ROS-Responsive Nanosystem Targeted Co-Delivery YC-1 and Regorafenib to Alleviate Hypoxia Enhancing Hepatocellular Carcinoma Therapy

  • Int J Nanomedicine. 2025 Jul 1:20:8481-8496. doi: 10.2147/IJN.S518120.
Liming Song  1  2  3 ,  Yahui Wu  1  2  3 ,  Senfeng Zhao  1  2  3 ,  Yin Liu  1  2  3 ,  Zhipu Liu  1  2  3 ,  Yunpeng Zhai  1  2  3 ,  Jiahui Cao  1  2  3 ,  Yaning Xia  4 ,  Ruopeng Liang  1  2  3 ,  Weijie Wang  1  2  3 ,  Rongtao Zhu  1  2  3 ,  Binghua Sun  5 ,  Yupeng Shi  4 ,  Yuling Sun  1  2  3
Affiliations
  • 1. Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China.
  • 2. Institute of Hepatobiliary and Pancreatic Diseases, Zhengzhou University, Zhengzhou, 450052, People's Republic of China.
  • 3. Zhengzhou Basic and Clinical Key Laboratory of Hepatopancreatobiliary Diseases, Zhengzhou, 450052, People's Republic of China.
  • 4. Department of Magnetic Resonance Imaging, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China.
  • 5. Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People's Republic of China.
PMID: 40620686 DOI: 10.2147/IJN.S518120
Abstract

Purpose: The current treatment of hepatocellular carcinoma (HCC) is confronted with anoxic drug resistance and significant side effects. To address these issues, a Reactive Oxygen Species (ROS)-responsive and targeted nano drug delivery system named REG/YC-1@PTP-RGD NPs (RYP-RGD NPs) was designed for the co-delivery of Regorafenib (REG) and the hypoxia inhibitor 3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole (YC-1).

Methods: RYP-RGD NPs were fabricated through the self-assembly method. A series of techniques, such as transmission electron microscopy (TEM), UV-visible spectroscopy, and Others, were employed to characterize their properties. In Vitro investigations encompassed drug release assays, cytotoxicity evaluations using Cell Counting Kit-8 (CCK-8) and Other methods, cell uptake experiments, and Western blot analysis. In vivo, the biodistribution of RYP-RGD NPs was tracked by IVIS imaging, and their antitumor efficacy and biosafety were assessed in a HepG2 tumor-bearing mouse model with histological staining and biochemical analysis.

Results: RYP-RGD NPs exhibited a spherical morphology with an appropriate size and excellent dispersion. They demonstrated ROS-triggered drug release behavior. In vitro studies revealed good tumor-targeting ability, enhanced cytotoxicity against HCC cells, and the downregulation of hypoxia-inducible factor-1α (HIF-1α) by YC-1. In vivo experiments showed improved tumor targeting, significant inhibition of tumor growth, and lower toxicity compared to single drugs.

Conclusion: The successfully developed RYP-RGD NPs offer a novel strategy for HCC treatment. They enhance drug targeting, synergistically boost the therapeutic effect, and maintain biosafety, showing great potential for clinical translation.

Keywords
drug delivery; hypoxia; nanocarrier; reactive oxygen species; regorafenib.
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