Targeted therapy of rheumatoid arthritis via macrophage repolarization

Drug Deliv. 2021 Dec;28(1):2447-2459. doi: 10.1080/10717544.2021.2000679.

Abstract

The polarization of macrophages plays a critical role in the physiological and pathological progression of rheumatoid arthritis (RA). Activated M1 macrophages overexpress folate receptors in arthritic joints. Hence, we developed folic acid (FA)-modified liposomes (FA-Lips) to encapsulate triptolide (TP) (FA-Lips/TP) for the targeted therapy of RA. FA-Lips exhibited significantly higher internalization efficiency in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells than liposomes (Lips) in the absence of folate. Next, an adjuvant-induced arthritis (AIA) rat model was established to explore the biodistribution profiles of FA-Lips which showed markedly selective accumulation in inflammatory paws. Moreover, FA-Lips/TP exhibited greatly improved therapeutic efficacy and low toxicity in AIA rats by targeting M1 macrophages and repolarizing macrophages from M1 to M2 subtypes. Overall, a safe FA-modified liposomal delivery system encapsulating TP was shown to achieve inflammation-targeted therapy against RA via macrophage repolarization.

Keywords: Rheumatoid arthritis; folate receptor; liposomes; macrophage repolarization; triptolide.

MeSH terms

  • Animals
  • Arthritis, Experimental / drug therapy*
  • Arthritis, Rheumatoid / pathology
  • Chemistry, Pharmaceutical
  • Cytokines / drug effects
  • Diterpenes / administration & dosage
  • Diterpenes / adverse effects
  • Diterpenes / pharmacology
  • Diterpenes / therapeutic use*
  • Drug Carriers / chemistry
  • Drug Liberation
  • Epoxy Compounds / administration & dosage
  • Epoxy Compounds / adverse effects
  • Epoxy Compounds / pharmacology
  • Epoxy Compounds / therapeutic use
  • Folic Acid / administration & dosage
  • Folic Acid / adverse effects
  • Folic Acid / pharmacology
  • Folic Acid / therapeutic use*
  • Inflammation Mediators / metabolism
  • Lipopolysaccharides / pharmacology
  • Liposomes / chemistry*
  • Macrophages / drug effects*
  • Male
  • Mice
  • Phenanthrenes / administration & dosage
  • Phenanthrenes / adverse effects
  • Phenanthrenes / pharmacology
  • Phenanthrenes / therapeutic use*
  • RAW 264.7 Cells
  • Rats
  • Rats, Sprague-Dawley

Substances

  • Cytokines
  • Diterpenes
  • Drug Carriers
  • Epoxy Compounds
  • Inflammation Mediators
  • Lipopolysaccharides
  • Liposomes
  • Phenanthrenes
  • triptolide
  • Folic Acid

Grants and funding

The authors gratefully acknowledge the financial support from The Scientific Research Project of Sichuan Provincial Orthopedic Hospital [2019QN03] and Sichuan Provincial Administration of Traditional Chinese Medicine Science Foundation [2021MS206].