Table 5.
Passively targeted nanomaterials for drug delivery to synovium or synoviocytes
| Nanomaterial type | Targeting Modality | Physical properties | Animal model | Major findings | Ref. |
|---|---|---|---|---|---|
| Gold nanoparticles (no drug) | Passive | 5nm – 52nm | Ex vivo porcine synovium | Effective tissue permeation was only achieved with the smallest particles (5nm). Exposure to pro-inflammatory factors did not affect permeation. | [143] |
| Chloroquine loaded solid lipid nanoparticle | Passive | 113.6nm | In vivo rat (CFA RA model) | TNF-α levels were significantly reduced when chloroquine was loaded into a solid lipid nanoparticle versus free suspension of chloroquine. | [141] |
| Brucine loaded PLGA nanoparticles in PLGA microparticles | Passive | 12.38nm | In vivo rat (air-pouch inflammatory model) | Burst release of brucine was slowed and particles stayed in the articular cavity for significant time. | [132] |
| Dendritic polyglycerol sulfate (no drug) | Passive | 3nm | Ex vivo human cells (articular chondrocytes and synovial fibroblasts) | Cells treated with NPs did not show any change in the synthesis of pro-inflammatory cytokines (TNF-α and IL-6) and a greater expression of antiinflammatory cytokines (IL-10). | [150] |
| Thiolated glycol chitosan nanoparticles encapsulating polymerized Notch 1 targeting siRNA | Passive | 200nm | In vitro murine macrophages In vivo mice (CIA RA model) | In vitro Notch-1 inhibition of siRNA-NPs in murine macrophage cell was confirmed. siRNA-NPs exhibited higher targeting efficiency in the arthritic joints of CIA mice. | [134] |
| Chitosan-graft-PEI nanoparticles complexed with plasmid enhanced green fluorescent protein | Passive (gene delivery) | 100nm–300nm | In vitro rabbit synoviocytes | NPs were able to carry plasmid DNA inside synoviocytes where the DNA was detected entering the cell nuclei. | [151] |
| Melittin-Derived Cationic Amphipathic Nanocomplexes combined with siRNA targeting the p65 subunit of NF-κB | Passive (gene delivery) | 55nm | In vivo mice (CAIA RA model) | Administration of p5RHH-p65 siRNA nanocomplexes decreased inflammatory cytokine expression and cellular influx into the joints, protected against bone erosions, and preserved cartilage integrity. | [152] |
| Multiwall Carbon Nanotubes (no drug) | Passive | 60nm diameter 10μm length |
In vitro human FLS In vitro RAW 264.7 cells In vivo rats (healthy) |
MWCNTs led to formation of granulation tissues within adipose tissues at higher concentrations in vivo. With RAW 264.7 cells, the MWCNTs increased the TNF-α, MCP-1 and RANTES induced inflammatory responses in a dose dependent manner while decrease MIP-1α. With HFLS, they decreased secretion of IL-6 and MCP-1. | [153] |
| Carbon nanotubes coated with PEG and DEX | Passive | 180nm (DEX-PEG-coated CNT) −18mV |
In vitro human FLS | DEX and PEG coated CNTs were able to decrease released of inflammatory cytokines (IL-1β, TNF-α and IL-6) and MMP3 at both a gene and protein expression level at a lower concentration than free DEX in vitro with FLS. | [138] |
| N-trimethyl chitosan-polysilicon acid nanoparticles coated with decoy oligodeoxynucleotides | Passive (gene delivery) | Without methotrexate: 159nm, +23mV With methotrexate: 184nm, +33mV |
In vitro human synovial sarcoma cells In vitro primary RA synovial fibroblasts |
Nanoparticles decorated with decoy oligodeoxynucleotides specific to transcription factor NFkB resulted in significant decreases in inflammatory mediators (IL-6 and IL-8). | [147] |
| Clodronate liposomes | Passive | 120nm –160nm | Human patients with RA | A single IA dose of clodronate liposomes significantly reduced the number of CD68-positive macrophages and the expression of ICAM-1 and VCAM-1 in the synovial lining. | [140] |
| Superparamagnetic iron oxide nanoparticles (no drug) | Passive (Stimuli Responsive - magnetic) | Not Reported | In vivo sheep (healthy) | Intraarticular and periarticular injection of the particles led to uptake in the synovium, with increased local concentration when an extracorporeal magnet was applied. | [148] |
| DEX-HPMA copolymer conjugate | Passive (Stimuli Responsive - pH sensitivity) | 73kDa (~2.8nm)[a] | In vivo rats (AIA RA model) | The conjugate has greater anti-inflammatory effects compared with systemically administered free DEX. This differential effect of the conjugate was related to its selective accumulation, potential macrophage-mediated retention, and pH-sensitive drug release in arthritic joints. | [68] |
| Mineralized nanoparticles composed of PEGylated hyaluronic acid as the hydrophilic shell, 5β-cholanic acid as the hydrophobic core, and calcium phosphate as the pH-responsive mineral and loaded with methotrexate | Passive (Stimuli Responsive - pH sensitivity) | 218nm–265nm | In vivo rats (CIA RA model) | The mineralized nanoparticles revealed pH-dependent demineralization followed by acceleration of methotrexate release into the cytosol. | [69] |
| PLGA gold / iron/ gold half-shell nanoparticles conjugated with RGD and loaded with methotrexate | Passive (Stimuli Responsive - NIR and magnetic) | 135nm | In vivo mice (CIA RA model) | When combined with consecutive NIR irradiation and external magnetic field application, these nanoparticles provide enhanced therapeutic effects. | [133] |
[a] Diameter in nm approximated using the equation reported by Erickson [87] as Minimum radius = 0.066 * [mass in Daltons]⅓
AIA = Adjuvant-induced Arthritis; CAIA = Collagen Antibody-Induced Arthritis; CIA = Collagen Induced Arthritis; CFA = Complete Freund’s Adjuvant; CNT = Carbon Nanotube; DEX = dexamethasone; FLS = Fibroblast-Like Synoviocytes; HFLS = Human Fibroblast-Like Synoviocytes; HPMA = N-(2-hydroxypropyl)methacrylamide; IA = Intra-articular; ICAM-1 = Intercellular Adhesion Molecule 1; IL = Interleukin; MCP-1 = Monocyte Chemoattractant Protein 1; MIP1α = Macrophage Inflammatory Protein 1 Alpha; MMP = Matrix Metalloproteinase; MWCNT = Multiwall Carbon Nanotubes; NFkB = nuclear factor kappa-light-chain-enhancer of activated B cells; NIR = Near infrared; PEI = Polyethylenimine; PEG = poly (ethylene glycol); PLGA = poly(lactic-co-glycolic acid); RA = Rheumatoid Arthritis; RANTES = Regulated on activation, normal T cell expressed and secreted; RAW 264.7 = Macrophage-like cell line derived from tumors induced in male BALB/c mice by the Abelson murine leukemia virus; RGD = arginine-glycine aspartic acid; SLNs = Solid Lipid Nanoparticles; TNF-α = Tumor Necrosis Factor Alpha; VCAM-1 = vascular cell adhesion molecule 1.