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Enhancing the Therapeutic Effect of 2-(211)At-astato-α-methyl-L-phenylalanine with Probenecid Loading
SIMPLE SUMMARY: To enhance the therapeutic effect of 2-(211)At-astato-α-methyl-L-phenylalanine (2-(211)At-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...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8583516/ https://www.ncbi.nlm.nih.gov/pubmed/34771676 http://dx.doi.org/10.3390/cancers13215514 |
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author | Hanaoka, Hirofumi Ohshima, Yasuhiro Suzuki, Hiroyuki Sasaki, Ichiro Watabe, Tadashi Ooe, Kazuhiro Watanabe, Shigeki Ishioka, Noriko S. |
author_facet | Hanaoka, Hirofumi Ohshima, Yasuhiro Suzuki, Hiroyuki Sasaki, Ichiro Watabe, Tadashi Ooe, Kazuhiro Watanabe, Shigeki Ishioka, Noriko S. |
author_sort | Hanaoka, Hirofumi |
collection | PubMed |
description | SIMPLE SUMMARY: To enhance the therapeutic effect of 2-(211)At-astato-α-methyl-L-phenylalanine (2-(211)At-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-(211)At-AAMP from the blood, increasing its accumulation in tumors. Consequently, the therapeutic effect of 2-(211)At-AAMP markedly improved. These results indicate that 2-(211)At-AAMP with probenecid loading is useful for the treatment of various types of cancers. ABSTRACT: 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 ((211)At)-labeled amino acid derivative, 2-(211)At-astato-α-methyl-L-phenylalanine (2-(211)At-AAMP), and demonstrated its therapeutic potential for LAT1-positive cancers. However, the therapeutic effect of 2-(211)At-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-(211)At-AAMP in mice. In biodistribution studies, the blood radioactivity of 2-(211)At-AAMP significantly increased with probenecid preloading. Consequently, the accumulation of 2-(211)At-AAMP in tumors was significantly higher with probenecid than without probenecid loading. In a therapeutic study, tumor growth was suppressed by 2-(211)At-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-(211)At-AAMP by increasing its accumulation in tumors. |
format | Online Article Text |
id | pubmed-8583516 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-85835162021-11-12 Enhancing the Therapeutic Effect of 2-(211)At-astato-α-methyl-L-phenylalanine with Probenecid Loading Hanaoka, Hirofumi Ohshima, Yasuhiro Suzuki, Hiroyuki Sasaki, Ichiro Watabe, Tadashi Ooe, Kazuhiro Watanabe, Shigeki Ishioka, Noriko S. Cancers (Basel) Article SIMPLE SUMMARY: To enhance the therapeutic effect of 2-(211)At-astato-α-methyl-L-phenylalanine (2-(211)At-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-(211)At-AAMP from the blood, increasing its accumulation in tumors. Consequently, the therapeutic effect of 2-(211)At-AAMP markedly improved. These results indicate that 2-(211)At-AAMP with probenecid loading is useful for the treatment of various types of cancers. ABSTRACT: 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 ((211)At)-labeled amino acid derivative, 2-(211)At-astato-α-methyl-L-phenylalanine (2-(211)At-AAMP), and demonstrated its therapeutic potential for LAT1-positive cancers. However, the therapeutic effect of 2-(211)At-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-(211)At-AAMP in mice. In biodistribution studies, the blood radioactivity of 2-(211)At-AAMP significantly increased with probenecid preloading. Consequently, the accumulation of 2-(211)At-AAMP in tumors was significantly higher with probenecid than without probenecid loading. In a therapeutic study, tumor growth was suppressed by 2-(211)At-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-(211)At-AAMP by increasing its accumulation in tumors. MDPI 2021-11-03 /pmc/articles/PMC8583516/ /pubmed/34771676 http://dx.doi.org/10.3390/cancers13215514 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Hanaoka, Hirofumi Ohshima, Yasuhiro Suzuki, Hiroyuki Sasaki, Ichiro Watabe, Tadashi Ooe, Kazuhiro Watanabe, Shigeki Ishioka, Noriko S. Enhancing the Therapeutic Effect of 2-(211)At-astato-α-methyl-L-phenylalanine with Probenecid Loading |
title | Enhancing the Therapeutic Effect of 2-(211)At-astato-α-methyl-L-phenylalanine with Probenecid Loading |
title_full | Enhancing the Therapeutic Effect of 2-(211)At-astato-α-methyl-L-phenylalanine with Probenecid Loading |
title_fullStr | Enhancing the Therapeutic Effect of 2-(211)At-astato-α-methyl-L-phenylalanine with Probenecid Loading |
title_full_unstemmed | Enhancing the Therapeutic Effect of 2-(211)At-astato-α-methyl-L-phenylalanine with Probenecid Loading |
title_short | Enhancing the Therapeutic Effect of 2-(211)At-astato-α-methyl-L-phenylalanine with Probenecid Loading |
title_sort | enhancing the therapeutic effect of 2-(211)at-astato-α-methyl-l-phenylalanine with probenecid loading |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8583516/ https://www.ncbi.nlm.nih.gov/pubmed/34771676 http://dx.doi.org/10.3390/cancers13215514 |
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