Protein 'Passport' Helps Nanoparticles Get Past Immune System
The body’s immune system exists to identify and destroy foreign objects, whether they are bacteria, viruses, flecks of dirt, or splinters. Unfortunately, nanoparticles designed to deliver drugs, and implanted devices, like pacemakers or artificial joints, are just as foreign and subject to the same response. Now, however, a team of researchers has identified a "passport" for such therapeutic devices, enabling them to get past the body’s security system.
This research was led by Dennis Discher of the University of Pennsylvania. He and his colleagues published the results of their studies in the journal Science.
The innate immune system attacks foreign bodies in a general way. Unlike the learned response of the adaptive immune system, which includes the targeted antibodies that are formed after a vaccination, the innate immune system tries to destroy everything it doesn’t recognize as being part of the body.
This innate response has many cellular components, including macrophages that find, engulf, and destroy invaders. Proteins in blood serum work in tandem with macrophages by adhering to objects in the blood stream and drawing the attention of circulating macrophages. If the macrophage determines these proteins are stuck to a foreign invader, they will engulf it or signal other macrophages to form a barrier around it.
Drug-delivery nanoparticles naturally trigger this response, so researchers’ earlier attempts to circumvent it involved coating the particles with various polymer coatings, such as polyethylene glycol, that create what looks like a layer of brushes. These brushes stick out from the nanoparticle and attempt to physically block various blood serum proteins from sticking to its surface.
Dr. Discher and colleagues tried a different approach: Convincing the macrophages that the nanoparticles were part of the body and should not be cleared. To do this, the Penn researchers took advantage of an earlier finding from Dr. Dischler that the human protein CD47, found on almost all mammalian cell membranes, binds to a macrophage receptor known as SIRP-alpha in humans. Like a patrolling border guard inspecting a passport, if a macrophage’s SIRP-alpha binds to a cell’s CD47 it tells the macrophage that the cell is not an invader.
"There may be other molecules that help quell the macrophage response," Dr. Discher said, "but human CD47 is clearly one that says, ‘Don’t eat me’."
Since that initial finding, other researchers worked out the combined three-dimensional structure of the bound CD47 and SIRP-alpha complex. Using this information, Dr. Discher’s group was able to computationally design the smallest sequence of amino acids that would act like CD47. This minimal peptide folds and fits well enough into the receptor of SIRP-alpha to serve as a valid passport. The Penn researchers included a linker on this passport peptide that they could use to attach it to a nanoparticle.
The research team demonstrated better imaging of tumors when the nanoparticles contain a passport peptide and when they do not. This effect is likely due to an increase tumor accumulation resulting from increased circulation times. The researchers found that the passport peptides also inhibit uptake of the particles by macrophages as the researchers hypothesized. Thus, these types of particles that bypass interaction with the immune system could be useful tools for efficient drug delivery.
This work is detailed in a paper titled, "Minimal ‘self" peptides that inhibit phagocytic clearance and enhance delivery of nanoparticles." An abstract of this paper is available at the journal’s website.