Synthesis and Evaluation of a Monomethyl Auristatin EâIntegrin αvß6 Binding Peptide-Drug Conjugate for Tumor Targeted Drug Delivery.
J Med Chem
; 66(14): 9842-9852, 2023 07 27.
Article
em En
| MEDLINE
| ID: mdl-37417540
ABSTRACT
Many anticancer drugs exhibit high systemic off-target toxicities causing severe side effects. Peptide-drug conjugates (PDCs) that target tumor-specific receptors such as integrin αvß6 are emerging as powerful tools to overcome these challenges. The development of an integrin αvß6-selective PDC was achieved by combining the therapeutic efficacy of the cytotoxic drug monomethyl auristatin E with the selectivity of the αvß6-binding peptide (αvß6-BP) and with the ability of positron emission tomography (PET) imaging by copper-64. The [64Cu]PDC-1 was produced efficiently and in high purity. The PDC exhibited high human serum stability, integrin αvß6-selective internalization, cell binding, and cytotoxicity. Integrin αvß6-selective tumor accumulation of the [64Cu]PDC-1 was visualized with PET-imaging and corroborated by biodistribution, and [64Cu]PDC-1 showed promising in vivo pharmacokinetics. The [natCu]PDC-1 treatment resulted in prolonged survival of mice bearing αvß6 (+) tumors (median survival 77 days, vs αvß6 (-) tumor group 49 days, and all other control groups 37 days).
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Cobre
/
Neoplasias
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article