This article is based on an NC State News article written by Deborah Strange, a Public Communications Specialist in University Communications.
To be effective, medications have to be delivered in the right dose to the right location at the right time. Dendrimers are a class of nano-scale macromolecules characterized by their elaborate chemical structures and high functionality that have been employed in a myriad of applications, ranging from drug and gene delivery to diagnostics and biosensing.
Professors Stefano Mengatti and Christopher Gorman (Department of Chemistry), graduate student Juliana O’Brian from the Department of Chemistry and Chemistry graduate Dr. Ryan Smith have created DendriPeps. These soft materials are a novel type of dendrimer the team developed for use as vehicles for delivery of drugs and biologics.
The structure of a DedriPep forms a protective cavity that surrounds the passenger therapeutic and maintains it in a closed, stable system that’s isolated from the external environment. The ability to isolate the therapeutic is important when the therapeutic is fragile. Also, with other types of drug-delivery dendrimers a portion of the therapeutic can leak away before the dendrimer reaches the target site, which can reduce the effectiveness of the treatment. DendriPeps don’t leak.
The widespread use of antibiotics to treat or prevent infections has led to the evolution of “superbug” bacteria that are resistant to treatment with standard doses of antibiotics. Bacteriaphages, or phages, are viruses that are harmless to humans and are an alternative to antibiotics for treatment of bacterial infections. Their use is advantageous because each type of phage is designed to attack only one strain of bacteria.
DendriPeps can protect bacteriophages, so their use offers a way of replacing antibiotics with bacteriophages that infect and kill only superbugs.
Unfortunately, bacteriaphages can be difficult to formulate and stabilize as medicines and in order to remain safe and effective they need to be protected from the surrounding environment until they reach the targeted site. Menegatti and his team speculated that known dendrimers combined with short chains of amino acids, or peptides, can surround nanoparticles, including phages, and keep them stable in a variety of conditions. That’s the origin of DendriPeps.
“These dendrimer coatings maintain the water content inside a virus while acting as a proton sponge, shielding the virus from salt or pH changes,” Menegatti said. “It’s a soft yet impermeable barrier. It maintains a nice environment for the virus.”
DendriPeps also have the ability to assemble and disassemble reversibly and rapidly upon command in aqueous conditions over a wide range of pH values. As a result, after a DendriPep that’s loaded with a therapeutic reaches the target site it can be “instructed” to disassemble, which releases the treatment, then self-reassemble when it’s no longer needed.
With DendriPeps, shear triggers the release and facilitates the therapeutic activity. Soft materials can be designed to respond physically and chemically to stimuli like temperature, pressure and moisture. However, shear is an ideal stimulus for drug delivery applications because it’s almost ubiquitous throughout the body. Eyelids cause shear when blinking; waste shears the gut wall during digestion; and shear is created when a person rubs something onto their skin.
“Shear is often a forgotten stimulus,” Menegatti said. “With this invention, we wanted to fill that gap, and DendriPeps offered an amazing opportunity to do so.”
When a cluster of DendriPep-coated nanoparticles is sheared, it degranulates, releasing the single particles. These particles can in turn release a therapeutic payload or, like the bacteriophages, infect and kill dangerous bacteria. That property allows using topical DendriPeps to treat localized skin infections with phages.
When therapeutic action is no longer needed, shear is removed and the particles are recoated with DendriPeps and recluster. This stops the payload release.
The research team is also developing DendriPep-based nanomedicines designed to deliver new drugs like viral vectors for gene therapy.
“DendriPeps could be the missing link in material sciences to make therapeutic viruses the center of the next-generation antimicrobials and drugs,” Menegatti said.
Recently, Prof. Menegatti shifted his research focus towards gene therapy manufacturing technology and creating more efficient production processes. He’s seeking ways to overcome natural and systematic hurdles in biomedicine. His goal is to improve manufacturing of, and access to, better medicines.
In the past few years, Menegatti has been honored as a Goodnight Early Career Innovator and an NC State Faculty Scholar. He has received an ALCOA Foundation Research Achievement Award, a Chancellor’s Innovation Fund grant, and a National Science Foundation Early Career award. Prof. Menegatti is also the recipient, or co-recipient, of 7 U.S, patents.