## 4 Brain Targeting  
The blood-brain barrier (BBB) hinders the successful delivery of potential and potent therapeutics to the brain. There are three strategies used to deliver therapeutics to the brain [36]: (i) The first strategy is to bypass the BBB by using other routes of drug delivery such as drug-encapsulated wafers inserted in the tumor cavity during surgical resection of the brain tumors, facial intradermal injection, and drugs administered via the nasal cavity; (ii) by interrupting the BBB using surfactants and hyperosmotic agents, cell-penetrating peptides, magnetic nanoparticle-induced hyperthermia; and (iii) by the application of endogenous transporters and receptors for enhanced neural penetration of drugs in a non-invasive approach. Passive targeting is the most commonly used approach to deliver nanoparticles into brain tumors for diagnostic and therapeutic applications. The nose-to-brain transport enhance drug targeting with reduced systemic side effects [37]. Bypassing the BBB and the direct targeting of the brain via olfactory and trigeminal neural pathways is a crucial approach for the delivery of therapeutics to the brain [38]. The transport of therapeutics via the olfactory mucosa pathway is rapid and it is achieved by drug administration via the nasal cavity. However, volume in the range of 25-200 \(\mu\)L can be intranasally administered resulting in the limitation of the concentration of drug that can be transported into the brain from the nasal cavity [39]. Trigeminal nerve pathway is connected to some parts of the brain such as the pons, medulla, and spinal cord. The trigeminal nerve has three branches known as the mandibular, ophthalmic, and maximally. However, only the ophthalmic and maxillary branches have been reported to be useful for drug delivery to the brain from the nose resulting from the neurons in this branches that pass via the nasal mucosa [40]. Drug uptake via nose through the trigeminal nerve pathway is by either intracellular transport or endocytosis. When a drug is administered intranasally, it can diffuse via the nasal mucosa to the branches of trigeminal nerves present in the olfactory and respiratory regions. The drug is then transported through the brain stem to the axonal route. It has also been reported that the trigeminal nerve that passes through the cribiform plate is involved in the delivery of drugs from the nose to the forebrain [41]. Research reports also further indicated that after the absorption of the drug from nasal cavity through the mucus, several mechanisms are involved when the drug is transported through mucosa such as the paracellular, transcellular, carrier-mediated transport, receptor-mediated transport, and transcytosis [42; 43]. Drug administered intranasally are also transported via the olfactory pathway to the olfactory mucosa which contains olfactory receptor neurons. The drug molecules are transported to the olfactory receptor neurons by paracellullar or transcellular mechanism. Factors such as the integrity of nasal epithelium, the tight junctions, space between the epithelial cells, etc., enhance drug uptake via paracellular mechanism [40]. The drug is transported via the axon and nerve bundle across the cribiform plate to the olfactory bulb on the surface of the brain. The drug transported from the olfactory nerves can enter the cerebrospinal fluid (CSF) and olfactory bulb to the brain by combining with the interstitial fluid in the brain [44]. The transportation of the drug from the nasal cavity to the brain via olfactory transport is rapid. The transportation of drug molecule via the olfactory pathway to the brain occurs by two known pathways, such as the intraneuronal and extra-neuronal pathways. In the intra-neuronal pathway, axonal transport is involved, and the drug transportation is slow. In the extra-neuronal pathway, drug transport to the brain via perineural channels and it is rapid [40].