Department of Pharmaceutical Sciences, School of Pharmacy, College of Health Professions, North Dakota State University, Fargo, ND, USA.
Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA.
Nanomedicine. 2020 Aug;28:102225. doi: 10.1016/j.nano.2020.102225. Epub 2020 May 30.
The limitations imposed on brain therapy by the blood-brain barrier (BBB) have warranted the development of carriers that can overcome and deliver therapeutic agents into the brain. We strategically designed liposomal nanoparticles encasing plasmid DNA for efficient transfection and translocation across the in vitro BBB model as well as in vivo brain-targeted delivery. Liposomes were surface modified with two ligands, cell-penetrating peptide (PFVYLI or R9F2) for enhanced internalization into cells and transferrin (Tf) ligand for targeting transferrin-receptor expressed on brain capillary endothelial cells. Dual-modified liposomes encapsulating pDNA demonstrated significantly (P < 0.05) higher in vitro transfection efficiency compared to single-modified nanoparticles. R9F2Tf-liposomes showed superior ability to cross in vitro BBB and, subsequently, transfect primary neurons. Additionally, these nanoparticles crossed in vivo BBB and reached brain parenchyma of mice (6.6%) without causing tissue damage. Transferrin receptor-targeting with enhanced cell penetration is a relevant strategy for efficient brain-targeted delivery of genes.
血脑屏障（BBB）对脑部治疗的限制促使人们开发能够穿透并将治疗剂递送到大脑的载体。我们策略性地设计了包封质粒 DNA 的脂质体纳米颗粒，以实现高效转染和跨体外 BBB 模型以及体内脑靶向递药。脂质体表面用两种配体进行修饰，即细胞穿透肽（PFVYLI 或 R9F2）以增强细胞内化，以及转铁蛋白（Tf）配体以靶向脑毛细血管内皮细胞上表达的转铁蛋白受体。与单修饰纳米颗粒相比，包封 pDNA 的双修饰脂质体显示出显著更高的体外转染效率（P<0.05）。R9F2Tf-脂质体显示出优越的体外 BBB 穿透能力，并随后转染原代神经元。此外，这些纳米颗粒穿透体内 BBB 并到达小鼠脑实质（6.6%）而不引起组织损伤。增强细胞穿透的转铁蛋白受体靶向是实现基因高效脑靶向递药的相关策略。
