It's a popular goal in nanotechnology these days: using tiny particles as containers to ferry drugs to tumors, among other targets. But immune sentries called macrophages quickly spot foreign invaders and gobble them up. Now, a team of Pennsylvania researchers has found a way to give particles a molecular "passport" that gets them past the sentries in mice, where the particles then deliver their lethal cargo to tumors and help destroy them. That success is stoking hope for a new way to improve the delivery of drugs.
The body's immune system exists to identify and destroy foreign objects, whether they are bacteria, viruses, flecks of dirt, or splinters. As one of the immune system's primary defenders, macrophages work to eliminate objects they don't recognize as being part of the body. All human cells contain a protein called CD47 on their outer membrane coat. Five years ago, researchers led by Dennis Discher, a cell biophysicist at the University of Pennsylvania, reported that in human cells CD47 binds to a receptor protein on macrophages called SIRPα. The binding lets macrophages know that the CD47-containing cell is a friend rather than a foe and should not be eaten.
Discher wondered whether he might be able to use a facsimile of CD47 as a molecular passport to help therapeutic nanoparticles bypass the immune system. In their current study, described online today in Science, Discher and his colleagues copied short snippets of the CD47 protein, known as peptides, and attached them to nanoparticles designed to ferry either imaging agents or anticancer compounds to tumors. The strategy worked just as they had hoped. In mice engineered so their macrophage cells would mimic those of people, expressing the human SIRPα protein, nanoparticles tagged with the CD47 peptide passports stuck around in the circulation rather than being gobbled up. When the group injected nanoparticles with and without the passport at the same time, 35 minutes later those with CD47 peptides were four times as abundant in the animals' blood as the control nanoparticles were.
In a separate study, Discher and colleagues tested whether their approach could improve the delivery of drugs. They loaded nanoparticles with the anticancer drug paclitaxel and decorated the particle surfaces with their passport peptides as well as with antibodies designed to attach to proteins on the surface of tumor cells. The targeted particles with the passports shrank tumors by 25% in a single day, while nanoparticles with the antibodies but without the peptide passports had no effect on the tumor size.
The paper has "really intriguing results," says Joseph DeSimone, a chemist and nanoparticle and drug delivery expert at the University of North Carolina, Chapel Hill. "It would be great to see this in other tumor models." Discher says his team is already at work on that. What's more, Discher says, unpublished work from his lab suggests that adding the molecular passports to viruses that deliver genes in gene therapy also helps them avoid immune detection. The new molecular passports still must prove their mettle in people, always a daunting hill to climb. If they do, they could potentially make nanomedicines already in clinical trials even more effective.
The body's immune system exists to identify and destroy foreign objects, whether they are bacteria, viruses, flecks of dirt, or splinters. As one of the immune system's primary defenders, macrophages work to eliminate objects they don't recognize as being part of the body. All human cells contain a protein called CD47 on their outer membrane coat. Five years ago, researchers led by Dennis Discher, a cell biophysicist at the University of Pennsylvania, reported that in human cells CD47 binds to a receptor protein on macrophages called SIRPα. The binding lets macrophages know that the CD47-containing cell is a friend rather than a foe and should not be eaten.
Discher wondered whether he might be able to use a facsimile of CD47 as a molecular passport to help therapeutic nanoparticles bypass the immune system. In their current study, described online today in Science, Discher and his colleagues copied short snippets of the CD47 protein, known as peptides, and attached them to nanoparticles designed to ferry either imaging agents or anticancer compounds to tumors. The strategy worked just as they had hoped. In mice engineered so their macrophage cells would mimic those of people, expressing the human SIRPα protein, nanoparticles tagged with the CD47 peptide passports stuck around in the circulation rather than being gobbled up. When the group injected nanoparticles with and without the passport at the same time, 35 minutes later those with CD47 peptides were four times as abundant in the animals' blood as the control nanoparticles were.
In a separate study, Discher and colleagues tested whether their approach could improve the delivery of drugs. They loaded nanoparticles with the anticancer drug paclitaxel and decorated the particle surfaces with their passport peptides as well as with antibodies designed to attach to proteins on the surface of tumor cells. The targeted particles with the passports shrank tumors by 25% in a single day, while nanoparticles with the antibodies but without the peptide passports had no effect on the tumor size.
The paper has "really intriguing results," says Joseph DeSimone, a chemist and nanoparticle and drug delivery expert at the University of North Carolina, Chapel Hill. "It would be great to see this in other tumor models." Discher says his team is already at work on that. What's more, Discher says, unpublished work from his lab suggests that adding the molecular passports to viruses that deliver genes in gene therapy also helps them avoid immune detection. The new molecular passports still must prove their mettle in people, always a daunting hill to climb. If they do, they could potentially make nanomedicines already in clinical trials even more effective.
