Triiodothyronine Nanoparticles for Cardiac Arrest

According to the CDC, more than 356,000 people have an out-of-hospital cardiac arrest in the United States every year. 60% to 80% of these patients die before reaching the hospital. For half a century, a 1mg dose of epinephrine (EPI), administered once every 3-5 minutes, has been the medication protocol for advanced life support in cardiac arrest. This is an old protocol, first implemented in Advanced Cardiac Life Support (ACLS) guidelines in 1974 and was based on research from 1905. Across numerous studies, reviews, and publications in resuscitation science, researchers have uncovered the shortcomings of this drug in cardiac arrest management including poor neurologic function and long-term mortality outcomes.1
Enter Pro-AL Medical Technologies Inc. 2021, based in New York State and founded by Edward Mattes and Leo Rubin. Pro-AL is one of a select few healthcare innovation firms working around-the-clock to revolutionize the field of emergency medicine through ground-breaking drug research. Currently, the company is working to develop a novel formulation of the drug triiodothyronine (T3) as a potential replacement for EPI. This fall, Brown Journal of Healthcare Advancement (BJHA) had a fantastic opportunity to sit down with Mr. Mattes and discuss the latest developments in Pro-AL’s work.
Dr. Rubin received his M.D. degree from the University of Zurich. Mr. Mattes holds degrees from the University of Pennsylvania (BA 1979, Political Science) and Vermont Law School (JD 1983). Before becoming the CEO of Pro-AL, Mr. Mattes founded and ran a global business consulting program at the United Nations. He is also an emergency medical technician with a knack for delivering excellent pre-hospital care in Tuxedo.
The mission statement of Pro-AL is to “bring energy to the energy-deprived cell.” Such is the most fundamental reason why cardiac arrests are so dangerous: cells die because of a lack of energy. Mitochondria are cellular organelles that produce a biochemical form of energy called ATP in a healthy person. In a cardiac arrest, the mitochondria’s oxygen supply is cut off, robbing it of its ability to provide energy. Cells die as a result. Irreplaceable neurons are the first to go, leading to permanent brain damage.
The old drug EPI does not stimulate ATP production in an oxygen-deprived cell. Rather, it constricts blood vessels to increase perfusion.2 While this does increase the patient’s chance of survival, they often end up suffering long-term neurological deficits.
Pro-AL’s novel formulation addresses this issue. It’s an active thyroid hormone capable of “rapid, non-genomic cytoprotective effects”.3 Instead of simply increasing perfusion of blood through the body’s tissues, this novel formulation stimulates the correct signaling pathways and triggers necessary ion pumps to protect cells and their components under cardiac arrest.3 The novel formulation can reach the mitochondria of a cell, stimulating the process of ATP production.
Mr. Mattes provided background information on how the novel formulation of T3 arose. Dr. Rubin, his longtime friend and cardiologist, was an avid researcher in resuscitation science; he had been doing patented medical research on defibrillators since the 1970s. In the context of this research, Dr. Rubin wondered if there would be a drug that could work more effectively than EPI to bring patients back from cardiac arrest. After co-founding Pro-AL with Mr. Mattes, the team discovered that triiodothyronine was a promising choice for such a drug; once believed to have only a genomic effect on the expression of certain genes, the team discovered that T3 plays a nongenomic role in energy production. It was with Dr. Rubin’s great wealth of knowledge that Pro-AL was able to move forward with its research on T3.
The Pro-AL team’s greatest challenge was finding a way to deliver this novel formulation of T3 to the mitochondria intact. According to the company’s executive summary, the focus of the research was to develop a chemical packaging for the T3 that could serve two purposes: 1) prevent T3’s denaturation in the bloodstream and 2) ensure that this chemical packaging could guide the drug through the cell’s cytoplasm and into the mitochondria. Under hypoxic conditions, the novel formulation activates cell membrane transport mechanisms, restoring the membrane’s electrical potential. This allows the cells to relax and contract, while simultaneously releasing energy, rescuing mitochondria, and redirecting their energy toward productive cell output.
In collaboration with the Department of Physiology and Biophysics at the University of Buffalo, Pro-AL has completed animal trials using pigs, which as Mr. Mattes explained, are “the closest in terms of cardiac structure” to humans. In this experiment, four groups of pigs were put in cardiac arrest for seven minutes and given twenty minutes of CPR and defibrillation. Each group then received a different type of injection. The control group was injected with saline, the second was injected with EPI, and the third and fourth groups were injected with T3 that came in different chemical packaging – either the base wrapping nanoparticle or that same nanoparticle attached to a phosphocreatine.3
The results were encouraging. After comparing slices of brain tissue across the four groups under an electron microscope, the team discovered that the neurons were better preserved in both groups of animals that received the novel T3 formulations than the groups receiving the standard EPI injection or saline control. In addition, the team monitored levels of troponin, a chemical that is released when cardiac tissue is damaged, in each group. Troponin levels were halved in the T3 groups compared to the saline and EPI groups, indicating T3’s increased effectiveness in combating hypoxia in the heart as well as the brain when administered during cardiac arrest.
When BJHA asked Mr. Mattes about his future plans, he replied that the next steps were to secure funding from the NIH and obtain a toxicology screening. He also pointed out that Pro-AL had reached out to the FDA several years ago regarding its plan to research T3. The company was told to make a large batch of the novel formulation and perform toxicology and human studies. This point piqued our interest since, as Mr. Mattes put it, “This is not a drug you give to a live human being.”
For the human subject phase of research, Mr. Mattes described to us his plans to follow the PARAMEDIC2 study done in England in 2018.4 In the planned double blinded, randomized study, the paramedics servicing a particular region would be chosen and divided into a control group and an experimental group. The standard EPI treatment would be placed into the medic bags of the control group, and the novel T3 formulation would be placed into the bags of the experimental group. Over the course of several months – a time sufficient for each paramedic in the study to receive at least one cardiac arrest call – the paramedics would treat cardiac arrest patients with the medication they were given and report on patient outcomes. Correlations between patient outcomes and treatment used would then be analyzed, and conclusions would be drawn.
As a parting remark, Mr. Mattes told us that energy is biology’s central underpinning. The scientific community has only “scratched the surface” in understanding this fundamental concept, which if mastered, could revolutionize the biomedical field. Our last question was, “For someone pursuing biomedical research, what advice would you give?” Mr. Mattes smiled and replied that the possibilities are endless – “Go for something that interests you and look for people who share that interest.” There are always resources available to passionate, motivated students, whether those be hospitals, local organizations, or professors.

Writer: Dawson Lin
Researcher: Sneha Tallam
Editor: Megan Vu
Illustrator: Rafael Mediodia

1. Kasha Bornstein, Brit Long, Alessandra Della Porta, and Guy Weinberg, "After a Century, Epinephrine's Role in Cardiac Arrest Resuscitation Remains Controversial," (American Journal of Emergency Medicine 39, 2021), 168–72.

2. Wongtanasarasin W, Srisurapanont K, Nishijima DK. “How Epinephrine Administration Interval Impacts the Outcomes of Resuscitation during Adult Cardiac Arrest: A Systematic Review and Meta-Analysis.” (Journal of Clinical Medicine 12, no. 2, 2023).

3, Brian R. Weil, Shannon E. Allen, Thomas Barbaccia, Kimberly Wong, Abigail M. Beaver, Elizabeth A. Slabinski, Jeffrey G. Mellott, Peter C. Taylor Dickinson, Shaker A. Mousa, “Preclinical Evaluation of Triiodothyronine Nanoparticles as a Novel Therapeutic Intervention for Resuscitation from Cardiac Arrest,” (Resuscitation 186, 2023).

4. Perkins GD, Ji C, Deakin CD, et al. “A Randomized Trial of Epinephrine in Out-of-Hospital Cardiac Arrest.” (New England Journal of Medicine, no. 8, 2018), 711-21.