Macromolecular derivatives of N,N-di-(2-chloroethyl)-4-phenylene diamine mustard. 2. In vitro cytotoxicity and in vivo anticancer efficacy.
J Control Release
; 57(2): 187-96, 1999 Feb 01.
Article
em En
| MEDLINE
| ID: mdl-9971901
ABSTRACT
Prodrugs of N,N-di-(2-chloroethyl)-4-phenylene diamine (PDM) based on soluble poly[N5-(2-hydroxyethyl)-l-glutamine] (PHEG) have been evaluated as tumour-targeted drugs. These materials are designed to exploit the enhanced permeability of tumour vasculature, combining a passive tumour tropism with systemic liberation of free PDM. Modification of PDM by coupling via oligopeptide spacers onto a polymeric carrier significantly reduced its cytotoxicity towards different cell types in vitro. On the other hand, incubation of the cells with the PHEG-Gly-Phe-Ala-Leu-PDM conjugate in the presence of collagenase IV led to the release of lethal amounts of free drug, resulting in higher cytotoxicity for this derivative. The PHEG-Gly-Phe-Ala-Leu-PDM conjugate, which is rapidly degraded by lysosomal and tumour-associated enzymes also showed a decreased systemic toxicity in vivo and could be administered at a dose of 8 mg PDM/kg body weight intravenously, compared with just 2 mg/kg for free PDM. Furthermore, this derivative also showed better antitumour activity against a C26 colorectal carcinoma tumour model, compared with no activity for the free drug. The results indicate that the PHEG-Gly-Phe-Ala-Leu-PDM conjugate is a promising candidate for cancer treatment.
Buscar no Google
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pró-Fármacos
/
Antineoplásicos Alquilantes
/
Mostarda de Anilina
Limite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
J Control Release
Assunto da revista:
FARMACOLOGIA
Ano de publicação:
1999
Tipo de documento:
Article
País de afiliação:
Bélgica