Ashish Ranjan1, Compton J Benjamin2, Ayele H Negussie1, Saurin Chokshi2, Paul H Chung2, Dmitry Volkin2, Nitin Yeram2, W Marston Linehan2, Matthew R Dreher1, Peter A Pinto2, Bradford J Wood3. 1. Center for Interventional Oncology, Radiology & Imaging Sciences, Clinical Center, National Institutes of Health, MSC 1182- building 10- room 1c -341, 10 Center Drive, Bethesda, Maryland, 20892, USA. 2. Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. 3. Center for Interventional Oncology, Radiology & Imaging Sciences, Clinical Center, National Institutes of Health, MSC 1182- building 10- room 1c -341, 10 Center Drive, Bethesda, Maryland, 20892, USA. bwood@cc.nih.gov.
Abstract
PURPOSE: Low temperature sensitive liposome (LTSL) encapsulated docetaxel were combined with mild hyperthermia (40-42°C) to investigate in vivo biodistribution and efficacy against a castrate resistant prostate cancer. METHOD: Female athymic nude mice with human prostate PC-3 M-luciferase cells grown subcutaneously into the right hind leg were randomized into six groups: saline (+/- heat), free docetaxel (+/- heat), and LTSL docetaxel (+/- heat). Treatment (15 mg docetaxel/kg) was administered via tail vein once tumors reached a size of 200-300 mm(3). Mice tumor volumes and body weights were recorded for up to 60 days. Docetaxel concentrations of harvested tumor and organ/tissue homogenates were determined by LC-MS. Histological evaluation (Mean vessel density, Ki67 proliferation, Caspase-3 apoptosis) of saline, free Docetaxel and LTSL docetaxel (+/- heat n = 3-5) was performed to determine molecular mechanism responsible for tumor cell killing. RESULT: LTSL/heat resulted in significantly higher tumor docetaxel concentrations (4.7-fold greater compared to free docetaxel). Adding heat to LTSL Docetaxel or free docetaxel treatment resulted in significantly greater survival and growth delay compared to other treatments (p < 0.05). Differences in body weight between all Docetaxel treatments were not reduced by >10% and were not statistically different from each other. Molecular markers such as caspase-3 were upregulated, and Ki67 expression was significantly decreased in the chemo-hyperthermia group. Vessel density was similar post treatment, but the heated group had reduced vessel area, suggesting thermal enhancement in efficacy by reduction in functional perfusion. CONCLUSION: This technique of hyperthermia sensitization and enhanced docetaxel delivery has potential for clinical translation for prostate cancer treatment.
PURPOSE: Low temperature sensitive liposome (LTSL) encapsulated docetaxel were combined with mild hyperthermia (40-42°C) to investigate in vivo biodistribution and efficacy against a castrate resistant prostate cancer. METHOD: Female athymic nude mice with human prostate PC-3 M-luciferase cells grown subcutaneously into the right hind leg were randomized into six groups: saline (+/- heat), free docetaxel (+/- heat), and LTSLdocetaxel (+/- heat). Treatment (15 mg docetaxel/kg) was administered via tail vein once tumors reached a size of 200-300 mm(3). Micetumor volumes and body weights were recorded for up to 60 days. Docetaxel concentrations of harvested tumor and organ/tissue homogenates were determined by LC-MS. Histological evaluation (Mean vessel density, Ki67 proliferation, Caspase-3 apoptosis) of saline, free Docetaxel and LTSLdocetaxel (+/- heat n = 3-5) was performed to determine molecular mechanism responsible for tumor cell killing. RESULT: LTSL/heat resulted in significantly higher tumordocetaxel concentrations (4.7-fold greater compared to free docetaxel). Adding heat to LTSLDocetaxel or free docetaxel treatment resulted in significantly greater survival and growth delay compared to other treatments (p < 0.05). Differences in body weight between all Docetaxel treatments were not reduced by >10% and were not statistically different from each other. Molecular markers such as caspase-3 were upregulated, and Ki67 expression was significantly decreased in the chemo-hyperthermia group. Vessel density was similar post treatment, but the heated group had reduced vessel area, suggesting thermal enhancement in efficacy by reduction in functional perfusion. CONCLUSION: This technique of hyperthermia sensitization and enhanced docetaxel delivery has potential for clinical translation for prostate cancer treatment.
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