Hypoxic targeting and activating TH-302 loaded transcatheter arterial embolization microsphere

Area of Science:

• Biomedical Engineering
• Oncology
• Drug Delivery Systems

Background:

• Hypoxia in hepatocellular carcinoma (HCC) correlates with poor prognosis.
• Transcatheter arterial chemoembolization (TACE) is a common HCC treatment, but localized hypoxia remains a challenge.

Purpose of the Study:

• To develop and evaluate poly(lactic-co-glycolic acid) (PLGA)-based microspheres loaded with the hypoxia-activated prodrug TH-302 for HCC treatment.
• To assess the localized and sustained drug delivery, in vitro, and in vivo antitumor efficacy, and safety of these TH-302 loaded microspheres.

Main Methods:

• Fabrication of TH-302 loaded PLGA microspheres using an oil-in-water emulsion solvent evaporation method.
• Characterization of microspheres using SEM, IR, XRD, and drug release studies.
• In vitro evaluation in HepG2 cells under normoxic and hypoxic conditions.
• In vivo assessment in a VX-2 tumor-bearing rabbit model with TACE, including tissue distribution and antitumor efficiency studies.
• Safety evaluation through blood routine and histopathological examinations.

Main Results:

• Microspheres with sizes 75-100 μm, 100-200 μm, and 200-300 μm were successfully prepared, exhibiting spherical morphology and sustained TH-302 release up to 360 hours.
• Under hypoxic conditions, TH-302 microspheres demonstrated significantly higher cytotoxicity, induced more cell apoptosis, and caused greater S-phase cell cycle arrest in HepG2 cells compared to free TH-302.
• In vivo studies showed continuous drug release in liver tissue and superior antitumor efficacy of the microspheres compared to TH-302 injection and lipiodol.
• No serious toxicity was observed during the treatment period.

Conclusions:

• TH-302 loaded PLGA microspheres are a feasible and effective formulation for TACE in HCC treatment.
• These microspheres hold significant promise for improving clinical chemoembolization therapy for HCC by targeting the hypoxic tumor microenvironment.