Penn Dental Study Shows New Nanocarriers Deliver Therapeutic Enzymes While Preserving Their Function

This nanotech innovation from the lab of Dr. Geelsu Hwang could enable improved methods of large-molecule drug delivery

PHILADELPHIA – Researchers at Penn Dental Medicine have developed a type of “nanocarrier”—a tiny, cage-like structure—that can encapsulate large molecules, protect them from degradation, and release them, intact, where they are needed. The technology could enable more targeted forms of drug delivery for oral health as well as in other areas of medicine.

The researchers were inspired to develop the new technology as a better way of delivering enzymes that disrupt biofilms made by microbes on teeth. In their study, published March 15 in ACS Applied Materials & Interfaces, they designed nanocarriers, made of metal atoms and organic molecules, that can efficiently load themselves with copies of the biofilm-disrupting enzymes mannanase and dextranase. The researchers showed that the nanocarrier structures protect the enzymes from damage, and can be designed to release their cargoes—with their functioning preserved—under desired conditions.

“The relatively easy and scalable synthesis of these nanocarriers, and their tunability for different cargoes and biological environments, suggests that this approach can be translated into a variety of dental and other medical applications,” said study senior author Geelsu Hwang, PhD, associate professor in the Department of Preventive & Restorative Sciences at Penn Dental Medicine.

The study’s lead author was Il-Chul Yoon, PhD, a postdoctoral researcher in the Hwang Laboratory.

Modern medicines usually are made from small molecules. Larger drug molecules such as enzymes, antibodies and other proteins can play a variety of therapeutic roles in treating and preventing many diseases in the sense that their complex 3D structures  allow them to bind more specifically to their targets and carry out diverse functions. However, large molecules are much more vulnerable to breakdown by factors including their own relative instability and are harder to deliver, as they do not easily cross biological barriers. When used as pharmaceuticals, they are typically delivered by injection, and even then tend to have short durations of therapeutic activity.

Nanotechnology offers a possible solution to this problem, and the development of nanoscale carrier structures is an active area of research. Such structures could, in principle, protect large therapeutic molecules and deliver them selectively to targeted tissues, thus eliminating small molecules’ delivery advantage—and enabling powerful new treatments that are otherwise out of reach.

For their nanocarriers, Hwang, Yoon, and lab member Hyejoo Kim chose a type of structure called a zeolitic imidazolate, which is roughly spherical and consists of zinc atoms linked by small, pentagon-shaped organic molecules called imidazolates. They designed the structures to efficiently absorb and carry mannanase and dextranase—several copies per nanocarrier.

“It’s very easy to lose the activity of an enzyme when loading it into a carrier structure, but our nanocarriers take on these enzyme cargoes without damaging them or affecting their ultimate activity—a reflection of the skills of lead author Il-Chul Yoon, a trained chemist,” Hwang said.

The nanocarriers also are tiny enough that they can effectively lodge within the microscopically porous surfaces of teeth.

The team’s experiments showed that the nanocarriers protected the enzymes in watery solutions similar to the salivary environment of the mouth, and could be made to come apart, releasing the functional enzymes, in acidic conditions such as cavity-making oral bacteria normally produce. There was no sign of toxicity in initial tests.

The team hopes to translate this work into a useful therapy for disrupting oral biofilms, and can see that the technology may have many other applications.

“Cancer cells, for example, often create an acidic conditions around tumors, so in principle we could make similar “smart” nanocarriers to deliver cancer-fighting therapeutic macromolecules selectively around tumors,” Hwang said.

Nanocarriers that take therapeutic molecules across the blood-brain barrier to treat neurodegenerative disorders would be another potential application, he added.

“We are actively looking for collaborators in other research fields, because we believe our nanocarrier technology has virtually unlimited potential,” Hwang said.

Hwang and his colleagues have applied for a patent for their nanocarrier technology.

The research was supported by the National Institute of Dental and Craniofacial Research (DE032162 and DE032343) and by the National Science Foundation (BMAT-2321384).