The body’s first line of defense, known as the innate immune system, protects against foreign invaders, including tiny microbes, bacteria or viruses. Yet it also poses a major challenge for therapeutic applications that rely on microscopic drug-delivering vehicles, or nanoparticles. These nanoparticles are in the same size range as many pathogens and are quickly detected and destroyed by macrophages, the innate immune system’s sentinel cells.
Macrophages rely on proteins in blood serum that stick to foreign objects in the bloodstream; these biological ‘red flags’ attract macrophages to engulf the intruders. In the past, scientists working on nanoparticles have attempted to circumvent this process by, for example, masking the engineered particles with a compound called polyethylene glycol, or PEG, to create a “stealth” coat that blocks these blood proteins from sticking to the nanoparticle surface.
A new approach exploits an Achilles’ heel of the innate immune system. Despite their veracious appetite, macrophages are discriminate consumers because they recognize a specific “don’t eat me” signal on the surface of our own cells, represented by a protein called ‘cluster of differentiation 47’, or CD47. On the basis of this insight, Dennis Discher, a biochemist at the University of Pennsylvania School of Engineering and Applied Science in Philadelphia, and his team devised a new way to get these nanoparticles past the body’s immune defenses. The scientists designed a short peptide sequence derived from CD47 and attached it to nanoparticles to fool macrophages into accepting them as ‘self’ rather than foreign. The details of the technique appear in today’s issue of Science.
“It opens the door for better therapeutic targeting because you suppress clearance by macrophages first and foremost,” says Discher.
Using this knowledge and computational modeling, Discher and his colleagues chemically synthesized a minimal self peptide sequence of 21 amino acids designed to resemble a portion of CD47 protein that is highly conserved in the human genome. The group attached this peptide to conventional nanoparticles that could be used in a variety of therapies. After mixing equal amounts of particles with or without the peptide and injecting this mixture into mice, the scientists measured the amount of particles remaining in the bloodstream 30 minutes later and saw that there were four times as many particles left with the peptide.
Donald Ingber, director of the Wyss Institute for Biologically Inspired Engineering at Harvard University in Boston who was not involved in the study, thinks the idea of mimicking CD47 is smart. “This is a wonderful example of how taking inspiration from nature is leading to development of new nanotechnologies with enhanced biocompatibility and unique capabilities,” Ingber says.
Discher’s team also ran another test in which they attached these CD47 peptide nanoparticles that contained anticancer drug paclitaxel to antibodies that allowed them to recognize cancer cells. They then did a head-to-head comparison of these peptide-bound nanobeads against nanobeads coated with PEG and also against the standard paclitaxel carrier molecule called Cremophor, which is known for its toxic side effects, including severe allergic reactions. These three different therapies were injected separately into various groups of mice with tumors implanted in their sides. After four days, the CD47 peptide beads containing paclitaxel shrank tumors to 70% of the size of the tumors that were treated with the PEG beads lacking the self-peptide and also did as well or better compared to Cremophor without any observable side effects.
The relative ease of synthesizing the CD47 peptide fragment and attaching it to nanoparticles means it could be applied to deliver a wide range of drugs, including gene therapy delivery vehicles. “The next step is to be more exotic and tailor particles of different shapes and flexibility to load more drugs for more realistic approaches with various disease models,” Discher says.
For more, click on the following interview with Dennis Discher in which he explains how his lab designed a protein to trick the body’s immune system: