Development of probes for radiotheranostics with albumin binding moiety to increase the therapeutic effects of astatine-211 ( 211 At)

Purpose We have developed probes for multiradionuclides radiotheranostics using RGD peptide ([ 67 Ga]Ga-DOTA-c[RGDf(4-I)K] ([ 67 Ga] 1 ) and Ga-DOTA-[ 211 At]c[RGDf(4-At)K] ([ 211 At] 2 )) for clinical applications. The introduction of an albumin binding moiety (ABM), such as 4-(4-iodophenyl)-butyric acid (IPBA), that has high affinity with the blood albumin and prolongs the circulation half-life can improve the pharmacokinetics of drugs. To perform more effective targeted alpha therapy (TAT), we designed and synthesized Ga-DOTA-K([ 211 At]APBA)-c(RGDfK) ([ 211 At] 5 ) with 4-(4-astatophenyl)-butyric acid (APBA), which has an astato group instead of an iodo group in IPBA. We evaluated whether APBA functions as ABM and [ 211 At] 5 is effective for TAT. In addition, we prepared 67 Ga-labeled RGD peptide without ABM, [ 67 Ga]Ga-DOTA-K-c(RGDfK) ([ 67 Ga] 3 ), and 125 I-labeled RGD peptide with ABM, Ga-DOTA-K([ 125 I]IPBA)-c(RGDfK) ([ 125 I] 4 ), to compare with [ 211 At] 5 . Methods Biodistribution experiments of [ 67 Ga] 3 without ABM, [ 125 I] 4 and [ 211 At] 5 with ABM were conducted in normal mice and U-87 MG tumor-bearing mice. In addition, two doses of [ 211 At] 5 (370 or 925 kBq) were administered to U-87 MG tumor-bearing mice to confirm the therapeutic effects. Results The blood retention of [ 125 I] 4 and [ 211 At] 5 was remarkably increased compared to [ 67 Ga] 3 . Also, [ 125 I] 4 and [ 211 At] 5 showed similar biodistribution and significantly greater tumor accumulation and retention compared to [ 67 Ga] 3 . In addition, [ 211 At] 5 inhibited tumor growth in a dose-dependent manner. Conclusion The functionality of APBA as ABM like IPBA, and the usefulness of [ 211 At] 5 as the radionuclide therapy agent for TAT was revealed.