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Generally, soluble materials can enter the brain across the BBB through several pathways. Substances can diffuse into the brain either by paracellular and transcellular route. Paracellular pathway (figure 3a) transports small water-soluble molecules, but not to a great extent while transcellular pathway (figure 3b) commonly facilitates small lipophilic compounds such as alcohol and steroid hormones to enter the brain (Yan and Liu, 2012).
Compounds that are not able to diffuse across BBB need active carriers or receptor-mediated or vesicular mechanisms (adsorptive transcytosis) to move across the BBB (Yan and Liu, 2012). Active carriers selectively transport molecules such as glucose (figure 3c), with supplied energy from the ATP (Yan and Liu, 2012). However, there are efflux transporters such as ATP binding cassette (ABC) transporter P-gp and multidrug resistant protein (MRP) (figure 3d) which expel compounds, regardless the lipophilicity, from the BBB (Begley, 2004a, 2004b, Yan and Liu, 2012). This is a major obstacle for delivering drugs to the brain (Yan and Liu, 2012).
Macromolecules such as growth factors and enzymes can pass the BBB through receptor-mediated transcytosis (RMT) (figure 3e) where the molecules are engulfed by the cells within a vesicle and then passed to the other side of membrane (Yan and Liu, 2012). Ionised compounds can interact electrostatically with negatively charged plasma membrane surface (for instance, heparin sulphate proteoglycans) and thus move across the BBB via adsorptive-mediated transcytosis (AMT), or pinocytosis route (figure 3f) (Yan and Liu, 2012). In cell-mediated transcytosis (figure 3g) the immune cells such as monocytes or macrophages are utilised to pass the BBB. This route can be used for particulate carrier systems (Yan and Liu, 2012).
Figure 3.Various pathways for substances to penetrate the brain (Yan and Liu, 2012)
1.4. Strategies for Drug Delivery to Central Nervous System
In this part, available strategies for CNS drug delivery are outlined. It includes pharmacochemistry approach, alternative routes and the use of carriers.
Physicochemical Properties Optimisation
Generally, most of CNS drugs have molecular weight ranging from 150 to 500 Da and, and log P of 0.5 to 6.0 (Begley, 2004). In contrast, when a compound has a great polarity, strong Lewis bond, rotatable bonds, and potentially forms a hydrogen bond, the compound is unlikely to penetrate the brain (Begley, 2004).
Therefore, careful drug design based on the mentioned criteria might be reasonable (Begley, 2004). However, there are some limitations in increasing drug lipophilicity, including poor solubility and bioavailability, substantial plasma protein binding and liver metabolism (Begley, 2004). Computer-based study to predict the BBB permeability has been developed but it is inapplicable for predicting drug-transporters interaction (Begley, 2004).
Prodrugs and chemical delivery systems
A drug can be designed in a way that it is inactive and lipophilic when administered, so as to penetrate the brain, but following metabolism is converted to the polar and active form, allowing it to give pharmacological effect and be locked in the brain (Begley, 2004). For an instance, diacetyl morphine, a prodrug-form of morphine is developed to improve brain penetration (Begley, 2004). Following brain penetration,diacetyl morphine is transformed back to morphine, which is polar and can actively interact with its target, opioid receptor (Begley, 2004). The polarity of morphine prevents it to be discharged from the brain (Begley, 2004).
Direct injection or infusion into the brain or through CSF is useful for implant settlement or delivery of stem cells into the brain (Begley, 2004). However, the brain tissues are in high risk of damage and infection when intracerebral administration is used (Begley, 2004).
Blood-brain barrier modulation
Paracelullar pathway for drugs can be improved by widening the tight junctions (Begley, 2004).One of the techniques is termed osmotic opening, the regulation of tight junction permeability by using osmotic agent like hypertonic mannitol administered into a carotid artery(Begley, 2004). Brain penetration of methotrexate (MTX) was reported to be 10- to 100-times better with osmotic opening method (Begley, 2004). The drawback of this method is the possibility of foreign matter entry such as microorganisms during the opening of the tight junctions (Begley, 2004).
Delivery via endogenous transporters
As mentioned earlier, BBB has various transporters taking up molecules selectively into the brain (Begley, 2004). Therefore drugs can be designed to mimic the substrates of certain transporters, especially those for large neutral amino acid, or L-system, in order to have a high brain penetration (Begley, 2004). As an example, L-DOPA can be transported by the L-system due to its affinity to the L-system transporter, despite the potential competition with the other endogenous amino acids (Begley, 2004).
Inhibition of efflux mechanisms
In contrast to the aforementioned transporter, efflux transporters reject drugs form the brain (Begley, 2004). To escape these transporters, drugs can be designed to be not similar to the substrates of efflux transporters or can be delivered together with specific efflux transporter inhibitor (Begley, 2004). Cyclosporin A, probenecid, and fumitremorgin C have been used as inhibitors for Pgp, MRP, and BCRP with satisfactory results (Begley, 2004). Efflux transporter inhibitor is not recommended for long-term therapy since the down-regulated transporter might not able to prevent harmful substances to penetrate the CNS (Begley, 2004).
Cell-penetrating peptide vectors
Currently, cell-penetrating peptides have been attempted to be used as drug carrier due to its ability to pass through the cells by virtue of their structure or possibly via endocytosis (Begley, 2004). In situ brain perfusion study on rat has shown 3- to 8-fold increase of brain penetration of doxorubicin when contained in cell-penetrating peptide, penetratin and SynB1 compared to doxorubicin alone (Begley, 2004).
Liposomes and nanoparticles
Liposomes and nanoparticles can deliver drugs preferably to the brain, and by surface modification of the particulate system, such as attaching targeting moieties, the drug-containing particles can enter the CNS by a specific BBB pathway (Begley, 2004). Liposomal digoxin with OX 26 mAb on the surface have been constructed to improve brain penetration overcoming the problem that digoxin is a substrate of Pgp efflux transporter (Begley, 2004).
The olfactory route
Olfactory region is a new alternative route for CNS delivery which is fascinating due to injection-free and possibility to avoid the BBB (Chen et al., 2008). There is a growing interest of the absorption route through the nasal cavity, CSF, and finally into the CNS (Illum, 2000). A number of drugs have been administrated intranasally to target the brain, such as sulfonamides, cephalexin, progesterone, zidovudine, insulin and hyaluronidase (Illum, 2000). The various pathways for drugs to penetrate the CSF and brain through nasal route are shown on figure 6 (Illum, 2000).
Figure 6. The biodistribution of drug administered nasally to the brain tissue, CSF and systemic circulation (Illum, 2000).
Lipid soluble drugs with low molecular weight (< 500 Da) can be quickly absorbed by nasal epithelial cells with maximum concentration achieved in 1 to 20 minutes after administration (Chen et al., 2008). Some of the drug will undergo clearance by the mucociliary clearance system, some will be absorbed into the systemic circulation and cleared out of the body (Hussain et al., 1980;Illum, 2000), and some can either reach the brain via BBB or CSF, or can be expelled by the BBB and CSF back into the blood circulation (Illum, 2000).
The drug absorption by nasal route can take place transcellularly, paracelularly or through olfactory nerve (Illum, 2000). The latter allows the drug uptake by the neuron cells and transfer by intracellular axonal towards the olfactory bulb (Illum, 2000). The extent of absorption by this route is influenced by the physicochemical properties of the drug, mainly lipophilicity and molecular weight, and the formulation aspect (Illum, 2000). According to previous study, molecular weight affects nasal absorption more obviously than lipophilicity (Chen et al., 2008), being restricted to a range of 20 to 40 kDa (Sakane et al., 1995).
1.5. Intranasal Delivery for Brain Tumour
CNS delivery via nasal route can be used for brain tumor therapy (Shingaki et al., 2010). Shingaki et al. (2010) has evaluated this strategy in delivering methotrexate (MTX) on rats with brain tumour and the result showed that MTX successfully reached the CSF and CNS to a great extent and significantly inhibited in vitro growth of glioma cells. Another study examined nasal route for brain tumor chemotherapy was performed by Taki et al. (2012). Anticancer agent camptothecin in a polymeric system based on methoxy poly(ethylene glycol) /poly(ÎÂµ-caprolactone) block copolymer and Tat analog-modified, a cell penetrating peptide was delivered intranasally to rats with intracranial glioma tumors (Taki et al., 2012). Sakane et al. (1999) has developed intranasal delivery to the brain for 5-fluorouracil.
1.6. Formulation Strategy for Intranasal Preparation
Intranasal preparation for pediatric is acceptable since it is pain-free and easy to use (Wolfe and Braude, 2010). For pleasant use, drug concentration in the preparation must be adjusted to allow administration of minimum volume, preferably 0.2 to 0.3 mL for each nostril (Warrington and Kuhn, 2011).
Generally, conventional nasal preparations have low viscosity so that easily running off, resulting in short mucosal residence time and poor bioavailability (Cai et al., 2011). In situ gelling system, which is liquid upon administration but then congealed into a gel in the nasal cavity, provides a novel strategy to enhance contact with mucosa and release profile (Cai et al., 2011; Han et al. , 2008). Such preparations evolve through a solââ‚¬"gel transition which is modulated by temperature, usually at 32ââ‚¬"35ÂÂ°C (Nazar et al., 2011).
Of all the viscoelastic polymers used in pharmaceutical preparation, chitosan has a great potential since they assist drug penetration via paracelullar pathway by modulating tight junctions (Nazar et al., 2011). Besides chitosan, thermoresponsive gel of chitosan/glycerophosphatehas been designed by Chenite et al. (Nazar et al., 2011).
In addition to thermoresponsive property, mucoadhesiveness of hydrogels is beneficial to enhance mucosal contact (Bertram and Bodmeier, 2006). Bioadhesive material such as carrageenan, hydroxypropyl methylcellulose (HPMC) and sodium alginate has been used to decrease nasal mucociliary clearance of incorporated drugs (Bertram and Bodmeier, 2006).