Enhanced Tumor Targeting and Penetration of Proteolysis-Targeting Chimeras through iRGD Peptide Conjugation: A Strategy for Precise Protein Degradation in Breast Cancer

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.