Mixed cationic liposomes for brain delivery of drugs by the intranasal route: The acetylcholinesterase reactivator 2-PAM as encapsulated drug model
Mixed cationic liposomes for brain delivery of drugs by the intranasal route: The acetylcholinesterase reactivator 2-PAM as encapsulated drug model
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DOI：
10.1016/j.colsurfb.2018.07.049
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发表时间：
2018-11-01
影响因子：
5.8
通讯作者：
Sinyashin, Oleg G.
中科院分区：
文献类型：
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作者：
Pashirova, Tatiana N.;Zueva, Irina V.;Sinyashin, Oleg G.
设计了一种新型的基于L-α-磷脂酰胆碱和双十六烷基甲基羟乙基溴化铵（DHDHAB）的混合阳离子脂质体，用于克服鼻内途径的血脑屏障穿越。对DHDHAB的合成和自组装进行了研究。低的临界缔合浓度（0.01 mM）、对疏水染料橙子OT的良好增溶性质、对革兰氏阳性细菌金黄色葡萄球菌（MIC=7.8 μ g mL（-1））和蜡样芽孢杆菌（MIC=7.8 μ g mL（-1））的抗微生物活性、对人红细胞的低溶血活性（小于10%）得以实现。确定了室温下具有良好胶体稳定性的阳离子囊泡和混合脂质体的制备条件。鼻内给药的罗丹明B-负载的阳离子脂质体被证明，以增加生物利用度到大脑相比，静脉注射。以胆碱酯酶再激活剂2-PAM为模型药物，制备了阳离子脂质体。2-PAM阳离子脂质体具有较高的包封率（接近90%）和接近100 nm的流体动力学直径。鼻内给药的2-PAM负载的阳离子脂质体有效对抗对氧磷诱导的脑中乙酰胆碱酯酶抑制。2-PAM负载的脂质体重新激活12 +/- 1%的脑乙酰胆碱酯酶。这一令人鼓舞的结果打开了可能性，使用市售的带正电荷的肟在医疗对策对有机磷中毒的中央乙酰胆碱酯酶的重新激活，通过实施一种非侵入性的方法，通过“鼻-脑”的途径。
New mixed cationic liposomes based on L-alpha-phosphatidylcholine and dihexadecylmethylhydroxyethylammonium bromide (DHDHAB) were designed to overcome the BBB crossing by using the intranasal route. Synthesis and self-assembly of DHDHAB were performed. A low critical association concentration (0.01 mM), good solubilization properties toward hydrophobic dye Orange OT and antimicrobial activity against gram-positive bacteria Staphylococcus aureus (MIC=7.8 mu g mL(-1)) and Bacillus cereus (MIC=7.8 mu g mL(-1)), low hemolytic activities against human red blood cells (less than 10%) were achieved. Conditions for preparation of cationic vesicles and mixed liposomes with excellent colloidal stability at room temperature were determined. The intranasal administration of rhodamine B-loaded cationic liposomes was shown to increase bioavailability into the brain in comparison to the intravenous injection. The cholinesterase reactivator, 2-PAM, was used as model drug for the loading in cationic liposomes. 2-PAM-loaded cationic liposomes displayed high encapsulation efficiency (similar to 90%) and hydrodynamic diameter close to 100 nm. Intranasally administered 2-PAM-loaded cationic liposomes were effective against paraoxon-induced acetylcholinesterase inhibition in the brain. 2-PAM-loaded liposomes reactivated 12 +/- 1% of brain acetylcholinesterase. This promising result opens the possibility to use marketed positively charged oximes in medical countermeasures against organophosphorus poisoning for reactivation of central acetylcholinesterase by implementing a non-invasive approach, via the "nose-brain" pathway.