2. Academic Validation
  3. Chitosan/dextran-based organohydrogel delivers EZH2 inhibitor to epigenetically reprogram chemo/immuno-resistance in unresectable metastatic melanoma

Chitosan/dextran-based organohydrogel delivers EZH2 inhibitor to epigenetically reprogram chemo/immuno-resistance in unresectable metastatic melanoma

  • Carbohydr Polym. 2024 Dec 15:346:122645. doi: 10.1016/j.carbpol.2024.122645.
Qi Tang 1,  Shaolong Leng 2,  Yinqiu Tan 3,  Huan Cheng 4,  Qi Liu 5,  Zhongjuan Wang 6,  Yunsheng Xu 7,  Linyu Zhu 8,  Cuifeng Wang 9
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
  • 2 Department of Dermatovenereology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, PR China.
  • 3 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China; Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, PR China.
  • 4 Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, PR China.
  • 5 The First Dongguan Affiliated Hospital Guangdong Medical University No. 42, Jiaoping Road Dongguan, Guangdong 523710, PR China.
  • 6 Department of Pharmacy, Yan'an Hospital Affiliated to Kunming Medical University, No.245, People East Road, Kunming 650051, PR China.
  • 7 Department of Dermatovenereology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, PR China. Electronic address: xuysh9@mail.sysu.edu.cn.
  • 8 Department of Dermatovenereology, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, PR China. Electronic address: zhuly35@mail.sysu.edu.cn.
  • 9 School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China; Department of neurosurgery, JiuJiang Hospital of Traditional Chinese Medicine, Jiujiang, PR China. Electronic address: wangcf6@mail.sysu.edu.cn.
PMID: 39245506 DOI: 10.1016/j.carbpol.2024.122645
Abstract

Melanoma either intrinsically possesses resistance or rapidly acquires resistance to anti-tumor therapy, which often leads to local recurrence or distant metastasis after resection. In this study, we found histone 3 lysine 27 (H3K27) demethylated by an inhibitor of Histone Methyltransferase EZH2 could epigenetically reverse the resistance to chemo-drug paclitaxel (PTX), or enhance the efficacy of immune checkpoint inhibitor anti-TIGIT via downregulating TIGIT ligand CD155. Next, to address the complexity in the combination of multiple bioactive molecules with distinct therapeutic properties, we developed a polysaccharides-based organohydrogel (OHG) configured with a heterogenous network. Therein, hydroxypropyl chitosan (HPC)-stabilized emulsions for hydrophobic drug entrapment were crosslinked with oxidized dextran (Odex) to form a hydrophilic gel matrix to facilitate antibody accommodation, which demonstrated a tunable sustained release profile by optimizing emulsion/gel volume ratios. As results, local injection of OHG loaded with EZH2 Inhibitor UNC1999, PTX and anti-TIGIT did not only synergistically enhance the cytotoxicity of PTX, but also reprogrammed the immune resistance via bi-directionally blocking TIGIT/CD155 axis, leading to the recruitment of cytotoxic effector cells into tumor and conferring a systemic immune memory to prevent lung metastasis. Hence, this polysaccharides-based OHG represents a potential in-situ epigenetic-, chemo- and immunotherapy platform to treat unresectable metastatic melanoma.

Keywords

Chemoresistance; Dextran; EZH2 inhibitor; Hydroxypropyl chitosan; Organohydrogel; TIGIT/CD155 axis.

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