Drug Research Program, Division of Pharmaceutical Biosciences, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5 E, 00014, Helsinki, Finland.
Pharmaceutics & Pharmacology Department, Global R&D, Santen Pharmaceutical Co., Ltd., 8916-16 Takayama-cho, Ikoma, Nara 630-0101, Japan.
Mol Pharm. 2021 Feb 1;18(2):699-713. doi: 10.1021/acs.molpharmaceut.0c00411. Epub 2020 Jul 8.
The vitreous humor is the first barrier encountered by intravitreally injected nanoparticles. Lipid-based nanoparticles in the vitreous are studied by evaluating their diffusion with single-particle tracking technology and by characterizing their protein coronae with surface plasmon resonance and high-resolution proteomics. Single-particle tracking results indicate that the vitreal mobility of the formulations is dependent on their charge. Anionic and neutral formulations are mobile, whereas larger (>200 nm) neutral particles have restricted diffusion, and cationic particles are immobilized in the vitreous. PEGylation increases the mobility of cationic and larger neutral formulations but does not affect anionic and smaller neutral particles. Convection has a significant role in the pharmacokinetics of nanoparticles, whereas diffusion drives the transport of antibodies. Surface plasmon resonance studies determine that the vitreal corona of anionic formulations is sparse. Proteomics data reveals 76 differentially abundant proteins, whose enrichment is specific to either the hard or the soft corona. PEGylation does not affect protein enrichment. This suggests that protein-specific rather than formulation-specific factors are drivers of protein adsorption on nanoparticles in the vitreous. In summary, our findings contribute to understanding the pharmacokinetics of nanoparticles in the vitreous and help advance the development of nanoparticle-based treatments for eye diseases.
玻璃体是眼内注射的纳米颗粒首先遇到的屏障。通过使用单颗粒跟踪技术评估它们的扩散，以及通过表面等离子体共振和高分辨率蛋白质组学来描述它们的蛋白质冠，来研究基于脂质的纳米颗粒在玻璃体中的情况。单颗粒跟踪结果表明，制剂在玻璃体内的迁移率取决于它们的电荷。阴离子和中性制剂是可移动的，而较大的（>200nm）中性粒子的扩散受到限制，阳离子粒子则固定在玻璃体内。PEG 化增加了阳离子和较大中性制剂的迁移率，但对阴离子和较小中性粒子没有影响。对流在纳米颗粒的药代动力学中起着重要作用，而扩散则驱动抗体的转运。表面等离子体共振研究表明，阴离子制剂的玻璃体冠稀疏。蛋白质组学数据显示 76 种差异丰度蛋白，其丰度特异性地富集在硬冠或软冠中。PEG 化不影响蛋白质的富集。这表明，在玻璃体中纳米颗粒上的蛋白质吸附是由蛋白质特异性而不是制剂特异性因素驱动的。总之，我们的发现有助于理解纳米颗粒在玻璃体内的药代动力学，并有助于推进基于纳米颗粒的眼部疾病治疗方法的发展。
