## 5 Chitosan Nanocarriers in Brain Targeting
### Nanoparticles (NPs)
In the treatment of epilepsy, multi-drug resistance transporter and P-glycoprotein in the BBB hinder the successful transportation of antiepileptic drug into the brain, thereby hampering treatment. In order to enhance the efficacy of drugs used to treat epilepsy such as carbamazepine, it was loaded into carboxymethyl chitosan nanoparticles. Carbamazepine mode of action is via the stabilization of the inactivated state of sodium channels, thereby resulting in a fewer opening of these channels and less excitation of the brain cells. However, after oral administration of the drug, the drug concentration in the liver was high leading to a rapid drug clearance and a short half-life with adverse side effects [75]. In order to overcome the rapid drug clearance after oral administration, chitosan-based nanoparticles loaded with carbamazepine was developed for intranasal administration. The particle size of the formulation was 219 nm with 35% and 80% drug-loading and drug entrapment efficacy, respectively. The drug concentration in the plasma and brain was high after intranasal administration of the NPs formulation when compared to the administration of the drug solution. This result revealed the transportation of the drug to the brain tissue from the nasal cavity. The brain drug concentration was high when compared to the plasma concentration after nasal administration revealing the direct transportation of the drug from the nasal olfactory area into the brain. Other factors that influenced the high brain uptake of the drug are the use of mucoadhesive material in the formulation which extended the contact time of the formulation in the nasal mucosa. The encapsulation of drug into the nanoparticles enhanced the drug bioavailability and brain targeting by adhering to the mucosal surface, thereby improving the drug dissolution in the mucosa [76]. Chitosan-dextran superparamagnetic nanoparticles with a uniform diameter of 55 nm exhibited enhanced internalization in the U87, C6 glioma, and HeLa when compared to dextran-coated particles. The NPs toxicity profile up to a concentration of 10 \(\upmu\)g/ml was acceptable and the magnetic properties of the NPs were retained after internalization into the cell. Intravenously administered NPs in orthotopic C6 gliomas in rats resulted in an accumulation of the NPs in the tumor site, suggesting that the NPs can be used to improve the tumor imaging and for targeted delivery of chemotherapeutic agents [77]. Coating the nanoparticles with chitosan increased the charge of the nanoparticles to +19.2 mV. The increased charge of the nanoparticles enhanced their high uptake by the tumor cells. The high intracellular uptake of the particles increased the cytotoxic effects of the formulation resulting from the production of reactive oxygen species (ROS) which affected mitochondrial DNA negatively. The formulation also acted as a negative MRI (Magnetic resonance imaging) contrast agent. The registered relaxation rates in the hybrid formulation were similar to the relaxation features of the commercial NPs formulations. The composite shell between the chitosan and dextran, which was cross-linked by TPP (Triphenylphosphine), did not hinder the diffusion of protons into dephasing volume around the formulation and hence, retained the MRI contrast-enhancing properties of the particles. Intravenous administration of the formulation in vivo revealed significant accumulation of the nanoparticles in the glioma cells, which significantly enhanced the contrasts of the tumor. The cytotoxicity effect of the nanoparticles on glioma C6 cell line was 30.1%. The cytotoxic effect of the NPs was influenced by the surface area and enhanced cellular uptake of the NPs. More modifications on the surface of the nanoparticles with targeting ligands have the potential to further increase the accumulation of the particles in the glioma tissue [77].