Nanotechnology-enabled delivery of NQO1 bioactivatable drugs.
J Drug Target
; 23(7-8): 672-80, 2015.
Article
em En
| MEDLINE
| ID: mdl-26453163
ABSTRACT
Current cancer chemotherapy lacks specificity and is limited by undesirable toxic side-effects, as well as a high rate of recurrence. Nanotechnology has the potential to offer paradigm-shifting solutions to improve the outcome of cancer diagnosis and therapy. ß-Lapachone (ß-lap) is a novel anticancer agent whose mechanism of action is highly dependent on NAD(P)H quinone oxidoreductase 1 (NQO1), a phase II detoxifying enzyme overexpressed in solid tumors from a variety of cancer types. However, the poor water solubility of ß-lap limits its clinical potential. A series of drug formulations were developed for systemic administration in preclinical evaluations. Encapsulation of ß-lap into polymeric micelles showed less side-effects and higher maximum tolerated dose (MTD), prolonged blood circulation time and preferential accumulation in tumors with greatly improved safety and antitumor efficacy. The prodrug strategy of ß-lap further decreases the crystallization of ß-lap by introducing esterase degradable side chains to the rigid fused ring structure. ß-Lap prodrugs considerably increased the stability, drug-loading content and delivery efficiency of nanoparticles. The optimized formulation of ß-lap-dC3 prodrug micelles showed excellent antitumor efficacy in treating orthotopic non-small cell lung tumors that overexpress NQO1, with target validation using pharmacodynamic endpoints.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Naftoquinonas
/
NAD(P)H Desidrogenase (Quinona)
/
Sistemas de Liberação de Medicamentos
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Drug Target
Assunto da revista:
FARMACOLOGIA
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Estados Unidos