In vivo enzyme inhibition improves the targeting of [177Lu]DOTA-GRP(13-27) in GRPR-positive tumors in mice.
Cancer Biother Radiopharm
; 29(9): 359-67, 2014 Nov.
Article
em En
| MEDLINE
| ID: mdl-25286347
ABSTRACT
INTRODUCTION:
Gastrin-releasing peptide receptors (GRPR) and GRP-derived analogs have attracted attention due to high receptor expression in frequently occurring human neoplasia. The authors recently synthesized a series of GRPR-affine peptide analogs based on the 27-mer GRP and derivatized with the DOTA chelator at the N-terminus for (111)In-labeling. In this study, the authors evaluated the most promising from these series, DOTA-GRP(13-27), after radiolabeling with (177)Lu for future therapeutic applications. In addition, to improve in vivo stability of the peptide against in vivo degradation by the protease neutral endopeptidase (NEP), the authors coinjected [(177)Lu]DOTA-GRP(13-27) with the potent NEP inhibitor phosphoramidon (PA). The authors also aimed at reducing renal uptake by coadministration of lysine.METHODS:
In vivo stability studies were performed in Swiss albino mice. Biodistribution studies were conducted in NMRI nu/nu mice bearing prostate cancer (PC)-3 xenografts. Ex vivo autoradiography was performed using frozen sections from PC-3 xenografts and kidneys. RESULTS ANDDISCUSSION:
Coadministration of PA significantly increased the percentage of intact radiopeptide in the mouse circulation. From biodistribution and ex vivo autoradiography studies, coadministration of both lysine and PA with [(177)Lu]DOTA-GRP(13-27) appeared to induce a clear improvement of tumor uptake as well as lower levels of renal radioactivity, causing a promising ninefold increase in tumor/kidney ratios.Palavras-chave
Texto completo:
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Próstata
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Glicopeptídeos
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Neprilisina
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Receptores da Bombesina
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Compostos Radiofarmacêuticos
Limite:
Animals
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Humans
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Male
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article