Evaluation of release and pharmacokinetics of hexadecylphosphocholine (miltefosine) in phosphatidyldiglycerol-based thermosensitive liposomes

Rysin, Alexander; Paal, Michael; Lokerse, Wouter J. M.; Wedmann, Barbara; Hossann, Martin; Vogeser, Michael; Winter, Gerhard und Lindner, Lars H. (2021): Evaluation of release and pharmacokinetics of hexadecylphosphocholine (miltefosine) in phosphatidyldiglycerol-based thermosensitive liposomes. In: Biochimica et Biophysica Acta-Biomembranes, Bd. 1863, Nr. 11, 183698

Abstract

Hexadecylphosphocholine (HePC, Miltefosine) is a drug from the class of alkylphosphocholines with an antineoplastic and antiprotozoal activity. We previously reported that HePC uptake from thermosensitive liposomes (TSL) containing 1,2-dipalmitoyl-sn-glycero-3-phosphodiglycerol (DPPG(2)) into cancer cells is accelerated at mild hyperthermia (HT) resulting in increased cytotoxicity. In this study, we compared HePC release of different TSL formulations in serum. HePC showed rapid but incomplete release below the transition temperature (T-m) of investigated TSL formulations in serum. Short heating (5 min) to 42 degrees C increased HePC release from DPPG(2)-TSL (T-m = 41 degrees C) by a factor of two in comparison to body temperature (37 degrees C). Bovine serum albumin (BSA) induced HePC release from DPPG(2)-TSL comparable to serum. Furthermore, multilamellar vesicles (MLV) were capable to extract HePC from DPPG(2)-TSL in a concentration- and temperature-dependent manner. Repetitive exposure of DPPG(2)-TSL to MLV at 37 degrees C led to a fast initial release of HePC which slowed down after subsequent extraction cycles finally reaching approx. 50% HePC release. A pharmacokinetic study in rats revealed a biphasic pattern with an immediate clearance of approx. 50% HePC whereas the remaining 50% HePC showed a prolonged circulation time. We speculate that HePC located in the external leaflet of DPPG(2)-TSL is rapidly released upon contact with suitable biological acceptors. As demonstrated by MLV transfer experiments, asymmetric incorporation of HePC into the internal leaflet of DPPG(2)-TSL might improve HePC retention in presence of complex biological media and still give rise to HT-induced HePC release.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0005-2736
• Sprache: Englisch