Mahanta Arun Kumar, Chaulagain Bivek, Gothwal Avinash, Singh Jagdish
Department of Pharmaceutical Sciences, School of Pharmacy, College of Health and Human Sciences, North Dakota State University, Fargo, North Dakota 58108-6050, United States.
ACS Biomater Sci Eng. 2025 Jun 9;11(6):3533-3546. doi: 10.1021/acsbiomaterials.5c00465. Epub 2025 May 17.
Neuroinflammation induced by the accumulation of amyloid beta plaques expedites the progression of Alzheimer's disease (AD). Reducing Aβ plaques and associated neuroinflammation could potentially help to delay the progression of AD. Cannabidiol (CBD) is well-known for its antioxidant, anti-inflammatory, and neuroprotective nature, and the ApoE2 is effective in binding and clearing Aβ plaques in the brain. Therefore, codelivery of CBD and pApoE2 to the brain would be a promising therapeutic approach in developing effective therapeutics against AD. This research aims to design a nonviral delivery agent that delivers both drugs and genes to the brain through a noninvasive intranasal route. We have developed mPEG-PLGA nanoparticles coated with mannose, a brain-targeting ligand, to deliver CBD and pApoE2. The designed CBD-loaded coated nanoparticles showed an average diameter of 179.3 ± 4.57 nm and a zeta potential of 30.3 ± 6.45 mV. The coated nanoparticles prolonged the CBD release and showed a 93% release of its payload in 30 days. CBD-loaded nanoparticles, as compared to the free CBD, significantly reduced lipopolysaccharide and amyloid beta-induced inflammation in immortalized microglia cells. Cytotoxicity of the designed nanoparticles was assessed against brain endothelial cells (bEND.3) and found to be nontoxic in nature. The mannose-conjugated chitosan-coated nanoparticles were cationic and able to bind with the pApoE2, protecting the encapsulated pApoE2 from enzymatic degradation. Quantitative in vitro transfection efficiency study in primary astrocytes and primary neurons revealed that the ApoE2 expression level is significantly ( < 0.0001) higher for mPLGA-CBD-MC/pApoE2 than the control. The ApoE2 expression level in the brain of C57BL6/J mice was significantly ( < 0.0001) increased after intranasal administration of mPLGA-CBD-MC/pApoE2. Henceforth, the mannose-conjugated chitosan-coated mPLGA nanoparticles could serve as a nonviral delivery system to deliver both drugs and genes to the brain through the intranasal route for the management of AD.
由β-淀粉样蛋白斑块积累引发的神经炎症会加速阿尔茨海默病（AD）的进展。减少β-淀粉样蛋白斑块及相关神经炎症可能有助于延缓AD的进展。大麻二酚（CBD）以其抗氧化、抗炎和神经保护特性而闻名，载脂蛋白E2（ApoE2）在结合并清除大脑中的β-淀粉样蛋白斑块方面很有效。因此，将CBD和pApoE2共同递送至大脑将是开发有效抗AD疗法的一种有前景的治疗方法。本研究旨在设计一种非病毒递送剂，通过无创鼻内途径将药物和基因递送至大脑。我们已开发出用脑靶向配体甘露糖包被的甲氧基聚乙二醇-聚乳酸-羟基乙酸共聚物（mPEG-PLGA）纳米颗粒，用于递送CBD和pApoE2。所设计的负载CBD的包被纳米颗粒平均直径为179.3±4.57nm，zeta电位为30.3±6.45mV。包被纳米颗粒延长了CBD的释放，并在30天内释放了93%的负载物。与游离CBD相比，负载CBD的纳米颗粒显著降低了永生化小胶质细胞中脂多糖和β-淀粉样蛋白诱导的炎症。评估了所设计纳米颗粒对脑内皮细胞（bEND.3）的细胞毒性，发现其本质上无毒。甘露糖共轭壳聚糖包被的纳米颗粒呈阳离子性，能够与pApoE2结合，保护包裹的pApoE2不被酶降解。原代星形胶质细胞和原代神经元中的定量体外转染效率研究表明，mPLGA-CBD-MC/pApoE2的ApoE2表达水平显著高于对照组（<0.0001）。鼻内给予mPLGA-CBD-MC/pApoE后，C57BL6/J小鼠大脑中的ApoE2表达水平显著升高（<0.0001）。因此，甘露糖共轭壳聚糖包被的mPLGA纳米颗粒可作为一种非病毒递送系统，通过鼻内途径将药物和基因递送至大脑，用于AD的治疗。
