Stanford Univ. School of Medicine researchers have developed a new formula for delivering the therapeutic peptide apelin to heart tissue. The delivery system, which dramatically increases the peptide’s stability, shows promise for treating heart disease in humans, the researchers said.

Mice with induced cardiac hypertrophy and heart failure that were given apelin through the new delivery system showed significant improvement, said Jayakumar Rajadas, PhD, founder and director of the school’s Biomaterials and Advanced Drug Delivery Laboratory.

A paper describing the findings was published online Oct. 13 in Biomaterials.

“This is a very important development in the field of cardiovascular therapeutics,” said Rajadas, a senior author of the paper, who is also assistant director of the cardiovascular pharmacology division of the Stanford Cardiovascular Institute. The lead author is postdoctoral scholar Vahid Serpooshan, MD, PhD.

The heart condition known as hypertrophy, which is commonly attributed to sudden death in athletes, is generally a hereditary disease that is triggered by cardiac stress due to extreme exercise, hypertension, valve malfunction or ventricular infarction.

Short plasma half-life of apelin

G-protein-coupled receptors on the surface of heart tissue function as stress sensors. They bind with the apelin peptide in a process crucial to preventing cardiac dysfunction. When the heart is overloaded by various stressors, the body produces more apelin for this process. Although it’s unclear why, patients with hypertrophy have low levels of apelin, which are further used up with added stressors, such as hypertension.

In a treatment model similar to giving insulin to diabetes patients, physicians have attempted to treat these heart conditions with doses of apelin. The therapeutic agent is delivered intravenously to the cardiovascular tissue, but because of its short half-life—the drug is quickly eliminated from the blood plasma—the success of this treatment has been limited.

“This approach turned out to be challenging since apelin has a very short half-life of about eight minutes in the blood and hence limited bioavailability,” Rajadas said.

Rajadas, an expert in the field of nanotechnology—the engineering of functional systems at a molecular scale to create “nanostructures”—saw a potential for improving the delivery system of the peptide to the heart tissue. Nanotechnology has been used to stabilize therapeutic agents in the body and target them to specific tissues for the past 10 years, he said. In this case, the idea was to protect the quickly degrading apelin peptides with large, stable molecules during their transport to the target tissue.

The Trojan horse

The research team developed a novel technique to increase the stability of the fragile apelin peptides by protecting them with a lipid cover that Rajadas calls the “Trojan horse” method of delivery. The liposome “nanocarriers” encapsulate the apelin and sneak it through the blood to the heart tissue.

The resulting apelin “nanobullets,” as the researchers refer to them, were then delivered through the blood system to the cardiovascular tissue of mice with induced hypertrophic heart conditions. The theory was that the apelin would not be released until it was near the heart tissue.

When researchers delivered the nanoparticle preparation in two shots over 14 days to the mice, the animals showed dramatic recovery compared with those in the control group, which only received saline or treatment with uncovered apelin, Rajadas said.

“Apelin in this form could eventually be used as treatment for humans delivered as a shot rather than intravenously as in the past,” said Rajadas. “The idea is that regular monthly or bimonthly shots could lesson symptoms.”

Additional senior authors are Stanford’s Pilar Ruiz-Lozano, PhD, associate professor of pediatric cardiology; Daniel Bernstein, MD, professor of pediatric cardiology; and Joseph Wu, MD, PhD, professor of cardiovascular medicine. Other Stanford co-authors are postdoctoral scholars Senthilkumar Sivanesan, PhD, Xiaoran Huang, PhD, Andrey Malkovskiy, PhD, and Scott Metzler, PhD; and senior scientists Mingming Zhao, MD, Mohammed Inayathullah, PhD, Morteza Mahmoudi, PhD, Dhananjay Wagh, PhD, and Xuexiang Zhang, PhD.

This work was supported by National Institutes of Health and the Oak Foundation.

Source: Stanford Univ. School of Medicine