## 5 Chitosan Nanocarriers in Brain Targeting
### In Situ Gel  
Chitosan-based in situ gels are useful in biomedical applications, such as regeneration medicine and drug delivery systems. The effect of cross-linking of polymer chains in in situ gels has been  
\begin{table}
\begin{tabular}{c c c c c} \hline \hline
**Drugs** & **Composition** & **Physicochemical Properties** & **Biological Studies Outcome** & **References** \\ \hline \multirow{8}{*}{Saxagliptin} & \multirow{8}{*}{Chitosan, valine} & \multirow{8}{*}{Good stability} & 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 C\({}_{\text{max}}\) of the free drug (51 ng/mL). The (AUC\({}_{\text{o}}\)) of the drug from the NPs was over 3.42 times lower than the free drug. & \multirow{8}{*}{[70]} \\  & & & In vitro drug release was an initial burst release followed by a sustained drug release mechanism over a period of 10 h. 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. & \multirow{8}{*}{[73]} \\  & & & High drug release occurred in vitro and a high concentration of galantamine was observed in the brain in vivo. & \\ \hline \multirow{2}{*}{Carbamazepine} & \multirow{2}{*}{Chitosan} & \multirow{2}{*}{Particle size of 219 nm with 35\% drug loading and 80\% entrapment efficiency} & High drug concentration in the brain. & \multirow{2}{*}{[76]} \\  & & & Improved internalization of the NPs in the C6 glioma cell line in vitro. Retained magnetic properties of the NPs after internalization into the cell. & \\ \hline \multirow{8}{*}{Docetaxel} & \multirow{8}{*}{D-\(\alpha\)-tocopherol polyethylene glycol 1000 succinate, chitosan, transferrin} & \multirow{8}{*}{Particle size of 130–300 nm} & The in vitro cytotoxic effect of the formulation on C6 glioma cell lines was lower when compared to \multirow{8}{*}{[77]} \\  & & & & [PERSON]\({}^{\text{Inv. }}\) The nanoparticles with transferrin exhibited a high AUC with a prolonged circulation in blood when compared to \multirow{8}{*}{[78]} \\  & & & & [PERSON]\({}^{\text{Inv. }}\) The NPs were cytotoxic against C6 glioma cells line and were able to overcome MDCKII-MDR1 cell barrier. & \\ \hline \multirow{8}{*}{Methotrexate} & \multirow{8}{*}{Chitosan, Tween 80, Poly(lactide-co-glycolide)} & \multirow{8}{*}{Particle size range of 177–408 nm.} & The NPs were cytotoxic against C6 glioma cells line and were able to overcome MDCKII-MDR1 cell barrier. & \\ \cline{1-1} \cline{3-3} \cline{5-3} \cl  
reported to influence their external stimuli such as temperature and pH, and these effects have been studied extensively. Natural and synthetic polymers are used for the production of in situ gels [87]. In the last decade, in situ gels have been designed for intranasal delivery of therapeutics. Different biodegradable polymers have been used for the development of in situ gel formulations such as alginic acid, gellan gum, xyloglucan, chitosan, pectin, poly(D-lactic acid), etc. In situ gel formulations have unique advantages such as sustained drug action when compared to the conventional therapeutics [88]. Chitosan-based in situ gels have been developed for the intranasal administration of drugs (Table 2). Chitosan/glycerophosphate-based hydrogels are effectively used in the delivery of growth factors, proteins/peptides, drugs, etc. [88; 89]. Injectable thermosensitive chitosan-gelatin-\(\beta\)-Glycerol phosphate hydrogels loaded with ferulic acid inhibited neurological oxidative stress and was biocompatible with Neuro-2a cell [90]. The biodegradation and gelation capability of the injectable gels influenced the drug release ability of the system. Chitosan-alginate hydrogel showed an improved alternative for neural tissue engineering [91]. The hydrogel was hydrophilic with a porous structure.