Surfactant-Free, Self-Assembled Nanomicelles-Based Transdermal Hydrogel for Safe and Targeted Delivery of Methotrexate against Rheumatoid Arthritis

Abstract

Methotrexate (MTX) is the first line agent for therapy against rheumatoid arthritis (RA); however, orally its efficacy is hampered by poor solubility, less permeability, short plasma half-life, and reduced bioavailability. Meanwhile, parenteral formulations are associated with severe adverse effects. In an attempt to improve the efficacy of MTX, we synthesized polycaprolactone-polyethylene glycol-polycaprolactone (PCL-PEG-PCL) triblock copolymer by a ring-opening copolymerization reaction and used it as a carrier for the fabrication of MTX-loaded nanomicelles. Surfactant-free, self-assembled nanomicelles were prepared by nanoprecipitation technique and optimized through central composite design. The optimized nanomicelles exhibited a size distribution of 31 nm and an encapsulation efficiency of 91%. In vitro, the nanomicelles exhibited hemocompatibility, sustained release, and significantly high uptake in lipopolysaccharide activated macrophages. To facilitate application on the skin, optimized nanomicelles were loaded into a Carbopol 934-based hydrogel with eucalyptus oil as a penetration enhancer. Eucalyptus oil significantly improved the permeation of nanomicelles through the skin (p < 0.001). When the hydrogel was applied on the RA mice model, nanomicelles exhibited preferentially highest accumulation in the inflamed joints than other organs. As compared with the free MTX, MTX nanomicelles significantly improved the pharmacokinetic (4.34-fold greater half-life, 3.68-fold higher AUC0–t , and 3.15-fold higher mean residence time) and pharmacodynamic profile ascertained through low inflammatory cytokines expression, improved oxidation protection, recovered behavioral responses, and radiological analysis. MTX nanomicelles-based hydrogel also significantly reduced the hepatotoxicity and did not activate the immune system. These results suggest that the MTX-loaded nanomicelles-based transdermal hydrogel can prove to be a promising agent against RA.

Disrupting the Redox Balance with a Diselenide Drug Delivery System: Synergistic or Antagonistic?

“…The amphiphilicity of the MSePCL‐P was shown by its critical micelle concentration (CMC, 0.44 µg mL −1 ) (Figure S3, Supporting Information), which was within the typical CMC range for polyester‐based amphiphilic polymers. [ 6 ] In addition, after two poly(ethylene glycol) methyl ether (mPEG; 5 kDa) blocks were conjugated with PCL dicarboxyl (PCL‐diCBX; 5 kDa), the resultant mPEG‐PCL‐mPEG (MPCL‐P) and its corresponding NP (MPCL‐NP) were used as diselenide‐free controls (Figure S4, Supporting information). The synthesis of MPCL‐P was also confirmed by 1 H‐NMR and GPC (Figure S5 and Table S1, Supporting Information), and the CMC was 1.17 µg mL −1 (Figure S3, Supporting Information).…”

Nanomaterials Manipulate Macrophages for Rheumatoid Arthritis Treatment

“…As an enhancer of penetration, eucalyptus oil can improve the skin permeability and release of MTX. This allows MTX nanomicelles to selectively accumulate in inflammatory joints and be internalized by activated macrophages through clathrin- and scavenger receptor–dependent endocytic pathways ( Qindeel et al, 2020a ). In another study, researchers developed a hydrogel with co-incorporated chemical enhancers (CEs) and lipid nanocarriers for the efficient transdermal delivery of MTX (MTX-nanostructured lipid carrier gel).…”

Recent Progress of Nanogenerators Acting as Self‐Powered Drug Delivery Devices

“…Since the 1990s, as the interdisciplinary fusion of material science, bionics and modern biomedical makes great progress in the studies of drug release, the research of drug dosage forms has entered the era of DDS, mainly including controlled DDS, [ 5 ] targeted DDS [ 6 ] and intelligent pulsed DDS. [ 7 ] Recently, Trani et al.…”