Catalan Institute of Nanoscience and Nanotechnology (ICN2), CSIC and BIST, Campus UAB, 08193 Bellaterra, Barcelona, Spain.
Institut de Biotecnologia i de Biomedicina (IBB), Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.
ACS Nano. 2021 May 25;15(5):8592-8609. doi: 10.1021/acsnano.1c00453. Epub 2021 Apr 22.
Dopamine (DA) is one of the main neurotransmitters found in the central nervous system and has a vital role in the function of dopaminergic (DArgic) neurons. A progressive loss of this specific subset of cells is one of the hallmarks of age-related neurodegenerative disorders such as Parkinson's disease (PD). Symptomatic therapy for PD has been centered in the precursor l-DOPA administration, an amino acid precursor of DA that crosses the blood-brain barrier (BBB) while DA does not, although this approach presents medium- to long-term side effects. To overcome this limitation, DA-nanoencapsulation therapies are actively being searched as an alternative for DA replacement. However, overcoming the low yield of encapsulation and/or poor biodistribution/bioavailability of DA is still a current challenge. Herein, we report the synthesis of a family of neuromelanin bioinspired polymeric nanoparticles. Our system is based on the encapsulation of DA within nanoparticles through its reversible coordination complexation to iron metal nodes polymerized with a bis-imidazol ligand. Our methodology, in addition to being simple and inexpensive, results in DA loading efficiencies of up to 60%. , DA nanoscale coordination polymers (DA-NCPs) exhibited lower toxicity, degradation kinetics, and enhanced uptake by BE(2)-M17 DArgic cells compared to free DA. Direct infusion of the particles in the ventricle of rats showed a rapid distribution within the brain of healthy rats, leading to an increase in striatal DA levels. More importantly, after 4 days of nasal administrations with DA-NCPs equivalent to 200 μg of the free drug per day, the number and duration of apomorphine-induced rotations was significantly lower from that in either vehicle or DA-treated rats performed for comparison purposes. Overall, this study demonstrates the advantages of using nanostructured DA for DA-replacement therapy.
多巴胺（DA）是中枢神经系统中发现的主要神经递质之一，在多巴胺能（DArgic）神经元的功能中起着至关重要的作用。这种特定细胞亚群的逐渐丧失是与年龄相关的神经退行性疾病（如帕金森病（PD））的标志之一。PD 的症状治疗一直集中在前体 l-DOPA 的给药上，l-DOPA 是 DA 的氨基酸前体，可以穿过血脑屏障（BBB），而 DA 则不能，尽管这种方法存在中到长期的副作用。为了克服这一限制，正在积极寻找 DA 纳米封装疗法作为 DA 替代物的替代方法。然而，克服 DA 封装的低产量和/或差的生物分布/生物利用度仍然是当前的挑战。在此，我们报告了一系列神经黑色素仿生聚合物纳米颗粒的合成。我们的系统基于通过可逆配位络合将 DA 封装在纳米颗粒内，该配位络合通过铁金属节点聚合双咪唑配体进行。除了简单且廉价之外，我们的方法还导致高达 60%的 DA 负载效率。与游离 DA 相比，DA 纳米级配位聚合物（DA-NCPs）表现出更低的毒性、降解动力学和增强的被 BE(2)-M17 DArgic 细胞摄取。将这些颗粒直接注入大鼠脑室中，发现它们在健康大鼠的大脑中迅速分布，导致纹状体 DA 水平升高。更重要的是，与载体或 DA 处理的大鼠相比，每天通过鼻内给予相当于 200μg 游离药物的 DA-NCPs4 天后，阿扑吗啡诱导的旋转次数和持续时间明显减少。总体而言，这项研究表明使用纳米结构 DA 进行 DA 替代治疗的优势。
