Marwan Moussa1, S Nahum Goldberg2, Gaurav Kumar1, Rupa R Sawant3, Tatyana Levchenko3, Vladimir Torchilin3, Muneeb Ahmed4. 1. Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, 1 Deaconess Road, WCC 308-B, Boston, MA 02215. 2. Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, 1 Deaconess Road, WCC 308-B, Boston, MA 02215; Division of Image-guided Therapy and Interventional Oncology, Department of Radiology, Hadassah Hebrew University Medical Center, Jerusalem, Israel. 3. Department of Pharmaceutical Sciences and Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, Massachusetts. 4. Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, 1 Deaconess Road, WCC 308-B, Boston, MA 02215. Electronic address: mahmed@bidmc.harvard.edu.
Abstract
PURPOSE: To characterize upregulation of hypoxia-inducible factor (HIF)-1α after radiofrequency (RF) ablation and the influence of an adjuvant HIF-1α inhibitor (bortezomib) and nanodrugs on modulating RF ablation-upregulated hypoxic pathways. MATERIALS AND METHODS: Fisher 344 rats (n = 68) were used. First, RF ablation-induced periablational HIF-1α expression was evaluated in normal liver or subcutaneous R3230 tumors (14-16 mm). Next, the effect of varying RF ablation thermal dose (varying tip temperature 50°C-90°C for 2-20 minutes) on HIF-1α expression was studied in R3230 tumors. Third, RF ablation was performed in R3230 tumors without or with an adjuvant HIF-1α inhibitor, bortezomib (single intraperitoneal dose 0.1 mg/kg). Finally, the combination RF ablation and intravenous liposomal chemotherapeutics with known increases in periablational cellular cytotoxicity (doxorubicin, paclitaxel, and quercetin) was assessed for effect on periablational HIF-1α. Outcome measures included immunohistochemistry of HIF-1α and heat shock protein 70 (marker of nonlethal thermal injury). RESULTS: RF ablation increased periablational HIF-1α in both normal liver and R3230 tumor, peaking at 24-72 hours. Tumor RF ablation had similar HIF-1α rim thickness but significantly greater percent cell positivity compared with hepatic RF ablation (P < .001). HIF-1α after ablation was the same regardless of thermal dose. Bortezomib suppressed HIF-1α (rim thickness, 68.7 µm ± 21.5 vs 210.3 µm ± 85.1 for RF ablation alone; P < .02) and increased ablation size (11.0 mm ± 1.5 vs 7.7 mm ± 0.6 for RF ablation alone; P < .002). Finally, all three nanodrugs suppressed RF ablation-induced HIF-1α (ie, rim thickness and cell positivity; P < .02 for all comparisons), with liposomal doxorubicin suppressing HIF-1α the most (P < .03). CONCLUSIONS: RF ablation upregulates HIF-1α in normal liver and tumor in a temperature-independent manner. This progrowth, hypoxia pathway can be successfully suppressed with an adjuvant HIF-1α-specific inhibitor, bortezomib, or non-HIF-1α-specific liposomal chemotherapy.
PURPOSE: To characterize upregulation of hypoxia-inducible factor (HIF)-1α after radiofrequency (RF) ablation and the influence of an adjuvant HIF-1α inhibitor (bortezomib) and nanodrugs on modulating RF ablation-upregulated hypoxic pathways. MATERIALS AND METHODS: Fisher 344 rats (n = 68) were used. First, RF ablation-induced periablational HIF-1α expression was evaluated in normal liver or subcutaneous R3230 tumors (14-16 mm). Next, the effect of varying RF ablation thermal dose (varying tip temperature 50°C-90°C for 2-20 minutes) on HIF-1α expression was studied in R3230 tumors. Third, RF ablation was performed in R3230 tumors without or with an adjuvant HIF-1α inhibitor, bortezomib (single intraperitoneal dose 0.1 mg/kg). Finally, the combination RF ablation and intravenous liposomal chemotherapeutics with known increases in periablational cellular cytotoxicity (doxorubicin, paclitaxel, and quercetin) was assessed for effect on periablational HIF-1α. Outcome measures included immunohistochemistry of HIF-1α and heat shock protein 70 (marker of nonlethal thermal injury). RESULTS: RF ablation increased periablational HIF-1α in both normal liver and R3230 tumor, peaking at 24-72 hours. Tumor RF ablation had similar HIF-1α rim thickness but significantly greater percent cell positivity compared with hepatic RF ablation (P < .001). HIF-1α after ablation was the same regardless of thermal dose. Bortezomib suppressed HIF-1α (rim thickness, 68.7 µm ± 21.5 vs 210.3 µm ± 85.1 for RF ablation alone; P < .02) and increased ablation size (11.0 mm ± 1.5 vs 7.7 mm ± 0.6 for RF ablation alone; P < .002). Finally, all three nanodrugs suppressed RF ablation-induced HIF-1α (ie, rim thickness and cell positivity; P < .02 for all comparisons), with liposomal doxorubicin suppressing HIF-1α the most (P < .03). CONCLUSIONS: RF ablation upregulates HIF-1α in normal liver and tumor in a temperature-independent manner. This progrowth, hypoxia pathway can be successfully suppressed with an adjuvant HIF-1α-specific inhibitor, bortezomib, or non-HIF-1α-specific liposomal chemotherapy.
Authors: Wei Yang; Muneeb Ahmed; Mostafa Elian; El-Shymma A Hady; Tatyana S Levchenko; Rupa R Sawant; Sabina Signoretti; Michael Collins; Vladimir P Torchilin; S Nahum Goldberg Journal: Radiology Date: 2010-09-21 Impact factor: 11.105
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