Reconstituted high density lipoprotein (rHDL) has been regarded as a promising brain-targeting vehicle for anti-glioma drugs under the mediation of apolipoprotein A-I (apoA-I). However, some stability issues relating to drug leakage and consequent reduced targeting efficiency in the course of discoidal rHDL (d-rHDL) circulating in blood hinder its broad application. The objective of the study was to develop a novel stabilized d-rHDL by replacing cholesterol and apoA-I with mono-cholesterol glutarate (MCG) modified apoA-I (termed as mA) and to evaluate its allosteric behavior and glioma targeting. MCG was synthesized through esterifying the hydroxyl of cholesterol with glutaric anhydride and characterized by FI-IR and 1H NMR. d-rHDL assembled with mA (termed as m-d-rHDL) presented similar properties such as minute particle size and disk-like appearance resembling nascent HDL. Morphological transformation observation and in vitro release plots convinced that the modification of cholesterol could effectively inhibit the remolding of d-rHDL. The uptake of m-d-rHDL by LCAT-pretreated bEND.3 cells was significantly higher than that of d-rHDL, thereby serving as another proof for the capability of m-d-rHDL in enhancing targeting property. Besides, apoA-I anchoring into m-d-rHDL played a critical role in the endocytosis process into bEND.3 cells and C6 cells, which implied the possibility of traversing blood brain barrier and accumulating in the brain and glioma. These results suggested that the modification toward cholesterol to improve the stability of d-rHDL is advantageous, and that this obtained m-d-rHDL revealed great potential for realization of suppressing the remolding of d-rHDL in the brain-targeted treatment of glioma for drug delivery.

中文翻译：

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由修饰的载脂蛋白 AI 组成的空间稳定的重组 HDL，可有效靶向神经胶质瘤细胞。

重组高密度脂蛋白（rHDL）被认为是载脂蛋白 AI（apoA-I）介导下的一种有前景的脑靶向抗神经胶质瘤药物载体。然而，与药物渗漏相关的一些稳定性问题以及随之而来的盘状rHDL（d-rHDL）在血液循环过程中靶向效率的降低阻碍了其广泛应用。该研究的目的是通过用单胆固醇戊二酸 (MCG) 修饰的 apoA-I（称为 mA）取代胆固醇和 apoA-I，开发一种新型稳定的 d-rHDL，并评估其变构行为和神经胶质瘤靶向。通过戊二酸酐酯化胆固醇羟基合成MCG，并通过FI-IR和1H NMR表征。与 mA 组装的 d-rHDL（称为 md-rHDL）具有相似的特性，例如微小的粒径和类似于新生 HDL 的盘状外观。形态转化观察和体外释放曲线证实胆固醇的修饰可以有效抑制d-rHDL的重塑。LCAT预处理的bEND.3细胞对md-rHDL的摄取显着高于d-rHDL，从而再次证明md-rHDL增强靶向性的能力。此外，锚定在md-rHDL上的apoA-I在bEND.3细胞和C6细胞的内吞过程中发挥了关键作用，这意味着有可能穿过血脑屏障并在大脑和神经胶质瘤中积累。这些结果表明，对胆固醇进行修饰以提高d-rHDL的稳定性是有利的，并且所获得的md-rHDL在脑胶质瘤的脑靶向治疗药物递送中显示出实现抑制d-rHDL重塑的巨大潜力。