Adavosertib-encapsulated metal-organic frameworks for p53-mutated gallbladder cancer treatment via synthetic lethality.
Sci Bull (Beijing)
; 69(9): 1286-1301, 2024 May 15.
Article
em En
| MEDLINE
| ID: mdl-38519399
ABSTRACT
Adavosertib (ADA) is a WEE1 inhibitor that exhibits a synthetic lethal effect on p53-mutated gallbladder cancer (GBC). However, drug resistance due to DNA damage response compensation pathways and high toxicity limits further applications. Herein, estrone-targeted ADA-encapsulated metal-organic frameworks (ADA@MOF-EPL) for GBC synthetic lethal treatment by inducing conditional factors are developed. The high expression of estrogen receptors in GBC enables ADA@MOF-EPL to quickly enter and accumulate near the cell nucleus through estrone-mediated endocytosis and release ADA to inhibit WEE1 upon entering the acidic tumor microenvironment. Ultrasound irradiation induces ADA@MOF-EPL to generate reactive oxygen species (ROS), which leads to a further increase in DNA damage, resulting in a higher sensitivity of p53-mutated cancer cells to WEE1 inhibitor and promoting cell death via conditional synthetic lethality. The conditional factor induced by ADA@MOF-EPL further enhances the antitumor efficacy while significantly reducing systemic toxicity. Moreover, ADA@MOF-EPL demonstrates similar antitumor abilities in other p53-mutated solid tumors, revealing its potential as a broad-spectrum antitumor drug.
Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Pirimidinonas
/
Proteínas Tirosina Quinases
/
Proteína Supressora de Tumor p53
/
Estruturas Metalorgânicas
/
Neoplasias da Vesícula Biliar
/
Antineoplásicos
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article