Experiments point to improved nanomedicine designs
For nanomedicine to achieve the anticipated advances in treating diseases, scientists must learn why the immune system often responds inhospitably to these therapies. An NIH-funded team at the University of Colorado (UC) has put together a clearer picture of the molecular activity that occurs when nanoparticles injected into the body are tagged to attack the immune system.
Supported by the National Institute of Biomedical Imaging (NIBIB) and the National Cancer Institute (NCI), the team led by Dmitri Simberg, Ph.D., associate professor of pharmaceutical sciences at UC, examined the composition of the nanoparticle corona: proteins that form a shell around the nanoparticle once it is introduced into the bloodstream. Among the corona proteins are natural antibodies that are part of the unique immune structure of each person. Simberg’s study found that these natural antibodies lead some people to mount an immune system attack against the nanoparticles prepared to treat their conditions. Their work is described in a January 14, 2019 study in Nature Nanotechnology.
With his NIBIB fellowship, Simberg studies the complement system, an aspect of the immune system that originates from birth and is programmed to activate when faced with harmful viruses and bacteria. Their studies explore how nanoparticles activate the complement system and how to create new designs that could serve to prevent that activation and the adverse outcomes that can occur in patients’ bodies.
Nanoparticles are microscopic structures (less than 100 nanometers in diameter) designed to localize and interrupt pathological processes in the body. They may also be composed of metals that can be detected during diagnostic imaging once they have traveled to a specific region of the body. Simberg’s team conducted tests that included iron-containing nanoparticles, as well as two other nanoparticles of a type called liposomes, both approved for the treatment of breast cancer and gastrointestinal cancer. They performed their tests in the laboratory, looking at molecular activity in two forms of blood products: serum and plasma from healthy donors and plasma only from donors diagnosed with metastatic breast cancer.
The team observed that natural antibodies, called immunoglobulins, were among other proteins that formed on the nanoparticle corona. In the presence of immunoglobulins, a complement protein called C3, bound to those immunoglobulins, was the switch that targeted the nanoparticle for immune attack. In the body, this process results in the destruction of the nanoparticle before it can impart any benefit or may result in a sudden and dangerous immune response, called anaphylaxis.
To further demonstrate the mechanism of immune activation, the team removed natural antibodies from blood product samples and observed that no complementary immune activation occurred. When they returned antibodies to the blood products, complement activation occurred as before or even stronger.
“In all the nanoparticles we tested, complement activation depended on the binding of certain of these natural antibodies to the nanoparticles,” Simberg said. “Interestingly, the antibodies bind to the corona proteins, rather than to the pristine surface of the nanoparticle itself. If a person has a high level of antibodies that can recognize a particular type of nanoparticle, this person will have high complement activation. The study gave us an interesting new angle on how the system recognizes nanomaterials.”
“Advances in nanomedicine require a combination of specialized skills, from engineering, pharmacology, biochemistry, immunology and more.”
The team had previously published that the corona of a nanoparticle is important for complement attack, but this is the first study to point to natural antibodies as the fundamental player in triggering immune attacks. This discovery will guide future research into ways in which nanoparticles can be designed to protect them from attacks by the complement immune system. However, there are still no tools that can predict which patients are likely to derive positive benefit from nanoparticle therapies and which would experience an immunological reaction to the therapy. Simberg suggests that personalized medicine approaches are needed to predict the effects that nanomaterials can produce in the bodies of different individuals.
“This step of knowledge is important to design a better coating so that the particles can be more biocompatible and safe,” Simberg said. “I am a big fan and advocate of mechanistic studies in the field of nanodrug delivery that can guide us toward better designs.”
“This is a study with important lessons for the development and use of nanoparticle therapy,” said David Rampulla, Ph.D., director of the NIBIB program in Biomaterials. “In their findings, Simberg’s team has shown that advances in nanomedicine require a combination of specialized skills, from engineering, pharmacology, biochemistry, immunology and more. It is truly complex, but the potential applications are promising.”
In future studies, Simberg’s team will investigate the mechanisms that allow natural antibodies to bind to corona proteins and how the surface of the nanoparticles can be designed to prevent adverse immune reactions.
The researchers received support from the NIH, including funding from NIBIB (EB022040) and the National Cancer Institute (CA194058 and CA174560).
The deposition of immunoglobulins in the corona of biomolecules determines the opsonization efficiency of the complement of clinical and preclinical nanoparticles. Vu VP, Gifford GB, Chen F, Benasutti H, Wang G, Groman EV, Scheinman R, Saba L, Moghimi SM, Simberg D. Nature Nanotechnology. January 14, 2019.
