New Study Describes an Important Step in Activation of the Immune System Against Nanoparticles

Doctors would prefer to use all kinds of nanoparticles in the body, for instance, to create comprehensive images of anatomy and disease, and to deliver cancer-fighting drugs deep inside the tumor tissue.

However, millions of years of evolution have prepared the body to recognize and eliminate foreign particles, even nanoparticles. Hence, one major problem in using nanomedicine has been the unfortunate efficiency of the immune system in reacting to what it views as infection, at best removing nanoparticles before they can complete their goals, and at worst resulting in harmful immune overreaction that causes serious risks and side effects.

A University of Colorado Cancer Center study reported in the Nature Nanotechnology journal on January 14^th, 2019, illustrates a significant stride in the activation of the immune system against nanoparticles. The finding may enable scientists and ultimately doctors to conceal nanoparticles from the immune system, enabling these particles to execute their therapeutic business.

Earlier, the lab of CU Cancer Center investigator Dmitri Simberg, PhD, has demonstrated the ability of blood proteins (collectively known as protein corona) to cover nanoparticles, marking them for the immune system to invade. Specifically, the Simberg lab demonstrated that one of the most important constituents of the immune system, viz., the complement system, does not have the ability to attack nanoparticles if they are not coated with protein corona. Currently, the Simberg lab has shown another step in this process: Natural antibodies inside the protein corona are responsible for the potential of the complement system to identify and invade nanoparticles.

Basically, we found that C3 deposition on nanoparticles (and thus immune system activation against nanoparticles) really depends on natural antibodies in each person’s blood. We can remove these antibodies and there is very little complement system activation. Then we can add these antibodies back and there is activation.

Dmitri Simberg, PhD, Associate Professor, Skaggs School of Pharmacy and Pharmaceutical Sciences.

The research, which was carried out in collaboration with Moein Moghimi, PhD, Professor at Newcastle University in the United Kingdom, considered the ability of a common complement system protein, called C3, to identify and attack extensively employed nanoparticle-based anti-cancer pharmaceuticals Onivyde and LipoDox, (and also the nanoparticle-based iron oxide supplement Feraheme). Upon washing out antibodies called immunoglobulins from the blood of healthy donors and cancer patients, Simberg and team found that the potential of C3 to identify and mark these nanoparticles was decreased to 70%–95%. On restoring these immunoglobulins back, the team again observed buildup of C3 on these nanomedicines.

Our immunological memory is made up of antibodies that help us to recognize pathogens that we may have encountered long ago. Each person has a set of natural antibodies that recognizes nanoparticles. The individual reactivity of a person to a specific kind of nanoparticle depends to some extent on how much of these antibodies a person has. There’s variability—one person may have more antibodies that recognize a certain kind of nanoparticle, while another person has different antibodies that recognize another kind of nanoparticle. What is really exciting is that all these antibodies seem not to bind to naked nanoparticles. The particle needs to be coated with a protein corona—binding of these antibodies is much more efficient when you have these other proteins sticking to the nanoparticles first.

Dmitri Simberg, PhD, Associate Professor, Skaggs School of Pharmacy and Pharmaceutical Sciences.

It is expected that ongoing research will find out the origin and source of antibodies that identify nanoparticles, providing a clearer picture of why some people exhibit immune over-response in response to nanoparticle-based medicines. By gaining insights into how antibodies identify nanoparticles, Simberg and his colleagues hope to develop methods to selectively obstruct this action, resulting in more effect and less side effect of nanomedicines.