Overexpression of the drug efflux transporter multidrug resistance-associated protein 2 (MRP2) in the gastrointestinal tract and blood-brain barrier compromises the oral delivery of drugs to the circulation system and brain in the treatment of Parkinson’s disease (PD). In this study, we aim to develop small-sized Pluronic P85/F68 micelles loaded with baicalein (B-MCs) to overcome MRP2-mediated efflux and to investigate related mechanism, as well as the anti-Parkinsonian efficacy. Spherical and sustained-release B-MCs have a mean particle size of 40.61 nm, a low critical micelle concentration (CMC) of 5.01 × 10^–3 mg/mL with an encapsulation efficiency of 95.47% and a drug loading of 7.07%. In comparison with the free baicalein, the cellular uptake and apparent permeability coefficient (P_app) of B-MCs were significantly enhanced (p < 0.01). Fluorescence resonance energy transfer (FRET) analysis indicated that micelles carrying the hydrophobic fluorophores were internalized intact, followed by a rapid release of fluorophores inside the cells, and then the released free fluorophores were transported across the cell monolayers to the basolateral side. Further study on the MRP2 inhibitory effect showed that B-MCs could reverse the MRP2-mediated efflux of baicalein via interfering with the structure and function of mitochondria, i.e., reducing mitochondrial membrane potential and intracellular ATP level and influencing the respiration chain of mitochondria. In addition, B-MCs exerted strong neuroprotective effects on zebrafish model of PD. In summary, Pluronic P85/F68 micelles could be considered as a promising drug delivery system to reverse MRP2-mediated efflux and improve the bioactivity of this MRP2 substrate, baicalein, for the treatment of PD.

中文翻译：

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黄ical素的Pluronic P85 / F68胶束可干扰线粒体以克服MRP2介导的外排并提供改善的抗帕金森病活性

胃肠道和血脑屏障中药物外排转运蛋白多药耐药相关蛋白2（MRP2）的过度表达会影响帕金森病（PD）的口服向循环系统和大脑的药物递送。在这项研究中，我们旨在开发载有黄ical素（B-MC）的小型Pluronic P85 / F68胶束，以克服MRP2介导的外排并研究相关机制以及抗帕金森氏症的功效。球形和缓释B-MC的平均粒径为40.61 nm，临界胶束浓度（CMC）低，为5.01×10 ^–3 mg / mL，包封率为95.47％，载药量为7.07％。与游离黄ical素相比，细胞摄取和表观通透性系数（P_app）B-MCs显着增强（p<0.01）。荧光共振能量转移（FRET）分析表明，携带疏水性荧光团的胶束被完整内在化，随后在细胞内迅速释放出荧光团，然后释放的游离荧光团穿过细胞单层转运至基底外侧。对MRP2抑制作用的进一步研究表明，B-MCs可以通过干扰线粒体的结构和功能，即降低线粒体膜电位和细胞内ATP水平并影响线粒体的呼吸链，从而逆转黄ical素的MRP2介导的流出。此外，B-MC对PD的斑马鱼模型具有强大的神经保护作用。总之，