In recent years, MIT engineers have developed and tested various drug-delivery vehicles in living animals, allowing chemical substances and molecules to reach specific tissues in an organism. This has led to design new ways to deliver to human patients a new kind of drugs called biologics, which includes antibodies, peptides, RNA, and DNA.
“Biologics is the fastest growing field in biotech, because it gives you the ability to do highly predictive designs with unique targeting capabilities,” says senior author Mehmet Fatih Yanik, an associate professor of electrical engineering and computer science and biological engineering. “However, delivery of biologics to diseased tissues is challenging, because they are significantly larger and more complex than conventional drugs.”
In a study appearing in the journal Integrative Biology, the researchers used this technology to identify materials that can efficiently deliver RNA to zebrafish and also to rodents.
Zebrafish are commonly used to model human diseases, in part because their larvae are transparent, making it easy to see the effects of genetic mutations or drugs. In 2010, Yanik’s team developed a technology to observe these drugs’ behavior in zebrafish larvae, by rapidly moving to an imaging platform, orienting them correctly, and imaging them. This kind of automated system made possible to do large-scale studies; since analyzing each larva took less than 20 seconds, compared with the several minutes it would have taken for a scientist evaluating the larvae by hand.
For this study, Yanik’s team developed a new technology to inject RNA carried by nanoparticles called lipidoids; which have shown promise as delivery vehicles for RNA interference, a process that allows disease-causing genes to be turned off with small strands of RNA.
The specialists group designed each nanoparticle to carry RNA expressing a fluorescent protein, allowing them to easily track the genetic material delivery. Then they injected the lipidoids into the spinal fluid of the zebrafish. A few hours, the researchers imaged the zebrafish to see if they displayed any fluorescent protein in the brain, indicating whether the RNA successfully entered the brain tissue, was taken up by the cells, and expressed the desired protein.
The researchers found that several lipidoids that had not performed well in cultured cells did deliver RNA efficiently in the zebrafish model. They next tested six randomly selected best- and worst-performing lipidoids in rats and found that the correlation between performance in rats and in zebrafish was 97 percent, suggesting that zebrafish are a good model for predicting drug-delivery success in mammals.
Jeff Karp, an associate professor of medicine at Harvard Medical School who was not part of the research team, says this work is “an excellent example of harnessing a multidisciplinary team to partner complementary technologies for the purpose of solving a unified problem. Yanik and colleagues, who have extensive expertise with high-throughput screening in zebrafish and other small animals, have teamed up with Anderson et al., who are leading experts in RNA delivery, to create a new platform for rapidly screening biologics and methods to deliver them. This approach should have utility across multiple disease areas.”
Currently, the researchers are using what they learned about the most successful lipidoids identified in this study to try to design even better possibilities.“If we can pick up certain design features from the screens, it can guide us to design larger combinatorial libraries based on these leads,” Yanik said.
Through: MIT News