Abstract
Multifunctional nanomedicines with active targeting and stimuli-responsive drug release function utilizing pathophysiological features of the disease are regarded as an effective strategy for treatment of rheumatoid arthritis (RA). Under the inflammatory environment of RA, activated macrophages revealed increased expression of folate receptor and elevated intracellular reactive oxygen species (ROS) level. In this study, we successfully conjugated folate to polyethylene glycol 100 monostearate as film-forming material and further prepared methotrexate (MTX) and catalase (CAT) co-encapsulated liposomes, herein, shortened to FOL-MTX&CAT-L, that could actively target to activated macrophages. Thereafter, elevated intracellular hydrogen peroxide, the main source of ROS, diffused into liposomes and encapsulated CAT catalyzed the decomposition of hydrogen peroxide into oxygen and water. Continuous oxygen-generation inside liposomes would eventually disorganize its structure and release the encapsulated MTX. We characterized the in vitro drug release, cellular uptake and cytotoxicity studies as well as in vivo pharmacokinetics, biodistribution, therapeutic efficacy and safety studies of FOL-MTX&CAT-L. In vitro results revealed that FOL-MTX&CAT-L possessed sufficient ROS-sensitive drug release, displayed an improved cellular uptake through folate-mediated endocytosis and exhibited a higher cytotoxic effect on activated RAW264.7 cells. Moreover, in vivo results showed prolonged blood circulation time of PEGylated liposomes, enhanced accumulation of MTX in inflamed joints of collagen-induced arthritis (CIA) mice, reinforced therapeutic efficacy and minimal toxicity toward major organs. These results imply that FOL-MTX&CAT-L may be used as an effective nanomedicine system for RA treatment.
Highlights
Rheumatoid arthritis (RA) is a chronic inflammatory relapsing autoimmune disorder that causes progressive articular destruction and associated comorbidities in vascular, metabolic, bone and psychological domains [1]
Dimethyl sulfoxide (DMSO), MTT, phosphate-buffered saline (PBS), 4,6-diamidino-2-phenylindole (DAPI), folate-deficient Dulbecco’s modified eagle mediun (DMEM) medium (Hyclone®), penicillin-streptomycin solution, trypsin-EDTA solution (Hyclone®) and fetal bovine serum (FBS, Hyclone®) were all provided by Sunshine Biotechnology Co., Ltd. (Nanjing, China)
The expression of folate receptor (FR) over the surface of RAW 264.7 cells before and after LPS activation were evaluated by an indirect confocal laser scanning microscope (CLSM) method
Summary
Rheumatoid arthritis (RA) is a chronic inflammatory relapsing autoimmune disorder that causes progressive articular destruction and associated comorbidities in vascular, metabolic, bone and psychological domains [1]. Under the stimulation of inflammatory cytokine such as TNF-α, IL-1β and interferon-γ, ROS was generated by activated macrophages in the synovial membrane, by chondrocytes and through activated neutrophils in the synovial cavity [36] This excessive production of ROS can damage protein, lipids, nucleic acids and matrix components in synovial tissue [40], break the balance between oxidant and antioxidant to cause a state of oxidant stress [37] and partially contribute to local tissue hypoxia [41]. We design a novel folate receptor-targeting and ROS-responsive liposome co-encapsulating methotrexate and catalase to actively target to activated macrophages through folate receptor-mediated endocytosis and subsequently release the drug by oxygen-generation induced structural failure of liposome through catalyzed reaction between catalase and elevated intracellular H2O2 for RA treatment. We evaluated the in vitro physicochemical properties, ROS-responsive drug release, cellular uptake and cytotoxicity as well as in vivo pharmacokinetics, biodistribution, therapeutic efficacy and safety of all prepared liposomes
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