Hepatocellular carcinoma: Intraarterial delivery of doxorubicinloaded hollow gold nanospheres for photothermal ablation-chemoembolization therapy in rats

Purpose: To determine if combretastatin A-4 phosphate disodium (CA4P) can enhance the tumor uptake of doxorubicin (Dox)-loaded, polyethylene glycol (PEG)-coated hollow gold nanospheres (HAuNS) mixed with ethiodized oil for improved photothermal ablation (PTA)-chemoembolization therapy (CET) of hepatocellular carcinoma (HCC) in rats. Materials and Methods: Animal experiments were approved by the institutional animal care and use committee and performed from February 2014 to April 2015. Male Sprague-Dawley rats (n = 45; age, 12 weeks) were inoculated with N1S1 HCC cells in the liver, and 8 days later, were randomly divided into two groups of 10 rats. Group 1 rats received intrahepatic arterial injection of PEG-HAuNS and ethiodized oil alone; group 2 received pretreatment with CA4P and injection of PEG-HAuNS and ethiodized oil 5 minutes later. The gold content of tumor and liver tissue at 1 hour or 24 hours after injection was quantified by using neutron activation analysis (n = 5 per time point). Five rats received pretreatment CA4P, PEG-copper 64-HAuNS, and ethiodized oil and underwent micro-positron emission tomography (PET)/computed tomography (CT). In a separate study, three groups of six rats with HCC were injected with saline solution (control group); CA4P, Dox-loaded PEG-coated HAuNS (Dox@PEG-HAuNS), and ethiodized oil (CET group); or CA4P, Dox@PEG-HAuNS, ethiodized oil, and near-infrared irradiation (PTA-CET group). Temperature was recorded during laser irradiation. Findings were verified at postmortem histopathologic and/or autoradiographic examination. Wilcoxon rank-sum test and Pearson correlation analyses were performed. Results: PEG-HAuNS uptake in CA4P-pretreated HCC tumors was significantly higher than that in non-CA4P-pretreated tumors at both 1 hour (P <.03) and 24 hours (P <.01). Mean± standard deviation of tumor-to-liver PEG-HAuNS uptake ratios at 1 hour and 24 hours, respectively, were 5.63± 3.09 and 1.68± 0.77 in the CA4P-treated group and 1.29± 2.40 and 0.14± 0.11 in the non-CA4P-treated group. Micro-PET/CT allowed clear delineation of tumors, enabling quantitative imaging analysis. Laser irradiation increased temperature to 60°C and 43°C in the tumor and adjacent liver, respectively. Mean HCC tumor volumes 10 days after therapy were 1.68 cm³ ± 1.01, 3.96 cm³± 1.75, and 6.13 cm³ 6 2.27 in the PTA-CET, CET, and control groups, respectively, with significant differences between the PTA-CET group and other groups (P <.05). Conclusion: CA4P pretreatment caused a higher concentration of Dox@ PEG-HAuNS to be trapped inside the tumor, thereby enhancing the efficacy of anti-HCC treatment with PTA-CET in rats.