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

Graphical Abstract

Keywords:

• Alendronate
• chitosan
• intranasal
• Alzheimer’s disease
• amyloid β
• memory

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Acknowledgments

The authors are thankful to members of the Pharmaceutics lab, SPER, Jamia Hamdard for providing the necessary facilities.

Disclosure statement

All the authors declare no competing financial interest in publishing this research work.

Additional information

Funding

This study was supported by Sun Pharmaceutical Industries Ltd and Council of Scientific and Industrial Research (CSIR), India. The experimental work was carried out in the Neurobehavioral Pharmacology lab, Jamia Hamdard.