Targeted Combination of Antioxidative and Anti‐Inflammatory Therapy of Rheumatoid Arthritis using Multifunctional Dendrimer‐Entrapped Gold Nanoparticles as a Platform

Abstract

Abundant reactive oxygen species and tumor necrosis factor-α (TNF-α) cytokine supply of M1-type macrophages boost rheumatoid arthritis (RA) pathological process. For efficient RA therapy, here a multifunctional nanoplatform is presented based on generation 5 (G5) poly(amidoamine) dendrimer-entrapped gold nanoparticles (Au DENPs) to achieve co-delivery of antioxidant alpha-tocopheryl succinate (α-TOS) and anti-inflammatory anti-TNF-α siRNA to macrophage cells. G5 dendrimers with amine termini are sequentially functionalized with 1,3-propane sultone (1,3-PS), α-TOS through a polyethylene glycol (PEG) spacer, and PEGylated folic acid (FA), and subsequently entrapped with Au NPs. The generated functional Au DENPs exhibit desired cytocompatibility, zwitterion-rendered antifouling property, and FAmediated targeting specificity, enabling serum-enhanced siRNA delivery to M1-type macrophage cells. Meanwhile, the attached α-TOS affords enhanced oxidation resistance of macrophage cells. In vivo investigation shows that the treatment of a collagen-induced arthritis mouse model using α-TOSmodified Au DENPs/TNF-α siRNA polyplexes can achieve excellent combination therapy effect in inflammatory cytokines downregulation of RA lesion and bone erosions. The therapeutic efficacy is also supported by 3D microcomputed tomography analysis and TNF-α cytokine reduction of RA lesion joints in the mRNA, protein, and histology levels. The created multifunctional nanoplatform may be employed in antioxidative and anti-inflammatory combination therapy of RA.

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

“…Therefore, the elevated level of ROS can be a trigger to develop drug delivery systems for RA. Notably, most of the ROS-responsive drug delivery systems are made of inorganic or artificially polymerized nanomaterials with potential advances [18][19][20][21]. Nevertheless, their safety has become nonignorable concerns [22].…”

Antifouling Strategies of Nanoparticles for Diagnostic and Therapeutic Application: A Systematic Review of the Literature

“…Moreover, the drug release from the nanocarriers was not observed in blood circulation but was induced after cell internalization by acidic lysosomal compartment, with successful photodynamic ablation of cancer cells compared to free ALA. Recently Li et al [ 50 ] proposed dendrimer-entrapped Au NPs as a multifunctional platform to trigger a dual anti-inflammatory and antioxidative response for arthritis rheumatoid treatment. In detail, G5 PAMAM dendrimers were conjugated with PEGylated FA (PEG-FA) for targeting specificity, modified with 1, 3-propane sultone (1,3-PS) for antifouling properties, and loaded with alpha-tocopheryl succinate (PEG-αTOS) and tumor necrosis factor-α (TNF-α) siRNA, for its antioxidative and anti-inflammatory activity, respectively.…”

Polysaccharide-based nanomedicines for cancer immunotherapy: A review

“…With the rapid growth of nanobiotechnology, nanomaterials have become more and more clinically applicable for medical treatment [ 18 , 19 ]. These nanomaterials with a size of 10–500 nm are able to increase the therapeutic efficacy and reduce the toxicity of therapeutic drugs by encapsulating or conjugating them to form stabilized nanomedicines [ 20 , 21 ].…”