<i>In vivo</i> biodistribution of venlafaxine-PLGA nanoparticles for brain delivery: plain vs. functionalized nanoparticles

<b>Background</b>: Actually, no drugs provide therapeutic benefit to approximately one-third of depressed patients. Depression is predicted to become the first global disease by 2030. So, new therapeutic interventions are imperative. <b>Research design and methods</b>: Venlafaxine-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) were surface functionalized with two ligands against transferrin receptor to enhance access to brain. An <i>in vitro</i> blood–brain barrier model using hCMEC/D3 cell line was developed to evaluate permeability. <i>In vivo</i> biodistribution studies were performed using C57/bl6 mice. Particles were administered intranasal and main organs were analyzed. <b>Results</b>: Particles were obtained as a lyophilized powder easily to re-suspend. Internalization and permeability studies showed the following cell association sequence: TfRp-NPs&gt;Tf-NPs&gt;plain NPs. Permeability studies also showed that encapsulated VLF was not affected by P-gP pump efflux increasing its concentration in the basolateral side after 24 h. <i>In vivo</i> studies showed that 25% of plain NPs reach the brain after 30 min of one intranasal administration while less than 5% of functionalized NPs get the target. <b>Conclusions</b>: Plain NPs showed the highest ability to reach the brain vs. functionalized NPs after 30 min by intranasal administration. We suggest plain NPs probably travel via direct nose-to-brian route whereas functionalized NPs reach the brain by receptor-mediated endocytosis.

**研究背景**：目前约有三分之一的抑郁症患者无法从现有药物中获得治疗获益。据预测，到2030年抑郁症将成为全球首位高发疾病，因此开发新型治疗干预手段迫在眉睫。
**研究设计与方法**：以载有文拉法辛（Venlafaxine）的聚乳酸-羟基乙酸共聚物（PLGA）纳米粒（NPs）为载体，通过两种靶向转铁蛋白受体的配体对其表面进行功能化修饰，以增强其脑部递送效率。采用hCMEC/D3细胞系构建体外血脑屏障模型，用于评估纳米粒的通透性能；选用C57/bl6小鼠开展体内生物分布研究，通过鼻内给药方式给予纳米粒，并对主要脏器进行分析检测。
**研究结果**：纳米粒以冻干粉末形式制备获得，可轻松重悬使用。细胞摄取与通透性能研究显示，纳米粒的细胞结合能力排序为：转铁蛋白受体靶向纳米粒（TfRp-NPs）＞转铁蛋白修饰纳米粒（Tf-NPs）＞空白纳米粒（plain NPs）。通透性能研究同时表明，包载的文拉法辛（VLF）未受到P-糖蛋白（P-gP）外排泵的影响，在给药24小时后，其在基底外侧膜侧的浓度有所提升。体内研究结果显示，单次鼻内给药30分钟后，有25%的空白纳米粒可抵达脑部，而功能化修饰纳米粒的脑部靶向效率不足5%。
**研究结论**：单次鼻内给药30分钟后，空白纳米粒的脑部递送效率高于功能化修饰纳米粒。我们推测，空白纳米粒可能通过鼻-脑直接通路抵达脑部，而功能化修饰纳米粒则通过受体介导的内吞作用进入脑部。