Nanoparticles Mediated Drug Delivery across the Blood Brain Barrier (BBB)
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 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 disadvantage of BBB is that many therapeutic molecules show inability to cross it leading to the majority of brain associated diseases remain untreated. Two important gateways for drugs to enter into the brain are blood and cerebrospinal fluid circulation systems.
Pathogens, immune cell extravasation, auto antibodies, angiogenic factors and inflammatory cytokines are the reasons of breakdown of BBB. After this breakdown components of neurovascular unit i.e. astrocytes reduced, transport function damaged, pericytes detached, trans junction protein expression reduced and basement membrane disrupts. All of this becomes reason of 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 nontoxic. It should not damage the barrier and selectively transport drug across BBB. It should increase efficacy of drug.
In this context nanoparticles (Nps) can be considered as important candidate to deliver drug across blood brain barrier and to overcome other protective mechanisms. Solid lipid Nps (SLNs) show stability with controlled release. Liposomes show biocompatibility but they have 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 nanogels show low toxicity and high capacity of loading drug. Mechanisms by which drugs can be transported across BBB are decided on the basis of chemistry, architecture and properties of Nps.
After intravenous administration of drug it is distributed to 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 result of screening of their hydrophobic character due to which they are not recognized by reticuloendothelial system, their phagocytosis reduced and bioavailability increases. After modification of surface of Nps with surfactants they can absorb apolipoproteins from blood stream. Polysorbates are important surfactant of this category.
One possibility of translocation of Nps seems to be 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 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 carrier through endothelial cell. Nps are used for 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 also a need of further investigation to design nanoformulations that can release the drug only after reaching specific cells of brain. Investigations should be done on developing multifunctional Nps which can serve both as diagnostic and therapeutic tools. Organized Investigations in this area will result in 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.
Kreuter, J., 2005. Application of nanoparticles for the delivery of drugs to the brain. In: International Congress Series. Elsevier: pp: 85-94.
Miller, D.S., B. Bauer and A.M. Hartz, 2008. Modulation of p-glycoprotein at the blood-brain barrier: Opportunities to improve central nervous system pharmacotherapy. Pharmacological Reviews, 60(2): 196-209.
Zanaira Talat and Dr. Muhammad Irfan Majeed
Department of Chemistry, University of Agriculture Faisalabad