Enhanced Tumor Targeting and Penetration of Proteolysis-Targeting Chimeras through iRGD Peptide Conjugation: A Strategy for Precise Protein Degradation in Breast Cancer.
J Med Chem
; 66(24): 16828-16842, 2023 12 28.
Article
en En
| MEDLINE
| ID: mdl-38055861
ABSTRACT
Proteolysis-targeting chimeras (PROTACs) have recently emerged as a promising technology for drug development. However, poor water solubility, limited tissue selectivity, and inadequate tumor penetration pose significant challenges for PROTAC-based therapies in cancer treatment. Herein, we developed an iRGD-PROTAC conjugation strategy utilizing tumor-penetrating cyclic peptide iRGD (CRGDK/RGPD/EC) to deliver PROTACs deep into breast cancer tissues. As a conceptual validation study, iRGD peptides were conjugated with a bromodomain-containing protein 4 (BRD4) PROTAC through a GSH-responsive linker. The resulting iRGD-PROTAC conjugate iPR showed enhanced water solubility, tumor-targeting capability, and penetration within tumor tissues, resulting in increased antibreast cancer efficacy in animal models and patient-derived organoids. This study demonstrates the advantages of combining iRGD and PROTACs in improving drug delivery and highlights the importance of tissue selectivity and penetration ability in PROTAC-based therapeutics.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Neoplasias de la Mama
Límite:
Animals
/
Female
/
Humans
Idioma:
En
Revista:
J Med Chem
Asunto de la revista:
QUIMICA
Año:
2023
Tipo del documento:
Article
País de afiliación:
China