Researchers at North Carolina State University and the University of North Carolina at Chapel Hill have developed the “nano-terminators,” which use a biodegradable liquid metal to target cancer cells.
“The advance here is that we have a drug-delivery technique that may enhance the effectiveness of the drugs being delivered, can help doctors locate tumors, can be produced in bulk, and appears to be wholly biodegradable with very low toxicity,” explained Zhen Gu, an assistant professor in the joint biomedical engineering program at NC State and UNC-CH.
The researchers were inspired by the work of their collaborator, Prof. Michael Dickey, who has published research on 3D printing free standing liquid metal microstructures.
“The unique and exciting properties of liquid-metal caught our eyes,” Yue Lu, a Ph.D. student in Gu’s lab, told OutsourcingPharma.com. “We noticed the low-toxicity of liquid-metal, and immediately thought about its biomedical applications.”
The technique
“Our biggest concern during the development process was the potential systematic toxicity of the liquid-metal formulation,” explained Lu, as literature regarding this issue was very limited. “In order to evaluate the biomedical potential of this technique, we conducted a thorough toxicology study.”
To the researcher’s excitement, the formulation displayed no side effects during observation.
Additionally, the “nano-terminators” showed some unique properties in the physiological environment, “different from conventional inorganic nanoparticles,” said Lu, which required unconventional characterization designs.
The terminator
To create the nano-terminators, the researchers placed the bulk liquid metal (gallium indium alloy) into a solution containing two types of polymeric ligands.
“The solution is then hit with ultrasound, which forces the bulk liquid metal to burst into nanoscale droplets approximately 100 nanometers in diameter,” explained Lu. “The ligands in the solution attach to the surface of the droplets as they break away from the bulk liquid metal.”
Theanticancer drug, doxorubicin (Dox), was then introduced into the solution and held onto by the nanodroplet – the “nano-terminators” that are then separated from the solution before being introduced into the bloodstream.
The injection
Due to a combination of passive and active targeting effects, the “nano-terminator” accumulates at tumor sites after intravenous injection.
“Upon endocytosis, they are expected to fuse with each other in the mildly acidic endosome microenvironment, leading to the dissociation of chemotherapeutic-containing ligands and therefore promote drug release,” explained Lu. “The aggregates of fused nanoparticles are expected to degrade due to the synergistic effect of oxidative corrosion.”
Moreover, the main degradation product (gallium ions) could also act as an anticancer agent, helping to reverse drug resistance in drug-resistant cancer cells.
According to Lu, the technique is not limited to anticancer agents, and can be used with a wide range of therapeutics.
She also told us, that it should be noted that the “nano-terminators” can be produced easily within a short time period, which is favorable for the clinical translation.
While the study serves only as a proof-of-concept, the researchers are encouraged with the results.
“Like the fictional Terminator, this carrier is transformable: smashed from bulk material, fused inside cancer cells and eventually degraded and cleared,” said Gu. “We are hoping to do additional testing in a large animal study to get closer to potential clinical trials.”