Drexel researchers exploit the “sweet tooth” of hungry immune cells in this emerging era of immune-targeted therapies.
Our immune system is known for its ability to protect the body against pathogens, such as viruses and bacteria, but it also plays a crucial role in maintaining tissue health. This system also dictates tissue repair and regeneration by producing small proteins used in cell signaling, such as chemokines, cytokines, growth factors and enzymes that either combat or support disease-causing inflammation or help repair tissue.
Macrophages — deriving from Greek meaning “large eaters” for its skill at swallowing and breaking down pathogens, particles and dying cells — continuously devour dead cells and coordinate immune cell function throughout the body to play defense in response to injuries or infection.
Macrophages can be a double-edged sword, however.
“In many chronic diseases, such as cancer and heart failure, macrophages adopt states that further promote tissue dysfunction,” said Christopher B. Rodell, PhD, an assistant professor in Drexel University’s School of Biomedical Engineering, Science and Health Systems, whose lab team has figured out how to program the behavior of macrophages via materials based on sugar molecules. “In solid tumors, for example, macrophages generally suppress the body’s immune response against the cancer and negatively impact state-of-the-art treatments like checkpoint immunotherapies. On the other hand, macrophages can contribute to the establishment of chronic inflammation after injuries (like a heart attack or kidney injury), leading to eventual organ failure.”
In a series of three recently published papers, Rodell and colleagues report that the immune cells have a strong preference for eating materials containing cyclodextrin, a molecule built from sugar. By hiding drugs to change macrophages’ behavior within these sweet cyclodextrin nanomaterials, Rodell says that “immune cells could be tricked into taking their meds.” For more than six years, the research team has documented the processes by which macrophages eat the drug-loaded materials, harnessed these materials to promote an anti-tumor immune response, and developed methods to promote tissue repair that include the long-term delivery of modified proteins that control macrophage behavior.
This research, supported by the National Institutes of Health and American Heart Association, was published consecutively in ACS Applied Bio Materials led by graduate student Shreya S. Soni, ACS Biomaterials Science & Engineering led by graduate student Arielle M. D’Elia and Frontiers in Immunology led by Biplab Sarkar, PhD, a Cotswold Foundation Postdoctoral Fellow, all from the School of Biomedical Engineering, Science and Health Systems. The researchers aim to build on the success of these projects by developing novel treatment strategies that control macrophage function in diverse disease conditions that include cancer, heart failure and autoimmune diseases.
We caught up with Rodell and Sarkar for their perspective on the emerging era of immune-targeted therapies.
What is the major role of macrophages in disease?
Sarkar: Many people might be familiar with the role of white blood cells (including macrophages) in preventing infection – they eat foreign pathogens such as bacteria. But the role of macrophages in disease doesn’t end there. The research field is continually finding new ways in which macrophages interact with other cells to maintain tissue function. This includes things we might expect, like macrophages eating dead or dying cells throughout the body during regular tissue turnover. There are also many examples of things we might expect less, like how they actively conduct electric currents that makes your heart beat.
Unfortunately, macrophages sometimes misbehave and promote the progression of chronic diseases. For example, they can be hijacked by tumors to suppress inflammation. This prevents the immune system from recognizing and attacking the tumor and is a major issue limiting the efficacy of state-of-the-art immune checkpoint therapies. On the other hand, macrophages can contribute to the establishment of chronic inflammation after injuries, like a heart attack or kidney injury. This type of response continues to damage the tissue and can lead to long-term organ failure. Our work aims to re-educate these misbehaving macrophages to re-invigorate the immune response in cancer treatment or promote a healing environment in the context of tissue injury.
How and when did you start your work in macrophages?
Rodell: As with many good things in research, I suppose it was a bit of a happy accident at first. During my PhD, I developed hydrogels that could be easily injected and was applying these primarily to treat heart attacks. Since the hydrogels can include therapeutic drugs or cells, it led to collaborations with an outstanding pediatric nephrologist Danielle Soranno, MD, now an associate professor at Indiana University School of Medicine. In a series of manuscripts, we’ve since shown that the hydrogels stay where injected, slowly degrading to deliver the included drugs or cells. The delivery of proteins or cells that encourage macrophages to take on a pro-healing function has been very effective in preventing the development of injury-associated inflammation in the kidney and preventing later kidney failure.
This work ultimately led me to pursue other related projects, including to change the inflammatory response after heart attack and a postdoc at Massachusetts General Hospital. There, I developed techniques to examine how effective drugs are for re-educating macrophage behavior and biomaterials to target delivery of these drugs to macrophages in the body for therapy. My Drexel lab is now working to apply these toolsets to cancer immunotherapy and to promote tissue repair after injury.
How does cyclodextrin work to deliver drugs to white blood cells in the body?
Sarkar: We can target macrophages from the outside or from the inside. We call these modes ‘outside-in signaling’ and ‘inside-out signaling,’ respectively. In the first scenario, we deliver drugs or proteins that bind to receptors on the outside surface of macrophages, signaling the intracellular machinery to change the expression of genes and proteins. In the second scenario, we hide drugs inside sugary nanoparticles that macrophages inherently love to eat. Once inside the macrophages, the drugs are released and re-program cell behavior.
Rodell: We use cyclodextrin to achieve these modes of delivery in different ways. First, nanoparticles made of cyclodextrin can serve as drug carriers to improve water solubility, bioavailability and cell targeting of small-molecule drugs for ‘inside-out signaling.’ When we first developed these materials, we expected them to have a propensity to be eaten by macrophages because the cells are covered in specific receptors for sugars and cyclodextrin is made of sugar – specifically, glucose. Years later, Shreya Soni’s recent manuscript has finally tracked down the specific receptors that macrophages use to eat the particles.
For ‘outside-in signaling,’ we typically are delivering larger drugs (e.g., biotherapeutic cytokines that are protein signals known to change macrophage behavior). Since these proteins are too large to be included in nanoparticles and because receptors for these are on the cell surface, we modify the proteins with chemical groups that stick to cyclodextrin-containing hydrogels. Arielle D’Elia’s recent paper demonstrated the ability of these hydrogels to release the drugs long-term and at controlled rates needed for therapy.
In these papers, you use a variety of delivery techniques. How can the delivery method affect treatment?
Sarkar: One of our key goals is to target specific cell types or tissue impacted by disease. This is important for preventing side effects that occur when other tissues are exposed to the drugs. This is a widespread problem in cancer chemotherapy — drugs that kill tumor cells are also toxic to normal cells. Similar issues arise with drugs that alter the immune system. Simply delivering drugs to the entire body to suppress the inflammatory response can be effective in treating tissue injuries like heart attack. However, it also prevents our immune system from doing things it needs to do, like fighting off infection. This has led to the failure of multiple clinical trials in this area. By targeting drug delivery specifically to the site or cell type, we believe these clinical barriers can be overcome.
What are you and your colleagues exploring now? What are the biggest questions you’re seeking to answer?
Rodell: We are continuing our work to target tumor-associated macrophages, where we look to directly examine the response to locally delivered signals versus the same signals delivered throughout the body. We expect that local delivery will concentrate drugs at the site to improve outcomes while limiting side effects. Building on the cyclodextrin nanoparticle’s macrophage-targeting ability, we are also developing nanotherapeutics to promote tissue repair in the context of organ injury, such as in the heart and kidneys. A major goal is preventing the establishment of chronic inflammation that is known to lead to continued tissue injury and organ failure.
In both cases, we are interested in answering open questions about how the therapies work. In the big picture, little is known about how therapeutically altering macrophage behavior affects the broader environment. This includes (1) other immune cells (e.g., neutrophils, monocytes, and T cells) that communicate with macrophages in the tissue and (2) inflammatory signaling throughout the body that is known to result in co-morbidities, such as kidney failure after a heart attack.
Will changing macrophage behavior directly change T cell behavior in the same tissue? Will local changes in macrophage behavior prevent systemic inflammation and damage to distant organs? We hope to find out!
What are you most excited about for the future of biomaterials and drug delivery?
Rodell: I tend to see great potential and broad applications in every project, so it’s easy for me to get excited about everything in this field! Recently, the things I have been most excited to think about are developing modular drug-delivery platforms where the material itself serves as a therapeutic adjuvant (a substance that enhances the body’s immune response) and harnessing new biological insights to identify novel signals to deliver. For example, we have considered re-designing some of our material platforms to include metabolites that modulate the immune response. Such an approach could re-enforce drug actions by using bioactive materials.
Ultimately, what would make me most excited is to see these materials reach the clinic and help people. We have shown that re-education of tumor-associated macrophages works in pre-clinical mouse models of highly aggressive glioma and that the approach is an exceptional adjuvant to improve the response to state-of-the-art checkpoint immunotherapies. There are many precedent nanotherapeutics already used in cancer treatment and over 1,000 clinical trials past or current seeking adjuvants to improve patient response to checkpoint immunotherapies. This may help aid our transition into clinical trials. While there are far fewer precedents for the use of hydrogel-based systems to locally modulate inflammation, we are excited to build a better understanding of how these therapies can overcome clinical barriers.
Media interested in speaking with Rodell and/or Sarkar should contact Greg Richter, assistant director of News & Media Relations, at gdr33@drexel.edu or 215.895.2614.
