title: In depth study on thermosensitive liposomes: Optimizing formulations for tumor specific therapy and in vitro to in vivo relations.
abstract: In numerous studies, thermosensitive liposomes (TSLs) for local heat-triggered delivery of Doxorubicin (Dox) to tumors have been investigated, with TSLs having different lipid formulations, drug loading methodology and testing procedures. To gain more insight in these parameters, we investigated TSLs with four variable DSPC-DPPC lipid ratios (50, 60, 70 or 80% DPPC and 5 mol% of DSPE-PEG2000) using either ammonium sulfate or a citrate buffer for Dox loading. Ammonium sulfate loading of Dox yielded more stable TSLs than citrate loading. At 37 °C, leakage was unnoticeable for all ammonium sulfate TSLs. At 42 °C, complete release occurred within seconds, except for 50% DPPC TSLs, where slow and incomplete release was observed in vitro but also in vivo using a dorsal skinfold window chamber. In contrast to in vitro assays, blood kinetics studies indicated a burst release of Dox upon injection and higher leakage for all TSLs. In therapeutic studies, hyperthermia in combination with TSLs repressed BFS-1 sarcoma growth. Our study shows that prediction of therapeutic efficacy purely based on differences found in vitro is difficult, instead, parameters obtained from pharmacokinetic studies in vivo, and the exact timing of the delivery protocol need to be taken into account.
authors.affiliation: Laboratory Experimental Surgical Oncology, Section Surgical Oncology, Department of Surgery, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Wouter J M
authors.initials: WJ
authors.lastname: Lokerse
authors.affiliation: Eindhoven University of Technology, Dept. of Biomedical NMR, Eindhoven, The Netherlands.
authors.forename: Esther C M
authors.initials: EC
authors.lastname: Kneepkens
authors.affiliation: Laboratory Experimental Surgical Oncology, Section Surgical Oncology, Department of Surgery, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Timo L M
authors.initials: TL
authors.lastname: ten Hagen
authors.affiliation: Institut Gustave Roussy, Villejuif, France.
authors.forename: Alexander M M
authors.initials: AM
authors.lastname: Eggermont
authors.affiliation: Eindhoven University of Technology, Dept. of Biomedical NMR, Eindhoven, The Netherlands; Philips Research Eindhoven, Dept. of Oncology Solutions, Eindhoven, The Netherlands. Electronic address: H.Gruell@tue.nl.
authors.forename: Holger
authors.initials: H
authors.lastname: Grüll
authors.affiliation: Laboratory Experimental Surgical Oncology, Section Surgical Oncology, Department of Surgery, Erasmus Medical Centre, Rotterdam, The Netherlands.
authors.forename: Gerben A
authors.initials: GA
authors.lastname: Koning
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003692:Delayed-Action Preparations / Q000737:chemistry; D004317:Doxorubicin / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D004339:Drug Compounding / Q000379:methods; D008081:Liposomes / Q000737:chemistry*; D008657:Metabolic Clearance Rate; D051379:Mice; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D010743:Phospholipids / Q000737:chemistry*; D013696:Temperature; D016896:Treatment Outcome
chemical_list: D000903:Antibiotics, Antineoplastic; D003692:Delayed-Action Preparations; D008081:Liposomes; D010743:Phospholipids; D004317:Doxorubicin
keywords: Cancer; Drug delivery; Hyperthermia; Liposome