title: Biodistribution and Efficacy of Low Temperature-Sensitive Liposome Encapsulated Docetaxel Combined with Mild Hyperthermia in a Mouse Model of Prostate Cancer.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  This technique of hyperthermia sensitization and enhanced docetaxel delivery has potential for clinical translation for prostate cancer treatment.
authors.affiliation: 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.
authors.forename: Ashish
authors.initials: A
authors.lastname: Ranjan
authors.affiliation: Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Compton J
authors.initials: CJ
authors.lastname: Benjamin
authors.affiliation: 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.
authors.forename: Ayele H
authors.initials: AH
authors.lastname: Negussie
authors.affiliation: Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Saurin
authors.initials: S
authors.lastname: Chokshi
authors.affiliation: Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Paul H
authors.initials: PH
authors.lastname: Chung
authors.affiliation: Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Volkin
authors.affiliation: Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Nitin
authors.initials: N
authors.lastname: Yeram
authors.affiliation: Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: W Marston
authors.initials: WM
authors.lastname: Linehan
authors.affiliation: 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.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Dreher
authors.affiliation: Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Pinto
authors.affiliation: 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.
authors.forename: Bradford J
authors.initials: BJ
authors.lastname: Wood
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000378:metabolism*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D000077143:Docetaxel; D016503:Drug Delivery Systems / Q000379:methods; D005260:Female; D006801:Humans; D006979:Hyperthermia, Induced / Q000379:methods*; D008081:Liposomes; D008297:Male; D051379:Mice; D008819:Mice, Nude; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality; D011897:Random Allocation; D015996:Survival Rate / Q000639:trends; D043823:Taxoids / Q000008:administration & dosage / Q000378:metabolism*; D013696:Temperature; D014018:Tissue Distribution / Q000187:drug effects / Q000502:physiology; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000970:Antineoplastic Agents; D008081:Liposomes; D043823:Taxoids; D000077143:Docetaxel
keywords: HIFU; LTSL; cancer; docetaxel; prostate