Abstract
Simple SummaryTo enhance the therapeutic effect of 2-211At-astato-α-methyl-L-phenylalanine (2-211At-AAMP), a radiopharmaceutical for targeted alpha therapy, we evaluated the effect of probenecid loading on its biodistribution and therapeutic effect in mice. Probenecid preloading significantly delayed the clearance of 2-211At-AAMP from the blood, increasing its accumulation in tumors. Consequently, the therapeutic effect of 2-211At-AAMP markedly improved. These results indicate that 2-211At-AAMP with probenecid loading is useful for the treatment of various types of cancers.L-type amino acid transporter 1 (LAT1) might be a useful target for tumor therapy since it is highly expressed in various types of cancers. We previously developed an astatine-211 (211At)-labeled amino acid derivative, 2-211At-astato-α-methyl-L-phenylalanine (2-211At-AAMP), and demonstrated its therapeutic potential for LAT1-positive cancers. However, the therapeutic effect of 2-211At-AAMP was insufficient, probably due to its low tumor retention. The preloading of probenecid, an organic anion transporter inhibitor, can delay the clearance of some amino acid tracers from the blood and consequently increase their accumulation in tumors. In this study, we evaluated the effect of probenecid preloading on the biodistribution and therapeutic effect of 2-211At-AAMP in mice. In biodistribution studies, the blood radioactivity of 2-211At-AAMP significantly increased with probenecid preloading. Consequently, the accumulation of 2-211At-AAMP in tumors was significantly higher with probenecid than without probenecid loading. In a therapeutic study, tumor growth was suppressed by 2-211At-AAMP with probenecid, and the tumor volume was significantly lower in the treatment group than in the untreated control group from day 2 to day 30 (end of the follow-up period) after treatment. These results indicate that probenecid loading could improve the therapeutic effect of 2-211At-AAMP by increasing its accumulation in tumors.
Highlights
General2-211At-AAMP was prepared from the stannyl precursor as previously described [13]
Targeted alpha therapy (TAT), a cancer treatment with a delivered αemitter, is an attractive potential therapy because of its high therapeutic effect without ssiiggnniifificcaanntt ttooxxiicciittyy [[11––33]]
The renal accumulation of 2-211At-AAMP was significantly lower at 10 min and higher at 1 h and 3 h after injection in the probenecid preloading group compared with that in the control group. This is probably because probenecid inhibited the renal accumulation of 2-211At-AAMP at an early point in time, which delayed renal excretion
Summary
2-211At-AAMP was prepared from the stannyl precursor as previously described [13]. After purification via reversed-phase high-performance liquid chromatography, 2-211At-AAMP was obtained with high radiochemical purity (>95%). Probenecid was purchased from Tokyo Chemical Industry (Tokyo, Japan) and dissolved in 1 M NaOH solution. The pH of the solution was adjusted to approximately 8 using 1 M HCl and 1 M phosphate buffer (pH 7.4) and diluted with water in order to become an isotonic solution ready for injection. Six-week-old male ICR mice were purchased from Japan SLC (Hamamatsu, Japan). Five-week-old female BALB/c nude mice were purchased from CLEA Japan (Tokyo, Japan)
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