Abstract：
Brain-targeted drug delivery poses a great challenge due to the blood-brain barrier (BBB). In a previous study, we have developed a peptide-modified stealth liposome (SP-sLip) to enhance BBB penetration via the adsorption of apolipoproteins in plasma. SP is an 11-amino acid peptide derived from 25 to 35 of the Amyloid β peptide (Aβ1-42), which is a nature ligand of apolipoproteins. Although freshly prepared SP-sLip exhibited efficient brain targeting performance, it occured self-aggregation and instability in storage. In this study, we developed a D-peptide ligand according to the reverse sequence of SP with D-amino acids, known as DSP, to improve the stability in storage. Notably, DSP exhibited a reduced tendency for self-aggregation and improved stability in comparison to the SP peptide. Furthermore, compared to SP-sLip, DSP-modified sLip (DSP-sLip) demonstrated enhanced stability (>2 weeks), prolonged blood circulation (AUC increased 44.4%), reduced liver and spleen accumulation (reduced by 2.23 times and 1.86 times) with comparable brain-targeting efficiency. Similar to SP-sLip, DSP-sLip selectively adsorbed apolipoprotein A1, E, and J in the blood to form functionalized protein corona, thus crossing BBB via apolipoprotein receptor-mediated transcytosis. These findings underscored the importance of ligand stability in the in vitro and in vivo performance of brain-targeted liposomes, therefore paving the way for the design and optimization of efficient and stable nanocarriers.
摘要：
由于血脑屏障（BBB），脑靶向药物递送提出了巨大的挑战。在之前的研究中,我们开发了一种肽修饰的隐形脂质体（SP-sLip），通过血浆中载脂蛋白的吸附来增强BBB的渗透。SP是源自淀粉样蛋白β肽（Aβ1-42）的25至35的11个氨基酸的肽，这是载脂蛋白的天然配体。尽管SP-sLip表现出有效的脑靶向性能，自聚合和存储的不稳定性限制了其进一步的应用。在这项研究中,我们根据具有D-氨基酸的SP的反向序列开发了D-肽配体，被称为DSP，来解决问题。值得注意的是,与SP肽相比,DSP表现出降低的自聚集倾向和优异的稳定性。此外，与SP-sLip相比，DSP修饰的sLip（DSP-sLip）显示出增强的稳定性（>2周），延长血液循环（AUC增加44.4%），减少肝脏和脾脏积累（减少2.23倍和1.86倍），具有相当的脑靶向效率。类似于SP-sLip,DSP-sLip选择性吸附载脂蛋白A1，E，和J在血液中形成功能化的蛋白质电晕，从而通过载脂蛋白受体介导的胞吞作用穿过BBB。这些发现强调了配体稳定性在脑靶向脂质体的体外和体内性能中的重要性。从而为高效稳定的纳米载体的设计和优化铺平了道路。
