Gothwal Avinash, Muolokwu Chinenye Edith, Chaulagain Bivek, Mahanta Arun Kumar, Singh Jagdish
Department of Pharmaceutical Sciences, School of Pharmacy, College of Health and Human Sciences, North Dakota State University, Fargo, ND 58108-6050, USA.
Department of Pharmaceutical Sciences, School of Pharmacy, College of Health and Human Sciences, North Dakota State University, Fargo, ND 58108-6050, USA.
Int J Biol Macromol. 2025 May;310(Pt 4):143542. doi: 10.1016/j.ijbiomac.2025.143542. Epub 2025 Apr 26.
The phosphorylated tau accumulation is a classical pathological hallmark of future cognitive decline and a cause of neuronal death in Alzheimer's disease (AD). In this study, we developed multi-functionalized chitosan (CS) based polymeric micelles to effectively deliver pApoE2 via intranasal administration to the brain. The CS was modified with caproic acid (CA), cell-penetrating peptide penetratin (PEN), and GLUT-1 transporter ligand mannose (MAN) for selective and enhanced delivery to the brain. The multi-functionalized Cap-g-CS-PEN-MAN polymeric micelles were ≤200 nm in size, cationic in charge, and uniformly distributed (PDI ≤ 0.3). The multi-functionalized polymeric micelles did not exhibit toxicity against bEnd.3 cells and erythrocytes up to polymer concentrations of 500 μg/mL. The Cap-g-CS-PEN-MAN /pDNA polyplex was stable against a DNase rich environment. The Cap-g-CS-PEN-MAN/pAPoE2 polyplex demonstrated elevated expression of ApoE in primary astrocytes and neurons, 9.47 ± 2.13 and 5.67 ± 2.69 ng/mg of protein, respectively. The therapeutic efficacy of the Cap-g-CS-PEN-MAN/pApoE2 polyplex was analyzed against the PS19 tauopathy mice model. Total tau burden was significantly (p ≤ 0.05) reduced by 4.09 ± 1.4 ng/mg of protein in Cap-g-CS-PEN-MAN/pApoE2 polyplex administered mice over the other groups. Phosphorylated tau pT181 level was also significantly (p ≤ 0.05) reduced in Cap-g-CS-PEN-MAN/pApoE2 polyplex administered mice over saline, pApoE2 and Cap-g-CS/pApoE2 treated groups.
磷酸化tau蛋白的积累是未来认知能力下降的经典病理标志，也是阿尔茨海默病（AD）中神经元死亡的一个原因。在本研究中，我们开发了基于多功能化壳聚糖（CS）的聚合物胶束，通过鼻内给药将pApoE2有效递送至大脑。用己酸（CA）、细胞穿透肽穿膜肽（PEN）和GLUT-1转运体配体甘露糖（MAN）对CS进行修饰，以实现对大脑的选择性和增强递送。多功能化的Cap-g-CS-PEN-MAN聚合物胶束尺寸≤200 nm，带正电荷，且分布均匀（PDI≤0.3）。在聚合物浓度高达500 μg/mL时，多功能化聚合物胶束对bEnd.3细胞和红细胞均无毒性。Cap-g-CS-PEN-MAN /pDNA多聚体在富含DNase的环境中稳定。Cap-g-CS-PEN-MAN/pAPoE2多聚体在原代星形胶质细胞和神经元中显示ApoE表达升高，分别为9.47±2.13和5.67±2.69 ng/mg蛋白质。针对PS19 tau病小鼠模型分析了Cap-g-CS-PEN-MAN/pApoE2多聚体的治疗效果。与其他组相比，给予Cap-g-CS-PEN-MAN/pApoE2多聚体的小鼠总tau负担显著（p≤0.05）降低，为4.09±1.4 ng/mg蛋白质。与生理盐水、pApoE2和Cap-g-CS/pApoE2处理组相比，给予Cap-g-CS-PEN-MAN/pApoE2多聚体的小鼠中磷酸化tau pT181水平也显著（p≤0.05）降低。
