MMAE-Based Peptide–Drug Conjugates Targeting GPC3 for Precision Chemoradiotherapy in Hepatocellular Carcinoma

Hepatocellular
carcinoma (HCC), the third leading cause
of cancer
mortality, lacks effective therapies. Current chemoradiotherapy faces
challenges from systemic toxicity and radiation side effects. We developed
a series of GPC3-targeting peptide–drug conjugates (PDCs) integrating
monomethyl auristatin E (MMAE) to enhance tumor-specific delivery.
Among them, PDC 22 demonstrated efficient tumor cell
internalization, drug release, G2/M cell cycle arrest (the most radiosensitive
phase), and induced immunogenic cell death of GPC3-positive tumor
cells. Mechanistically, PDC 22 reduced clonogenic survival
by increasing γH2AX foci formation, activating DNA damage repair,
and blocking cell progression. In xenograft models, PDC 22 specifically accumulates in tumor regions and significantly delays
tumor growth with minimal toxicity. Notably, combining PDC 22 with radiotherapy resulted in superior tumor control compared with
monotherapy, highlighting its potential for precision chemoradiotherapy
in HCC. Thus, leveraging GPC3-targeting PDC technology for auristatin
delivery with radiotherapy presents a promising therapeutic strategy
for HCC.