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Chitosan/dextran-based organohydrogel delivers EZH2 inhibitor to epigenetically reprogram chemo/immuno-resistance in
Qi Tang1, Shaolong Leng2, Yinqiu Tan3
1School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, PR China.
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.
Insights
This study shows an organohydrogel can deliver an EZH2 inhibitor, chemotherapy, and immunotherapy to reverse melanoma drug resistance and suppress metastasis. This platform offers a novel approach for treating unresectable metastatic melanoma.
Area of Science:
- Biomaterials Science
- Cancer Biology
- Immunology
Background:
- Melanoma exhibits intrinsic or acquired resistance to therapies, leading to recurrence and metastasis.
- Epigenetic modifications, like H3K27 demethylation, can reverse therapy resistance.
- Combining multiple therapeutic agents presents formulation and delivery challenges.
Purpose of the Study:
- To develop a novel drug delivery system for combined epigenetic, chemo-, and immunotherapy.
- To investigate the synergistic effects of an EZH2 inhibitor, paclitaxel, and anti-TIGIT in melanoma.
- To evaluate the efficacy of a polysaccharides-based organohydrogel for treating metastatic melanoma.
Main Methods:
- Development of a polysaccharides-based organohydrogel (OHG) using hydroxypropyl chitosan and oxidized dextran.
- Formulation of the OHG to encapsulate an EZH2 inhibitor (UNC1999), paclitaxel (PTX), and anti-TIGIT antibody.
- In-situ local injection of the drug-loaded OHG in a melanoma model.
- Assessment of drug-induced cytotoxicity, immune cell infiltration, and systemic immune memory.
Main Results:
- The OHG demonstrated tunable sustained release of encapsulated agents.
- Combined therapy synergistically enhanced paclitaxel cytotoxicity and reversed immune resistance.
- The treatment reprogrammed the TIGIT/CD155 axis, recruiting cytotoxic effector cells.
- Systemic immune memory was established, preventing lung metastasis.
Conclusions:
- A polysaccharides-based organohydrogel serves as an effective platform for in-situ epigenetic-, chemo-, and immunotherapy.
- This approach shows promise for treating unresectable metastatic melanoma by overcoming resistance and preventing metastasis.
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