Imaging-assisted nanoimmunotherapy for atherosclerosis in multiple species

Abstract

A nanoimmunotherapy reduces inflammation in mouse, rabbit, and pig models of atherosclerosis. Particle production Scale-up is a nontrivial part of translating a therapy from preclinical work in small animal models toward clinical utility. Binderup, Duivenvoorden, Fay, and colleagues previously developed simvastatin-loaded high-density lipoprotein (S-HDL) particles that inhibited macrophage proliferation in the blood vessel walls of mouse models of atherosclerosis. Here, they tested methods to produce large amounts of S-HDL needed for larger animal studies and imaging protocols to evaluate therapeutic efficacy. The scaled-up particles showed anti-inflammatory effects in the blood vessels of rabbit and porcine models of atherosclerosis, reducing vessel wall enlargement. This study highlights challenges encountered when scaling a nanoimmunotherapy for use in larger animal models and strategies to overcome these challenges. Nanomedicine research produces hundreds of studies every year, yet very few formulations have been approved for clinical use. This is due in part to a reliance on murine studies, which have limited value in accurately predicting translational efficacy in larger animal models and humans. Here, we report the scale-up of a nanoimmunotherapy from mouse to large rabbit and porcine atherosclerosis models, with an emphasis on the solutions we implemented to overcome production and evaluation challenges. Specifically, we integrated translational imaging readouts within our workflow to both analyze the nanoimmunotherapeutic’s in vivo behavior and assess treatment response in larger animals. We observed our nanoimmunotherapeutic’s anti-inflammatory efficacy in mice, as well as rabbits and pigs. Nanoimmunotherapy-mediated reduction of inflammation in the large animal models halted plaque progression, supporting the approach’s translatability and potential to acutely treat atherosclerosis.