Cationic Amphiphiles with Fatty Acyl Chain Asymmetry of Coconut Oil Deliver Genes Selectively to Mouse Lung
Cationic Amphiphiles with Fatty Acyl Chain Asymmetry of Coconut Oil Deliver Genes Selectively to Mouse Lung
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DOI：
10.1021/bc100537r
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发表时间：
2011-03-01
影响因子：
4.7
通讯作者：
Chaudhuri, Arabinda
中科院分区：
文献类型：
--
作者：
Chandrashekhar, Voshavar;Srujan, Marepally;Chaudhuri, Arabinda
最近的结构活性研究揭示了疏水链不对称性对增强合成阳离子两亲物的基因递送功效具有显着影响（Nantz, M. H. et al. Mol. Pharmaceutics 2010, 7, 786-794；Koynova, R et al. Mol. Pharmaceutics 2009, 6, 951-958）。目前的研究结果首次证明，在纯合成阳离子两亲物中观察到的这种转染增强不对称烃链的影响也适用于用食品级油的天然不对称脂肪酰基链设计的阳离子两亲物。在此，我们证明利用食品级椰子油的天然脂肪酰基链不对称性设计的阳离子两亲物的细胞毒性较小，并且可以选择性地将基因递送至小鼠肺部。尽管月桂酰链是椰子油的主要脂肪酰基链，但此类阳离子两亲物的体外和体内基因转移效率均明显优于其纯二月桂酰类似物（> 4 倍）。涉及荧光共振能量转移（FRET）技术的机理研究表明，椰子两亲物的阳离子脂质体比对称二月桂酰类似物具有更高的生物膜融合性。 AFM 研究揭示了椰子两亲物脂质体的明显融合非层状结构。 FRET 和细胞摄取研究的结果共同支持这样的观点：椰子两亲物 1 脂质体的融合性更强，导致更高的细胞摄取可能在使椰子两亲物转染能力方面发挥主导作用。
Recent structure activity studies have revealed a dramatic influence of hydrophobic chain asymmetry in enhancing gene delivery efficacies of synthetic cationic amphiphiles (Nantz, M. H. et al. Mol. Pharmaceutics 2010, 7, 786-794; Koynova, R et al. Mol. Pharmaceutics 2009, 6, 951-958). The present findings demonstrate for the first time that such a transfection enhancing influence of asymmetric hydrocarbon chains observed in pure synthetic cationic amphiphiles also works for cationic amphiphiles designed with natural, asymmetric fatty acyl chains of a food-grade oil. Herein, we demonstrate that cationic amphiphiles designed with the natural fatty acyl chain asymmetry of food-grade coconut oil are less cytotoxic and deliver genes selectively to mouse lung. Despite lauroyl chains being the major fatty acyl chains of coconut oil, both the in vitro and In vivo gene transfer efficiencies of such cationic amphiphiles were found to be remarkably superior (> 4-fold) to those of their pure dilauroyl analogue. Mechanistic studies involving the technique of fluorescence resonance energy transfer (FRET) revealed higher biomembrane fusibility of the cationic liposomes of the coconut amphiphiles than that of the symmetric dilauroyl analogue. AFM study revealed pronounced fusogenic nonlamellar structures of the liposomes of coconut amphiphiles. Findings in the FRET and cellular uptake study, taken together, support the notion that the higher cellular uptake resulting from the more fusogenic nature of the liposomes of coconut amphiphiles 1 are likely to play a dominant role in making the coconut amphiphiles transfection competent.