title: Pharmacokinetics, Tissue Distribution and Therapeutic Effect of Cationic Thermosensitive Liposomal Doxorubicin Upon Mild Hyperthermia.
abstract: OBJECTIVE
  To evaluate pharmacokinetic profile, biodistribution and therapeutic effect of cationic thermosensitive liposomes (CTSL) encapsulating doxorubicin (Dox) upon mild hyperthermia (HT).
  
  
  METHODS
  Non-targeted thermosensitive liposomes (TSL) and CTSL were developed, loaded with Dox and characterized. Blood kinetics and biodistribution of Dox-TSL and Dox-CTSL were followed in B16BL6 tumor bearing mice upon normothermia (NT) or initial hyperthermia conditions. Efficacy study in B16BL6 tumor bearing mice was followed with Dox-TSL or Dox-CTSL upon NT or HT. Efficacy study in LLC tumor bearing mice was performed upon two HT conditions. Intravital microscopy was performed on B16BL6 tumors implanted in dorsal-skin fold window-bearing mice.
  
  
  RESULTS
  Targeting did not cause faster blood clearance of CTSL compared to TSL. Highest uptake of liposomes was observed in spleen, kidneys and liver. Applying HT prior to CTSL administration increased drug delivery to the tumor and CTSL delivered ~1.7 fold higher Dox concentration compared to TSL. Efficacy in B16BL6 murine melanoma showed that HT had a significant effect on CTSL in tumor suppression and prolonged survival. Efficacy in LLC Lewis lung carcinoma tumor model demonstrates that two HT treatments hold promises for a successful treatment option.
  
  
  CONCLUSIONS
  CTSL have potency to increase drug efficacy in tumors due to their targeted and drug release functions.
authors.affiliation: Laboratory Experimental Surgical Oncology, Section Surgical Oncology, Department of Surgery, Erasmus Medical Center, POBox 1738, 3000, DR, Rotterdam, The Netherlands.
authors.forename: Bilyana M
authors.initials: BM
authors.lastname: Dicheva
authors.affiliation: Laboratory Experimental Surgical Oncology, Section Surgical Oncology, Department of Surgery, Erasmus Medical Center, POBox 1738, 3000, DR, Rotterdam, The Netherlands.
authors.forename: Ann L B
authors.initials: AL
authors.lastname: Seynhaeve
authors.affiliation: Laboratory Experimental Surgical Oncology, Section Surgical Oncology, Department of Surgery, Erasmus Medical Center, POBox 1738, 3000, DR, Rotterdam, The Netherlands.
authors.forename: Thomas
authors.initials: T
authors.lastname: Soulie
authors.affiliation: Laboratory Experimental Surgical Oncology, Section Surgical Oncology, Department of Surgery, Erasmus Medical Center, POBox 1738, 3000, DR, Rotterdam, The Netherlands.|Institut Gustave Roussy, Villejuif, France.
authors.forename: Alexander M M
authors.initials: AM
authors.lastname: Eggermont
authors.affiliation: Laboratory Experimental Surgical Oncology, Section Surgical Oncology, Department of Surgery, Erasmus Medical Center, POBox 1738, 3000, DR, Rotterdam, The Netherlands. t.l.m.tenhagen@erasmusmc.nl.
authors.forename: Timo L M
authors.initials: TL
authors.lastname: Ten Hagen
authors.affiliation: Laboratory Experimental Surgical Oncology, Section Surgical Oncology, Department of Surgery, Erasmus Medical Center, POBox 1738, 3000, DR, Rotterdam, The Netherlands.
authors.forename: Gerben A
authors.initials: GA
authors.lastname: Koning
mesh_terms: D000818:Animals; D002412:Cations / Q000008:administration & dosage*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000379:methods; D005334:Fever / Q000188:drug therapy* / Q000378:metabolism*; D008081:Liposomes / Q000008:administration & dosage*; D008545:Melanoma / Q000188:drug therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D011092:Polyethylene Glycols / Q000493:pharmacokinetics / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: D002412:Cations; D008081:Liposomes; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin
keywords: cationic thermosensitive liposomes; doxorubicin; hyperthermia; therapeutic efficacy