Abstract

The current study aimed to develop alendronate (ALN)-loaded chitosan nanoparticles (CS-ALN-NPs) for brain delivery via intranasal route. These CS-ALN-NPs reduced the peripheral side effects and released ALN directly to brain. These NPs were formulated through ionic gelation technique by mixing sodium tripolyphosphate (1.5 mg/ml) in ALN-CS (1.75 mg/ml) solution. CS-ALN-NPs attained 135.75 ± 5.80 nm, 0.21 ± 0.013, 23.8 ± 3.69 mV, 72.46 ± 0.879% and 30.92 ± 0.375% mean particle size, PDI, zeta potential, entrapment efficiency and loading capacity, respectively. Furthermore, the TEM and SEM analysis of CS-ALN-NPs, respectively, revealed the particle size in 200 nm range and spherical shape. The in vitro and ex vivo release profile revealed a sustained drug release through CS-ALN-NPs as compared to pure drug solution. Also these NPs acquired a high concentration in mice brain and better pharmacokinetic profile than ALN solution (intranasal) CS-ALN-NPs were then evaluated against intracerebroventricular-streptozotocin (ICV-STZ) induced Alzheimer’s disease (AD)-like pathologies in mice. The intranasal CS-ALN-NP altered the ICV-STZ induced neurobehavioral, neurochemical and histopathological changes in mice. These effects were significant to those of ALN solution (intranasal). The neuroprotective potential of CS-ALN-NPs observed in ICV-STZ mice model of AD may be a promising brain-targeted delivery system for AD treatment along with further extensive exploration at both pre-clinical and clinical edge.

• HIGHLIGHTS

• CS-ALN-NPs were developed and optimised to overcome the poor pharmacokinetic profile and associated side effects of ALN

• CS-ALN-NPs showed particle size within 200 nm range as well as controlled and sustained release in in vitro release study

• These optimised NPs of ALN attained higher brain:blood ratio and better pharmacokinetic profile (Cmax, tmax, AUC)

• CS-ALN-NPs markedly altered ICV STZ induced impairment in cognitive functions of mice and changes in APP processing, neuroinflammatory cytokines and other biochemical parameters in mice hippocampus

摘要

目前的研究旨在开发载有阿仑膦酸盐 (ALN) 的壳聚糖纳米颗粒 (CS-ALN-NPs)，用于通过鼻内途径进行脑递送。这些 CS-ALN-NP 减少了外周副作用并将 ALN 直接释放到大脑。通过将三聚磷酸钠 (1.5  mg/ml) 与 ALN-CS (1.75  mg/ml) 溶液混合，通过离子凝胶技术配制这些 NP。CS-ALN-NPs 达到 135.75  ±  5.80  nm、0.21  ±  0.013、23.8  ±  3.69  mV、72.46  ±  0.879% 和 30.92  ± 分别为 0.375% 的平均粒径、PDI、zeta 电位、包封效率和负载能力。此外，CS-ALN-NPs 的 TEM 和 SEM 分析分别揭示了 200 nm 范围内的粒径 和球形。体外和离体与纯药物溶液相比，释放曲线显示通过 CS-ALN-NP 的药物持续释放。此外，这些 NPs 在小鼠大脑中获得了高浓度，并且比 ALN 溶液（鼻内）获得了更好的药代动力学特征，然后评估了 CS-ALN-NPs 对脑室内链脲佐菌素 (ICV-STZ) 诱导的小鼠阿尔茨海默氏病 (AD) 样病理的影响。鼻内 CS-ALN-NP 改变了 ICV-STZ 诱导的小鼠神经行为、神经化学和组织病理学变化。这些影响对于 ALN 溶液（鼻内）的影响是显着的。在 AD 的 ICV-STZ 小鼠模型中观察到的 CS-ALN-NPs 的神经保护潜力可能是一种有前途的用于 AD 治疗的脑靶向递送系统，以及在临床前和临床边缘的进一步广泛探索。

• 强调

• 开发和优化 CS-ALN-NP 以克服 ALN 的不良药代动力学特征和相关副作用

• CS-ALN-NPs 在体外释放研究中显示粒径在 200 nm 范围内以及受控和持续释放

• 这些经过优化的 ALN NP 获得了更高的脑血比和更好的药代动力学特征（Cmax、tmax、AUC）

• CS-ALN-NPs 显着改变 ICV STZ 诱导的小鼠认知功能损伤和小鼠海马 APP 处理、神经炎症细胞因子和其他生化参数的变化