Cathepsin B-labile dipeptide linkers for lysosomal release of doxorubicin from internalizing immunoconjugates: model studies of enzymatic drug release and antigen-specific in vitro anticancer activity.
Bioconjug Chem
; 13(4): 855-69, 2002.
Article
em En
| MEDLINE
| ID: mdl-12121142
ABSTRACT
The anticancer drug doxorubicin (DOX) has been linked to chimeric BR96, an internalizing monoclonal antibody that binds to a Lewis(y)-related, tumor-associated antigen, through two lysosomally cleavable dipeptides, Phe-Lys and Val-Cit, giving immunoconjugates 72 and 73. A self-immolative p-aminobenzyloxycarbonyl (PABC) spacer between the dipeptides and the DOX was required for rapid and quantitative generation of free drug. DOX release from model substrate Z-Phe-Lys-PABC-DOX 49 was 30-fold faster than from Z-Val-Cit-PABC-DOX 42 with the cysteine protease cathepsin B alone, but rates were identical in a rat liver lysosomal preparation suggesting the participation of more than one enzyme. Conjugates 72 and 73 showed rapid and near quantitative drug release with cathepsin B and in a lysosomal preparation, while demonstrating excellent stability in human plasma. Against tumor cell lines with varying levels of BR96 expression, both conjugates showed potent, antigen-specific cytotoxic activity, suggesting that they will be effective in delivering DOX selectively to antigen-expressing carcinomas.
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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Catepsina B
/
Doxorrubicina
/
Reagentes de Ligações Cruzadas
/
Dipeptídeos
/
Lisossomos
/
Anticorpos Monoclonais
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Bioconjug Chem
Ano de publicação:
2002
Tipo de documento:
Article