克服血脑屏障(BBB)仍然是关于药物递送至脑的重大挑战。通过掺入靶向配体,通过仔细调整颗粒大小,可以定制纳米载体以改善药物递送。在这些靶向配体中,转铁蛋白由于其受体的高表达水平而脱颖而出(即,转铁蛋白受体)在BBB上。多孔硅纳米粒子(pSiNPs)是一种有前途的药物纳米载体,由于其可生物降解性,生物相容性,和特殊的药物装载能力。然而,深入了解最佳纳米颗粒尺寸和转铁蛋白表面密度,为了最大限度地渗透BBB,仍然缺乏。为了解决这个差距,使用具有甲氧基或/和羧基末端基团的双官能聚(乙二醇)接头合成多种pSiNP库。这些变化使我们能够探索除了颗粒大小之外的不同转铁蛋白表面密度。这些参数对细胞关联的影响,摄取,使用多个复杂程度越来越高的体外系统研究了永生化人脑微血管内皮细胞(hCMEC/D3)中的胞吞作用。这些系统包括:2D细胞培养,静态Transwell模型,和动态BBB芯片模型。我们的结果揭示了配体表面密度和pSiNPs的大小对它们穿透BBB的能力的显著影响,其中中等水平的转铁蛋白密度和较小的pSiNP在体外表现出最高的BBB转运效率。此外,测试的体外试验之间出现了显著的差异,进一步强调使用更多生理相关测定法的必要性,例如微流控BBB-on-a-chip模型,用于纳米载体测试和评估。
Overcoming the blood-brain barrier (BBB) remains a significant challenge with regard to drug delivery to the brain. By incorporating targeting ligands, and by carefully adjusting particle sizes, nanocarriers can be customized to improve drug delivery. Among these targeting ligands, transferrin stands out due to the high expression level of its receptor (i.e., transferrin receptor) on the BBB. Porous silicon nanoparticles (pSiNPs) are a promising drug nanocarrier to the brain due to their biodegradability, biocompatibility, and exceptional drug-loading capacity. However, an in-depth understanding of the optimal nanoparticle size and transferrin surface density, in order to maximize BBB penetration, is still lacking. To address this gap, a diverse library of pSiNPs was synthesized using bifunctional poly(ethylene glycol) linkers with methoxy or/and carboxyl terminal groups. These variations allowed us to explore different transferrin surface densities in addition to particle sizes. The effects of these parameters on the cellular association, uptake, and transcytosis in immortalized human brain microvascular endothelial cells (hCMEC/D3) were investigated using multiple in vitro systems of increasing degrees of complexity. These systems included the following: a 2D cell culture, a static Transwell model, and a dynamic BBB-on-a-chip model. Our results revealed the significant impact of both the ligand surface density and size of pSiNPs on their ability to penetrate the BBB, wherein intermediate-level transferrin densities and smaller pSiNPs exhibited the highest BBB transportation efficiency in vitro. Moreover, notable discrepancies emerged between the tested in vitro assays, further emphasizing the necessity of using more physiologically relevant assays, such as a microfluidic BBB-on-a-chip model, for nanocarrier testing and evaluation.