From extending lifespan to bolstering the immune system, the drug’s effects are only just beginning to be understood.
Researchers have created a molecule that helps nanoparticles evade immune attack and could improve drug delivery.
February 21, 2013|
FLICKR, MAGNARAM A synthetic molecule attached to nanoparticles acts like a passport, convincing immune cells to let the particles pass unimpeded through the body, according to a study published today (February 21) in Science. The computationally designed “self”-peptide could be used to better target drugs to tumors, to ensure pacemakers are not rejected, and to enhance medical imaging technologies.
“It’s the first molecule that can be attached to anything to attenuate the innate immune system, which is currently limiting us from delivering therapeutic particles and implanting devices,” said Dennis Discher, a professor of biophysical engineering at the University of Pennsylvania and a coauthor of the study.
“This is really interesting work,” said Joseph DeSimone, a chemical engineer at the University of North Carolina, Chapel Hill, who was not involved in the research, in an e-mail to The Scientist. “[It] strongly validates the idea of using biological evasion strategies.”
Macrophages recognize, engulf, and clear out foreign invaders, whether they’re microbes entering through a wound or a drug-loaded nanoparticle injected to target disease. Previously, researchers have attempted to escape this response by coating nanoparticles with polymer “brushes” to physically block the adhesion of blood proteins that alert macrophages to the particles’ presence. But these brushes can only delay the macrophage-signaling proteins for so long, and they can hinder uptake by the diseased cells being targeted.
With that in mind, Discher and colleagues tried instead to find a way to convince macrophages that nanoparticles are part of the body. Their previous research had shown that a membrane protein called CD47, which binds to macrophages in humans, signals “self” to the immune system, so that particles with this protein are not attacked.
Examining the architecture of the bond between CD47 and its macrophage receptor, SIRPα, the researchers were able to design a synthetic self-peptide with a similarly snug fit. “This is the key, literally, to unlocking innate immune pacification,” said Discher.
When they chemically synthesized the 21-amino-acid self-peptide and attached it to nanobeads as small as viruses in mice genetically engineered to have human-like SIRPα receptors, the researchers showed that beads with the self-peptide stayed in the blood of for longer than beads with no peptide: 30 minutes after being injected with equal numbers of each type, there were 4 times as many beads with the peptide attached than without. The results demonstrate that the synthetic molecule can reduce the rate at which phagocytes clear the beads from the body, said Discher.
Then, in mice with human lung cancer, the researchers injected fluorescently dyed beads with and without the peptide, and saw that the “self”-beads got through the macrophage-filled spleen and liver and accumulated in greater numbers in the tumor, providing a brighter signal under when imaged. In fact, the self-beads provided a signal from the tumor as strong as beads coated with human CD47.
Finally, to see whether the biological evasion strategy can be successfully combined with targeting, the researchers loaded an anticancer drug into self-beads also coated with antibodies that target cancer cells. Sure enough, these antibody-coated self-beads consistently shrank tumors more than antibody-coated beads lacking the peptide. This confirmed that when antibodies draw the attention of the macrophage, the self-peptides inhibit the macrophage’s response, acting as a “don’t-eat-me” signal, said Discher.
The results demonstrate that the synthetic peptide can provide therapeutic nanoparticles with extra time in the body—time that improves drug delivery. Furthermore, the relative simplicity of the peptide means it can be easily synthesized, making it an attractive component for use in a variety of future applications.
“The findings are “compelling” and “the technology merits moving forward,” Omid Farokhzad, director of the Laboratory of Nanomedicine and Biomaterials at Brigham and Women’s Hospital, part of Harvard Medical School, said in an e-mail to The Scientist.
A crucial next step is to test the efficacy of synthetic self-peptides in humans, Farokhzad added. “The truly relevant test is looking at human pharmacokinetics to see circulating half-life advantages of nanoparticles and their effect on therapeutic outcome.”
P.L. Rodriguez et al., “Minimal ‘self’ peptides that inhibit phagocytic clearance and enhance delivery of nanoparticles,” Science, 339: 971-74, 2013.
February 22, 2013
There is no doubt that abstractions facilitate both the conceptualization and the communication of ideas.
However I've wondered,for decades, how often the particular figures of speech we become habituated to, might blur for us the natures of some complex dynamics.
Please understand that I am not out to fault a writer for speaking colorfully and skillfully, and making some facts more clear and more transparent for his reader.
I merely wonder if we do not, all of us, tend at times to fall into metaphor ruts, where we all tend to use the same concrete surrogates to try to exemplify what we are researching, or what issues we are trying to solve.
If we try to strip some scientific explanations of any and all metaphors, we quickly become frustrated or, at best, bogged down in efforts to express how something has come about, how a perceived mechanism works, what we suspect might explain a phenomenon, or what we have tested and found support for believing is a more likely explanation for a predictable experimental outcome.
But isn't it possible that our concrete and dynamic surrogate words and images might -- on some occasions at least -- steer our would-be-least-incumbered creative thinking on some phenomena in directions that are somewhat too driven by metaphors themselves?
Nowhere, I think, is there any greater reliance upon convenience of metaphor than in evolutionary biology. In that special realm much archeological data requires a substantial amount of fudging to fit things together. And, no, this message is NOT aimed at denying that models of pattern continuities are false or a waste of time. They are indeed, however, TENTATIVE, or they wax over into dogma, rather than science (science being open-ended). If many interstices between samplings are not assumed into place, no useful pattern at all is possible. And no science is about "arriving" at either first principles or final perfected answers. No, the point I seek to make here is about whether, in availing ourselves of the wonderful benefit of concrete metaphors, we might on occasion become hampered a little bit by some of them.
We all know that in the history of the development of the field of evolutionary theory to date, we have enjoyed benefit of an evolutionary "tree" of advances of species along certain modeled lines. Those lines were determined taxonomically, and that was as good as things got for a while. But then, when studies of crystalography and physical chemistry were merged in certain ways with our biological observations, and our awareness of DNA came into being, many of our taxonomically-driven connections between species were not supported by DNA comparisons. And even then our methodologies of preparing most archeological specimens -- although it took us some time to become aware of that -- was rendering soft tissue undecipherable as to its DNA. As newer and better methods of maintaining and preparing specimens were developed, still further adjustments were found to be indicated to our biological heritage "trees."
That surfs over many increments of progress to the current day when we are making inroads into goings on at the nano-level. Here, as before, new technology, new methodologies and new findings are requiring us to edit and upgrade our models of some signal transductions and some of the "things" and inter-relations and interactions between "things" we were completely unable to observe or measure until now. Not having yet found solutions to oncological questions, including how and why cellular health can persist where it does, as well as what goes wrong -- if we choose to call it that, and leads to organism dysfunctionaly and death. Generally speaking,we are finding once again, as always, that our scientific "knowledge" does not advance linearly, but rather, in remorphings of our abstract models to accomodate new rulings in and new rulings out of what is going on "down in there."
And this brings us to the point this message is meant to examine: Why do we tend to use metaphors which imply things that are not supported by historical facts. More particularly, why do we sometimes speak as if our science changes the way nature is (or should we say "natures," plural, now that physicists have established that the nature of how things are, and inter-relate at the Newtonian level is not the same as at the quantum scale). For all we know there may be different nature dynamical systems at parallel scales as well as "out there" scales and "down in there" scales.
Science, as a conceptual framework, does not -- let me argue -- progress linearly insofar as abstract models of how things behave and interrelate are concerned. On the contrary, if we view science not as defined as what is experientially the way things are but, rather, the on-going process of our upgrading our perceptions of how things actually are, then would we not do well to choose our abstract concrete surrogates accordingly?
For example: Rather than speaking of ourselves as having found a way to "fool" the immune system, wouldn't it be more intuitive to view ourselves as made one more small step in the direction of disabusing ourselves of fooling ourselves in how we perceive how some of the things "down in there" actually are, and how they actually work?
Do we ever fool nature? Or do we only seek to fine-tune our observations and measurements and experiments so as to lift ourselves from a lower level of ignorance to a somewhat less self-fooled one?
February 22, 2013
This is very promising work. Finally, a group that understands the workings of the reticuloendothelial system.