Critical Review of Modern Methods for delivery of drugs across the blood-brain barrier, Yan Chen, Lihong Liu, 2011

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

1. 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.
2. 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
3. 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.
4. 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.
5. 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.
6. 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

Reflection on Pfizer visit on 14/11/14

This piece of writing is a detailed reflection of a college based visit to the Pfizer biotechnology manufacturing plant situated in grange castle, Dublin. this trip was directly related to both immunology and drug delivery modules and was intended to broaden our knowledge on the topics and to view the real life applications of various academic concepts. we were given in sight as to what the tour would entail, it would comprise of a short lecture, a problem based  workshop followed by a short tour of the laboratories. this aided us as it provided an opportunity to re-familiarise with relevant course material and to think of some relevant questions to ask the Pfizer employees.

although we received this brief description of our day i still did not know what to expect. the first thing that struck me about Pfizer was the sheer size of the building, it is understandable as it is a manufacturing plant with many different sectors and operations but is still a surprise. As we entered we were given visitor identification cards and taken to a conference room in which we would begin our activities. the first activity was a detailed talk by Orla Cunningham in which a presentation was given on drug discovery and bio-therapeutics as a whole. we were eased into this presentation and as it went on it became apparent that i have covered the material in the presentation to some extent in college modules. Orla began by giving a brief  background to Pfizer, i was surprised to hear that Pfizer is currently the only company to be doing drug discovery as i thought every company underwent drug discovery to some extent. this trip continuously challenged my preconceptions about the modern day pharmaceutical industry and painted a picture as to what a multinational pharmaceutical company is truly like. i have a avid interest in drug discovery, research and development, which made this presentation exciting to view. related modules such as drug discovery, drug delivery, immunology and biotechnology aided me hugely when it came to understanding some of the more advanced sections of the presentation.

after the presentation by Orla we received a short break, when we returned we underwent a two hour workshop that was ran by two researchers named Fred and Matthew. we were split into our predetermined groups and were presented with a pharmaceutical research based problem. the problem put forward involved a newly found cytokine that has the ability to induce asthma in humans. we were tasked with finding a way to neutralise the cytokine using the information provided. the neutralising agent had to be safe, efficacious and have an acceptable manufacturing profile. we were given relevant information to aid us in solving this problem. we were shown that a secreted decoy receptor protein existed that neutralises cytokine binding to the receptor one chain. also Receptor one had a moderate binding affinity; receptor two had no detectable binding affinity but Together the two chains bind cytokine with high affinity. from this information there were several routes we could take to neutralise the cytokine and it was seen that each group’s approaches varied to some extent. there were five main questions to be answered with regards to this problem, these covered the method of neutralising, pre clinical models, anticipated challenges, half life and other aspects of the drug discovery process. we were given an hour to organize a solution to the problems proposed, this required us think logically and apply knowledge learnt in college to a real pharmaceutical problem. we chose to use the decoy receptor as a method of neutralising the cytokine. the decoy receptor will block the cytokine from binding to receptor one. with regards to assays we proposed an in-vitro assays along with ex-vivo cell based assays to find a lead neutralising agent and to optimise it. In preclinical testing we had a choice to use mice, sheep or monkeys for toxicity and efficacy testing. The percentage sequence homology with human cytokine was given; the mouse was 55%, the sheep was 76% and the monkey was 94% we chose to use mice for toxicity testing as they are cheap and can be easily used in multiple generation studies. if the therapeutic is non toxic  then preclinical studies can proceed on cynomologous monkeys in which efficacy studies can be done. the next question was to assess the challenges that may be encountered in developing a therapeutic. possible challenges proposed would be thermal stability as biotherapeutics can be temperature sensitive, therapeutic dose and toxicity. we also took into account the solubility and viscosity of the product as it will be delivered as a subcutaneous injection. the next question was to propose how to increase the half life of the therapeutic therefore increasing the length of time needed between doses which will enhance patient compliance. as a group we proposed ways to achieve a longer half life, one way was to increase the concentration within acceptable limits to stay in the system longer. another way is to bind the drug to a polymer such as polyethylene glycol (PEG). this will increase the size of the compound lengthening half life. the last question we were asked was to assess how the body would react to the therapeutic. we deduced that every protein that enters the body can be considered foreign therefor there is a capacity for immunogenicity. ways of correcting or improving this would be to humanize the protein and use anti histamines to reduce the localized reaction.

The final task was to present this material to the class, lectures and speakers. we went as a group to present our solution and listened to the other presentations. this was beneficial as we could see what route other groups went to reach a solution. the workshop as a whole was an interesting and beneficial experience, we used and improved skills that are very applicable to pharmaceutical research such as logical thinking, teamwork, time management and presentation skills. the content matter of the workshop was somewhat new to me, most of my college modules focus primarily on small-molecule therapeutics but this workshop focused on bio-therapeutics this was refreshing and highly interesting as bio-therapeutics is an established and ever growing market.

After the workshop we were split into two groups and were taken on a tour of the research labs. the labs were somewhat more basic than what i expected but this was one of many laboratories present in the plant. from observing some of the instrumentation in the lab I could apply and understand some of the techniques and assays that Orla had previously talked about in the presentation better. my only disappointment was that we did not get to see the manufacturing sector of the plant as this is strong interest of mine. I feel that the day as a whole was helpful in various areas of my academics, it gave me an insight to the workings of a corporate research job and aided me in choosing my career choice post academia.

 

 

A Critical review of Robert Langer, Drug delivery and targeting, Nature,Vol. 392, April 1998

Drug delivery and drug targeting is a scientific article written by Robert Langer for the nature publishing group. Langer uses his previously written journal articles along with external sources to compose a detailed overview of current and future lipid and polymer based drug delivery systems. This article covers the progression of drug delivery systems in 1998 along with the challenges faced by scientists with regards to delivery systems and delivery routes. This article provides a good analysis of the drug delivery systems that were present or in development in 1998 using illustrations and an extensive source of literature. Langer had a significant involvement in many of the delivery systems and claims in the discussion section that in “10 to 20 years many of the systems discussed would be introduced and in place”¹. This enables a comparative of the delivery systems in present day.

Langer begins his article by introducing the topic of drug delivery by stating the impact of new drug delivery systems on various branches of medicine at the time. This is followed by a short description of the advantages of improved drug delivery systems weighed against the concerns this provides a good overview of the position of drug delivery in 1998. Langer then moves into the topic of polymer based drug delivery systems he firstly explains the mechanisms by which polymers can deliver drugs. Langer explains these mechanisms in detail using an efficient illustration of four different polymer systems. The author then further describes polymer based drug delivery regarding the challenges faced with regards to controlled release of the drug inside the polymer. One of these challenges is bulk erosion of the polymer causing dose dumping of the drug. There are several systems outlined in the article to achieve controlled release of drugs in polymer based systems. Such synthesised polymers include hydrophobic polyanhydrides, biodegradable hydrogels and also drug-polymer conjugates that are involved in passive targeting. Langer then proceeds to describe issues and developments regarding liposome based delivery systems. Langer begins by providing concise description of what liposomes are before directly comparing liposomes to polymers stating that liposome systems have “the advantage of providing a higher drug carrying capacity”² but had issues regarding shelf life, targeting specific tissues and negative immune responses. These issues were resolved by altering the liposome surface. Intelligent delivery systems are also described by Langer with the purported purpose of pulsatile delivery as some drugs will not be as efficacious with constant or decreasing drug delivery rates. Early approaches to pulsatile delivery using magnetic beads are described using an illustration. Ways of improving intelligent delivery designs are outlined in the article such methods include the use of ultrasound, electric current, hydrogels and antibodies are used. These methods can alter the drug release rates of drugs along with the cells at which the drug targets.  Langer goes on to describe the delivery systems specific to different delivery routes. The first route described is pulmonary in which the author compares liquid form inhalers which only 10% of the drug is received by the lung to a more efficient powder form inhaler in which 20-50% can be received by the lung. Langer goes on to describe the challenges associated with oral and transdermal delivery routes along with new systems and new approaches to overcome the common issues arising with each route.

The author throughout the article talks about new drug delivery systems along with new approaches to improve drug delivery systems 1998. As Langer was involved in the development of many of the articles systems and approaches he may show a certain amount of bias to a degree towards the effectiveness and prevalence of some of these systems. Reviewing this article 16 years later places me in the unique position as to view some of these systems in present day to asses which of these concepts have been refuted and which concepts have come to fruition.

Langer states early  in the introduction that the “Potential advantages of improved drug delivery systems include (1) continuous maintenance of drug levels in a therapeutically desirable range, (2) reduction of harmful side effects due to targeted delivery to a particular cell type or tissue. (3) Potentially decreased amount of drug needed. Langer goes on further to state that  these  advantages are important as up to $136 billion in health care costs in the USA are attributed to Adverse drug events”³. In modern times these costs have dropped considerably, “it is estimated that the cost of Adverse Drug Events in 2006 was 3.5 billion US dollars”⁴.  This decrease in cost would suggest that in present times the previously mentioned advantages have somewhat been achieved with the use of improved drug delivery systems. Langer uses a solid illustration to describe the common polymeric drug delivery systems, the pictures used are somewhat simplistic however the description of each picture is extensive and relates to delivery systems that are being used at the time.

In relation to active targeting Langer talks about the addition of galactose to a HPMA copolymer drug conjugate this in turn targets the liver due to the asialoglycoprotein receptor. He states that these systems as well as HPMA taxol conjugates are in clinical trials. From present day research it was seen that in 2002 a study using HPMA-doxorubin-galactosamine to treat primary a secondary liver cancer had specific targeting towards the liver. This was confirmed using gamma camera imaging and iodine labelled analogue ⁵. Therefore it should be noted that these polymer systems are now prominent.

With regards to liposome based delivery systems Langer states that an area of intense investigation is the use of cationic liposome for gene therapy. “Gene therapy was only approved in 1990 and the human genome was not mapped until 2001”6 therefore gene therapy was still in the early stages of development. However the use of cationic liposomes in gene therapy is used widely today one such example can be found in a review article from 2010. A solution of cationic lipids, often formed with neutral helper lipids, can be mixed with DNA to form a positively charged complex termed a lipoplex. One such lipolex is N-[1-(2,3-dioleyloxy) propyl]-N,N,N-trimethylammonium chloride, or DOTMA which was one of the first synthesized and commercially available cationic lipids used for gene delivery”⁷.

In conclusion it has to be said that this article was very well written by Robert Langer the material provided is informative and with a basic knowledge of drug delivery it is easy to understand. The use of illustrations and subheadings make the article very descriptive and relevant for the time. Although this article was written in 1998 it is years ahead of its time. Robert Langer makes some closing points in the discussion section stating that progress in certain sectors will improve drug delivery such points include progress in immunology and human genomics which can achieve site specific delivery, advancement in combinatorial chemistry which will lead to the production of new bio materials and finally the development of mathematical models can predict delivery performance. These closing points are important as they look to the future of drug delivery. It is the influx of funding into these areas of science has led to many of these sectors rapid progression and I believe they will continue to grow in further years.

Bibliography

1. Langer, R (1998).Drug delivery and targeting, Nature. .: Macmillan publishers. 5-10.
2. Gregoiraidis G. Engineered Liposomes for drug delivery, progress and problems, trends biotechnol. 13, 527-537, 1997
3. Classen D, C Pestotnik, S.L Evans, SR, Lloyd, J.F Burke, J.P. Adverse drug events in hospitalised patients,J. Ann Assoc 277, 301-306 (1997)
4. Aspden P, Wolcott JA, Bootman JL, Cronenwett LR. Preventing Medication Errors: Quality Chasm Series, The National Academic Press, Washington, DC 2007.
5. Muzykantov, V (2002). Biomedical Aspects of drug targeting. ,: Kluwer Academic publishers. 202.
6. NIOH. (2003). http://www.genome.gov/11006943. Available: http://www.genome.gov/11006943. Last accessed 5 Nov 2014.
7. Balazs,DA Godbey,Wt. (2011). Liposomes for Use in Gene Delivery.Journal of Drug Delivery. Volume 2011 (.), 12.

Professional Development

I believe that I have grown a huge amount professionally. since my first year in college I changed my study methods and general approach to learning . I found that the most successful way of learning for me personally was to take the time to truly understand a concept rather than to memorize it. this method of learning has impacted my grades hugely and i am progressing each year with better grades and an improved knowledge of the various modules and concepts. with the exception of a few the college modules I have undergone throughout my five years here at DIT have set me up for various different industries and environments. such examples would start with my laboratory practicals I have gained a massive amount of knowledge throughout my lab practicals. it is important in industry and college that the basic techniques regarding safety and equipment are thoroughly known and the experience gained from the college practical labs gave me that knowledge. I also became accustomed to certain instrumentation that is used the college labs but also in the labs of numerous different industries. I gained valuable practical experience with such instruments as the Polarimeter, UV-VIS Spectrometer, HPLC, GC-MS, Atomic flame spectrometer, NMR and PCR along with computer applications which has made me more competent and confident with various related hardware and software. other modules that I feel have given me the understanding to progress professionally include Organic Chemistry, Biochemistry, Pharmaceutical Instrumentation, Pharmaceutical Formulation and manufacturing, Pharmacology & toxicology, Microbiology, Occupational Health & Safety Management, Quality systems and regulatory affairs amongst others. in my third year of pharmaceutical healthcare i was required to do six months of work placement in a real working lab. The lab i was placed in was a microbiology lab in the Midlands regional hospital in Tullamore. Although microbiology was not one of my preferred fields of science this work placement ignited an interest in microbiology that was not previously there. This work placement gave me more experience than I could have expected, I soon knew for the first time what working in a professional environment entailed. I had encountered to some extent most of the techniques used in the microbiology lab in college microbiology modules and labs but it was a learning curve to perform them to the standard that is required in a working lab. during my time on placement i learnt new concepts that were directly related to pharmaceuticals, for several weeks I was taught extensively about antibiotics. this was an interesting branch of pharmaceuticals and it was exciting to learn about there emergence into the scientific world, there shortcomings regarding Resistance and the future of antibiotics. along with specific pharmaceutical related aspects of microbiology I learnt a considerable amount about quality in a lab environment. Quality systems is an important subject in any lab no matter what branch of science, I performed tasks and assignments while on placement that really broadened my knowledge of quality and how its implemented which will surely help me in future endeavours. This work placement also gave me insight and reinforced my career goals of drug related research or academic progression, although I enjoyed my placement I could not picture myself pursuing a career in microbiology or in a medical laboratory.