In Pakistan, almost ten percent of total population (more than 20 million people) is suffering from some sort of neurological disorders and this number is greater than the people suffering from cardiac diseases and cancer. Various reasons of neurological disorders involve genetic disorders, congenital disorders, environmental health problems including malnutrition and brain injury, spinal injury or nerve injury. In order to tackle this situation, physiology of the blood brain barrier and its permeability during different pathological conditions is needed to be understood. Blood brain barrier (BBB) is an active barrier which protects the brain against unwanted harmful substances and plays an important role in maintaining the stability of brain. However, the disadvantage of BBB is that many therapeutic molecules show an inability to cross it leading to the majority of the brain associated diseases untreated. Two important gateways for drugs to enter into the brain are blood and cerebrospinal fluid circulation systems.
Neurons, brain capillary endothelial cells, astrocytes, pericytes, microglia and extracellular base membrane are components of a neurovascular unit. Efflux, active efflux, and passive diffusion are permeation mechanism to pass through BBB. Paracellular aqueous pathway is used by water soluble agents, the transcellular lipophilic pathway is used by lipid soluble agents and receptor mediated transcytosis is used by insulin and transferrin. Efflux pump, adsorptive transcytosis are also used as transport routes. Pathogens, immune cell extravasation, auto antibodies, angiogenic factors and inflammatory cytokines are the reasons for the breakdown of BBB. After this breakdown astrocytes reduced, the transport function damaged, pericytes detached, trans junction protein expression reduced and basement membrane disrupts. All of this results in the release of cytokines, leakage of plasma proteins, imbalance of ions and entry of pathogens which results in inflammation, degeneration, and dysfunction of nervous tissues.
Ideal drug delivery technologies should be well controlled, biodegradable and non-toxic. It should not damage the barrier and selectively transport the drug across BBB. It should increase the efficacy of the drug. In this context nanoparticles (Nps) can be considered as an important candidate to deliver drug across blood brain barrier and to overcome other protective mechanisms. Inorganic, organic, polymeric nanoparticles, liposomes, nanocrystals, dendrimers, and nanotubes are different forms of nanotechnology which are being used for this purpose.
Solid lipid Nps (SLNs) are useful for the treatment of brain diseases. They show stability with controlled release. Liposomes show biocompatibility but they have a high cost. Polymeric nanoparticles are also potential carriers for drug delivery because they can encapsulate drugs and protect them from excretion and metabolism. They don’t damage BBB during drug delivery across it and are biodegradable. Chilostan Nps can deliver complex drug like plasmid DNA, insulin, and genes. Dendrimers and nano gels show low toxicity and high capacity of loading drug. Mechanisms by which drugs can be transported across BBB are determined on the basis of chemistry, architecture, and properties of Nps.
After intravenous administration of the drug, it is circulated to the liver (60-90% of injected dose), spleen (2-10%), lungs (3-20%) and bone marrow (1%). By simple modification of size and surface properties, we can change this biodistribution. When the surface of Nps is coated by hydrophilic polymers or surfactant their blood circulation time increases. This is the result of screening of their hydrophobic character due to which they are not recognized by the reticuloendothelial system. Their phagocytosis reduced and bioavailability increases. After modification of the surface of Nps with surfactants, they can absorb apolipoproteins from the blood stream. Polysorbates are an important surfactant of this category. One possibility of translocation of Nps seems to be the interaction of apolipoproteins which is adsorbed on their surface with different receptors on BBB. This mechanism is recently confirmed by albumin coated with apolipoproteins and delivered to the brain after intravenous injection (Kreuter, 2005; Miller et al., 2008).
Nps have the ability to deliver drugs through endothelial cell layer where they inhibit transmembrane efflux system. Nps can also open the tight junctions for transport of drug in free form or with the carrier through endothelial cells. Surfactants can increase the solubilization of endothelial cell membrane lipids and transport of the drug is enhanced. Most recent brain targeting strategies based on surface engineering which is achieved by coating with specific ligands. These can facilitate endocytosis of the NPs by the endothelial cells, which remain the principal mechanism whereby drug transport to the central nervous system (CNS) can be enhanced. Nps are used for the treatment of cerebral ischemia, Alzheimer’s disease (AD), and Parkinson’s disease (PD).
Future emphasis should be on designing nanoformulations that can be tested in clinical trials for stroke, AD, and PD treatment. There is a need for further investigation to design nanoformulations that can release the drug only after reaching specific cells of the brain. Investigations should be performed in developing multifunctional Nps which can serve both as diagnostic and therapeutic tools. Organized Investigations in this area will lead to the development of personalized medicines. Attention is required for creating efficient platforms that can provide refined research in this area. Using these strategies growing neurological problems can be solved and we can have healthy Pakistan.
This article is collectively authored by Zanaira Talat and Dr. Muhammad Irfan Majeed. Department of Chemistry, University of Agriculture Faisalabad.