Trivalent GalNAc-Mediated Delivery of Cucurbitacin B Overcomes Systemic Toxicity for Potent HCC Chemoradiotherapy

  • Biomacromolecules. 2026 May 11;27(5):3080-3108. doi: 10.1021/acs.biomac.5c02396.
Longxiao Sha  1 ,  Fangbin Wu  1 ,  Shubo Pan  2 ,  Cheng Hu  1 ,  Guofeng Ding  1 ,  Xiangcheng Sun  3 ,  Ning Wang  3 ,  Xiaoshen Zhou  1 ,  Xiaomin Zhang  3 ,  Song Zhou  3 ,  Hong Yang  3 ,  Kaizhi Li  3 ,  Junhua Xu  3 ,  Gang Guo  3 ,  Yan Li  3 ,  Yan Zhou  4 ,  Zhixing Cao  1 ,  Kun Yin  5 ,  Tao Yuan  6 ,  Lei Zhong  6 ,  Bo Mu  7 ,  Jiangping Li  8 ,  Wenjie Zhang  9 ,  YuZhi Li  1 ,  Shulei Pan  3
Affiliations
  • 1. State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, China.
  • 2. Department of General Sugery, The Second Hospital of Anhui Medical University, Hefei, Anhui 230601, China.
  • 3. Institute of Biopharmaceuticals, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
  • 4. NHC Key Laboratory of Nuclear Technology Medical Transformation, Mianyang Central Hospital, Mianyang, Sichuan 621099, China.
  • 5. Anhui Provincial Key Laboratory of Green Carbon Chemistry, School of Chemistry and Material Engineering, Fuyang Normal University, Fuyang, Anhui 236037, China.
  • 6. Department of Pharmacy, Personalized Drug Research and Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China.
  • 7. School of Basic Medicine and Forensic Medicine, North Sichuan Medical College, Nanchong, Sichuan 637000, China.
  • 8. Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
  • 9. Department of Nuclear Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
PMID: 41950466 DOI: 10.1021/acs.biomac.5c02396
Abstract

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide, with limited therapeutic options. Cucurbitacin B (CuB) demonstrates potent anti-HCC activity but suffers from systemic toxicity and poor pharmacokinetics. To address these challenges, we developed a series of asialoglycoprotein receptor (ASGPR)-targeted small molecule-drug conjugates (SMDCs) for the precision delivery of CuB. The trivalent conjugate SMDC 23 exhibited efficient ASGPR-mediated cellular uptake and controlled drug release. It induced both Autophagy and immunogenic cell death, triggered ROS-mediated DNA damage, activated the DNA damage response, and arrested the cell cycle, consequently enhancing the radiosensitivity of HCC cells. In HepG2-derived models, SMDC 23 achieved superior tumor accumulation, suppressed tumor growth by 76% at 30 mg/kg, and synergized with low-dose radiotherapy (2 Gy) to achieve 98% tumor inhibition, all with no observable systemic toxicity. This ASGPR-targeted CuB platform, particularly in combination with radiotherapy, represents a promising precision chemoradiotherapy strategy for HCC.

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