Abstract：
Improving target versus off-target ratio in nanomedicine remains a major challenge for increasing drug bioavailability and reducing toxicity. Active targeting using ligands on nanoparticle surfaces is a key approach but has limited clinical success. A potential issue is the integration of targeting ligands also changes the physicochemical properties of nanoparticles (passive targeting). Direct studies to understand the mechanisms of active targeting and off-targeting in vivo are limited by the lack of suitable tools. Here, the biodistribution of a representative active targeting liposome is analyzed, modified with an apolipoprotein E (ApoE) peptide that binds to the low-density lipoprotein receptor (LDLR), using zebrafish embryos. The ApoE liposomes demonstrated the expected liver targeting effect but also accumulated in the kidney glomerulus. The ldlra-/- zebrafish is developed to explore the LDLR-specificity of ApoE liposomes. Interestingly, liver targeting depends on the LDLR-specific interaction, while glomerular accumulation is independent of LDLR and peptide sequence. It is found that cationic charges of peptides and the size of liposomes govern glomerular targeting. Increasing the size of ApoE liposomes can avoid this off-targeting. Taken together, the study shows the potential of the zebrafish embryo model for understanding active and passive targeting mechanisms, that can be used to optimize the design of nanoparticles.
摘要：
改善纳米医学中的靶标与脱靶比率仍然是提高药物生物利用度和降低毒性的主要挑战。在纳米颗粒表面上使用配体的主动靶向是关键方法,但临床成功有限。潜在的问题是靶向配体的整合也改变了纳米颗粒的物理化学性质(被动靶向)。了解体内主动靶向和脱靶机制的直接研究由于缺乏合适的工具而受到限制。这里,分析了代表性活性靶向脂质体的生物分布，用与低密度脂蛋白受体（LDLR）结合的载脂蛋白E（ApoE）肽修饰，使用斑马鱼胚胎。ApoE脂质体显示了预期的肝靶向作用，但也在肾小球中积累。开发了ldlra-/-斑马鱼以探索ApoE脂质体的LDLR特异性。有趣的是,肝脏靶向取决于LDLR特异性相互作用，而肾小球的积累与LDLR和肽序列无关。发现肽的阳离子电荷和脂质体的大小控制肾小球靶向。增加ApoE脂质体的大小可以避免这种脱靶。一起来看,这项研究表明，斑马鱼胚胎模型具有理解主动和被动靶向机制的潜力，可用于优化纳米粒子的设计。
