In Vivo Assessment of Thermosensitive Liposomes for the Treatment of Port Wine Stains by Antifibrinolytic Site-Specific Pharmaco-Laser Therapy
In Vivo Assessment of Thermosensitive Liposomes for the Treatment of Port Wine Stains by Antifibrinolytic Site-Specific Pharmaco-Laser Therapy
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通过抗纤维蛋白溶解位点特异性药物激光疗法治疗鲜红斑痣的热敏脂质体的体内评估
DOI：
10.3390/pharmaceutics12060591
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发表时间：
2020-06-01
期刊：
影响因子：
5.4
通讯作者：
Heger, Michal
中科院分区：
文献类型：
--
作者：
Li, Mingjuan;van Raath, M. Ingmar;Heger, Michal
抗纤溶位点特异性药物激光治疗（SSPLT）是一种治疗难治性鲜红斑痣（PWS）的实验性治疗方法。从概念上讲，封装在热敏脂质体中的抗纤维蛋白溶解药物被递送到常规激光治疗后在半光凝PWS血管中形成的血栓。抗纤溶药物的局部释放由轻度高温诱导，导致血栓形成过度和靶血管完全闭塞（临床终点）。在这项研究中，20温敏脂质体制剂含有氨甲环酸（TA）的理化性质，TA：脂质比，包封率，和囊泡内TA浓度进行了测定。基于最佳性质选择两种候选制剂（DPPC：DSPE-PEG、DPPC：MPPC：DSPE-PEG），并分析在体温（T）、相变温度（T-m）和T > T-m时的热诱导TA释放。测定血浆对37 ℃下脂质体稳定性的影响，并通过流式细胞术检查脂质体与血小板的结合。在仓鼠背部皮褶模型和活体荧光显微镜下研究了聚乙二醇化磷酸胆碱脂质体在激光诱导血栓中的积聚。两种制剂在37 ℃下均不释放TA。在T（m）下，在加热2.0-2.5 min内实现TA几乎完全释放，在T > T-m时加速释放。血浆对两种制剂均具有稳定作用。脂质体与血小板轻度相关。尽管在体外的结果是积极的，荧光标记的脂质体并没有充分积累在激光诱导的血栓在仓鼠，以保证其用于抗纤维蛋白溶解SSPLT，这可以通过偶联血栓靶向配体的脂质体解决。
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.