Enhancing the Therapeutic Effect of 2-211At-astato-α-methyl-L-phenylalanine with Probenecid Loading

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-phenylala...

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Autores principales:	Hirofumi Hanaoka, Yasuhiro Ohshima, Hiroyuki Suzuki, Ichiro Sasaki, Tadashi Watabe, Kazuhiro Ooe, Shigeki Watanabe, Noriko S. Ishioka
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	2-<sup>211</sup>At-astato-α-methyl-L-phenylalanine targeted alpha therapy tumor retention probenecid blood clearance Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/395ecf01c6c44e3abc45a197c9cd2f33
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spelling	oai:doaj.org-article:395ecf01c6c44e3abc45a197c9cd2f332021-11-11T15:33:48ZEnhancing the Therapeutic Effect of 2-<sup>211</sup>At-astato-α-methyl-L-phenylalanine with Probenecid Loading10.3390/cancers132155142072-6694https://doaj.org/article/395ecf01c6c44e3abc45a197c9cd2f332021-11-01T00:00:00Zhttps://www.mdpi.com/2072-6694/13/21/5514https://doaj.org/toc/2072-6694L-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 (<sup>211</sup>At)-labeled amino acid derivative, 2-<sup>211</sup>At-astato-α-methyl-L-phenylalanine (2-<sup>211</sup>At-AAMP), and demonstrated its therapeutic potential for LAT1-positive cancers. However, the therapeutic effect of 2-<sup>211</sup>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-<sup>211</sup>At-AAMP in mice. In biodistribution studies, the blood radioactivity of 2-<sup>211</sup>At-AAMP significantly increased with probenecid preloading. Consequently, the accumulation of 2-<sup>211</sup>At-AAMP in tumors was significantly higher with probenecid than without probenecid loading. In a therapeutic study, tumor growth was suppressed by 2-<sup>211</sup>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-<sup>211</sup>At-AAMP by increasing its accumulation in tumors.Hirofumi HanaokaYasuhiro OhshimaHiroyuki SuzukiIchiro SasakiTadashi WatabeKazuhiro OoeShigeki WatanabeNoriko S. IshiokaMDPI AGarticle2-<sup>211</sup>At-astato-α-methyl-L-phenylalaninetargeted alpha therapytumor retentionprobenecidblood clearanceNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancers, Vol 13, Iss 5514, p 5514 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	2-<sup>211</sup>At-astato-α-methyl-L-phenylalanine targeted alpha therapy tumor retention probenecid blood clearance Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	2-<sup>211</sup>At-astato-α-methyl-L-phenylalanine targeted alpha therapy tumor retention probenecid blood clearance Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Hirofumi Hanaoka Yasuhiro Ohshima Hiroyuki Suzuki Ichiro Sasaki Tadashi Watabe Kazuhiro Ooe Shigeki Watanabe Noriko S. Ishioka Enhancing the Therapeutic Effect of 2-<sup>211</sup>At-astato-α-methyl-L-phenylalanine with Probenecid Loading
description	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 (<sup>211</sup>At)-labeled amino acid derivative, 2-<sup>211</sup>At-astato-α-methyl-L-phenylalanine (2-<sup>211</sup>At-AAMP), and demonstrated its therapeutic potential for LAT1-positive cancers. However, the therapeutic effect of 2-<sup>211</sup>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-<sup>211</sup>At-AAMP in mice. In biodistribution studies, the blood radioactivity of 2-<sup>211</sup>At-AAMP significantly increased with probenecid preloading. Consequently, the accumulation of 2-<sup>211</sup>At-AAMP in tumors was significantly higher with probenecid than without probenecid loading. In a therapeutic study, tumor growth was suppressed by 2-<sup>211</sup>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-<sup>211</sup>At-AAMP by increasing its accumulation in tumors.
format	article
author	Hirofumi Hanaoka Yasuhiro Ohshima Hiroyuki Suzuki Ichiro Sasaki Tadashi Watabe Kazuhiro Ooe Shigeki Watanabe Noriko S. Ishioka
author_facet	Hirofumi Hanaoka Yasuhiro Ohshima Hiroyuki Suzuki Ichiro Sasaki Tadashi Watabe Kazuhiro Ooe Shigeki Watanabe Noriko S. Ishioka
author_sort	Hirofumi Hanaoka
title	Enhancing the Therapeutic Effect of 2-<sup>211</sup>At-astato-α-methyl-L-phenylalanine with Probenecid Loading
title_short	Enhancing the Therapeutic Effect of 2-<sup>211</sup>At-astato-α-methyl-L-phenylalanine with Probenecid Loading
title_full	Enhancing the Therapeutic Effect of 2-<sup>211</sup>At-astato-α-methyl-L-phenylalanine with Probenecid Loading
title_fullStr	Enhancing the Therapeutic Effect of 2-<sup>211</sup>At-astato-α-methyl-L-phenylalanine with Probenecid Loading
title_full_unstemmed	Enhancing the Therapeutic Effect of 2-<sup>211</sup>At-astato-α-methyl-L-phenylalanine with Probenecid Loading
title_sort	enhancing the therapeutic effect of 2-<sup>211</sup>at-astato-α-methyl-l-phenylalanine with probenecid loading
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/395ecf01c6c44e3abc45a197c9cd2f33
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Enhancing the Therapeutic Effect of 2-<sup>211</sup>At-astato-α-methyl-L-phenylalanine with Probenecid Loading

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