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Researchers help nanoparticles carrying tumor-fighting drugs evade the immune system 

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Introduction

This is a production of the National Institute of Biomedical Imaging and Bioengineering, part of the National Institutes of Health.

Host-Margot Kern

Welcome to the NIBIB science highlights podcast.  Nanoparticles are being used by researchers and most recently in clinical trials to ferry cancer-fighting drugs to tumors.  The use of nanoparticles as a drug delivery mechanism could allow doctors to give patients higher doses of toxic medications while sparing healthy tissue. But the immune system poses a major obstacle to nanoparticle delivery.  That’s because nanoparticles are viewed by immune cells as foreign bodies that should be eliminated.

I recently spoke with an NIBIB grantee, Dr. Dennis Discher, a molecular and cell biophysicist in Chemical and Biomolecular Engineering at the University of Pennsylvania. Discher published a paper in Science on Feberury 22, 2013 in which he describes a new method developed by his lab that helps nanoparticles escape attacks from cells of the immune system, specifically macrophages.

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Host-Margot Kern

Dr. Discher, for those of us who aren’t familiar with the biology of the immune system, what is a macrophage?

Interviewee-Dennis Discher

A macrophage is a giant (macro), phage or (phagos); it means eating in Greek.  So it’s a giant eater.  And, they’ll eat nanoparticles, they’ll eat microparticles, microbes, but even in implants, if you implant a giant object that’s much bigger than the size of the cell, these cells will try to eat it and in frustration they’ll start fusing and forming a giant multi-nucleated cell, a true giant macrophage.  So often with particles in modern times or implants, we really don’t want this innate immune system to attack what it’s had eons to evolve its expertise to do.

Host-Margot Kern

In the Science paper you attached a protein called CD47 to particles and this prevented them from being recognized by macrophages as foreign.  How was your attention first called to this particular protein?

Interviewee-Dennis Discher

So we, like many other people, in fact I would say most people, as we injected particles into the bloodstream in studies more than ten years ago, we’d find that too many of our particles were taken up by macrophages.  And then a paper appeared in Science about thirteen years ago from a group in St. Louis that reported a mouse that has a specific protein on the surface of really all the cells.  It’s a protein called CD47. They described it as a marker of self as passivating macrophages, as a protein that normally, on normal cells, limits macrophages from eating the cells, and when they knocked it out in a mouse, well they see macrophages in other mice eating cells taken from the mice that had the CD47 protein missing.

Host-Margot Kern

So then, what did your lab do with this new information regarding CD47?

Interviewee-Dennis Discher

There were clearly questions that arose. This was obviously a study in a knockout mouse that left us scratching our heads. And we really wanted to know, would this work on humans and would it work on our particles and maybe other types of materials. I mean macrophage interactions not only with particles but with everything we implant in the body.  

Host-Margot Kern

So then how did your lab determine if human CD47 has the same function as mouse CD47?

Interviewee-Dennis Discher

We aimed to understand human CD47 on human cells starting with human blood cells because mouse blood cells is where this other paper from the St. Louis group had started.  And we worked up to understanding the integration and the differences with mouse and then expressing the protein and showing that  we could put human protein on a plastic microparticle and inhibit phagocytosis in a dish.

Host-Margot Kern

How then did your lab bring this to studies in animals?   

Interviewee-Dennis Discher

About the same time that our paper appeared, a group in Toronto published that there was one strain of mouse and this NOD/SCID strain of mouse, human CD47 interacts with macrophages of that strain of mouse and no other strains of mice. The receptor is called SIRPα. (It doesn’t really matter.) But, you now have a mouse receptor compatible with human CD47 that prompted us together with additional information to really take this in vivo.

Host-Margot Kern

In the Science paper, you inject these NOD/SCID mice with nanoparticles that have human CD47 attached to them. But you don’t attach the full CD47 protein. Why?

Interviewee-Dennis Discher

Human CD47 is somewhat different within the population.  The receptor, the SIRPα, is certainly different within the human population as it is within different strains of mice.  So we studied a crystal structure of the two bonded together and realized that maybe we could minimize CD47 to a universal donor peptide.  So we simulated it in a computer, showed that it would doc in silico, and then synthesized it, put it on particles, injected it in this NOD/SCID mouse, and showed ultimately that it was inhibiting uptake of our particles by macrophages.

Host-Margot Kern

Discher went on to report in the Science article that he was able to use his CD47-bound nanoparticles to deliver the anti-tumor drug paclitaxel to mice who had been given human-like tumors and that his particles were as good or better at shrinking the mice’s tumors as paclitaxel’s standard carrier, Cremophore, without causing any of the side effects.

For NIBIB News, I’m Margot Kern

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