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 investi...

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Published in:	Biomaterials Vol. 82; pp. 138 - 150
Main Authors:	Lokerse, Wouter J.M, Kneepkens, Esther C.M, ten Hagen, Timo L.M, Eggermont, Alexander M.M, Grüll, Holger, Koning, Gerben A
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier Ltd 01-03-2016
Subjects:	Advanced Basic Science Ammonium sulfates Animals Antibiotics, Antineoplastic - administration & dosage Antibiotics, Antineoplastic - pharmacokinetics Cancer Cell Line, Tumor Cell Survival - drug effects Citrates Delayed-Action Preparations - chemistry Dentistry Doxorubicin - administration & dosage Doxorubicin - pharmacokinetics Drug Compounding - methods Drug delivery Hyperthermia In vitro testing In vivo methods and tests Leakage Lipids Liposome Liposomes - chemistry Metabolic Clearance Rate Mice Mice, Inbred C57BL Neoplasms, Experimental - drug therapy Neoplasms, Experimental - metabolism Neoplasms, Experimental - pathology Phospholipids - chemistry Temperature Thermosensitive Treatment Outcome Tumors Liposome Drug delivery Hyperthermia Cancer
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0142-9612 1878-5905
DOI:	10.1016/j.biomaterials.2015.12.023