Heart attack treatment: targeted delivery of dangerous enzyme inhibitors
"Smart" hydrogel prevents the consequences of a heart attack
NanoNewsNet based on the materials of the University of Pennsylvania:
New Penn-Designed Gel Allows for Targeted Therapy After Heart Attack
The fight against enzymes that have a long–term negative effect on the heart muscle tissue after a myocardial infarction is a difficult task. Each patient reacts to a heart attack differently, and the damage inflicted on one part of the heart muscle may differ from the damage inflicted on another part of it. The current treatment methods are not perfect enough to take into account these differences.
Scientists from the University of Pennsylvania have found how to solve this problem by creating a hydrogel that works directly in the damaged heart tissue. Potentially dangerous enzymes break down this gel, releasing enzyme inhibitors contained in it. This balanced approach is ideal for maintaining optimal enzyme levels and minimizes the risk of congestive heart failure.
"When treating patients who have had a heart attack, the priority is to restore cardiac blood flow," says study leader Jason Burdick, professor of bioengineering at the School of Engineering and Applied Science at the University of Pennsylvania. "Secondary effects, such as ventricular remodeling, are neglected."
Remodeling is a phenomenon that ultimately changes the shape and function of the heart. After a heart attack, as part of an inflammatory response to injury, the body releases enzymes. But if this reaction continues for too long, the enzymes begin to destroy the extracellular matrix of the muscle tissue that makes up the walls of the heart, making them thinner and weaker. And since the pumping function of the heart remains normal, the chambers of the heart expand. As a result, the volume of the heart increases, but the thinned and weakened muscle wall is able to push out only a small amount of blood. The so–called congestive heart failure is developing - an incurable chronic disease today.
Synthetic inhibitors of tissue-destroying enzymes have already been tested in clinical trials, but only as inappropriate drugs. Patients receive them intravenously or orally, in the hope that the inhibitor molecules will get into the heart.
"As you can imagine, this type of delivery can lead to problems," says Professor Burdick. "In other tissues where enzymes and their inhibitors are in balance, excess inhibitors can disrupt the balance. This can lead, for example, to joint damage."
"That's where our approach helps," explains Burdick Lab postdoctoral fellow Brendan Purcell. (Brendan Purcell). "We used injectable gels for local, not systemic, delivery of inhibitors. And in order to fine-tune targeting even more, we applied one innovation: this material releases an inhibitor depending on the level of enzyme activity."
The material used by the researchers is known as a hydrogel, which in this design is a network of polysaccharide molecules that well mimics various tissue media. Having created a hydrogel from natural polysaccharides, scientists introduced enzyme inhibitors into it.
"We simulated how this specific inhibitor is localized and stored in normal tissues," Purcell continues. "Physically, the inhibitors are held in the gel by electrostatic interaction with sugar molecules."
The scheme of the gel. Protease enzymes that destroy the heart muscle,
the hydrogel cross-links are broken and the protease inhibitor is released.
Protease inhibitor – inhibitor of protease enzymes; protease is an enzyme that destroys muscle tissue;
polymer – polymer; protease degradable crosslink – polymer cross-links decomposed by proteases.
(Fig. University of Pennsylvania)
"If we didn't include this chemistry," says Burdick, "our experiments showed that about 80 percent of the inhibitor is released within a few days. Thanks to these bonds, only about 20 percent of the inhibitor is released within a few weeks."
The researchers chose the chemistry of the cross-links holding the hydrogel molecules together so that enzymes damaging the heart tissue could destroy them. This was the key to the whole gel design. In the absence of the enzyme, the gel prevents the release of inhibitor molecules until they are needed.
"However, if we add enzymes, the gel breaks down within a few hours. In addition, we have shown that the level of enzymes correlates very well with how quickly the gel degrades and the inhibitor is released," continues Professor Burdick.
Scientists have demonstrated this reactivity in a Petri dish and proved its potential on an animal model. The experiments were carried out on pigs as animals with the closest to the human anatomy of the heart.
This study is part of an ongoing collaboration between the research group of Joseph and Robert Gorman (Gorman Cardiovascular Research Group) and the Burdick Biomaterials Laboratory (Burdick Biomaterials Laboratory), developing treatments aimed at improving the "delayed" response of the heart to myocardial infarction.
"While most groups working in this field are trying to develop regenerative methods of myocardial therapy, we are focused on biomechanical stabilization of the post–infarction heart," explains Robert Gorman. "Most researchers working in the field of regenerative therapy often overlook an important fact, namely, that in the vast majority of patients who have survived a heart attack, heart function is initially sufficient. We are convinced that optimizing the function of a heart muscle that has survived a heart attack will be a more realistic and effective strategy than trying to regenerate a muscle that has already been lost."
"What's attractive about our approach," says Burdick, "is that we're trying to get involved quickly. We want to weaken the remodeling process in order to limit its negative effects and prevent the development of congestive heart failure."
The researchers hope that the technique they have developed will be applied in clinical practice. It is envisaged that the gel will be injected into the heart through a catheter after the immediate threat to the patient's life has passed.
The ability of the new gel to deliver enzyme inhibitors as needed suggests that the newly developed method may find application in other inflammatory diseases, for example, osteoarthritis, when the same enzymes destroy cartilage tissue.
Portal "Eternal youth" http://vechnayamolodost.ru04.04.2014