Effective delivery of drugs to their targets has long plagued researchers and clinicians. There are also concerns related to the large-scale production of drug-delivery tools required for commercialization, especially in light of our aging population who present an increasing strain on our healthcare system.
Therapy for chronic diseases like hypertension, cancer, and diabetes require the affected tissues to be specifically targeted by drugs. Researchers and clinicians need to ensure that the drug is delivered to the correct target tissue, is not lost on its way to its target tissue, and is taken up by the target tissue. Otherwise, a larger dose is usually required in order to achieve the desired effect on the target tissue, which comes with its own host of risk factors, including adverse side effects. This is why researchers are seeking increasingly more to create biocompatible vectors that can deliver therapeutic drugs to a target site, without losing them on the way, or risking an adverse immune reaction in the patient. To further complicate this situation, there are many different classes of drugs, each with their own unique physical properties. To accommodate the variety of drugs, tunable vectors are urgently needed for effective drug delivery. This is where the research of Xavier Banquy comes in with their development of new biocompatible vectors for drug delivery.
Dr. Xavier Banquy with assistant professor Eva Navarro and intern Teresita Rode (first author of the article in question). Source: “Faculté de pharmacie – Rapport d’activités pharm.umontreal.ca,” Docplayer, image obtained from internet: https://docplayer.fr/40285531-Faculte-de-pharmacie-rapport-d-activites-pharm-umontreal-ca.html [Online Access: April 9, 2019]
In the past ten years, a popular class of vectors called liposomes have reached the market and clinics. However, they come with their own drawbacks. These include stability, where they can degrade prematurely before reaching their target, while passing through the bloodstream to a target site. They also suffer from low encapsulation efficiency, which is the ability to trap a drug inside the vector structure. Imagine it like the likelihood that a vector can engulf a drug, and the drug remains inside. It thus appears that more vectors need to be developed, that are not only more stable, but able to efficiently capture and store a wide class of drugs.
Schematic of a standard liposome used for drug delivery. The interior is able to encapsulate water-soluble drugs, while the lipid bilayer is able to encapsulate oil-soluble (or lipid-soluble) drugs. Source: Torchilin, V (2006). “Multifunctional nanocarriers”. Advanced Drug Delivery Reviews. 58 (14): 1532–55.
The lab of Xavier Banquy is one of these labs focusing on streamlining the production of biocompatible drug-delivery vectors. Xavier Banquy, a tenured professor at l’Université de Montréal Pharmacy School, and research chair for biomaterials inspired by living things, has turned to the fabrication of new vectors that are different from standard liposomes, and which are adapted to a wide range of drugs. These are invisible to the naked eye, and are called polylactic acid-polyethylene glycol (PLA/PEG)-nanoparticles. The two main components of this have different properties which were taken advantage of by Dr. Banquy’s group. PEG is a common polymer used for biomedical applications, due to its biocompatibility with living organisms. It also improves the stability of other materials, extending their lifespan. Finally, it is a polar molecule that will interact with water, helping to make other materials more soluble in water. PLA, on the other hand, is an organic polymer that will form compact structures when placed in water, shielding itself from water molecules. This allows it to interact with more oil-soluble materials, making them more soluble.
When I asked Dr. Banquy about his motivations to produce PLA/PEG-nanoparticles for drug-delivery vectors, he told me that these vectors are cheaper than other conventional biomaterials, and as a result, can be scaled up to an industrial level at a lower cost, which makes them attractive from a commercialization viewpoint. In spite of all the progress in recent years in drug-delivery vector research and development, one of the largest challenges that still remains is translating these vectors to the market. One of the other issues is inconsistency between batches produced. This is where the research of Xavier Banquy comes in. He is attempting to develop robust protocols for producing any type of vector meant for drug delivery. He stressed to me the importance of the process in finding success during scale up to the industry. By thoroughly developing and characterizing processes for producing these vectors, many of the issues related to scale up for clinics and hospitals could be mitigated.
Naturally, this talk about drug-delivery vectors sparked my interest in finding out more about the attractiveness of PLA/PEG-nanoparticles in this publication of Dr. Banquy.
He said two factors were behind their choice of developing PLA/PEG-nanoparticles. The first factor was their ability to spontaneously assemble into nanoparticles in water at a low energetic cost. Furthermore, PEG, due to its versatility in water environments, and its ability to increase the stability of other materials, can be conjugated to other polymers, which allows researchers to impart them with a diverse range of physical properties.
A diagram showing some of the various biomedical applications PEG can confer to other materials when they are conjugated to each other. Source: “New Polyethylene Glycols (PEG) as versatile biochemical linkers,” Tebu-Bio Blog, image obtained from internet: https://www.tebu-bio.com/blog/2016/07/13/polyethylene-glycols-peg-as-versatile-biochemical-linkers/ [Online Access: April 9, 2019]
With these two factors in mind, Banquy’s group changes the dynamics of PLA/PEG-nanoparticles, by playing with the conditions required for precipitating and forming these nanoparticles. By creating large nanoparticles, they were able to create amphipathic particles, or particles that have an equal ability to mix and interact with drugs that are more water-soluble (hydrophilic drugs), and ones that are not (hydrophobic drugs). Imagine their properties being like that of soap particles fighting against grease stains. One region serves to interact with substances that are more soluble in oil, while the other region serves to interact with water molecules. However. unlike soap particles, they have added an additional region which is the innermost core of their nanoparticles (see schematic below). This new region allows them to encapsulate water-soluble drugs like insulin, in addition to the region that can interact with oil-soluble drugs like Vitamin D. This presents huge advantages with these nanoparticles, in that they can accommodate a larger range of drugs.
Schematic of the two outcomes resulting from mixing of PEG/PLA nanoparticles. The experimental approach of Dr. Banquy’s group looked to optimize production of large particles in order to create a water-soluble block of PEG trapped in the centre of the nanoparticle. This rendered these nanoparticles capable of accommodating both water-soluble and oil-soluble drugs. Τmix and τcis are mathematical parameters known in the literature to influence precipitation of these nanoparticles. Image taken from Dr. Banquy’s article (reference at bottom of page).
Drug compatibility with their delivery vectors is so crucial to being able to effectively store them until they reach their targets. This is why the Banquy lab has focused on developing processes and materials that could improve the efficiency of encapsulation. Techniques that optimize the mixing efficiency of two different substances (such as in this article), such as the physical design of the mixing apparatus, temperature, concentration, or solvents, are all factors that need to be taken into consideration when designing polymers like PLA/PEG-nanoparticles. Dr. Banquy told me that by optimizing the technical process used to synthesize these materials, issues related to production costs and scaling up to industrial levels could be better resolved, as the process would be more thoroughly characterized and reproducible.
Now you might ask, how is the experimental approach of the Banquy lab unique?
He told me that what makes this approach stand out, is that a parallel comparison of three methods for precipitating and producing PLA/PEG-nanoparticle polymers is carried out (see schematic below). The first one relies on a standard batch method, which mixes all the important reagents together at once. Imagine it like making a hot soup on one of these frigid winter days in Montreal, and letting the ingredients brew together. This technique is unlike continuous flow, which relies on a constant inflow and outflow of reagents in the mixture. Think of it running very similarly to how a chlorinated swimming pool works, where an outflow removes waste and excess, while an inflow brings in fresh, clean solution. In this paper, they compare two techniques for continuous flow against each other, the main difference for them being the mixing apparatus’ design. We can see below the schematics for the three apparatuses they used.
Schematic showing the three techniques compared in parallel by Dr. Banquy’s group. The first relies on batch precipitation to form the nanoparticles, while the latter two rely on continuous flow, with input for two different phases, aqueous (PEG) and organic (PLA). Image taken from Dr. Banquy’s article.
I was particularly drawn to the design of their apparatuses for continuous flow, and thus, I asked Dr. Banquy to elaborate more on what makes their design so reliable for producing consistent nanoparticles of all sorts of different shapes, sizes and compositions. He told me that the apparatuses used allowed for better control of the structure of the growing nanoparticle and its physical properties, resulting in less dispersion between nanoparticles produced. This would mean an improved consistency between batches of production, and an improved capacity to scale this up to larger volumes as a result.
After producing PLA/PEG-nanoparticle polymers by these three different techniques, his lab was able to characterize their properties by evaluating their ability to load and encapsulate drugs. This was essential in order to not only prove that the nanoprecipitation (formation of nanoparticles) worked, but that the nanoparticles could be applied to future studies.
Schematic showing the PLA/PEG-nanoparticles Dr. Banquy’s group fabricated. Arrows show the loading and unloading of drugs that can occur in each of the two regions. Encapsulation is achieved when the drugs are successfully trapped inside a region. Source: ”PLA/PEG-Nanoparticle Structure,” Kurt Ebeling, GBM6330, Technologies Biomédicales Émergeantes, 2019.
Encapsulation of the drugs was tested by titrating the drug into the nanosuspension (or the nanoparticles in solution), and measuring the rate of its uptake. The faster the drug is taken up the nanoparticle (or loaded), the better the affinity it has for the nanoparticle, and thus the more efficient the process of encapsulation.
In this paper, the ability of these PLA/PEG-nanoparticles to encapsulate a wide range of drugs was enhanced in the continuous flow processes when compared to the batch process. This proves how important the thorough development of their techniques was in ensuring a successful and consistent production of reliable nanoparticles.
The refining of the techniques of PLA/PEG-nanoparticle polymerization really pique our interest. It makes us wonder where the Banquy lab is now, and what new drugs and materials they have been testing.
formulations, and incorporating them into their micromixing apparatuses. Some of their strategies involve synthesizing and characterizing polymeric nanoparticles with different properties, and morphologies, and subsequently adapting them onto to the apparatuses they have worked so hard to develop. Because optimization of the synthesis process was so crucial to paving the way to future research in the Banquy group, further adaptation of different polymers will further validate the effectiveness, flexibility and reliability of their developed equipment and methods. This bodes exciting not only for the Banquy group, but the future of the pharmaceutical industry. The more we optimize the process, the larger the quantities of reliable drugs we can produce (and hopefully produced at faster rates too!).
Finally, I asked Dr. Banquy where he feels pharmaceutical research will be in the years to come. He said that while many strides have been made in recent years developing newer and better drugs, what is most lacking are the engineering tools to allow for a cost-effective and successful scale-up of these products to levels that can be commercialized and distributed to our population in need of healthcare. Despite the promise of many products that have been developed, many have yet to reach the market and clinics. This shows a gap between the research and development phase of pharmaceutical products, and their scale-up. This is where the Banquy lab comes in to fill this void.
Overall, the research of the Banquy lab seems very promising and is helping steer pharmaceutical research closer towards a faster, more reliable and more cost-effective production of therapeutic drug-delivery vectors. For our aging population in desperate need of these drugs, this could be music to their ears.
Reference for Article:
Rode García, T. et al. (2018). Unified Scaling of the Structure and Loading of Nanoparticles Formed by Diffusion-Limited Coalescence. Langmuir, 34(20), 5772-5780.