Brain drug delivery: Problems and prospects

Advanced pharmaceutical technology is aiming to boost drug delivery to many parts of body today. But for the scientists designing new medicines and drug delivery systems to treat various central nervous system (CNS) diseases like epilepsy, Alzheimer’s disease, schizophrenia, brain tumours, etc., the brain (Fig. 1) is proving to be a formidable challenge.

The major hiccup in drug delivery to the CNS has been the presence of highly impregnable defense, the blood brain barrier (BBB), as depicted in Fig. 2.

Drugs, that are effective against CNS diseases and reach the brain via the blood compartment, must pass through the BBB. Situated at the interface of blood and brain, the primary function of the BBB is to maintain the homoeostasis of the brain. Furthermore, the BBB is not uniform throughout the brain tissue, because the capillaries in the circumventricular organs are fenestrated. Fig. 3 gives a schematic representation of the barriers present in the CNS.

The BBB is mainly formed by brain capillary endothelial cells (BCEC), although other cell types, as described below, also play a vital role in the function of the BBB:

Astrocytes form the structural framework for the neurons and control their biochemical environment. The ‘foot processes’ or ‘limbs’ of astrocytes spread out, abutting one another, to encapsulate the capillaries.

Oligodendrocytes are responsible for the formation and maintenance of the myelin sheath, which surround the axons and is essential for the fast transmission of action potential by salutatory conduction Microglias are blood-derived mono nuclear macrophages.

The BCEC are different from peripheral endothelial cells, as can be seen schematically in Fig. 4, wherein the specific surroundings of the brain capillaries have been shown. The BCEC have specific characteristics, such as tight junctions, which prevent para cellular transport of small and large (water-soluble) compounds from blood to the brain. Furthermore, transcellular transport from blood to brain is limited as a result of low vesicular transport, high metabolic activity, and a lack of fenestrae. It functions as a physical, metabolic, and an immunological barrier.

Micro-vessels make up an estimated 95 per cent  of the total surface area of the BBB, and represent the principal route by which chemicals enter the brain. Vessels in brain were found to have somewhat smaller diameter and thinner walls than vessels in other organs. The BBB also has an additional enzymatic aspect. Solutes crossing the cell membrane are subsequently exposed to degrading enzymes present in large numbers inside the endothelial cells that contain large densities of mitochondria, the metabolically highly active organelles.

Primordial approaches to cross BBB
Traditionally, the pharmaceutical companies have chosen uncharged, lipophilic compounds as CNS drugs, as they have a greater plausibility of getting across the BBB. Apart from this, early efforts to manipulate BBB in favour of drug delivery have focused on prising apart the tight junctions between the endothelial cells.

Hypertonic solutions were introduced into the circulation via carotid artery essentially shrinking the cells so that the junctions open up. This provided a window of about 30 minutes during which a CNS drug was to be administered, again through the carotid artery. But the mechanism was non-specific and during the treatment, brain was open to other potentially toxic substances in the blood too.

Novel strategies for enhanced CNS drug delivery
To circumvent a multitude of barriers inhibiting CNS penetration by potential therapeutic agents, myriad drug delivery strategies have been developed. These strategies generally fall into one or more of the following three categories:

• manipulating drugs
• disrupting the BBB
• finding alternative routes for drug delivery

Lipid-mediated transport
The penetration of a xenobiotic into the CNS tissue is favoured by its low molecular weight, lack of ionization at physiological pH, and lipophilicity. Heroin, a diacyl derivative of morphine, is a notorious example that crosses the BBB about 100 times more easily than its parent drug just by being more lipophilic. Thus, a long-standing goal of a drug delivery scientist has been the lipidization of water soluble drugs, whereby chemical medications are used to block existing hydrogen bond-forming groups on the parent drug molecule. Despite extensive applications of medicinal chemistry, till date, there is not even a single FDA-approved drug that exemplifies the conversion of a poor brain penetrating molecule into a high brain-penetrating one.

Carrier mediated transport
An alternative technique to increase brain penetration is to modify drugs, such that there is increased carrier-mediation of the drug. For instance, a-carboxylation of the water-soluble catecholamine drug results in the formation of a neutral amino acid. Whereas the BBB penetration of the catecholamine is very low, the a-amino acid may then penetrate the BBB at pharmacologically significant rates via carrier-mediated transport.

Intraventricular/ Intrathecal route
The intracerebroventricular (ICV) approach injects drug into the cerebrospinal fluid (CSF) compartment, which is reported to be 140 ml in volume in humans. The entire CSF pool in the human brain is turned over every 4–5 h and four to five times per day. Drugs can be infused intraventricularly using an Ommaya reservoir, a plastic basin implanted subcutaneously in the scalp and connected to the ventricles within the brain via an outlet catheter.

Intranasal drug administration
The neural connections between the nasal mucosa and the brain provide a unique pathway for the delivery of therapeutic agents to the CNS. Intranasally administered therapeutic agents reach the CNS via the olfactory and trigeminal neural pathways More recently, the contribution made by the trigeminal pathway to intranasal delivery to the CNS has also been recognized, especially to caudal brain regions and the spinal cord. Extracellular delivery, rather than axonal transport, is strongly indicated by the short time frame (= 10 minutes) observed for intranasal therapeutics to reach the brain from the nasal mucosa. Possible mechanisms of transport may involve bulk flow and diffusion within perineuronal channels, perivascular spaces, or lymphatic channels directly connected to brain tissue or cerebrospinal fluid. An obvious advantage of this method vis-à-vis other strategies is that it is noninvasive.

Nonetheless, there have been certain difficulties that need to be overcome to achieve successful brain drug delivery through nasal route, like an enzymatically active and low pH nasal epithelium, and possibility of mucosal irritation, or the possibility of large variability caused by nasal pathology, such as common cold.

Brain drug targeting through liposomes
The work that has been most accomplished in the domain of brain targeting with colloidal drug carriers has been carried out with PEGylated immunoliposomes. These liposomal carriers access the brain from blood via receptor mediated transcytosis and deliver their content (small drug molecules, plasmid) into the brain parenchyma, without damaging the BBB. This requires the presence of receptor-specific targeting ligands at the tip of 1-2% of the PEG 2000 strands. Targeting ligands are peptidomimetic monoclonal antibodies, i.e., able to trigger the activation of receptors (transferring or insulin receptors) that are highly expressed on the brain capillary endothelium. These antibodies, directed against external receptor epitopes, do not interfere with the natural ligand binding sites, thus avoiding competition. Colloidal carriers should have diameter less than 100 nm to fit the loading capacity of these transport systems. Because immunoliposomes are not able to sustain the release of transported compounds, they require frequent administrations to exhibit an extended pharmacological effect.

Nanoparticulate drug delivery
Nanoparticles are solid colloidal particles, ranging in size from 1 to 1000 nm, and consisting of various macromolecules in which drugs could be adsorbed, entrapped, or covalently attached. Generally administered by the intravenous route like liposomes, they have been developed for the targeted delivery of therapeutic or imaging agents. Their stellar merits over liposomes comprise, low number of excipients used in their formulations, the simple procedures for preparation, a high physical stability, and the possibility of sustained drug release that may be suitable in the treatment of chronic diseases. Strategies for nanoparticulates targeting to the brain rely on their interaction with specific receptor-mediated transport systems in the BBB, as portrayed in Fig. 5.

Nanoparticles, made of polybutylcyanoacrylate (PBCA) have been intensively investigated for delivering drugs to brain. Among other biodegradable polymers employed for production of nanoparticles, polymers derived from glycolic acid and from D,L-lactic acid enantiomers are presently the most attractive compounds owing to their biocompatibility and resorbability through natural pathways. Because polylactic acid (PLA) and polylactide-co-glycolide (PLGA) are hydrophobic polymers, lipophilic drugs are easier to formulate (in dissolved state) in PLA/PLGA nanoparticles, than hydrosoluble ones. Despite the water-in-oil in water solvent evaporation technique, the entrapment of hydrophilic drugs may be a challenge due to the drug diffusion from the inner to the outer aqueous phases promoted by the large surface area developed. Basically, drug entrapment efficiency depends on the solid-state drug solubility in the polymer (solid dissolution or dispersion), which is related to the polymer composition, the molecular weight, the drug polymer interaction and the presence of end-functional groups.

Considering the success of nanoparticles to pass through the BBB and their limitation(s) especially toxicity and stability, a better option developed for drug delivery into the brain is solid lipid nanoparticles (SLNs). The SLNs constitute an attractive colloidal drug carrier system. The SLNs consist of spherical solid lipid particles in the nanometer range, which are dispersed in water or in aqueous surfactant solution. They are generally made up of solid hydrophobic core having a monolayer of phospholipid coating. The solid core may contain the drug dissolved or dispersed in the solid high melting fat matrix with the hydrophobic end of the phospholipid chains embedded in the fat matrix. The body distribution of SLNs is strongly dependent on their surface characteristics in relation to size, surface hydrophobicity, surface mobility etc.

Biochemical blood brain disruption
Biochemical disruption of BBB is a potentially safer technique of brain drug delivery. Selective openings of brain tumourr capillaries by intracarotid infusion of leukotriene C4 is achieved without concomitant alteration of the adjacent BBB. The biochemical opening utilizes a novel observation that normal brain capillaries appear to be unaffected when vasoactive leukotriene treatments are used to increase their permeability.

However, brain tumor capillaries or injured brain capillaries appear to be sensitive to treatment with leukotrines, and the permeation is dependent on molecular size.

Prodrugs with improved brain permeability
Brain uptake of drugs can be efficiently ameliorated via pro drug formation. Pro drugs are pharmacologically inactive compounds that result from transient chemical modifications of biologically active species. The chemical change is usually designed to improve some deficient physicochemical property, such as membrane permeability or water solubility. Following administration, the pro drug, by virtue of its improved characteristics, is brought closer to the receptor site and is maintained there for longer periods of time. Here, it gets converted to the active form, usually via a single activating step.

Chemical delivery systems
Another method called redox chemical delivery systems involves linking a drug to the lipophilic dihydropyridine carrier, thus creating a complex that after systemic administration readily transverses the BBB because of its lipophilicity. Once inside the brain parenchyma, the dihydropyridine moiety is enzymatically oxidized to the ionic pyridinium salt. The acquisition of charge has the dual effect of accelerating the rate of systemic elimination by the kidney and bile and trapping the drug-pyridinium salt complex inside the brain. Subsequent cleavage of the drug from the pyridinium carrier leads to sustained drug delivery in the brain parenchyma.

Biotechnological approaches
Recombinant protein neurotherapeutics can be delivered across the human BBB following genetic engineering, expression, and purification of recombinant fusion proteins. In this approach, the non-transportable protein therapeutic, e.g., a neurotrophin, is fused to the carboxyl or amino terminus of either the heavy chain or light chain of the genetically engineered monoclonal antibody, thus enabling the complex to cross BBB.

Epilogue
Despite serious endeavours by the drug development scientists, there is still an unmet need for better treatment of brain diseases. In addition to the currently available drugs, there are many other promising medicinal agents that, haplessly, cannot enter the brain tissue in sufficient quantities to be effective. Newer technologies, therefore, have to be developed and implemented to address this alarming hiccup. In this review, we have attempted to highlight the current research work that is underway to improve drug delivery and targeting of therapeutic agents to the brain. The development of technologies to actively target such agents to the diseased brain will also open a wider area for diagnostic investigations, the possibility of monitoring disease progression, and the treatment of diseases involving the brain. Notwithstanding the recent fruition of some potential approaches, much work is still expedient to ratify and validate their efficacy and cost-efficacy in brain disorders.