Translational gaps in animal models of human infusion reactions to nanomedicines

Abstract

Adverse infusion reactions to regulatory approved nanomedicines in human subjects are idiosyncratic, but outwardly reproducible in pigs. A large body of evidence suggests that the porcine reactions are related to robust nanoparticle clearance by pulmonary intravascular macrophages (PIMs), and rapid release of arachidonate metabolites from these cells. Similar to pigs, other animals that have resident PIMs in their lungs also respond to intravenously injected particles, where rapid particle clearance by PIMs correlate with peak periods of cardiopulmonary distress. Normal human lungs, however, do not have PIMs, but 'induced' PIMs have been identified in pulmonary circulation under certain pathological conditions. We question suitability, and limitation of these preclinical models for global assessment of nanomedicine safety, and discuss alternative models and approaches.