In Vivo Assessment of Thermosensitive Liposomes for the Treatment of Port Wine Stains by Antifibrinolytic Site-Specific Pharmaco-Laser Therapy

M.J. Li, M.I. van Raath, S. Khakpour, A. Secilir, B.C. Sliggers, X. Huang, B.Y. Ding, G. Storm, R.R. van der Hulst, A.I.P.M. de Kroon, M. Heger*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Antifibrinolytic site-specific pharmaco-laser therapy (SSPLT) is an experimental treatment modality for refractory port wine stains (PWS). Conceptually, antifibrinolytic drugs encapsulated in thermosensitive liposomes are delivered to thrombi that form in semi-photocoagulated PWS blood vessels after conventional laser treatment. Local release of antifibrinolytics is induced by mild hyperthermia, resulting in hyperthrombosis and complete occlusion of the target blood vessel (clinical endpoint). In this study, 20 thermosensitive liposomal formulations containing tranexamic acid (TA) were assayed for physicochemical properties, TA:lipid ratio, encapsulation efficiency, and endovesicular TA concentration. Two candidate formulations (DPPC:DSPE-PEG, DPPC:MPPC:DSPE-PEG) were selected based on optimal properties and analyzed for heat-induced TA release at body temperature (T), phase transition temperature (T-m), and at T > T-m. The effect of plasma on liposomal stability at 37 degrees C was determined, and the association of liposomes with platelets was examined by flow cytometry. The accumulation of PEGylated phosphocholine liposomes in laser-induced thrombi was investigated in a hamster dorsal skinfold model and intravital fluorescence microscopy. Both formulations did not release TA at 37 degrees C. Near-complete TA release was achieved at T(m)within 2.0-2.5 min of heating, which was accelerated at T > T-m. Plasma exerted a stabilizing effect on both formulations. Liposomes showed mild association with platelets. Despite positive in vitro results, fluorescently labeled liposomes did not sufficiently accumulate in laser-induced thrombi in hamsters to warrant their use in antifibrinolytic SSPLT, which can be solved by coupling thrombus-targeting ligands to the liposomes.
Original languageEnglish
Article number591
Number of pages27
JournalPharmaceutics
Volume12
Issue number6
DOIs
Publication statusPublished - 1 Jun 2020

Keywords

  • circulation time
  • drug-delivery
  • endovascular laser-tissue interactions
  • fluorescent thrombus staining
  • hyperthermia
  • intravital fluorescence microscopy
  • lipid monolayers
  • pegylated lecithin liposomes
  • photodynamic therapy
  • pulsed dye-laser
  • release
  • selective photothermolysis
  • targeted drug delivery
  • thrombosis
  • tranexamic acid
  • vascular malformations
  • vitro
  • DRUG-DELIVERY
  • PEGYLATED LECITHIN LIPOSOMES
  • PULSED DYE-LASER
  • SELECTIVE PHOTOTHERMOLYSIS
  • VITRO
  • PHOTODYNAMIC THERAPY
  • LIPID MONOLAYERS
  • RELEASE
  • TRANEXAMIC ACID
  • CIRCULATION TIME

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