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Enzyme-triggered degradation of a drug loaded peptide-crosslinked nucleic acid nanocapsule. First a peptide is crosslinked at the nanoparticle surface (1), then an enzyme recognizes the peptide crosslinker (2), and finally the enzyme cleavage leads to the release of the drug and any intact DNA (3). (Artwork by Joseph Luciani/UConn)

A new drug delivery system is able to focus largely on the diseased cells while leaving the healthy cells alone.

Researchers from the University of Connecticut have developed a system that uses a synthetic-biological hybrid nanocapsule, which could provide a smart technology for targeted treatment for several diseases at the genetic level.

The new hybrid approach offers a way to correct diseased cells at the genetic level while leaving the healthy cells alone, which increases the effectiveness of treatments and reduces unwanted side effects.

“There's no one-size-fits-all delivery system,” Jessica Rouge, an assistant professor of chemistry at UConn, and author of the new paper, said in a statement. “The beauty of this system is that it is programmable, modular, and has the ability to rapidly integrate diverse peptide sequences.

“It can be tailored to combat new disease challenges as they emerge,” she added.

The new platform combines synthetic peptides, surfactants and nucleic acids to form a nanocapsule that allows time-appropriate, enzyme-specific co-release of a given pharmaceutical and an oligonucleotide, which generates a nanocapsule capable of shepherding genetic or pharmaceutical molecules to a target on or within a cell.

In the new system, the encapsulated materials aren’t released unless the peptide cross-linker is triggered by specific enzymes that cause the nanocapsule to deteriorate and eventually biodegrade.

The researchers conducted in vitro testing with two trigger enzymes often present in elevated concentrations in malignant cells—cathepsin B, an intracellular protease  and MMP9, an extracellular protease.

After they are synthesized, the cathepsin B and MMP9 targeted nanocapsules successfully released their cargo when treated with their intended enzyme targets and under biologically relevant conditions. The researchers found no signs of biodegradation when treated with non-target enzymes, crucial in proving that only the right enzymatic key can unlock the drug they carry.

They also found that the nanocapsules remained intact unless pH levels specific to the target enzymes were present, indicating that the pH of the cellular environment can regulate the enzyme-specific cargo release.

Nanocapsules synthesized using the new method were not unintentionally set off by enzymes similar to their target, which is different from conventional pH-sensitive drug delivery approaches.

According to Rogue, along with cancer treatments, she is tailoring her lab’s materials for other diseases and disorders that don’t currently have effective treatment options.

The study was published in Bioconjugate Chemistry.

 

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