Researchers take inspiration from viruses to improve delivery of nucleic acid therapies to cancer cells

A researcher in Purdue University’s College of Science is developing a patent-pending platform technology that mimics the bilayer structure of viruses to deliver nucleic acid (NA)-based therapies to targeted cancer cells.

David Thompson leads a team developing the carrier system called LENN. He is the James Tarpo Jr. and Margaret Tarpo Professor in the Department of Chemistry and a faculty member at the Purdue Institute for Cancer Research and the Purdue Institute for Drug Discovery.

“LENN has two protective layers. The inner layer condenses the nucleic acid; the outer layer shields it from the immune system so it can circulate freely and target cancer cells,” he explained. “We are mimicking the strategies of viral particles that have been doing this effectively for millions of years.”

Thompson and his team, including postdoctoral researcher Aayush Aayush, used LENN to deliver NA-based therapies to bladder cancer cells. Their research was published in Biomacromolecules.

“The data show that our agile nanocarrier is flexible in its targeting capability, cargo size, and disassembly kinetics,” Aayush said. “It offers an alternative route for nucleic acid delivery using a biofabricable, biodegradable, biocompatible, and highly tunable vehicle that can target a variety of cells based on their tumor-specific surface markers.”

Structure of the nanotransporter system

According to Thompson, nucleic acid-based therapies are revolutionizing biomedical research because of their ability to control cellular functions at the genetic level. Therapies involving multiple constructs are currently being explored to expand druggable sites in the human genome.

“Unfortunately, estimates suggest that only 1% or less of the NA cargo that enters the cell reaches the cytosol where it is active,” he said. “That’s one of the motivations for developing this new approach: borrowing design principles from viruses, biological machines that have been delivering cargo to cells for millions of years. Our nonviral delivery system efficiently protects and releases NA therapies into the cytoplasm of target cells.”

The inner core of the LENN system is made of a complex of nucleic acids and modified cyclodextrins, a product of corn processing. Its outer core is made of elastin, one of the most abundant proteins in the body. Thompson said this design has several advantages.

“Because elastin is so abundant, there are no known antibodies against it. From a drug delivery perspective, this is interesting because the body’s immune system won’t recognize it as a foreign nanoparticle,” he said. “LENN can also deliver payloads as short as silencing RNA, which is 19 or 20 nucleotides long, and as long as huge plasmids that exceed 5,000 base pairs in length.”

Thompson said the LENN system can be manufactured in a biofabricable manner.

“All the building blocks are made from renewable resources: cyclodextrin (from corn) and elastin-like polypeptide from bacterial fermentation,” he explained. “This is in contrast to most traditional pharmaceuticals that are derived from petroleum.”

Validation and next development steps

Thompson said previous efforts to deliver NA therapies have used lipid- or polymer-based vehicles.

“Unfortunately, these approaches suffer from very low efficacy, rapid clearance by the immune system, and poor storage stability,” he said. “Chemically modified nucleic acids show promise in experimental systems; however, the safety of this approach has not yet been demonstrated clinically.”

The recent Biomacromolecules This publication complements four previously published papers based on Thompson’s research on the components of the LENN system.

“These first articles in Biomaterials Sciences, Oncotarget And Biomacromolecules “We demonstrate the effectiveness of our method to rapidly purify elastin-like polypeptides for use in biomedical applications and its ability to retain the function of attached targeting proteins and enzymes,” he said.

“Two of these papers show the specific case of targeting bladder tumor cells and the other shows that material purified by our patent-pending technology is capable of targeting human bladder tumors in human and canine surgical specimens.”

Thompson said bladder cancer is the LENN system’s first target, but he and his team are expanding efforts into other types of cancer to explore the technology’s reach.

“We are learning how to work with materials and optimize them,” he said. “Treating bladder cancer is a more localized therapeutic approach than would be necessary to develop a subcutaneous or intravenous injection. However, we plan to increase this scale of difficulty to impact other types of cancer.”