GPC3 and CD133-targeted peptide dual modification enhances the therapeutic effect of doxorubicin carried by OMVs on hepatocellular carcinoma - PubMed
3 days ago
- #hepatocellular-carcinoma
- #drug-delivery
- #nanomedicine
- Hepatocellular carcinoma (HCC) has a high mortality rate due to limitations of conventional chemotherapies like doxorubicin (DOX), including poor tumor targeting, systemic toxicity, and chemoresistance.
- Bacterial outer membrane vesicles (OMVs) are promising drug carriers but face challenges like nonspecific phagocytosis and weak targeting.
- A dual-targeted nanosystem ((GPC3 + CD133)T-OMVs@DOX) was developed using GPC3/CD133 peptide-modified OMVs loaded with DOX to enhance HCC-specific targeting, optimize drug release, and reduce off-target toxicity.
- Dual-targeted OMVs significantly increased binding/internalization in GPC3/CD133-coexpressing Huh-7 cells compared to single-targeted or unmodified OMVs (p < 0.05).
- DOX loading achieved high loading efficiency (81%), with pH-responsive release (40% at pH 7.4 vs. 80% at pH 5.0 over 48 h).
- Sparstolonin B (SsnB), a TLR2/4 inhibitor, reduced macrophage phagocytosis by 60%, prolonging circulation time of DOX-loaded OMVs.
- In vivo, the dual-targeted system inhibited tumor growth by 75%, outperforming free DOX (40%) and single-targeted OMVs-DOX (55%).
- Mice treated with dual-targeted OMVs maintained stable weight, while free DOX caused 15% weight loss.
- Histology showed minimal organ damage in the dual-targeted group vs. severe cardiomyocyte injury with free DOX.
- The dual-targeted OMV system enhances tumor specificity via GPC3/CD133 recognition, optimizes pH-responsive release, and reduces nonspecific clearance by modulating macrophages.