Development of lactoferrin-coated multifunctional copolymer micelles to cross the blood-brain barrier
Development of lactoferrin-coated multifunctional copolymer micelles to cross the blood-brain barrier
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DOI：
10.1007/s13346-023-01432-6
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发表时间：
2023-09
影响因子：
5.4
通讯作者：
Na Ouyang;Chunhua Yang;Xia Li;Zhenting Zheng;Yuanyuan Xu;Yinan Wang;Wei Xiong;Haiqiang Wu
中科院分区：
文献类型：
--
作者：
Na Ouyang;Chunhua Yang;Xia Li;Zhenting Zheng;Yuanyuan Xu;Yinan Wang;Wei Xiong;Haiqiang Wu
血脑屏障（BBB）阻止血流中的病原体和毒素到达大脑，但也抑制旨在治疗中枢神经系统疾病（如阿尔茨海默病（AD））的药剂的递送。在这项研究中，我们制备和评价了一种新型的纳米传递载体系统组成的乳铁蛋白共轭（Lf-PIC@Se）胶束。我们使用基于COOH-PEG-PAsp-PV@Se合成的方法来制备胶束，该方法涉及自组装，然后是EDC-NHS偶联。以Lf-PIC@Se胶束为模型药物，制备了Lf-PIC@Se胶束。体外实验结果表明，Lf-PIC@Se/8胶束在中性和酸性溶液中均稳定，并证实了其在PC 12和bEND. 3细胞中的生物安全性和相容性。值得注意的是，Lf-PIC@Se/C6胶束的细胞摄取远高于PIC@Se胶束，并且通过LfR介导的内吞作用发生。Se的存在意味着Lf-PIC@Se胶束在H2 O2诱导的氧化应激下可作为ROS清除剂，抑制氧化损伤并提高线粒体膜电位。溶血测定进一步证明Lf-PIC@Se代表生物相容性载体。最后，小鼠体内实验表明，Lf-PIC@Se胶束成功地穿过了血脑屏障，证实了它们作为治疗AD和其他中枢神经系统疾病的药物递送载体的潜力。
The blood-brain barrier (BBB) prevents pathogens and toxins in the bloodstream from reaching the brain, but also inhibits the delivery of agents intended to treat central nervous system disorders, such as Alzheimer’s disease (AD). In this study, we prepared and evaluated a novel nano-delivery vehicle system composed of lactoferrin-conjugated (Lf-PIC@Se) micelles. We used a COOH-PEG-PAsp-PV@Se synthesis-based method to prepare the micelles, which involved self-assembly followed by EDC-NHS coupling. Using glutaminyl cyclase inhibitor8as a model encapsulated chemical, Lf-PIC@Se micelles achieved a good loading capacity. In vitro analysis demonstrated that Lf-PIC@Se/8micelles were stable in both neutral and acidic pH solutions in the presence or absence of H2O2, and confirmed their biosafety and compatibility in PC12 and bEND.3 cells. Notably, the cell uptake of Lf-PIC@Se/C6 micelles was much higher than that of PIC@Se micelles, and occurred through LfR-mediated endocytosis. The presence of Se meant that Lf-PIC@Se micelles acted as ROS scavengers in PC12 cells under H2O2-induced oxidative stress, which inhibited oxidative damage and increased mitochondrial membrane potential. Hemolysis assays further demonstrated that Lf-PIC@Se represent a biocompatible carrier. Finally, in vivo experiments in mice suggested that Lf-PIC@Se micelles successfully crossed the BBB, confirming their potential as vehicles for drug delivery when treating AD and other central nervous system disorders.Graphical Abstract