Papadia Konstantina, Giannou Anastasios D, Markoutsa Eleni, Bigot Christian, Vanhoute Greejte, Mourtas Spyridon, Van der Linded Annemie, Stathopoulos Georgios T, Antimisiaris Sophia G
Laboratory of Pharmaceutical Technology, Department of Pharmacy, University of Patras, Rio 26510, Greece.
Laboratory for Molecular Respiratory Carcinogenesis, Department of Physiology, Faculty of Medicine, University of Patras, Rio 26504, Greece.
Eur J Pharm Sci. 2017 May 1;102:180-187. doi: 10.1016/j.ejps.2017.03.010. Epub 2017 Mar 8.
Multifunctional liposomes (mf-LIPs) having a curcumin-lipid ligand (to target amyloids) together with two ligands to target the transferrin, and the low-density apolipoprotein receptor of the blood-brain-barrier (BBB) on their surface, were previously studied (in vitro) as potential theranostic systems for Alzheimer's disease (AD) (Papadia et al., 2017, Eur. J. Pharm. Sciences; 101:140-148). Herein, the targeting potential of mf-LIPs was compared to that of BBB-LIPs (liposomes having only the two BBB-specific ligands) in FVB mice (normal), as well as in double transgenic mice (APP/PS1) and their corresponding littermates (WT), by live-animal (in vivo) and explanted organ (ex vivo) imaging. In FVB mice, the head-signals of mf-LIPs and BBB-LIPs are either similar, or signals from mf-LIP are higher, suggesting that the co-presence of the curcumin derivative on the liposome surface does not disturb the functionality of the BBB-specific ligands. Higher brain/liver+spleen ratios (ex vivo) were calculated post-injection of mf-LIP, compared to those found after BBB-LIP injection, due to the reduced distribution of mf-LIPs in the liver and spleen; showing that the curcumin ligand increases the stealth properties of liposomes by reducing their uptake by liver and spleen. The later effect is more pronounced when the density of the BBB-specific ligands on the mf-LIPs is 0.1mol%, compared to 0.2%, highlighting the importance of this parameter. When a high lipid dose (4mg/mouse) is injected in WT and APP/PS1 mice, the head-signals of mf-LIPs are significantly higher than those of BBB-LIPs, but no differences are observed between WT and APP/PS1 mice. However, after administration of a low liposome dose (0.05mg/mouse) of mf-LIPs, significant differences in the head-signals are found between WT and transgenic mice, highlighting the AD theranostic potential of the multifunctional liposomes, as well as the importance of the experimental parameters used in such in vivo screening studies.
多功能脂质体（mf-LIPs）表面含有姜黄素-脂质配体（用于靶向淀粉样蛋白）以及两种靶向转铁蛋白和血脑屏障（BBB）低密度载脂蛋白受体的配体，此前已作为阿尔茨海默病（AD）的潜在诊疗系统进行了体外研究（Papadia等人，2017年，《欧洲药理学杂志》；101:140 - 148）。在此，通过活体动物（体内）和离体器官（体外）成像，在FVB小鼠（正常）以及双转基因小鼠（APP/PS1）及其相应同窝小鼠（WT）中，比较了mf-LIPs与BBB-LIPs（仅具有两种BBB特异性配体的脂质体）的靶向潜力。在FVB小鼠中，mf-LIPs和BBB-LIPs的头部信号要么相似，要么mf-LIP的信号更高，这表明脂质体表面姜黄素衍生物的共存不会干扰BBB特异性配体的功能。与注射BBB-LIPs后相比，注射mf-LIP后计算出的脑/肝 + 脾比率（体外）更高，这是由于mf-LIPs在肝脏和脾脏中的分布减少；表明姜黄素配体通过减少脂质体被肝脏和脾脏摄取来增加其隐身特性。当mf-LIPs上BBB特异性配体的密度为0.1mol%时，与0.2%相比，后一种效果更明显，突出了该参数的重要性。当向WT和APP/PS1小鼠注射高剂量脂质（4mg/小鼠）时，mf-LIPs的头部信号显著高于BBB-LIPs，但WT和APP/PS1小鼠之间未观察到差异。然而，在给予低剂量脂质体（0.05mg/小鼠）的mf-LIPs后，WT和转基因小鼠之间的头部信号存在显著差异，突出了多功能脂质体的AD诊疗潜力以及此类体内筛选研究中所用实验参数的重要性。
