Prednisolone-containing liposomes accumulate in human atherosclerotic macrophages upon intravenous administration

Abstract

Drug delivery to atherosclerotic plaques via liposomal nanoparticles may improve therapeutic agents' risk-benefit ratios. Our paper details the first clinical studies of a liposomal nanoparticle encapsulating prednisolone (LN-PLP) in atherosclerosis. First, PLP's liposomal encapsulation improved its pharmacokinetic profile in humans (n=13) as attested by an increased plasma half-life of 63h (LN-PLP 1.5mg/kg). Second, intravenously infused LN-PLP appeared in 75% of the macrophages isolated from iliofemoral plaques of patients (n=14) referred for vascular surgery in a randomized, placebo-controlled trial. LN-PLP treatment did however not reduce arterial wall permeability or inflammation in patients with atherosclerotic disease (n=30), as assessed by multimodal imaging in a subsequent randomized, placebo-controlled study. In conclusion, we successfully delivered a long-circulating nanoparticle to atherosclerotic plaque macrophages in patients, whereas prednisolone accumulation in atherosclerotic lesions had no anti-inflammatory effect. Nonetheless, the present study provides guidance for development and imaging-assisted evaluation of future nanomedicine in atherosclerosis.

From the clinical editor: In this study, the authors undertook the first clinical trial using long-circulating liposomal nanoparticle encapsulating prednisolone in patients with atherosclerosis, based on previous animal studies. Despite little evidence of anti-inflammatory effect, the results have provided a starting point for future development of nanomedicine in cardiovascular diseases.

Keywords: Atherosclerosis; Glucocorticoids; Macrophages; Nanomedicine.

Figure 1

Local accumulation of LN-PLP in macrophages of iliofemoral plaques. (A) Microscopic images of cells isolated from a plaque of a patient treated with LN-PLP stained for cell nuclei (DAPI) and macrophages (CD68) and the liposome-coating polyethylene glycol (PEG). Below, the enlargement of two cells corroborates the co-localization of CD68 cells and PEG. (B) Microscopic images illustrating that CD68 positive cells isolated from a plaque of a patient treated with saline do not show positivity for PEG.

Figure 2

Arterial wall permeability after LN-PLP infusion in patients. (A–B) Representative axial T1-weighted MR images of the carotid arteries; the inset shows a magnification of the left carotid artery with a superimposed AUC map before and after LN-PLP treatment. (C–F) Bar graphs demonstrating the lack of reduction in AUC and K^trans for the left carotid artery (C–D) and right carotid artery (E–F).

Figure 3

Arterial wall inflammation after LN-PLP infusion in patients. (A–B) Representative axial computed tomography (CT) and positron emission tomography (PET)/CT images of the carotid arteries before and after LN-PLP treatment, with region of interest (ROI) shown in green. (C–F) Bar graphs showing the change in TBR_max and TBR_mean in the left carotid artery (C–D) and right carotid artery (E–F).