Optimizing the pharmacokinetics of an 211At-labeled RGD peptide with an albumin-binding moiety via the administration of an albumin-binding inhibitor

Purpose A probe for targeted alpha therapy (TAT) using the RGD peptide (Ga-DOTA-K([ 211 At]APBA)-c(RGDfK) ([ 211 At] 1 )) with albumin-binding moiety (ABM) was recently developed. [ 211 At] 1 highly accumulated in tumors and significantly inhibited tumor growth in U-87 MG tumor-bearing mice. However, high [ 211 At] 1 retention in blood may cause critical adverse events, such as hematotoxicity. Therefore, we attempted to accelerate the blood clearance of [ 211 At] 1 by competitively inhibiting the binding of [ 211 At] 1 to albumin to modulate the pharmacokinetics of the former. Methods To evaluate the effects of albumin-binding inhibitors in normal mice, sodium 4-(4-iodophenyl)butanoate at 2, 5, or 10 molar equivalents of blood albumin was administered at 1-h postinjection of [ 211 At] 1 . The biodistribution of [ 211 At] 1 , SPECT/CT imaging of [ 67 Ga]Ga-DOTA-K(IPBA)-c(RGDfK) ([ 67 Ga] 2 ), and the therapeutic effects of [ 211 At] 1 were compared with or without IPBA administration in U-87 MG tumor-bearing mice. Results Blood radioactivity of [ 211 At] 1 was decreased in a dose-dependent manner with IPBA in normal mice. In U-87 MG tumor-bearing mice, the blood radioactivity and accumulation in nontarget tissues of [ 211 At] 1 were decreased by IPBA. Meanwhile, tumor [ 211 At] 1 accumulation was not changed at 3-h postinjection of IPBA. In SPECT/CT imaging of [ 67 Ga] 2 , IPBA administration dramatically decreased radioactivity in nontarget tissues, and only tumor tissue was visualized. In therapeutic experiments, [ 211 At] 1 with IPBA injected-group significantly inhibited tumor growth compared to the control group. Conclusion IPBA administration (as an albumin-binding inhibitor) could modulate the pharmacokinetics and enhance the therapeutic effects of [ 211 At] 1 .