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