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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.

ABSTRACT: OBJECTIVES:This study investigates the effectiveness of local application of doxorubicin(Dox)-loaded, polydopamine (PDA)- coated single crystal hematite (α- Fe2O3) nanocubes (Fe2O3-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+Fe2O3-PDA-Dox + NIR), and CA4P + pTACE (CA4P+ Lipidol+Fe2O3-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:Fe2O3-PDA-Dox nanoparticles are effective for TACE-PTA. Pretreatment with CA4P increases nanoparticle uptake by tumors, increasing the treatment effectiveness without increasing hepatorenal toxicity.

SUBMITTER: Yuan H

PROVIDER: S-EPMC6829940 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description: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 ± 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. © RSNA, 2016 Online supplemental material is available for this article.

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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.

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