Rapamycin-Loaded Biomimetic Nanoparticles Reverse Vascular Inflammation

Circ Res. 2020 Jan 3;126(1):25-37. doi: 10.1161/CIRCRESAHA.119.315185. Epub 2019 Oct 24.

Abstract

Rationale: Through localized delivery of rapamycin via a biomimetic drug delivery system, it is possible to reduce vascular inflammation and thus the progression of vascular disease.

Objective: Use biomimetic nanoparticles to deliver rapamycin to the vessel wall to reduce inflammation in an in vivo model of atherosclerosis after a short dosing schedule.

Methods and results: Biomimetic nanoparticles (leukosomes) were synthesized using membrane proteins purified from activated J774 macrophages. Rapamycin-loaded nanoparticles were characterized using dynamic light scattering and were found to have a diameter of 108±2.3 nm, a surface charge of -15.4±14.4 mV, and a polydispersity index of 0.11 +/ 0.2. For in vivo studies, ApoE-/- mice were fed a high-fat diet for 12 weeks. Mice were injected with either PBS, free rapamycin (5 mg/kg), or rapamycin-loaded leukosomes (Leuko-Rapa; 5 mg/kg) once daily for 7 days. In mice treated with Leuko-Rapa, flow cytometry of disaggregated aortic tissue revealed fewer proliferating macrophages in the aorta (15.6±9.79 %) compared with untreated mice (30.2±13.34 %) and rapamycin alone (26.8±9.87 %). Decreased macrophage proliferation correlated with decreased levels of MCP (monocyte chemoattractant protein)-1 and IL (interleukin)-b1 in mice treated with Leuko-Rapa. Furthermore, Leuko-Rapa-treated mice also displayed significantly decreased MMP (matrix metalloproteinases) activity in the aorta (mean difference 2554±363.9, P=9.95122×10-6). No significant changes in metabolic or inflammation markers observed in liver metabolic assays. Histological analysis showed improvements in lung morphology, with no alterations in heart, spleen, lung, or liver in Leuko-Rapa-treated mice.

Conclusions: We showed that our biomimetic nanoparticles showed a decrease in proliferating macrophage population that was accompanied by the reduction of key proinflammatory cytokines and changes in plaque morphology. This proof-of-concept showed that our platform was capable of suppressing macrophage proliferation within the aorta after a short dosing schedule (7 days) and with a favorable toxicity profile. This treatment could be a promising intervention for the acute stabilization of late-stage plaques.

Keywords: atherosclerosis; biomimetic; drug delivery system; inflammation; macrophages.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 1,2-Dipalmitoylphosphatidylcholine / administration & dosage
  • Animals
  • Aorta / drug effects
  • Aorta / metabolism
  • Aorta / pathology
  • Aortitis / complications
  • Aortitis / drug therapy*
  • Aortitis / pathology
  • Apolipoproteins E / deficiency
  • Atherosclerosis / drug therapy*
  • Atherosclerosis / pathology
  • Biomimetics
  • C-Reactive Protein / metabolism
  • Cryoelectron Microscopy
  • Cytokines / metabolism
  • Drug Evaluation, Preclinical
  • Macrophage Activation / drug effects
  • Macrophages / metabolism
  • Mechanistic Target of Rapamycin Complex 1 / drug effects*
  • Membrane Proteins / administration & dosage
  • Mice
  • Mice, Inbred C57BL
  • Nanoparticles / administration & dosage
  • Neovascularization, Pathologic / prevention & control
  • Organ Specificity
  • Phosphatidylcholines / administration & dosage
  • Plaque, Atherosclerotic / prevention & control*
  • Random Allocation
  • Sirolimus / administration & dosage*
  • Sirolimus / pharmacology
  • Sirolimus / therapeutic use

Substances

  • Apolipoproteins E
  • Cytokines
  • Membrane Proteins
  • Phosphatidylcholines
  • 1,2-Dipalmitoylphosphatidylcholine
  • C-Reactive Protein
  • Mechanistic Target of Rapamycin Complex 1
  • 1,2-oleoylphosphatidylcholine
  • Sirolimus