astatine show very similar blood profiles over time as well as a similar uptake in biodistribution after 20-22 h following i.p. injection. Upon i.v. injection a larger difference in blood profiles between the species could be observed, which in turn was different compared to the curve obtained after i.p. injection. In addition, an unexpected uptake of astatide in stomach was found. In all cases the blood profile and biodistribution of astatine was significantly different compared to iodine, which displayed a greater and more rapid blood clearance and specific accumulation in thyroid.

CONCLUSION Different forms of unbound astatine differ in their association to albumin. However, all investigated forms of free astatine associates to albumin to a much higher degree than iodine. This behavior could explain the prolonged blood circulation of free astatine compared to iodine.