Catheter-directed organ-targeting immune augmentation using a nanoparticle-based therapeutic in a rat de novo HCC model.

To evaluate whether selective intra-arterial administration (IA) of PD-L1-conjugated nanoparticles (Antigen Release Agent and Checkpoint Inhibitor, ARAC^TM) with tumor-homing capabilities can augment the tumor immune environment in a rat HCC model.

Materials and Methods:

ARAC is a mesoporous silica nanoparticle coated with cross-linked polyethylenimine andpolyethylene glycol for co-delivering 5 wt.% PD-L1 antibody, 2 wt.% PLK1 inhibitor (volasertib), and 5 wt.% CpG. The intra-arterial dosage used was 2.5 mg/kg or 10% of the effective intravenous dose established in the previous study{1}. A rat HCC model was created by administering 0.01% diethylnitrosamine -containing water to 6-week-old Wistar rats for 12 weeks, inducing cirrhosis and de novo HCC. Rats with MRI-confirmed HCC were assigned to either the ARAC selective hepatic IA group or the untreated control group (n=3 each). ARAC was administered twice via selective hepatic IA at 7-day intervals. Seven days after the final injection, flow cytometry was performed on tumors (two tumors collected per rat). For adverse event evaluation, Lewis rats underwent sham selective hepatic angiography and ARAC selective hepatic IA, with liver and kidney function assessed pre and three days post-treatment.

Results:

Angiography procedures via femoral or tail cutdown were successfully performed in all cases, with no procedure-related mortality in the treatment group after two repeated procedures. In the ARAC group, the intratumoral T-cell population (CD3+ CD45+) significantly increased compared to the control group (median: treatment 46.8% vs. control 26.7%, P< 0.05). The Treg population (CD4+ FoxP3+) significantly decreased (16.1% vs. 29.2%, P< 0.05), and the CD8+/Treg ratio significantly increased (2.54 vs. 1.26, P< 0.05). Regarding adverse events, control group median AST/ALT levels were 58/39 U/L pre-treatment and 58/43 U/L post-treatment. Treatment group median AST/ALT levels were 57/40 U/L pre-treatment and 63/46 U/L post-treatment, showing minimal changes in both groups.

Conclusion: Selective hepatic ARAC IA increased T-cell infiltration and suppressed Treg populations within tumors, indicating a favorable immune response against HCC. Transarterial delivery of ARAC to the liver minimizes systemic adverse effects and maximizes anticancer efficacy with reduced doses compared to intravenous administration. This study suggests nanoparticle-based therapeutics are compatible with transarterial therapy and demonstrates the feasibility of organ-selective antitumor immunity augmentation.