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Evaluation of Actinium-225 Labeled Minigastrin Analogue [(225)Ac]Ac-DOTA-PP-F11N for Targeted Alpha Particle Therapy

The overexpression of cholecystokinin B receptor (CCKBR) in human cancers led to the development of radiolabeled minigastrin analogues for targeted radionuclide therapy, which aims to deliver cytotoxic radiation specifically to cancer cells. Alpha emitters (e.g., actinium-225) possess high potency i...

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Autores principales: Qin, Yun, Imobersteg, Stefan, Blanc, Alain, Frank, Stephan, Schibli, Roger, Béhé, Martin P., Grzmil, Michal
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696055/
https://www.ncbi.nlm.nih.gov/pubmed/33198403
http://dx.doi.org/10.3390/pharmaceutics12111088
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author Qin, Yun
Imobersteg, Stefan
Blanc, Alain
Frank, Stephan
Schibli, Roger
Béhé, Martin P.
Grzmil, Michal
author_facet Qin, Yun
Imobersteg, Stefan
Blanc, Alain
Frank, Stephan
Schibli, Roger
Béhé, Martin P.
Grzmil, Michal
author_sort Qin, Yun
collection PubMed
description The overexpression of cholecystokinin B receptor (CCKBR) in human cancers led to the development of radiolabeled minigastrin analogues for targeted radionuclide therapy, which aims to deliver cytotoxic radiation specifically to cancer cells. Alpha emitters (e.g., actinium-225) possess high potency in cancer cell-killing and hold promise for the treatment of malignant tumors. In these preclinical studies, we developed and evaluated CCKBR-targeted alpha particle therapy. The cellular uptake and cytotoxic effect of actinium-225 labeled and HPLC-purified minigastrin analogue [(225)Ac]Ac-PP-F11N were characterized in the human squamous cancer A431 cells transfected with CCKBR. Nude mice bearing A431/CCKBR tumors were used for biodistribution and therapy studies followed by histological analysis and SPECT/CT imaging. In vitro, [(225)Ac]Ac-PP-F11N showed CCKBR-specific and efficient internalization rate and potent cytotoxicity. The biodistribution studies of [(225)Ac]Ac-PP-F11N revealed CCKBR-specific uptake in tumors, whereas the therapeutic studies demonstrated dose-dependent inhibition of tumor growth and extended mean survival time, without apparent toxicity. The histological analysis of kidney and stomach indicated no severe adverse effects after [(225)Ac]Ac-PP-F11N administration. The post-therapy SPECT-CT images with [(111)In]In-PP-F11N confirmed no CCKBR-positive tumor left in the mice with complete remission. In conclusion, our study demonstrates therapeutic efficacy of [(225)Ac]Ac-PP-F11N without acute radiotoxicity in CCKBR-positive cancer model.
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spelling pubmed-76960552020-11-29 Evaluation of Actinium-225 Labeled Minigastrin Analogue [(225)Ac]Ac-DOTA-PP-F11N for Targeted Alpha Particle Therapy Qin, Yun Imobersteg, Stefan Blanc, Alain Frank, Stephan Schibli, Roger Béhé, Martin P. Grzmil, Michal Pharmaceutics Article The overexpression of cholecystokinin B receptor (CCKBR) in human cancers led to the development of radiolabeled minigastrin analogues for targeted radionuclide therapy, which aims to deliver cytotoxic radiation specifically to cancer cells. Alpha emitters (e.g., actinium-225) possess high potency in cancer cell-killing and hold promise for the treatment of malignant tumors. In these preclinical studies, we developed and evaluated CCKBR-targeted alpha particle therapy. The cellular uptake and cytotoxic effect of actinium-225 labeled and HPLC-purified minigastrin analogue [(225)Ac]Ac-PP-F11N were characterized in the human squamous cancer A431 cells transfected with CCKBR. Nude mice bearing A431/CCKBR tumors were used for biodistribution and therapy studies followed by histological analysis and SPECT/CT imaging. In vitro, [(225)Ac]Ac-PP-F11N showed CCKBR-specific and efficient internalization rate and potent cytotoxicity. The biodistribution studies of [(225)Ac]Ac-PP-F11N revealed CCKBR-specific uptake in tumors, whereas the therapeutic studies demonstrated dose-dependent inhibition of tumor growth and extended mean survival time, without apparent toxicity. The histological analysis of kidney and stomach indicated no severe adverse effects after [(225)Ac]Ac-PP-F11N administration. The post-therapy SPECT-CT images with [(111)In]In-PP-F11N confirmed no CCKBR-positive tumor left in the mice with complete remission. In conclusion, our study demonstrates therapeutic efficacy of [(225)Ac]Ac-PP-F11N without acute radiotoxicity in CCKBR-positive cancer model. MDPI 2020-11-12 /pmc/articles/PMC7696055/ /pubmed/33198403 http://dx.doi.org/10.3390/pharmaceutics12111088 Text en © 2020 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Qin, Yun
Imobersteg, Stefan
Blanc, Alain
Frank, Stephan
Schibli, Roger
Béhé, Martin P.
Grzmil, Michal
Evaluation of Actinium-225 Labeled Minigastrin Analogue [(225)Ac]Ac-DOTA-PP-F11N for Targeted Alpha Particle Therapy
title Evaluation of Actinium-225 Labeled Minigastrin Analogue [(225)Ac]Ac-DOTA-PP-F11N for Targeted Alpha Particle Therapy
title_full Evaluation of Actinium-225 Labeled Minigastrin Analogue [(225)Ac]Ac-DOTA-PP-F11N for Targeted Alpha Particle Therapy
title_fullStr Evaluation of Actinium-225 Labeled Minigastrin Analogue [(225)Ac]Ac-DOTA-PP-F11N for Targeted Alpha Particle Therapy
title_full_unstemmed Evaluation of Actinium-225 Labeled Minigastrin Analogue [(225)Ac]Ac-DOTA-PP-F11N for Targeted Alpha Particle Therapy
title_short Evaluation of Actinium-225 Labeled Minigastrin Analogue [(225)Ac]Ac-DOTA-PP-F11N for Targeted Alpha Particle Therapy
title_sort evaluation of actinium-225 labeled minigastrin analogue [(225)ac]ac-dota-pp-f11n for targeted alpha particle therapy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7696055/
https://www.ncbi.nlm.nih.gov/pubmed/33198403
http://dx.doi.org/10.3390/pharmaceutics12111088
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