## 5 Chitosan Nanocarriers in Brain Targeting
### Nanoparticles (NPs)  
Chtosan nanoparticles (CsNPs) are excellent nanocarriers because of their unique properties such as good biocompatibility, non-toxicity, biodegradability, and cationic nature [23; 49]. Nanoparticles protect labile drugs from enzymatic degradation in the gastrointestinal tract. Chitosan nanoparticles are prepared by various methods such as sieving method, nanoprecipitation, emulsion, coacervation  
Figure 4: Diagram illustrating the nose-to-brain transport of drug molecules. Figure 3: Illustration of extracellular and intracellular pathway for nose-to-brain delivery. or precipitation, ionic gelation, and reverse micellar method, etc. [50]. CsNPs have been developed for intranasal formulations (Table 1). [PERSON] et al. optimized chitosan nanoparticles loaded with Rivastigmine for brain targeting [51]. Rivastigmine is used to treat [PERSON]'s disease. However, its poor bioavailability and limited entry into the brain resulting from its hydrophilic nature requires frequent dosing resulting in side effects such as nausea, anorexia, dysppepsia, severe bradycardia, etc. [52; 53; 54]. NPs loaded with rivastigmine were prepared by modified ionotropic gelation method to isolate high yields of stable nanoparticles. The particle size of the nanoparticles was influenced by the concentration of chitosan. The particle size of the NPs influenced their endocytosis rate across the brain capillary endothelial cells leading to the extended residence of the NPs in the blood and its capability to cross the BBB. The size of the prepared nanoparticles was optimized below 200 nm. The high positive ZP (Zeta Potential) value of the NPs also revealed the good stability, strong repulsion, and the absence of particle aggregation. The positive ZP is attributed to the positively charged chitosan on the surface of the particles. The high drug entrapment efficiency of the drug into the NPs was 96% due to the interaction between the drug and the chitosan matrix. Over 50% of the entrapped drug was released over a period of 4 h with a 20% initial burst release in 30 min which was influenced by the small size of drug molecules from the surface of the NP entrapped on the surface of the particles. T80-coated nanoparticles encapsulated with the drug enhanced the anti-amnesic effect of the drug significantly. The maximum tolerated dose suitable without any adverse side effects in vivo was 2.0 mg/kg. Encapsulation of the drug onto the nanoparticles increased the maximum tolerated dose of the drug by 10%. The uptake of the coated nanoparticles by the Sertoli cells was low, resulting in reduced toxicity of the formulation. The uncoated nanoparticles were toxic to Sertoli cells because they are prone to phagocytosis. The use of targeting ligand such as Tween 80\({}^{\text{\text  
which was administered intravenously. Over a period of 2-3 h after the intranasal administration of the formulation, the drug concentration in the brain was sustained. The C\({}_{\text{max}}\) was 2417.17 counts and the K\({}_{\text{el}}\) was 0.0696 counts/h indicating that the low C\({}_{\text{max}}\) uptake of the drug solution via intranasal is due to the rapid mucociliary clearance of the instilled drug solution while the drug-loaded NPs has an intrinsic mucoadhesive property which extends the contact time of the drug-loaded NPs with the nasal mucosa, thereby increasing the AUC (Area under curve) and C\({}_{\text{max}}\)[57]. The uptake of the nanoparticles into the brain is also due to the nano size range of the formulation and their capability to stretch the tight junctions within the nasal mucosa, revealing it is a promising approach for brain targeting that can reduce the side effects. [PERSON] et al. studied the toxic effects and biodistribution of chitosan nanoparticles. Tween 80-modified chitosan nanoparticles with particles sizes of 240 nm were prepared. The NP uptake into the brain was significant in the frontal cortex and cerebellum, 30 min after systemic injection.