Modern pharmacology problems require modern polyzwitterion-polyelectrolyte solutions: adventures in polymer physics and medicine

Solving challenges in oral drug delivery requires new ways of thinking about charged macromolecules and soft matter. Here, the author describes his unique academic journey, and how it enabled him to see this problem in a new light.
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When I began my first year as an undergraduate student, my impression was that I would study mathematics. By the end of the following year, I was performing experiments with charged polymers, and preparing to apply to medical school. When I went to medical school, I realized that many challenges in clinical medicine could be tackled and improved through new ways of thinking about healthcare materials, and I decided to temporarily pause my medical training to pursue a PhD. My winding road through science has been somewhat unusual and complicated, but I have had the immense fortune of working closely with several very inspiring mentors whose guidance helped me navigate this challenging journey, and shaped me into the person I am today. 

The long and winding road

During my time in college, I became very interested in the physics and chemistry of materials. I was fascinated by the prospect of understanding how the ensemble of fundamental, microscopic characteristics of a material worked together to lead to bulk properties that could be put to good use. In particular, the behavior of charged polymers caught my eye, because the phenomenology elucidated from work on synthetic polymers could also be used to answer deep questions about the nature of the basic building blocks of life (DNA, RNA, proteins), which are themselves also charged polymers. While working in Matt Tirrell’s research group to answer some of these questions, I took a course in biochemistry with Marvin Makinen, which opened my eyes to the relationships between the charged macromolecules of life, and the fundamental basis of human health. With these two experiences in conjunction, I had a unique perspective that allowed me to briefly glimpse at every level of life—from the molecule, up to the person. I realized that by understanding how molecules work, it would be possible to improve human health by uncovering previously unknown mechanisms that explain disease processes, and by applying advanced materials to the healthcare setting.

The experience of medical school is often aptly described as “drinking water from a firehose.” Each week, we are expected to absorb hundreds of pages worth of class notes, radiology images, histology slides, anatomical diagrams, etc. As a student of the physical sciences, I initially struggled to memorize and regurgitate facts that I couldn’t derive from first principles. However, with every lecture, I was exposed to a new and fascinating set of ideas related to each facet of medicine presented to the class. As I became more accustomed to the brisk pace of medical education, I began to realize that there are many yet-unexplored avenues for materials research within the biomedical arena, and I decided that it was time I equip myself with the tools to solve those problems. I took a risk, and decided to take time off from medicine to pursue a PhD degree in polymer science.

As a PhD student, one’s experience in the lab can sometimes feel at odds with the fast pace of medical training. This dichotomy boils down to the differences in one’s progress through each program. In medical school, your expectations and milestones are well-defined, and the educational content is an enormous volume of fairly well-accepted facts. Medical students learn to synthesize these facts to determine accurate diagnoses and treatment plans for their future patients. In graduate school, expectations and milestones can vary enormously between students, and the content of one’s study is typically focused on the pursuit of a deep solution to a very narrow problem. A successful scientist applies their own flavor of deep methodical thinking to new problems later in their career.

Finding a problem that is suitably deep but also of broad applicability in the biomedical context was one of the more challenging aspects of my training. Of course, I could have chosen to focus on a more standard problem in the repertoire of research within the field of polymeric materials. However, my overarching thesis, my meta-thesis so to speak, is that there are questions in biomedicine that students of materials science (and in particular, polymer science) are uniquely poised to answer. My experience working on this project was as much an exercise in physics and chemistry as it was in leveraging my training as a medical student. To that end, I remembered that in the delivery of medicines through the oral route, challenges from gastric degradation severely limit the use of advanced therapeutics within the gastrointestinal tract. Using a form of complexation between charged polymers, I realized that it may be possible to shield sensitive cargo from these harsh environments, which would then improve the availability of a wider range of medications to patients.

Summary of the paper

Complex coacervation has been studied extensively over the last century, and is typically characterized by the entropically-driven association of two oppositely charged polyelectrolytes in solution to form spherical droplets with length scales encompassing the hundreds of nanometers to tens of microns regime. These droplets are stable around neutral pH conditions, and the addition of acid or base can induce the degradation of the droplets. This pH-dependent property has been harnessed to encapsulate cargo at neutral pH, and release that cargo in strongly acidic or basic regimes. However, in physiological conditions, it is desirable to invert this regime of pH-dependent stability/instability, such that encapsulation occurs at strongly acidic pH values, and release occurs at neutral pH values. Such a pH-triggered property is of great interest to address imminent challenges regarding the delivery of pharmaceuticals into the gastrointestinal tract via the oral route, since the harsh environment of the stomach precludes the ingestion of many chemically sensitive therapies.

In this work, we introduce a new class of materials, called polyzwitterionic complexes (“pZC”s), formed by the liquid-liquid phase separation between polyzwitterions and polyelectrolytes. (Recall, polyzwitterions are polymers whose monomer units each carry a discrete positive and a discrete negative charge simultaneously. Polyelectrolytes, in contrast, carry one kind of positive or negative charge within each monomer unit.) These droplets exhibit “orthogonal phase behavior” with respect to pH—in other words, they remain intact in very acidic conditions, and disassemble in gentler conditions.

We characterize a set of relevant physical properties of the pZC droplets in this paper. We test the effect of the mixing stoichiometry between the polyzwitterion and polyelectrolyte components on the resulting solution’s optical density, and determine the effect of pH and temperature on the propensity of these polymers to associate. Furthermore, intrigued by the fact that the self-assembly of these molecules does not fit neatly into existing models of complexation between charged polymers, we compose a new theoretical framework to explain and justify our findings. This framework can be generalized to numerous systems which use pH as a chemical trigger to controllably tune the phase behavior of charged macromolecules.

With a fuller picture of the experimental variables that dictate the phase behavior of pZCs, and the physical phenomena that contribute to complexation, we test the possibility of retention and release of biomolecules that motivates our work in the first place. Firstly, we demonstrate the real-time dissolution of pZC droplets upon exposure to increasing ambient pH with video microscopy. Next, using fluorescently labelled bovine serum albumin (BSA) as our model cargo, we induce encapsulation of the BSA into pZC droplets. Finally, we demonstrate that this observed encapsulation property is sensitive to pH—the BSA is retained in the polymer droplets in acidic conditions, and released as the pH increases. 

In summary, we discovered a new class of self-assembling materials called pZCs, formed by the complexation between polyzwitterions and polyelectrolytes. After characterizing the physical properties of these materials and formulating a new theory to explain our observations, we harnessed our system to show the pH-dependent retention and release of a model protein. We envision that the ideas and methods outlined in this paper lay the groundwork to tackle the imminent problem of advanced drug delivery into the gastrointestinal tract.

Some parting thoughts

To conclude, a few thoughts. Firstly, this effort would not have been possible without the support of my fantastic collaborators Marcel Brown, Todd Emrick, and of course my thesis advisor Murugappan Muthukumar, to whom I am deeply grateful. For any younger readers—if you are interested in a journey through science of your own, three words my scientist father often told me that have rang true during the last decade or so of my life in research: “just keep pushing.”

References

1.Margossian, K.O., Brown, M.U., Emrick, T. and Muthukumar, M., 2022. Coacervation in polyzwitterion-polyelectrolyte systems and their potential applications for gastrointestinal drug delivery platforms. Nature communications13(1), pp.1-11. 

2.  Liu, J., Perry, S.L., Tang, B.Z. and Tirrell, M.V., 2022. Liquid capsules for gastrointestinal drug delivery. Matter5(10), pp.3107-3109.

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