Li Ye, Wang Chunliu, Zong Shiyu, Qi Jianping, Dong Xiaochun, Zhao Weili, Wu Wei, Fu Qiang, Lu Yi, Chen Zhongjian
J Biomed Nanotechnol. 2019 Apr 1;15(4):686-702. doi: 10.1166/jbn.2019.2724.
Nasal drug delivery is a fascinating approach to bypass the blood-brain barrier, which instead directly transports drug molecules to the brain from the nasal cavity along the olfactory and trigeminal nerves. However, the feasibility of nose-to-brain transportation of intact nanoparticles and the possible corresponding pathways remain poorly understood. The purpose of the present study is to explore the intranasal fate of curcumin (Cur)-loaded polycaprolactone nanoparticles (PCL NPs) via fluorescent bioimaging strategies. The behavior of intact nanoparticles was tracked by aggregation-caused quenching (ACQ) probes, which provide on-to-off fluorescent switching from loaded to released states. Evidence for the translocation of intact nanoparticles and Cur was collected either via live imaging or histological examination in rats after nasal administration. Intact PCL NPs, irrespective of whether or not they are PEGylated, cannot enter into the olfactory bulb from the nasal cavity, whereas free Cur molecules that are released from the nanoparticles can diffuse into the olfactory bulb. Both PCL NPs and PEGylated PCL NPs carrying Cur can permeate into the mucosa and the trigeminal nerves. Although PEGylation improves the nasal retention of NPs and mucus-penetration, it reduces permeation of NPs into the trigeminal nerves. Transportation of NPs along the trigeminal nerves is slow. Neither the carriers nor the Cur signals are found in the brain at 1 h post-administration. However, starting at 2 h post-administration, both intact nanoparticles and Cur are transported into the brainstem, as exemplified by the presence of Cur-loaded PEGylated PCL NPs. Nanoparticles reaching the brainstem can further distribute to other parts of the brain such as the middle brain. We conclude that the trigeminal nerve pathway, instead of the olfactory nerve route, dominates the nose-to-brain delivery of intact polymeric nanoparticles.
鼻腔给药是一种绕过血脑屏障的迷人方法，它能直接将药物分子从鼻腔沿嗅神经和三叉神经输送到大脑。然而，完整纳米颗粒鼻脑转运的可行性以及可能的相应途径仍知之甚少。本研究的目的是通过荧光生物成像策略探索载有姜黄素（Cur）的聚己内酯纳米颗粒（PCL NPs）的鼻腔命运。完整纳米颗粒的行为通过聚集猝灭（ACQ）探针进行追踪，该探针可提供从负载状态到释放状态的荧光开关。通过鼻腔给药后大鼠的活体成像或组织学检查收集完整纳米颗粒和Cur转运的证据。无论是否聚乙二醇化，完整的PCL NPs都不能从鼻腔进入嗅球，而从纳米颗粒中释放的游离Cur分子可以扩散到嗅球中。携带Cur的PCL NPs和聚乙二醇化PCL NPs都可以渗透到黏膜和三叉神经中。尽管聚乙二醇化提高了纳米颗粒在鼻腔的滞留率和黏液穿透性，但它降低了纳米颗粒向三叉神经的渗透。纳米颗粒沿三叉神经的转运较慢。给药后1小时在大脑中未发现载体或Cur信号。然而，从给药后2小时开始，完整的纳米颗粒和Cur都被转运到脑干，以载有Cur的聚乙二醇化PCL NPs的存在为例。到达脑干的纳米颗粒可以进一步分布到大脑的其他部位，如中脑。我们得出结论，三叉神经途径而非嗅神经途径主导了完整聚合物纳米颗粒的鼻脑递送。
