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

  • J Med Chem. 2025 Jun 26;68(12):12950-12968. doi: 10.1021/acs.jmedchem.5c00847.
Shulei Pan  1 ,  Longxiao Sha  2 ,  Fangbin Wu  2 ,  Ning Wang  1 ,  Hong Yang  1 ,  Xiaomin Zhang  1 ,  Song Zhou  1 ,  Cheng Hu  2 ,  Guofeng Ding  2 ,  Junhua Xu  1 ,  Kaizhi Li  1 ,  Gang Guo  1 ,  YuZhi Li  2 ,  Zhixing Cao  2 ,  Yan Zhou  3 ,  Shubo Pan  4 ,  Wenjie Zhang  5
Affiliations
  • 1. Institute of Biopharmaceuticals, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
  • 2. State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, China.
  • 3. NHC Key Laboratory of Nuclear Technology Medical Transformation, Mianyang Central Hospital, Mianyang, Sichuan 621000, China.
  • 4. Department of General Surgery, The Second Hospital of Anhui Medical University, Hefei, Anhui 230601, China.
  • 5. Department of Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
PMID: 40513081 DOI: 10.1021/acs.jmedchem.5c00847
Abstract

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.

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