Chitosan/dextran-based organohydrogel delivers EZH2 inhibitor to epigenetically reprogram chemo/immuno-resistance in unresectable metastatic melanoma.
Carbohydr Polym
; 346: 122645, 2024 Dec 15.
Article
in En
| MEDLINE
| ID: mdl-39245506
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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Dextrans
/
Epigenesis, Genetic
/
Chitosan
/
Enhancer of Zeste Homolog 2 Protein
/
Melanoma
Limits:
Animals
/
Humans
Language:
En
Journal:
Carbohydr Polym
Year:
2024
Document type:
Article
Country of publication:
Reino Unido