Modern methods for delivery of drugs across the blood-brain barrier is a drug delivery article written by Yan Chen and Lihong Liu, found in the book “Advanced drug delivery reviews” for the Elsevier publishing company. Chen and Lui use a wide variety of sources to explain in detail issues surrounding the blood-brain barrier (BBB) from a biological and pathological perspective. The authors also describe many of the modern drug delivery methods for the Blood brain barrier (BBB) such as nano-technologies, cell mediated transport and receptor based transport amongst many others this article features a good in depth review of the methods of crossing the BBB and provides solid surrounding information to support the primary point.
The authors begin the article by explaining that even though we have advanced greatly in understanding the BBB still many of the central nervous diseases are under treated due to ineffective drugs, it is not that there is a lack of viable drugs to combat these diseases it is the drugs lack of capability in crossing the BBB that is the issue. The BBB acts as an efficient physical, transport, enzymatic and immunological barrier¹. This is due to the several transport routes for solutes to cross in and out of the BBB. The authors describe these transport routes in detail using an illustration (Fig 1).
Fig 1 Transport routes across the blood brain barrier
It can be seen from Fig 1. That there are seven different mechanisms shown to facilitate BBB diffusion. Each transport route requires a molecule to have specific set of criteria to pass it, such as solubility or size. An exception to this is cell mediated transcytosis. This transport route is the most recent to be discovered and is a method in which “some pathogens enter the brain, known as the Trojan horse model”2. This transport route is an exception as it does not require a drug to have specific properties therefore any drug could pass the BBB using this route. The authors move on from transport routes to discuss the biological and pathological properties of the BBB. This is important, as a better understanding of the molecular biology of the BBB in pathological and physiological settings along with response to external stimuli will lead to better development of novel drug delivery systems that utilize the increased knowledge of the BBB. The authors discuss BBB properties under the certain headings such as tight junction and adheron junction regulation, changes in permeability and drug transport systems under pathological conditions. The authors go on to discuss the primary point of modern methods of transporting drugs across the BBB. This section begins with a detailed description of tight junctions and how they’re permeability can be enhanced by the use of Biological, chemical and physical stimuli. Chen and Lui go on to discuss the benefits and requirements of nanocarriers for brain drug delivery before stating that the PEGylation of these nanocarriers extend half-life aiding drug delivery. Next the authors describe the significance and success of adsorptive-mediated transcytosis drug delivery. The authors provide detailed description as subheadings of receptor mediated transcytosis delivery and the delivery of drugs by the inhibition of efflux pumps but a full section is given to describe cell mediated drug transport. This section is used by the authors to describe how cell mediated drug transport works along with recent advances and current status of cell mediated transport as an effective treatment.
The scope of this article is to assess the opportunities for molecules and bio-therapeutics to be transported across the BBB when it’s in its normal physiological state but also when it’s in a pathological state. To some extent this has been achieved but I feel more information is required in certain aspects. The molecular biology of the BBB is explained in physiological and pathological settings and methods of transport were covered for a physiological barrier but methods for drug delivery across a pathologically affected BBB is not discussed in detail. This review article as a whole is an excellent representation of current and past blood brain barrier research compiled by Chen and Lui and supported by extensive literary research. Although this article is impressive there are some points that could be improved. Chen and Lui describe physiological approaches to crossing the BBB but they do not mention invasive approaches towards drug delivery to the BBB. Such methods of invasive approach include the use of: 1)
Intracerebro-ventricular infusion, 2) Convection-enhanced delivery and 3) polymer or microchip systems which directly release therapeutics after implantation in the CNS 3. Cheng and Lui could have compared and contrasted invasive approaches and physiological approaches in terms of safety, effectiveness and practicality. The authors could have added to their list of delivery systems with the addition of transnasal drug delivery. “Transnasal delivery would be beneficial in therapeutic situations where a rapid and/or specific targeting of drugs to the brain is required, The olfactory region located at the upper remote parts of the nasal passages offers the potential for certain compounds to circumvent the blood-brain barrier and enter into the brain” 4, therefore transnasal drug delivery should be included. The authors provide good descriptions of the effect of stimuli in tight junction modification but they do not describe the effect, if any of biological chemical or physical stimuli on any of the other transport routes, I feel that there should be somewhat similar information provided for each transport route in order to generate a full review.
This article focuses heavily on cell mediated drug transport more than the other transport routes. This is not the case with other BBB review articles which focus primarily on other pathways. Numerous articles focus on the use of nano carriers and receptor based drug transport heralding them as the most effective. The authors state that ” compared to other transport pathways, cell-mediated drug delivery has attracted far less attention for drug brain transport but there have been some promising results” 5. This lack of attention may be due to the relative newness of the transport route and its varied information on safety issue but with the capability of being able to allow any molecule to pass the BBB, it should at least feature as a possible method in other articles relating to drug delivery across the BBB.
Cheng and Lui have a created this review article by using a wealth of personal and external sources. The authors have used information from over 300 credible journals. In terms of style of writing the authors have structured the article in an efficient and coherent manner, the headings and sub headings are written in order of importance. The authors describe the BBBs biology, transport routes, and then how scientists are using this information to develop effective methods of drug transport. This provides a logical flow of argument as preceding sections provides information that is used and built upon in succeeding sections.
Blood brain barrier drug transport is an expansive topic and in this critical review I am only touching on the material covered by this review article. The information provided is extensive but very well presented by the authors. this article shows the progression of BBB research but also looks to the future and in the conclusion the authors using research by Jain et al. showed” using cell mediated drug transport and magnetic liposomes that 21% of the administered dose could target the BBB but this was under inflammatory conditions”6. Therefore to increase efficacy a multi-disciplined and multi therapeutic approach must be taken. Of these approaches each one should be tailored for efficacy and safety in a pathological environment such as that of the BBB.
Bibliography
- Chen, Y. and Liu, L. (2012). Modern methods for delivery of drugs across the blood–brain barrier.Advanced Drug Delivery Reviews, 64(7), pp.640-665.
- Chretien, O. Lortholary, I. Kansau, S. Neuville, F. Gray, F. Dromer, Pathogenesis of cerebralCryptococcus neoformans infection after fungemia, J. Infect. Dis., 186 (2002), pp. 522–530
- Gabathuler, R. (2010). Approaches to transport therapeutic drugs across the blood–brain barrier to treat brain diseases.Neurobiology of Disease, 37(1), pp.48-57.
- Jadhav, K., Gambhire, M., Shaikh, I., Kadam, V. and Pisal, S. (2007). Nasal Drug Delivery System-Factors Affecting and Applications.Current Drug Therapy, 2(1), pp.27-38.
- Chen, Y. and Liu, L. (2012). Modern methods for delivery of drugs across the blood–brain barrier.Advanced Drug Delivery Reviews, 64(7), pp.658.
- Jain, V. Mishra, P. Singh, P.K. Dubey, D.K. Saraf, S.P. Vyas, RGD-anchored magnetic liposomes for monocytes/neutrophils-mediated brain targeting, Int. J. Pharm., 261 (2003), pp. 43–55
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