Cationic lipids are well-known excipients for nanometric liposomal gene delivery systems. However, because of the suspected, collateral toxicity in normal cells, the use of cationic lipids for the treatment of human tumor is largely limited. Recently, we developed a glucocorticoid receptor (GR)-targeted liposomal, anticancer delivery system (DXE nano-lipoplex), which carried cationic lipid of saturated twin aliphatic chains. It exhibited efficient anti-tumor effect in aggressive and drug-resistant tumor models. Toward exploring lipoplex's human clinical use, we incorporated another nano-lipoplex (D1XE) group that carried cationic lipid with one of its aliphatic chain carrying unsaturation and compared in vivo genotoxicological profiling-based safety assessment and the respective anti-tumor efficacy of the lipoplexes. Thus, both the lipoplexes differ only by the chemical identity of one of their constituent cationic lipid. Unsaturated aliphatic chains in lipid generally impart efficient cell surface fusogenic property in lipid formulations. Herein, we report that nanoplex with unsaturated cationic lipid (D1XE) exhibited better physical appearance with less flocculent behavior than nanoplex with saturated lipid (DXE). Upon multiple injections, D1XE nanoplex imparted better tumor regression but most importantly, exhibited much lower overall toxicity (e.g. genotoxicity, weight loss, etc.) than DXE nanoplex. With a higher antitumor effect but a lower genotoxic effect, D1XE is proved to be a better nanoplex than DXE for the potential clinical trial. Thus, this study clearly delineates the importance of incorporating a constituent lipid that carries a single unsaturated aliphatic chain toward developing efficient anti-tumor nano-lipoplexes with reduced genotoxicity.

中文翻译：

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具有不饱和或饱和脂质的高效抗肿瘤纳米脂质复合物在小鼠中诱导不同的遗传毒性作用。

阳离子脂质是纳米脂质体基因递送系统的众所周知的赋形剂。然而，由于怀疑在正常细胞中具有附带毒性，因此在很大程度上限制了使用阳离子脂质治疗人类肿瘤。最近，我们开发了靶向糖皮质激素受体（GR）的脂质体抗癌递送系统（DXE纳米脂质复合物），该系统携带了饱和双脂族链的阳​​离子脂质。在侵袭性和耐药性肿瘤模型中显示出有效的抗肿瘤作用。为了探索lipoplex的人类临床用途，我们并入了另一个带有阳离子脂质的纳米脂质复合物（D1XE）组，其脂族链中的一个带有不饱和基团，并且比较了基于体内遗传毒理学分析的安全性评估以及脂质复合物的各自抗肿瘤功效。从而，两种脂质复合物的区别仅在于其组成阳离子脂质之一的化学同一性。脂质中的不饱和脂族链通常在脂质制剂中赋予有效的细胞表面融合特性。在本文中，我们报道了具有不饱和阳离子脂质（D1XE）的纳米复合物比具有饱和脂质（DXE）的纳米复合物具有更好的物理外观和更少的絮凝行为。多次注射后，D1XE纳米复合物具有更好的肿瘤消退作用，但最重要的是，其总毒性（例如遗传毒性，体重减轻等）比DXE纳米复合物低得多。具有较高的抗肿瘤作用但较低的遗传毒性作用，在潜在的临床试验中，D1XE被证明是比DXE更好的纳米复合物。从而，