Nanoparticles to prevent infiltration of immune cells into inflamed tissue

Many serious inflammatory conditions, including acute lung injury, sepsis and ischemia-reperfusion injury, result from excessive infiltration of neutrophils, and blocking this process has been shown effective in reducing inflammation. However, such inhibition has so far relied on antibodies against the adhesion molecules ß2 integrins, and these antibodies also reduce neutrophils’ ability to kill bacteria. This limitation motivated a team at the University of Illinois, Chicago to seek an alternative means of inhibiting neutrophil adherence to blood vessel walls. The team, led by vascular biologist Asrar Malik, demonstrated that albumin nanoparticles encapsulating an inhibitor of spleen tyrosine kinase (Syk) reduced neutrophil infiltration in a model of acute lung injury. While the concept of using nanoparticles to prevent neutrophil adherence to the endothelium could prove useful to the treatment of many severe diseases, whether the effect is indeed selective warrants further study.

Piceatannol-loaded albumin nanoparticles (NPs) block neutrophil adherence. Intravital microscopy in mice in a region adjacent to injection of TNF-α reveals neutrophils carrying either Alexa Fluor 488-conjugated anti-granulocyte receptor-1 (Gr1) antibodies (top) or Alexa Fluor 488-conjugated, drug-loaded NPs (lower panels). Antibody-carrying neutrophils remain in place for over 3 min, while those that have taken up the Syk inhibitor-loaded NPs move along the vessel. Used with permission from Nature Publishing Group.

 

The selectivity of both nanoparticle uptake and the drug’s effects are partially established in this early-phase investigation. While no uptake by macrophages is observed in inflamed regions, nanoparticle accumulation in other cell types and non-inflamed tissues remains to be examined. Similarly, nanoparticle uptake by neutrophils is shown to be blunted in mice lacking the FcγR, which is known to activate endocytosis upon binding of denatured proteins, but the potential contribution of nanoparticle attributes such as size and charge is not addressed. Study of the drug-carrying particles’ therapeutic effects focuses entirely on neutrophil adherence and infiltration, which are only one aspect of the inflammatory response. As the drug employed, piceatannol, also acts as an antioxidant and promotes apoptosis, the formulation could reduce inflammation via multiple mechanisms. 

Selective targeting of neutrophils would prove enormously useful for the delivery of many immune-modulating drugs. If albumin nanoparticles do possess such ability, the simplicity of their preparation and history of FDA approval in formulations such as Abraxane would facilitate development of future therapies.

Wang Z, Li J, Cho J, Malik A. Prevention of vascular inflammation by nanoparticle targeting of adherent neutrophils. Nature Nanotechnol 2014; 9: 204–210.