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The use of nanotechnology in medicine, a field otherwise known as “nanomedicine,” is spreading rapidly, particularly in applications that involve the improvement of current drug delivery methods. While advantageous for various reasons, little is known regarding the possible toxicity that can occur following nanoparticle administration.
In a recent study conducted by Researchers at the University of Michigan, they confirm the ability of nanoparticle drug carriers to interfere with the natural immune response.
The Role of Neutrophils in the Immune Response
When nanoparticle therapeutics are administered to a patient, they are often done through IV administration, in which the nanoparticles immediately enter the bloodstream. Once present in the blood, which is a complex fluid composed primarily of red blood cells and white blood cells, or leukocytes, the nanoparticles must mimic the natural localization of leukocytes in order to migrate to the treated organ. Current research indicates that nanoparticles will be primarily eliminated by organs of the reticuloendothelial system (RES), which involves both the liver and the spleen, however little is known about how the interaction between nanoparticles and leukocytes might play a role in this clearance mechanism1.
The largest and most abundant human leukocyte present in the blood is the neutrophil, which acts as the first line of defense against foreign materials like nanoparticles. As neutrophils migrate to the site of injury, they effectively destroy possible infectious pathogens through various immune response processes including phagocytosis, degranulation, the production of reactive oxygen species (ROS) and neutrophil extracellular traps2. There is therefore an obvious potential for nanoparticle drug therapies to interact with neutrophils upon IV administration, however little has been studied in this area to fully understand this impact.
Studying the in vivo Lung Injury Model
The preliminary experiments in the University of Michigan study involved the injection of approximately 30 mg/kg of polystyrene (PS) carboxylate-functionalize (COOH) particles at diameter measurements of either 2 or 5 mm to C57BL/6 mice. Two minutes after the particles were injected, the mice were euthanized and blood was obtained through cardiac puncture.
To visualize the interactions between the neutrophils and the administered particles, the Researchers used intravital microscopy of exposed vessels. Both single and multiple nanoparticles measuring at both diameter sizes were found to bind to the neutrophils outside of the RES organs, thereby confirming the involvement of neutrophils in the clearance process of IV administered particles before they are able to reach the liver or the spleen.
Once the Researchers were able to confirm the proportion of neutrophils that rapidly adhere to the particles of both sizes, they then looked to the acute murine mesentery inflammation model to quantify how neutrophil adhesion is affected overtime. In this model, the same diameter sizes and concentrations of the COOH particles were administered intravenously to mice. In the first minute following administration, both 0.5 and 2 mm COOH particles were capable of significantly reducing the localization of neutrophils onto the walls of the vessels.
In fact, normal neutrophil accumulation in this model was dramatically affected, as mice administered with nanoparticle therapy exhibited a 52%-60% accumulation of neutrophils, whereas untreated mice showed a normal neutrophil accumulation of 93% and 98%. This data indicates that the natural neutrophil migration is reduced when nanoparticles are administered into the bloodstream, thereby greatly suppressing the immune system to clear these and other possible threatening pathogens.
Moving Forward
The results provided in this study determine that there is a direct interaction between IV-injected nanoparticles and circulating neutrophils. While particle clearance is also affected by functions of other leukocytes and the RES organs, it is important to note how neutrophils are affected through a multitude of mechanisms. The Researchers are hopeful that the work produced in this study will enhance future drug delivery carrier designs to further develop effective therapeutic interventions.
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References:
- “Neutrophil-Particle Interactions in Blood Circulation Drive Paricle Clearance and Alter Neutrophil Responses in Acute Inflammation: C. Fromen, W. Kelley, et al. ACS Nano. (2017).DOI:10.1021/acsnano.7b03190.
- “Neutrophil migration in infection and wound repair: going forward in reverse” S. de Oliveira, E. Rosowski, et al. Nature Reviews Immunology. (2016). DOI: 10.1038/nri.2016.49.
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