Targeted drug delivery allows a treatment to act specifically at the site of disease while avoiding harmful side-effects elsewhere in the body.
A new proof-of-concept published in Nature Chemical Biology has made an important step forward in developing these technologies which one day may be used to treat cancer.
“We’ve now finally figured out how to produce these systems faster, at scale and with dramatically enhanced logical complexity” says Cole DeForest, a senior author of the study from the University of Washington (UW) in the US.
“We are excited about how these will lead to more sophisticated and scalable disease-honing therapies.”
Three theoretical biomarkers that are present in specific, sometimes overlapping areas of the body. A therapy designed to find the unique area of overlap between the three will act on only that area. Credit: DeForest et al. Nature Chemical Biology
The researchers designed a smart ‘tail’ structure that attaches to the ends of proteins used in drug therapies. The tail can control the location and movement of the protein based on specific environmental cues or ‘biomarkers’ in its surroundings.
The tails fold into preprogrammed shapes that dictate how it will react to different biomarkers, like pH or the presence of specific enzymes.
While similar strategies have been used in the past, they have only focused on a single biomarker which may be present in multiple areas of the body. This means that while the delivery may be intended for a specific target, the drug can end up elsewhere too.
“With the right combination of biomarkers, these materials will just get more and more precise,” says DeForest.
In previous work, the DeForest’s lab designed a new group of materials that can respond to multiple biomarkers using ‘Boolean logic’, a concept used in computer programming.
Linker structures can perform different logical operations. In box 1, the protein therapeutic (star) is released from a material (pink wedge) in the presence of either biomarker X or Y. In box 2, the protein will release only if both biomarkers X and Y are present. Linker structures can be connected in sequence or nested together to create more complex logical circuits. Future therapies could use these structures for highly targeted drug delivery. Credit: DeForest et al. Nature Chemical Biology
“We realised that we could program how therapeutics were released based simply on how they were connected to a carrier material,” says DeForest.
“For example, if we linked a therapeutic cargo to a material via 2 degradable groups connected in series – that is, each after the other – it would be released if either group was degraded, acting as an ‘OR’ gate.
“When the degradable groups were instead connected in parallel – that is, each on a different half of a cycle – both groups had to be degraded for cargo release, functioning as an ‘AND’ gate.
“Excitingly, by combining these basic gates we could readily create advanced logical circuits.”
Since then, the field has developed exciting new protein-based tools that can allow researchers to form permanent bonds between proteins, adds co-author Murial Ross, a UW doctoral student of bioengineering.
“It opened doors for new protein structures that were previously unachievable, which made more complex logical operations possible.”
The research team designed protein tails that fold into custom shapes to create sophisticated logical circuits. Box 1 shows a protein designed to be responsive to 5 different biomarkers. Box 2 shows the logical conditions that must be met to fully break apart the tail and release the protein. Credit: DeForest et al./Nature Chemical Biology
It also became practical to produce these complex proteins in living cells, like bacteria.
Traditional processes require months to produce only a few milligrams of the material. The team streamlined the process, taking the material from design to product in a matter of weeks.
The researchers plan to collaborate with other labs to help transform their design into real-world therapies. They are also continuing to find more biomarkers to enhance the precision of their approach.
“The dream is to be able to pick any arbitrary location inside of the body — down to individual cells — and program a material to go and act there,” says DeForest.
“That’s a tall order, but with these technologies we’re getting close.”