The University of Nottingham Science Public Lecture Seriesstarted 2017 with a talk by Claire Sycamore entitled "Thinking Outside the (Pill) Box - Alternative Drug Delivery Strategies". Claire is a PhD student in Prof Neil Thomas's research group in the UoN Faculty of Science. @Gav Squires was there and has kindly written this guest post summarising the event, with a few additions from NSB who was also at the event.
Local vs Systemic delivery
Pharmacology is the superhero of our time, different from other treatments such as surgery or radiology. It first came to prominence in the 1930s following the discovery of penicillin in 1928. These days a person will take on average 14,000 prescription pills and 40,000 non-prescription pills. The three most popular non-prescription drugs are all non-targeted and you can actually take quite large maximum doses in a day:
Paracetamol - 4.0g
Ibuprofen - 1.2g
Asprin - 3.6g
Drug delivery systems are all about the interaction at the point that the drug is taken. By working on these systems you can improve the efficacy and the safety of the drugs and control the rate and location of the drug being released. A drug delivery system is something that is given at the same time as the drug.
Ibuprofen has a ph of 4.4, is not very well absorbed and can lead to stomach ulcers. It acts on a fatty hormone called prostaglandin H2 and has two forms "R" & "S". It is only the "S" form that actually works as a painkiller (although the but R can be converted into S in your body over time).
Ideally, we would have something that works locally, not just systematically. For example, the anti-fungal drug Terbinafine can be applied as a cream to the affected area or taken as a tablet. When you take a tablet, the whole body is flooded with the drug. This can lead to strong side effects such as problems with the kidney and the liver.
Microneedles
So, we need to look at routes of delivery - how the drug gets into the body, for example orally, inhalation, injection. One of the latest inventions is the microneedle (see also here). Needles in general are a great way of getting a drug into a body quickly. They are easy to use and cheap to produce. However, not everyone likes needles and there can be issues with training people to use them properly, for example with diabetes patients. Microneedles avoid all pain, you don't actually feel them piercing the skin. There's less to be fearful of, it requires no training and it give precise localisation. They can even be used to deliver drugs straight into the eye. The only real issue with microneedles is that they can only be used for drugs that you inject.
For drugs that can't easily be delivered by microneedles, a key area of research is delivery vehicles - getting the drugs get to the places that they need to go. Nanotechnology and nanoparticles are the big thing here, allowing controlled targeting and greatly reducing side effects.
But why nanoparticles?
Due to their size nanoparticles have a greater mass to surface ratio. They also have some quantum properties, in that they act more like a wave in some respects. They also have the ability to absorb and carry other compounds. Can we assume that something that works at the "bulk" scale will be just as effective at the nano level?
Prodrugs
Getting drugs to the target areas is particularly important in cancer treatment, where the drugs are designed to kill cells and have harsh side effects. These side effects are one reason that an estimated 50% of cancer patients do not comply with their medication pathways. If we can target just the tumour then we can reduce these side effects and make treatment better for patients.
This can be done by using something called a pro-drug. These are drugs which are inactive when administered and are converted within the body, often by an enzyme, into a therapeutic drug.
Prodrugs have been tested on mice where the enzyme is added to a clostridia bacteria and then spores(dormant forms of the bacteria) are taken. These spores are injected into a mouse and then allowed to grow for a couple of weeks. Critically, clostridia bacteria (and the enzymes they carry) will only grow in a low oxygen environment - like a tumour. Then, when the pro-drug is injected it will only activate in the tumour because that is the only place where the bacteria (and hence enzymes) are. You can read more on this research here and here.
Polymer delivery systems
Another problem is the rise in antibiotic resistance. For example, an American woman died in January despite being given all 26 available antibiotics.
According to the World Health Organisation, "Without effective antimicrobials for prevention and treatment of infections, medical procedures such as organ transplantation, cancer chemotherapy, diabetes management and major surgery (for example, caesarean sections or hip replacements) become very high risk."
A potential answer to the threat of antibiotic resistance is to use plastics for drug delivery. Plastics are a type of polymer (incidentally so is DNA) and polymers have a number of advantages in the body:
Timeable
Versatile
Easy to prepare
Reduces dosing frequency
Maintain therapeutic concentration with one dose
Reduced side effects
Improved stability
Prolonged release
However, we need to consider what happens with this plastic long term. How long is acceptable to leave in the body? So, we need to find a biodegradable polymer. This isn't as straightforward as it could be as you need the right enzymes and bacteria to degrade the polymer. For example, a biodegradable polymer wouldn't actually degrade in a landfill because it is too dry and there is too little oxygen so the enzymes and bacteria can't survive there.
There are some very specific requirements for this plastic. It has to be bio-compatible, non-toxic, permeable, biodegradable, pure and with a high tensile strength. There are three plastics that are being looked at, PLA, PGA and PTMC. The later seems to be the best choice as it is resistant to hydrolysis, which means that it sticks around longer and it isn't brittle.
How can we alter the properties of PTMC to make it into the delivery system that we want? Through using technical processes such as cross-linking, copolymerization and functionalization to incorporate functional side chains. The idea is to attach antibiotics into the basic structure of the PTMC. The antibiotics Gentamicin and Clindamycin are both being looked at with regard to this process as they cause severe side effects (Gentamicin can cause permanent deafness). You can read more about this research here.
Different delivery vehicles to get drugs into the eye are also being looked at. 95% of dose placed in the eye using a dropper is washed away. Is there a better way? Work has started on a contact lens that would include an antibiotic imprinted into it. That way the drug is trapped between the contact lens and the cornea - See UoN's research here and also some work by Harvard here.
Another big area of research is on the cargo - the drug itself. Does it have to be a small molecule? For example, even though there is no human-human transmission at the moment, there are huge fears about H5N1 influenza, also known as bird flu. It has a 60% mortality rate and would be a massive issue if it became pandemic. So a nanovaccine has been created, which is preventative rather than curative (some background can be found in this UoN pdf presentation and this research from the US).
Virus Like Particles
The final area of research is targeting strategies. The exterior of a virus is often a protein polymer cage known as a capsid. So called "virus like particles" mimic these capsids and tripper an antibody resonse that protects the vaccine recipient from later infection. An example of this technology is the Gardasil HPV vaccine.
You can also make these biological cages from things such as Ferritin, a storage protein for iron. The cage can opened and closed by varying the pH of the environment - while the cage is open, the iron can replaced by other things such as cancer drugs.
Final Comments
Of course there are crossovers between lots of these areas of research. It may take a while for some to reach the public but these are exciting times in the field of drug delivery strategies.
Overall, it is clear that the direction of travel is for new drugs to be highly targetted so that only milligram dosages are required - aspirin certainly would not be licensed today!
The Public Lecture Series returns to the University of Nottingham on the 16th of February at 6:00pm where Julian Onions will talk about Things That Go Bang In The Night (Sky) For more information, please visit the Public Lecture Series site: https://www.nottingham.ac.uk/physics/outreach/science-public-lectures.aspx
Image Sources
Ferritin
Microneedles - Copyright: Ryan Donnelly, Queen''s University Belfast
Images from Talk - Copyright : Gav Squires
Flu Virus
 |
| Claire Sycamore |
Local vs Systemic delivery
Pharmacology is the superhero of our time, different from other treatments such as surgery or radiology. It first came to prominence in the 1930s following the discovery of penicillin in 1928. These days a person will take on average 14,000 prescription pills and 40,000 non-prescription pills. The three most popular non-prescription drugs are all non-targeted and you can actually take quite large maximum doses in a day:
Paracetamol - 4.0g
Ibuprofen - 1.2g
Asprin - 3.6g
Drug delivery systems are all about the interaction at the point that the drug is taken. By working on these systems you can improve the efficacy and the safety of the drugs and control the rate and location of the drug being released. A drug delivery system is something that is given at the same time as the drug.
Ibuprofen has a ph of 4.4, is not very well absorbed and can lead to stomach ulcers. It acts on a fatty hormone called prostaglandin H2 and has two forms "R" & "S". It is only the "S" form that actually works as a painkiller (although the but R can be converted into S in your body over time).
Ideally, we would have something that works locally, not just systematically. For example, the anti-fungal drug Terbinafine can be applied as a cream to the affected area or taken as a tablet. When you take a tablet, the whole body is flooded with the drug. This can lead to strong side effects such as problems with the kidney and the liver.
 |
| Common painkillers and their max allowed dosages |
Microneedles
So, we need to look at routes of delivery - how the drug gets into the body, for example orally, inhalation, injection. One of the latest inventions is the microneedle (see also here). Needles in general are a great way of getting a drug into a body quickly. They are easy to use and cheap to produce. However, not everyone likes needles and there can be issues with training people to use them properly, for example with diabetes patients. Microneedles avoid all pain, you don't actually feel them piercing the skin. There's less to be fearful of, it requires no training and it give precise localisation. They can even be used to deliver drugs straight into the eye. The only real issue with microneedles is that they can only be used for drugs that you inject.
For drugs that can't easily be delivered by microneedles, a key area of research is delivery vehicles - getting the drugs get to the places that they need to go. Nanotechnology and nanoparticles are the big thing here, allowing controlled targeting and greatly reducing side effects.
But why nanoparticles?
Due to their size nanoparticles have a greater mass to surface ratio. They also have some quantum properties, in that they act more like a wave in some respects. They also have the ability to absorb and carry other compounds. Can we assume that something that works at the "bulk" scale will be just as effective at the nano level?
 |
| Microneedles (Copyright: Ryan Donnelly, Queen''s University Belfast) |
Prodrugs
Getting drugs to the target areas is particularly important in cancer treatment, where the drugs are designed to kill cells and have harsh side effects. These side effects are one reason that an estimated 50% of cancer patients do not comply with their medication pathways. If we can target just the tumour then we can reduce these side effects and make treatment better for patients.
This can be done by using something called a pro-drug. These are drugs which are inactive when administered and are converted within the body, often by an enzyme, into a therapeutic drug.
Prodrugs have been tested on mice where the enzyme is added to a clostridia bacteria and then spores(dormant forms of the bacteria) are taken. These spores are injected into a mouse and then allowed to grow for a couple of weeks. Critically, clostridia bacteria (and the enzymes they carry) will only grow in a low oxygen environment - like a tumour. Then, when the pro-drug is injected it will only activate in the tumour because that is the only place where the bacteria (and hence enzymes) are. You can read more on this research here and here.
Polymer delivery systems
Another problem is the rise in antibiotic resistance. For example, an American woman died in January despite being given all 26 available antibiotics.
According to the World Health Organisation, "Without effective antimicrobials for prevention and treatment of infections, medical procedures such as organ transplantation, cancer chemotherapy, diabetes management and major surgery (for example, caesarean sections or hip replacements) become very high risk."
A potential answer to the threat of antibiotic resistance is to use plastics for drug delivery. Plastics are a type of polymer (incidentally so is DNA) and polymers have a number of advantages in the body:
Timeable
Versatile
Easy to prepare
Reduces dosing frequency
Maintain therapeutic concentration with one dose
Reduced side effects
Improved stability
Prolonged release
However, we need to consider what happens with this plastic long term. How long is acceptable to leave in the body? So, we need to find a biodegradable polymer. This isn't as straightforward as it could be as you need the right enzymes and bacteria to degrade the polymer. For example, a biodegradable polymer wouldn't actually degrade in a landfill because it is too dry and there is too little oxygen so the enzymes and bacteria can't survive there.
There are some very specific requirements for this plastic. It has to be bio-compatible, non-toxic, permeable, biodegradable, pure and with a high tensile strength. There are three plastics that are being looked at, PLA, PGA and PTMC. The later seems to be the best choice as it is resistant to hydrolysis, which means that it sticks around longer and it isn't brittle.
 |
| Polymers for drug delivery |
How can we alter the properties of PTMC to make it into the delivery system that we want? Through using technical processes such as cross-linking, copolymerization and functionalization to incorporate functional side chains. The idea is to attach antibiotics into the basic structure of the PTMC. The antibiotics Gentamicin and Clindamycin are both being looked at with regard to this process as they cause severe side effects (Gentamicin can cause permanent deafness). You can read more about this research here.
Different delivery vehicles to get drugs into the eye are also being looked at. 95% of dose placed in the eye using a dropper is washed away. Is there a better way? Work has started on a contact lens that would include an antibiotic imprinted into it. That way the drug is trapped between the contact lens and the cornea - See UoN's research here and also some work by Harvard here.
Another big area of research is on the cargo - the drug itself. Does it have to be a small molecule? For example, even though there is no human-human transmission at the moment, there are huge fears about H5N1 influenza, also known as bird flu. It has a 60% mortality rate and would be a massive issue if it became pandemic. So a nanovaccine has been created, which is preventative rather than curative (some background can be found in this UoN pdf presentation and this research from the US).
 |
| Flu Virus |
Virus Like Particles
The final area of research is targeting strategies. The exterior of a virus is often a protein polymer cage known as a capsid. So called "virus like particles" mimic these capsids and tripper an antibody resonse that protects the vaccine recipient from later infection. An example of this technology is the Gardasil HPV vaccine.
You can also make these biological cages from things such as Ferritin, a storage protein for iron. The cage can opened and closed by varying the pH of the environment - while the cage is open, the iron can replaced by other things such as cancer drugs.
 |
| Ferritin |
Final Comments
Of course there are crossovers between lots of these areas of research. It may take a while for some to reach the public but these are exciting times in the field of drug delivery strategies.
Overall, it is clear that the direction of travel is for new drugs to be highly targetted so that only milligram dosages are required - aspirin certainly would not be licensed today!
The Public Lecture Series returns to the University of Nottingham on the 16th of February at 6:00pm where Julian Onions will talk about Things That Go Bang In The Night (Sky) For more information, please visit the Public Lecture Series site: https://www.nottingham.ac.uk/physics/outreach/science-public-lectures.aspx
Image Sources
Ferritin
Microneedles - Copyright: Ryan Donnelly, Queen''s University Belfast
Images from Talk - Copyright : Gav Squires
Flu Virus
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