## 5 Chitosan Nanocarriers in Brain Targeting
### Nanoparticles (NPs)
An ionic gelation method was used to develop chitosan nanoparticles loaded with donepezil for enhanced bioavailability and the uptake of donepezil to the brain via intranasal administration [67]. Donepezil is a drug used to treat Alzheimer disease [68]. Intranasal administration of the drug-loaded NPs in rats resulted in a high percentage of radioactivity per gram in the brain when compared to the donepezil solution. The drug-loaded NPs exhibited a high drug transport efficiency and direct transport percentages of 191.4% and 1834.5%, respectively. These results indicate that intranasal administration of chitosan nanoparticles resulted in a significant brain targeting efficiency, indicating that NPs are promising approach for the treatment of AD [67]. A spontaneous emulsification method was used to prepare chitosan nanoparticles containing rivastigmine [69]. The formulation exhibited a biphasic drug release and the mechanism of drug release from the nanoparticles was diffusion controlled. Coating the nanoparticles with 1% polysorbate 80 influenced the uptake of nanoparticles in different organs and reduced the drug release from the NPs [69]. Carbodinide chemistry was employed for the synthesis of chitosan-valine conjugate loaded with saxagliptin, a dipeptidyl peptidase-4 enzyme inhibitor molecule used for the treatment of Alzheimer disease [70]. In vivo studies in rats indicated a good stability of the nanoparticles in the plasma with a release of only 2.5 ng/mL of the drug which is less than the Cmax of the free drug (51 ng/mL). The brain uptake studies indicated the accumulation of 53 ng/mL of the drug from the nanoparticles 24 h after the administration of the NPs formulation when compared to the free drug which was not detected. The (AUC0-t) of the drug from the NPs was over 3.42 times lower when compared to the free drug, which revealed the stability of the prepared formulation in the plasma [70]. [PERSON] et al. prepared chitosan nanoparticles loaded with peptides for brain targeting. The drug uptake from the nanoparticles was significant in the brain when compared to the liver and spleen indicating a targeted delivery of the drug to the brain [71]. Chitosan nanoparticles are suitable for non-invasive routes of drug administration such as nasal route, which results from the absorption-enhancing effect of chitosan [72]. A conventional emulsification crosslinking method was used to prepare chitosan-based nanoparticles loaded with ropinirole hydrochloride for enhanced brain uptake. In vitro drug release from the nanoparticles indicated an initial burst release of the drug followed by a sustained drug release mechanism over a period of 10 h. The drug release was rapid from the nanoparticles with higher drug content compared to NPs with lower drug content. The drug release profile was sustained in the uncoated drug-loaded chitosan nanoparticles with a decreased drug-to-polymer ratio. The thickness of the polymeric matrix of the uncoated drug-loaded chitosan NPs influenced the drug release profile which was dominated with a slow rate of drug diffusion. The coated nanoparticles were stable over a period of three months in storage. A high drug concentration in the brain with low drug concentrations in vital organs such as the liver, kidney, and spleen after 1 h intravenous administration of the drug-loaded coated NPs when compared to the uncoated drug-loaded NPs and free drug was significant in vivo. These findings suggest that the surface-coated drug-loaded chitosan nanoparticles can improve drug uptake in the brain [73]. [PERSON] et al. developed chitosan NPs loaded with galantamine and coated with polysorbate 80. The NPs were characterized by spherical shape and a size of 62 nm with a maximum drug entrapment of 68%. Over a period of 12 h, 97% of the drug was released. A high concentration of galantamine in the brain revealed the potential of NPs for the treatment of [PERSON]'s disease [74].