Local application of doxorubicin- loaded Iron oxid nanoparticles and the vascular disrupting agent via the hepatic artery: chemoembolization–photothermal ablation treatment of hepatocellular carcinoma in rats

OBJECTIVES: This study investigates the effectiveness of local application of doxorubicin(Dox)-loaded, polydopamine (PDA)- coated single crystal hematite (α- Fe(2)O(3)) nanocubes (Fe(2)O(3)-PDA-Dox) and combretastatin A-4 phosphate disodium(CA4P)in treating hepatocellular carcinoma (HCC) in rats. METHODS: The magnetic characteristics and photothermal effects of the nanoparticles were determined in vitro. Tumor-bearing Sprague–Dawley rats were divided into 3 groups of 8 according to treatment: controls, transarterial chemoembolization–photothermal ablation (pTACE) (Lipidol+Fe(2)O(3)-PDA-Dox + NIR), and CA4P + pTACE (CA4P+ Lipidol+Fe(2)O(3)-PDA-Dox + NIR). Drugs were administered through the hepatic artery, and the tumors exposed to 808-nm near-infrared radiation. The Fe content of tumors was assessed using neutron activation analysis. Treatment effectiveness was assessed using heating curves, magnetic resonance imaging, pathology results, and immunohistochemical analysis. RESULTS: The mean tumor Fe content was greater in rats treated with CA4P + pTACE (1 h, 23.72 ± 12.45 μg/g; 24 h, 14.61 ± 8.23 μg/g) than in those treated with pTACE alone (1 h, 5.66 ± 4.29 μg/g; 24 h, 2.76 ± 1.33 μg/g). The tumor T2 imaging signal was lower in rats treated with CA4P + pTACE. Following laser irradiation, the tumor temperature increased, with higher temperatures reached in the CA4P + pTACE group (62 °C vs 55 °C). Tumor cells exhibited necrosis, apoptosis, and proliferation inhibition, with greater effects in the CA4P + pTACE group. Transient liver and kidney toxicity were observed on day 3, with more severe effects after CA4P + pTACE. CONCLUSIONS: Fe(2)O(3)-PDA-Dox nanoparticles are effective for TACE–PTA. Pretreatment with CA4P increases nanoparticle uptake by tumors, increasing the treatment effectiveness without increasing hepatorenal toxicity.