Biological Modeling Software Means New Life for Red Blood Cells

Designed to Cure

The shapes of red blood cells in different contexts. Source: Anatomy of the Human Body by Henry Gray. Via Wikipedia.

Barring hematologists, mention of red blood cells (RBCs) is typically met with expressions of boredom or demure from many researchers. However, RBCs have fantastic drug delivery potential, according to a new review published in the journal Advanced Drug Delivery Reviews. The review summarizes recent breakthroughs in red blood cell engineering to exhort researchers to pick up RBCs as powerful tools in the biologic drug maker’s kit.1 Even though RBCs are ready for researchers to play with, modifying their properties while maintaining their general functionality will be a challenge without sufficiently advanced biologic modeling software.

Why RBCs?

Part of the reason why RBCs have such tremendous potential is that nature has already designed the majority of the delivery vehicle—and by extension, its immune-system evading camouflage— meaning that researchers will only need to customize the platform with a payload to fit their particular needs. As the original review as well as other reviews have noted, RBCs circulate for a long time in the body, which means that the half life of RBC derived biologics would be much longer than other drugs.2

Long circulation times are a blessing for therapies intended to treat chronic conditions, which is one more area where RBCs shine. Patients could potentially receive an infusion of RBC therapeutics and only return for another treatment after a full month when the RBCs are degraded. Long circulation times are also ideal for combating dangerous yet rare events like tumor fractionation and spread into the bloodstream; an RBC therapeutic could treat a primary tumor while also constantly acting as a patrol which could suppress any tumor cells which separate from the main malignancy.

Considering how lethal tumor contagion of the bloodstream can be, even an extant small molecule therapy tacked onto an RBC carrier could be the difference between life and death for patients. This is exciting because as the review notes, RBC therapeutics have the opportunity to massively increase the effectiveness of drugs that are already confirmed as useful, meaning that they have the potential to be rapidly developed.

From hematopoiesis to tumor lysis   

As the review examines, there are quite a few different directions that researchers could take to make RBCs into their biologic drug products, all of which take advantage of the RBC’s long circulation time and immune system invisibility. Some researchers have envisioned RBCs as mere “drug bag,” internal carriers of traditional small molecules or nanotherapies, intending to make use of the broad reach of the circulatory system to bolster already understood therapies.3 These systems aim to make use of the cells’ inherent fragility to easily trigger RBC lysis and thus drug release when at the intended location, often using novel methods.4

Other researchers have envisioned RBCs as therapeutic production factories that circulate through the host’s body, constantly secreting therapeutic proteins.5 Others still see RBCs as gigantic rafts that small molecules or proteins will extrude from, binding to their targets as the cell floats around. The tact that researchers decide to take to implement their RBC therapeutic won’t change the complexity of the process, however.

Let’s assume the simplest use case of an RBC therapeutic, in which researchers seek to genetically introduce a proven small molecule therapy to the surface of RBCs such that the drug will have a vastly extended half life. Leveraging the RBC as a ready-to-modify delivery mechanism means using hematopoietic stem cells, which will need to be genetically modified to correctly express the small molecule as a protein on the surface of their membranes before undergoing differentiation into RBCs.6

After the RBCs expressing the small molecule therapy are done differentiating in culture, they’re ready for infusion into the patient, who will benefit from the longer circulation time of the small molecule therapy extruded into the RBC’s membrane.7 If the small molecule has been produced and extruded correctly by the RBC during the differentiation process, it’ll maintain its effectiveness for much longer. Not too tough, in theory.

Things are never as easy as they seem, even when supposedly most of the work is already done. To design this hypothetical therapeutic, researchers must:

  • Model the biochemical and biophysical properties of the extant small molecule drug
  • Model the biochemical properties of the intended target of the small molecule
  • Model the binding between the small molecule and its intended target
  • Model the interactions between the RBC’s membrane and the tissues of the intended target
  • Model the RBC’s membrane with and without the embedded small molecule to ensure that the RBC itself isn’t a barrier to its embedded small molecule binding to its intended target
  • Model the small molecule’s extrusion from the intracellular space of the RBC into the phospholipid bilayer and subsequent extrusion into the outward-facing edge of the fluid mosaic; model the final state of protein presentation

These steps merely cover the therapeutic’s ability to stay out of its own way, though. Cells are rarely as uniform as small molecules and frequently suffer from malformations, which introduces an additional set of concerns that have to be dealt with:

  • Model the extrusion point of the small molecule from the RBC’s cell membrane when the small molecule is correctly formed and correctly extruded to determine whether there is any chance of the small molecule separating from the membrane unintentionally
  • Model the extrusion point of the small molecule from the RBC’s cell membrane when either the membrane itself, the small molecule, or the extrusion hasn’t occurred correctly
  • Quantify these aberrational cases and determine whether they occur on a single cell basis or if aberrations are evenly distributed across the RBC therapeutic product
  • Model the aberrational cases’ interaction with the intended target as well as with the immune system to ensure that aberrations don’t cause loss of immune invisibility

Experimentalists will note that many of these bullet points can indeed be fleshed out without resorting to using modeling software, though at an outrageous time expenditure that’s sure to have graduate students burning the candle from both ends.

Modeling erythrotherapies

Biologic therapy development is slow enough and expensive enough even without experimentally investigating all of the potential failure modes of the therapeutic. It’s more likely that labs without a powerful modeling resource simply wouldn’t be able to undertake RBC therapeutic development. Thankfully, there’s a software package which makes a biologic design suite and molecular modeling platform accessible to any research group interested in exploring RBCs as biologic therapies.

BIOVIA Designed to Cure is an advanced software solution experience that supports collaborative research driven by organizational knowledge and rigorous analysis. Contact us today to find out how you can use Designed to Cure to jump into the wild world of RBC therapeutics.

  1. “Red blood cells: Supercarriers for drugs, biologicals, and nanoparticles and inspiration for advanced delivery systems.” March 2016, http://www.sciencedirect.com/science/article/pii/S0169409X16300588
  2. “Advances of blood cell-based drug delivery systems.” January 2017, http://www.sciencedirect.com/science/article/pii/S0928098716302895
  3. “Next generation drug delivery: circulatory cells-mediated nanotherapeutic approaches.” October 2016, http://www.tandfonline.com/doi/full/10.1080/17425247.2017.1254614
  4. “Photosensitizer Decorated Red Blood Cells as an Ultrasensitive Light-Responsive Drug Delivery System.” January 2017, http://pubs.acs.org/doi/abs/10.1021/acsami.6b15444
  5. “Drug delivery with living cells.” November 2016, http://www.sciencedirect.com/science/article/pii/S0169409X16301314
  6. “Ex vivo large-scale generation of human red blood cells from cord blood CD34+ cells by co-culturing with macrophages.” May 2008, http://link.springer.com/article/10.1007/s12185-008-0062-y
  7. “Engineered red blood cells as carriers for systemic delivery of a wide array of functional probes.” July 2014, http://www.pnas.org/content/111/28/10131.short