Summary
Even though hyperthermia is a promising treatment for cancer, the relationship between specific temperatures and clinical benefits of and predictors of sensitivity of cancer to hyperthermia are poorly understood. Ovarian and uterine tumors have diverse hyperthermia sensitivities. Integrative analyses of the specific gene signatures in and the differences in response to hyperthermia between hyperthermia-sensitive and -resistant cancer cells identified CTGF as a key regulator of sensitivity. CTGF silencing sensitized resistant cells to hyperthermia. CTGF siRNA treatment also sensitized resistant cancers to localized hyperthermia induced by copper sulfide nanoparticles and near-infrared laser in orthotopic ovarian cancer models. CTGF silencing aggravated energy stress induced by hyperthermia and enhanced apoptosis of hyperthermia resistant cancers.
Circulating Nogo-B may be an effective indicator for liver cirrhosis. Nogo-B inhibition could diminish HSC activation, in which alleviating ER stress may be one of the mechanisms, suggesting a potential approach to interference Nogo-B in liver fibrosis.
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 Lipiodol (Dox@PEG-HAuNS/Lipiodol) for improved photothermal ablation (PTA)-chemoembolization therapy (CET; PTA-CET) of hepatocellular carcinoma (HCC) in rats.
Materials and Methods
All animal experiments were approved by the Institutional Animal Care and Use Committee, and were performed in 45 Sprague-Dawley rats (male, 12 weeks old) from Feb. 2014 to April 2015. Eight days after inoculation of N1S1 HCC cells in the liver of rats. Animals were randomly divided into 2 groups of 10 rats each. Rats in group 1 received intrahepatic arterial (IA) injection of PEG-HAuNS/Lipiodol alone, and rats in group 2 received IA injection of CA4P followed by PEG-HAuNS/Lipiodol 5 min later. Each group was subdivided, and the Au content of tumors and tissues excised at 1 h or at 24 h was quantified using neutron activation analysis (NAA, n=5/time point). Five rats received CA4P plus PEG-[64Cu]-HAuNS/Lipiodol and underwent μPET/CT. In a separate study, therapeutic effects were compared among 3 groups of 6 rats each that received IA injection of saline (control group), CA4P plus Dox@PEG-HAuNS/Lipiodol (CET group), or CA4P plus Dox@PEG-HAuNS/Lipiodol plus near-infrared irradiation (PTA-CET group). Temperature was recorded during laser irradiation. Findings were verified with postmortem histopathology and/or autoradiography. Wilcoxon rank-sum test was used to test the difference between groups, Pearson correlation analyses were performed to evaluate correlations.
Results
PEG-HAuNS uptake in CA4P-pretreated tumors was significantly higher than that in non–CA4P-pretreated tumors at both 1 h (P<0.03) and 24 h (P<0.01). The tumor-to-liver PEG-HAuNS uptake ratios at 1 h and 24 h were 5.63±3.09 and 1.68±0.77, respectively, in the CA4P-treated group and 1.29±2.40 and 0.14±0.11, respectively, in the non–CA4P-treated group. μPET/CT clearly delineated the tumors, enabling quantitative imaging analysis. Laser irradiation increases temperature to 60°C and 43°C in the tumor and adjacent liver, respectively. Tumor volumes 10 d after therapy were 1.68±1.01, 3.96±1.75, and 6.13±2.27 cm3 in the PTA-CET, CET, and control groups, respectively, with significant differences between the PTA-CET group and other groups (P<0.05).
Conclusion
CA4P pretreatment causes a higher concentration of Dox@PEG-HAuNS to be trapped inside the tumor, thereby enhancing the anti-HCC efficacy of PTA-CET in rats.
Owing to the better correlation coefficients between CT attenuation value and iodine concentration, GSI may be a preferred method for quantitative measurement compared with TPXI.
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