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Enhanced blood-brain barrier transmigration using a novel transferrin embedded fluorescent magnetoliposome nanoformulation

机译:使用新型转铁蛋白嵌入的荧光磁脂质体纳米制剂增强的血脑屏障迁移

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摘要

The blood-brain barrier (BBB) is considered as the primary impediment barrier for most drugs. Delivering therapeutic agents to the brain is still a big challenge to date. In our study, a dual mechanism, receptor mediation combined with external non-invasive magnetic force, was incorporated into ferrous magnet-based liposomes for BBB transmigration enhancement. The homogenous magnetic nanoparticles (MNPs), with a size of ~10 nm, were synthesized and confirmed by TEM and XRD respectively. The classical magnetism assay showed the presence of the characteristic superparamagnetic property. These MNPs encapsulated in PEGylated fluorescent liposomes as magneto-liposomes (MLs) showed mono-dispersion, ~130 ± 10 nm diameter, by dynamic laser scattering (DLS) using the lipid-extrusion technique. Remarkably, a magnetite encapsulation efficiency of nearly 60% was achieved. Moreover, the luminescence and hydrodynamic size of the MLs was stable for over two months at 4 °C. Additionally, the integrity of the ML structure remained unaffected through 120 rounds of circulation mimicking human blood fluid. After biocompatibility confirmation by cytotoxicity evaluation, these fluorescent MLs were further embedded with transferrin and applied to an in vitro BBB transmigration study in the presence or absence of external magnetic force. Comparing with magnetic force- or transferrin receptor-mediated transportation alone, their synergy resulted in 50-100% increased transmigration without affecting the BBB integrity. Consequently, confocal microscopy and iron concentration in BBB-composed cells further confirmed the higher cellular uptake of ML particles due to the synergic effect. Thus, our multifunctional liposomal magnetic nanocarriers possess great potential in particle transmigration across the BBB and may have a bright future in drug delivery to the brain.
机译:血脑屏障(BBB)被认为是大多数药物的主要障碍。迄今为止,将治疗剂运送到大脑仍然是一个巨大的挑战。在我们的研究中,受体介导与外部非侵入性磁力相结合的双重机制被纳入基于铁磁体的脂质体中,以增强BBB转运。分别通过TEM和XRD合成并确认了大小约为10 nm的均质磁性纳米颗粒(MNP)。经典的磁化验表明存在特征超顺磁特性。这些MNP以磁性脂质体(MLs)的形式封装在聚乙二醇化荧光脂质体中,通过脂质挤压技术通过动态激光散射(DLS)表现出直径约为130±10 nm的单分散。值得注意的是,磁铁矿的包封效率达到了近60%。此外,ML的发光和流体力学尺寸在4°C下稳定了两个月以上。此外,通过模拟人体血液的120轮循环,ML结构的完整性不会受到影响。通过细胞毒性评估确认生物相容性后,将这些荧光ML进一步与运铁蛋白包埋,并在存在或不存在外部磁力的情况下应用于体外BBB迁移研究。与单独的磁力或转铁蛋白受体介导的转运相比,它们的协同作用导致转运增加50-100%,而不会影响BBB的完整性。因此,共聚焦显微镜和BBB组成的细胞中的铁浓度进一步证实了由于协同作用,细胞对ML颗粒的摄取更高。因此,我们的多功能脂质体磁性纳米载体在通过BBB的粒子迁移中具有巨大潜力,并且在向大脑的药物输送方面可能具有光明的前景。

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