The results of a newly reported study may offer scientists a strategy for mitigating the negative side effects associated with intravenous injection of nanoparticles used in medicine. The new approach targets the complement system, a key part of the body’s immune response against invading bacteria and viruses, but also against nanoparticles.
Headed by Dmitri Simberg, PhD, professor of nanomedicine and nanosafety at the University of Colorado Skaggs School of Pharmacy on the University of Colorado Anschutz Medical Campus, the researchers reported the results of in vitro and in vivo studies evaluating the use of complement regulators to prevent complement activation after nanoparticle delivery. In their paper in Nature Nanotechnology “Inhibition of acute complement responses towards bolus-injected nanoparticles using targeted short-circulating regulatory proteins,” the team concluded that the results “suggest the potential of the targeted complement regulators for clinical evaluation.”
The complement system comprises a group of proteins in the immune system that recognize and neutralize bacteria and viruses, including nanoparticles, which are foreign to the body. This immune response against the nanoparticles triggers side effects that can include shortness of breath, elevated heart rate, fever, hypotension, and, in rare cases, anaphylactic shock. “Nanotechnology’s main advantage over conventional medical treatments is its ability to more precisely target tissues, such as cancer cells targeted by chemotherapy,” said Simberg, who is also co-director of the Colorado Center for nanomedicine and nanosafety co-director. “However, when nanoparticles are injected, they can activate part of the immune system called complement. The activation of the immune system after injection of nanoparticles can be challenging to understand and prevent.”
The researchers say that while some progress has been made in mitigating nanoparticle-related adverse reactions through slow infusion and premedication with steroids and antihistamines, a significant number of people still do experience such reactions. Moreover, as Simberg pointed out, “The goal is to prevent, avoid, and mitigate adverse reactions and immune activation.”
Attempts have been made to use natural regulators as a way of blocking complement activation on nanosurfaces and biomaterials either as free molecules, or by tethering via surface absorption, chemical modification with lipid anchors, antibodies or peptides, the team noted. For their reported study Simberg’s team collaborated with Michael Holers, MD, at the University of Colorado School of Medicine and the Medical University of South Carolina to investigate the use of complement inhibitors in animal models injected with nanoparticles.
The team focused on a fusion protein comprising human complement receptor 2 (CR2) and complement receptor 1 (CR1), which was designed to target complement C3 on the nanoparticle surface. Simberg and colleagues observed that this construct effectively inhibited complement activation by nanoparticles in human serum in vitro and in animal models. “ … we report that CR2-CR1 protein targets initial C3 deposits on nanoparticles and potently prevents complement activation,” they wrote.
Specifically, when injected at very low doses, the construct completely and safely blocked activation of complement by nanoparticles in the animal models, resulting in reduced adverse effects of nanoparticle delivery. According to the authors, this is significant because when nanoparticles activate complement, the resulting immune response can not only cause an adverse reaction but it can also reduce the efficacy of nanomedicines. “ … we show that a fusion construct consisting of human complement receptor 2 (CR2) (which recognizes nanosurface-deposited complement 3 (C3) and complement receptor 1 (CR1) (which blocks C3 convertases) inhibits complement activation with picomolar to low nanomolar efficacy on many types of nanomaterial,” they explained further. “… the inhibitor completely prevents lethargy caused by bolus-injected nanoparticles, without inducing long-lasting complement suppression.”
This reported research also provides a better understanding of why and how complement regulators could help the body respond more favorably to nanoparticles. The study team observed that of the trillions of nanoparticles entering the blood in a standard injection, only a small fraction activated complement. The complement regulators worked as soon as nanoparticles started activating complement, and so promptly mitigated immune activation. “We demonstrate that only a small percentage of nanoparticles are randomly opsonized with C3 both in vitro and in vivo, and CR2-CR1 immediately homes in on this subpopulation,” they wrote.
The researchers say the next step is to test the complement inhibitors with multiple nanoparticles and in different disease models to gain a more complete understanding of the potential of this approach. The ultimate goal is to apply the technology in a clinical setting “Our study presents compelling evidence for the effectiveness of short-circulating complement regulators that target activated C3 on nanosurfaces in inhibiting acute responses in rodents, including blood immune cell uptake and acute adverse reactions,” they wrote. “Targeted regulators induce potent complement blockade, inhibition of leucocyte uptake and prevent nanoparticle-induced toxicities in vivo, and therefore, they are candidates for clinical evaluation.”
Simberg added, “These results suggest we have an exciting opportunity to explore how to further optimize the use of regulators with nanoparticles, with the goal of improving the efficacy and tolerability of multiple nanotechnology-based therapeutics and vaccines … This research is one step closer to providing a better understanding and a solution for people to receive the benefits of nanoparticles without side effects.”