PHILADELPHIA — Targeted drug delivery is one of the more enticing applications of nanotechnology; by designing pharmaceuticals on an atomic scale, engineers hope to get them attacking diseases with newfound precision and efficiency.
A team of University of Pennsylvania researchers has recently been recognized by the National Science Foundation for the development of computer models that will be instrumental in improving these designs.
The team received a “Research Highlight” from the National Science Foundation’s Division of Chemical, Bioengineering, Environmental & Transport Systems.
Led by Ravi Radhakrishnan, associate professor in the departments of Bioengineering and Chemical and Biomolecular Engineering in Penn’s School of Engineering and Applied Science, the team also included Portonovo Ayyaswamy of Engineering as well as David Eckmann and Vladimir Muzykantov of Penn’s Perelman School of Medicine.
The work for which they were honored was published in the Biophysical Journal.
Nanocarriers are tiny, engineered particles that can hold small molecules in their hollow interiors and can be targeted to specific tissue types by means of the antibodies on their exteriors. Because the choice of antibodies determines what the nanocarriers can bind to, they can serve as markers or deliver a payload of medicine to diseased cells while ignoring healthy ones.
In order to get their payloads into cells, the nanocarriers need to bind to them long enough to be engulfed. Designers assumed that bigger particles with more antibodies would bind better but were not basing this assumption on evidence.
“There is some intuition that guides you about what is and isn't possible, but more often than not designing nanocarriers is a process of trial and error,” Radhakrishnan said. “We started this project to provide a more rational approach to design. Because of the tools available to us as engineers, we wrote models that would be able to guide design principles.”
The researchers developed a multifaceted simulation that allowed the researchers to test binding under different conditions; the force that flowing blood would exert on a nanocarrier in a narrow capillary is stronger than it would be in a wider artery. The researchers then populated these different simulated environments with different nanocarriers models, altering their sizes and the amount of antibodies on their exteriors to see which arrangements were optimal.
By comparing their simulations with real-life experiments, Radhakrishnan’s team showed that the intuition about what makes nanocarriers more effective was wrong in several ways.
The most important of these discoveries was that adding more antibodies may actually reduce the efficacy of nanocarriers.
“More antibodies means stronger adhesion. But when they aren't being bound by antibodies, the receptors on the target tissue are always moving around,” Radhakrishnan said. “They don't like being held in place, and the inability to move around decreases their stability.
“There's a sweet spot where you have just enough so it binds to diseased cells but not to healthy cells, but not so many that it pops off due to instability before it has a chance to deliver the drugs.”
The team’s experiments provided another counterintuitive finding: stronger blood flow can help the nanocarriers bind better. The force of the flow would often roll the nanocarriers across the surface of cell, allowing its antibodies to find more binding sites.
To ensure that the simulations held up in the real world, the team performed two kinds of physical experiments. In one, the researchers used an atomic force microscope to measure when antibody bindings popped off an in vitro tissue sample. The team also performed an in vivo experiment using mouse models, where the efficacy of marker nanocarriers binding to their intended targets could be directly tested.
With an unexpectedly high level of consistency between all three models, the researchers are confident that their findings will help inform the next generation of nanocarrier design.
“What intuition tells us is not always the best,” Radhakrishnan said. “We want to take drug delivery to the next level, so we need to understand these counterintuitive principles.”