Reactive Oxygen Species–Responsive Celastrol-Loaded Bilirubin Nanoparticles for the Treatment of Rheumatoid Arthritis

Abstract

Celastrol (CLT) has shown anti-rheumatic activity against rheumatoid arthritis, while its poor water solubility and high organ toxicity restrict its further therapeutic applications. To mitigate these challenges, a reactive oxygen species (ROS)-responsive nanoparticle was developed for celastrol delivery based on the excessive ROS at the pathologic sites, which was synthesized by conjugating bilirubin to a polyethylene glycol (PEG) chain. The PEGylated bilirubin self-assembled into nanoparticle (BRNP) in aqueous solution had a hydrodynamic diameter of around 68.6 nm, and celastrol was loaded into BRNP (CLT/ BRNP) with a drug encapsulation efficiency of 72.6% and a loading capacity of 6.6%. In vitro study revealed that CLT/BRNP exhibited the capacity of scavenging intracellular ROS and down-regulating the level of nitric oxide after it was effectively internalized by activated macrophages. Furthermore, in adjuvant-induced arthritis rats, BRNP was accumulated preferentially at inflamed joints, alleviating the joint swelling and bone erosion, which significantly decreased the secretion of pro-inflammatory cytokines to suppress the RA progression. Importantly, CLT/BRNP markedly enhanced its anti-arthritic effect and attenuated the toxic effect compared with free celastrol. Taken together, our results suggested that CLT/BRNP could be used for targeted drug delivery in rheumatoid arthritis.

Triterpenes Drug Delivery Systems, a Modern Approach for Arthritis Targeted Therapy

“…Zhao et al developed ROS-responsive polymeric micelles for 6 delivery by conjugating hydrophobic bilirubin (an endogenous antioxidant) to a hydrophilic PEG chain [ 79 ], taking advantage of excessive ROS production at inflamed sites in arthritic joints. The amphiphilic polymer self-assembled in aqueous solution at a CMC of 7 µg/mL to form nanoparticles (BRNPs) with a hydrodynamic diameter around 68.8 nm [ 79 ]. In vitro release studies showed faster and sustained-release of 6 from 6 -loaded BRNPs ( 6 -BRNPs) in the presence of H 2 O 2 , with up to 60% 6 release over the first 4 h in 100 mM H 2 O 2 .…”

“…In vitro release studies showed faster and sustained-release of 6 from 6 -loaded BRNPs ( 6 -BRNPs) in the presence of H 2 O 2 , with up to 60% 6 release over the first 4 h in 100 mM H 2 O 2 . 6 -BRNPs were able to scavenge intracellular ROS and down-regulated NO level in vitro after being effectively internalized by activated macrophages [ 79 ]. In vivo, 6 -BRNPs preferentially accumulated at inflamed joints of AA rats (presumably due to the long systemic circulation of PEGylated NPs and passive diffusion by extravasation through leaky vasculature and subsequent inflammatory cell-mediated sequestration), ameliorating joint swelling and bone erosion, and decreasing pro-inflammatory cytokine production [ 79 ].…”

“…6 -BRNPs were able to scavenge intracellular ROS and down-regulated NO level in vitro after being effectively internalized by activated macrophages [ 79 ]. In vivo, 6 -BRNPs preferentially accumulated at inflamed joints of AA rats (presumably due to the long systemic circulation of PEGylated NPs and passive diffusion by extravasation through leaky vasculature and subsequent inflammatory cell-mediated sequestration), ameliorating joint swelling and bone erosion, and decreasing pro-inflammatory cytokine production [ 79 ]. Compared with free celastrol ( 6 ), 6 -BRNPs had enhanced anti-arthritic effect and lower systemic toxicity [ 79 ].…”