Development, optimisation and evaluation of chitosan nanoparticles of alendronate against Alzheimer’s disease in intracerebroventricular streptozotocin model for brain delivery

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