Table 3.
Summary of Nanoparticles Drug Loading System
| Material (Carrier Type) | Drug | Carrier Effect | In vivo/vitro | Experimental Subject | Treatment Effect | Ref |
|---|---|---|---|---|---|---|
| Liposomes | ||||||
| DSPC/cholesterol/OCT | Rapamycin | Slow release | In vitro & vivo | Chondrocytes; HOACs; Guinea pigs | The release from rapamycin-loaded liposomes was around 85% after 72-hour incubation; Rapamycin-loaded liposomes largely up-regulated aggrecan and collagen II mRNA in human OA chondrocytes; Results on OARSI score showed that intra-articular injection of 5 μM liposomes-rapamycin with LIPUS displayed the greatest anti-OA effects; Immunohistochemistry revealed that liposomes-rapamycin with or without LIPUS predominantly reduced MMP-13 in vivo. |
[101] |
| DPPC | Fish oil protein | Slow release | In vitro & vivo | HIG-82 cells; Rats | Maximum fish oil protein released was 68.98 ± 7.09% within 24 h; The serum and synovial interleukins levels were restored after the treatment with fish oil protein-loaded liposomes; In vitro data also showed that treatment with fish oil protein-loaded liposome leads to apoptosis of the HIG-82 arthritic cells. |
[102] |
| DPPC /Cholesterol | Dex; Diclofenac | Slow release | In vitro & vivo | Chondrocytes; Mice | The continuous release time of liposomes is 7 days; Inhibiting neutrophil elastase and inflammation in vivo; Reducing arthritic inflammation and leukocytes infiltration. |
[103] |
| DSPC | D-glucosamine sulphate | Slow release | In vitro | Mouse chondrocyte | Liposomes prolong D-glucosamine sulphate release for 14 days; The liposomes accelerated the viability and proliferation of primary mouse chondrocytes while also providing the anti-inflammatory and cartilage protective potential for tumor necrosis factor (TNF-α) induced chondrocytes degeneration through the downregulation of pro-inflammatory cytokines, pain related gene and catabolic proteases, as well as the up-regulation of anabolic components. |
[104] |
| Soybean phosphatidylcholine /Cholesterol | Curcumin | Increasing drug stability and improving drug bioavailability | In vitro | Mouse osteoblast-like cells and macrophages | With interleukin (IL)-1β stimulation, curcumin-loaded liposomes successfully down regulated the expression of inflammatory markers on osteoblasts, and showed a high osteoprotegerin (OPG)/receptor activator of nuclear factor κB ligand (RANKL) ratio to prevent osteoclastogenesis. | [106] |
| Phosphatidyl choline/ Cholesterol | Adenosine or CGS21680 | Targeting A2A receptor | In vivo | Mice | Differential expression analysis of mRNA from chondrocytes harvested from knees of rats with OA treated with liposomal A2AR agonist revealed downregulation of genes associated with matrix degradation and upregulation of genes associated with cell proliferation as compared to liposomes alone. | [108,109] |
| Lipofectamine TM 2000 kit | miR-15a | Targeting SMAD2 | In vitro | Human normal chondrocytes | Inhibiting the proliferation and promoting apoptosis of knee arthritis chondrocytes. | [110] |
| Lipo2000 | microRNA-143-3p | Targeting BMPR2 | In vitro | BMSCs | MiR-143-3p could regulate the differentiation process by targeting BMPR2 in BMSCs. | [111] |
| DSPE-PEG-maleimide/ HAP-1 peptide | Prednisone / immunosuppressive peptide CP | Targeting Synovial; Targeting Inflammation |
In vitro & vivo | Synovial fibroblast like and endothelial cells; Rats | Targeted liposomes specifically bound to rabbit FLS and human FLS and showed a 7–10 folds increase in vivo localization in affected joints compared to unaffected joints.; The tissue sections from liposomes treated rats showed very little inflammatory cell infiltrate with normal bone contour. |
[113] |
| DOPC/DOPE/cholesterol/ART-2 | Dex | Targeting inflammation | In vitro & vivo | HUVEC; Rats | ART-2-targeted liposomes-Dex was more effective in suppressing arthritis in rats than untargeted liposomes-DEX or free DEX. | [114] |
| EPC/PEG/cholesterol | Dex | Targeting inflammation | In vivo | Mice | The results indicated that liposomes with 100 nm diameter, a slight negative charge, and 10% incorporation of 5 kDa PEG had better in vivo circulation time and inflamed joint targeting than did other liposomes; Pharmacodynamic studies demonstrated that Dex liposomes could significantly improve the antiarthritic efficacy of Dex in a CIA mouse model of RA. |
[115] |
| Lecithin/ pyrophosphorylated cholesterol; cholesterol | Salvianic acid A | Targeting bone | In vivo | Mice | Locally administered SAA-BTL was found to significantly improve fracture callus formation and micro-architecture with accelerated mineralization rate in callus when compared to the dose equivalent SAA, non-targeting SAA liposome (SAA-NTL) or no treatment on a prednisone-induced delayed fracture union mouse model. | [116] |
| DOPC/ DSPE-PEG2000/ DSPE-PEG2000- maleimide/ type II collagen | - | Targeting cartilage | In vivo | Mice | - | [117] |
| Micelles | ||||||
| DSPE-PEG2000/sPLA | sPLA inhibitor | Targeting lesion tissue | In vitro & vivo | Mice; Cartilage explants | sPLA2i-NPs were able to penetrate into the deep zone of the articular cartilage and exhibit high cartilage accumulation; SPLA2i-NPs prevented cartilage degeneration in OA cartilage explants and reduced joint damage in surgery-induced mouse OA model. In addition, sPLA2i-NPs blocked joint damage in a single load-induced mouse posttraumatic OA model. |
[120] |
| PCL-PEI/PCL-PEG | p65 siRNA and Dex | Targeting NF-κB signaling | In vitro & vivo | Raw264.7; HUVECs; Mice |
This novel hybrid micelles to co-deliver Dex and siRNA targeting p65 could potently suppresses nuclear translocation of p65 and secretion of pro-inflammatory cytokines by activated macrophages and also triggered the re-polarization of macrophages from the pro-inflammatory M1 type to the anti-inflammatory M2 type; The hybrid micelles to accumulate selectively in inflamed joints of the arthritic mice for as long as 24 h. |
[121] |
| PEPS | Celastrol | ROS-responsive | In vitro & vivo | Raw264.7; Mice | Celastrol-loaded micelles may inhibit the re-polarization of macrophages toward the pro-inflammatory M1 phenotype via regulating the NF-κB and Notch1 pathways, which resulted in significantly decreased secretion of multiple pro-inflammatory cytokines to suppress the RA progression and effectively alleviated the major RA-associated symptoms including articular scores, ankle thickness, synovial inflammation, bone erosion and cartilage degradation. | [122] |
| FA/PSA/Cholesterol | Dex | Synovial inflammation targeting | In vitro & vivo | Raw264.7; Mice; Rats | Micelles could also enhance the intracellular uptake of Dex and the suppression of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in vitro and in vivo; FA modification significantly improved the anti-inflammatory efficacy of micelles; Arthritis mice showed reduced paw thickness and clinical arthritis index using micelle treatment. |
[124] |
| PLGA-SeSe-mPEG | Dex and CDMP-1 | ROS-responsive | In vitro | BMSCs; Raw264.7 | The drug-loaded micelles effectively inhibited proliferation of activated macrophages, induced macrophage apoptosis with an anti-inflammatory effect, and caused the BMSCs to differentiate into chondrocytes. | [123] |
| LMWH-TOS | Methotrexate | Targeting inflammatory sites | In vitro & vivo | HUVECs; Mice | The hydrophilic fragment low molecular weight heparin (LMWH) acts as a shield which block the transvascular movement of neutrophils through inhibiting the adhesion cascade by binding to P-selectin on inflamed endothelium; Hydrophobic fragment d-α-tocopherol succinate reduced matrix metalloproteinase-9, which was secreted by neutrophils and degrades the main components of articular cartilage; In collagen-induced arthritis (CIA) mouse model, LT NPs showed significant targeting effect, and exhibited prominent therapeutic efficacy after enveloping the first-line anti-RA drug methotrexate. |
[125] |
| mPEG-PPF | Ibuprofen | pH-responsive | In vitro | HIG-82; | Ibuprofen release was observed to increase with increasing acidic conditions and could be controlled by varying the amount of crosslinker used; Micelles exerted anti-inflammatory effects by significantly decreasing monosodium urate crystal-induced prostaglandin E2 levels in rabbit synoviocytes cultures in vitro. |
[126] |
| Poly (β-amino ester) | Curcumin | Cartilage targeting and PH controlled release | In vitro & vivo | RAW264.7 cells; Mice | The polymer combined with curcumin can form its own micelles and released curcumin under acidic conditions; Micelles drastically protected the articular structures from arthritis through the suppression of tumor necrosis factor-alpha (TNF-α) and interleukin 1β (IL-1β). |
[127] |
| PCL-PEOz-NH2/ MR-Cy5.5/collagen type II | Psoralidin | Enzyme targeting and PH targeting. | In vitro & vivo | Chondrocytes; Mice | Anti-inflammatory effect of micelles on IL-1β-induced chondrocytes via the MAPK, NF-κB, and PI3K/Akt signaling pathways; The incorporation of collagen II peptides and the use of acid responsive polymer PAMAM promoted micelles targeting and retention in the joints of OA. |
[130] |
| Dendritic polymer | ||||||
| PAMAM; PEG | KGN | Improve drug bioavailability | In vitro & vivo | BMSCs; Rats | The combination with polymer could improve the effect of osteogenic induction of KGN; The fluorescein labeled PEG-PAMAM was capable to persist in the joint cavity for a prolonged time of both healthy and osteoarthritis (OA) rats. |
[138] |
| PAMAM; PEG | IGF-1 | Improve tissue binding, penetration and residence time. | In vivo | Rats | When conjugated to insulin like growth factor 1 (IGF-1), the dendrimer penetrated bovine cartilage of human thickness within 2 days and enhanced therapeutic IGF-1 joint residence time in rat knees by 10-fold, for up to 30 days; In the surgical model of osteoarthritis in rats, a single injection of dendrimer-IGF-1 saved cartilage and bone more effectively than free IGF-1. Dendrimer-IGF-1 reduced the width of cartilage degeneration by 60% and the burden of volume osteophyte by 80%. |
[49] |
| CAP-PEG-PAMAM | - | Cartilage targeting | In vitro & vivo | Chondrocytes; Rats | The conjugate was likely internalized by chondrocytes via clathrin and caveolin co-mediated endocytosis, and delivered to lysosomes; Fluorescence labeling showed that nanocarriers could be stored in rats for a very long time. |
[139] |
| Chondroitin sulphate/ PAMAM | Abs | Cartilage targeting | In vitro | ATDC 5; THP-1; Human T lymphocyte cells | Dendrimer nanoparticles did not affect the metabolic activity and proliferation of ATDC5 and THP-1 cells, showed good cytocompatibility and blood compatibility, and had good tumor necrosis factor-α capture ability. | [140] |
| ABP/PAMAM | - | Inflammation targeting | In vitro & vivo | Osteoclasts; Mice | Intravenous injection of dendritic macromolecules inhibited the development of inflammatory arthritis in mice, characterized by normal synovium, decreased levels of inflammatory cytokines and no cartilage destruction and bone erosion. The dendrimer ABP also showed anti-osteoclast activity in mouse and human cells by inhibiting c-FMS. | [141] |
| PNPs | ||||||
| PLGA | Oxaceprol | Slow release | In vitro | - | The in vitro drug release from these nanoparticles showed a sustained release of oxaceprol over 30 days. | [149] |
| PLGA | Diacerein | Slow release | In vitro & vivo | Synoviocytes; Rats | The in vitro studies revealed that DIA/PLGA NPs dose-dependently suppressed mRNA levels of pro-inflammatory cytokines and enzymes; In vivo studies have showed that intra-articular injection of DIA-PLGA nanoparticles could significantly reduce the mRNA level of the above pro-inflammatory factors, increase the mRNA level of anti-inflammatory cytokines (IL-4 and IL-10), and effectively prevent cartilage degeneration. |
[150] |
| PLA | KGN | Improve drug bioavailability; Slow release | In vitro & vivo | Synoviocytes; Mice | Polymer microparticles showed an extended drug release of 62% over 3 months; In vitro, these particles did not change the mitochondrial activity of cultured human osteoarthritis synovial cells. In vivo, KGN- nanocrystals showed higher biological activity than KGN solution in the mouse model of mechanical osteoarthritis. |
[151] |
| PLA/PVA/CS-Hcl | Etoricoxib | Slow release | In vitro | - | Enhanced ALP activity and increased calcium ion deposition and binding | [153] |
| MSNs/pSBMA | - | Lubrication; Slow release | In vitro | - | MSNs@ pSBMA was remarkably improved, with a reduction of 80% in friction coefficient compared with MSNs. | [155] |
| SNF | Celecoxib/ curcumin | Slow release | In vitro | Chondrocytes | Nanoparticles could achieve the controlled release of drugs by changing the drug loading, greatly improve the cytotoxicity of the two drugs, and play an anti-inflammatory effect. | [154] |
| PN | KGN | Slow release | In vitro & vivo | Chondrocytes; Rats | PN-KGN had no cytotoxicity and pro-inflammatory effect on chondrocytes and IA injection of PN-KGN also showed less cartilage degeneration and a significant decrease in OARSI score. | [152] |
| Hollow dextran/ Poly (N-isopropyl acrylamide) | KAFAK peptides. | Thermal response | In vivo | - | The KAFAK-loaded hollow dextran/PNIPAM nanoparticles effectively delivered therapeutic peptides in cartilage explants to suppress inflammation. | [156] |
| PNIPAM-PMPC | Diclofenac sodium | Thermo-Sensitive; Lubrication | In vitro | Chondrocytes | Due to the hydration and lubrication mechanism of zwitterionic head group, the lubrication performance of PNIPAM-PMPC nanospheres had been greatly improved under different experimental conditions, and PNIPAM-PMPC nanospheres could effectively embed anti-inflammatory drugs of DS and achieve temperature-sensitive release of drugs. In addition, in vitro experiments further showed that PNIPAM-PMPC nanospheres were biocompatible and protected chondrocytes from cytokine-induced degeneration. | [157] |
| HA/pNiPAM | - | Thermo-Sensitive; Slow release |
In vitro & vivo | Human synovial fibroblasts; Mice | Nanoparticles were biocompatible, providing a longer residence time at the injection site, protecting cartilage, reducing pro-inflammatory cytokines and maintaining callus thickness. | [158] |
| Chitosan oligosaccharide/ pluronic F127 | KGN/Diclofenac sodium | Thermo-Sensitive/Slow release | In vitro & vivo | Chondrocytes; Macrophage-like cells; BMSCs | In order to achieve dual drug release, KGN was covalently cross-linked to the outer layer of the nanospheres, while DCF was loaded into the core of the nanospheres, showing the immediate release of DCF and the continuous release of KGN, which were independently controlled by temperature changes; The hypothermic nanospheres effectively inhibited the inflammation of chondrocytes and macrophage-like cells induced by endotoxin and induced mesenchymal stem cells to differentiate into cartilage. The nanospheres inhibited the progress in the treatment of osteoarthritis in rats, which was further enhanced by cold therapy. Nanospheres also reduced the expression of cyclooxygenase-2 in serum and synovium of treated rats, and further decreased after cold treatment. |
[159] |
| PLGA | Rhein | pH-responsive | In vitro | THP-1 | Nanoparticles released rhein more effectively in synovial fluid environment (SFE) with low pH value, significantly affected inflammatory cytokines TNF- α and IL-1 β and reduced their release in THP-1 cells stimulated by LPS. It was also found that reactive oxygen species (ROS), a mediator, led to cartilage collapse. | [160] |
| PCFMN/collagen II-binding peptide | FMN | Cartilage targeting | In vitro & vivo | Chondrocytes; Rats | The in vitro test using IL-1β stimulated chondrocytes indicated that PCFMN was biocompatible and upregulated anabolic genes while simultaneously downregulated catabolic genes of the articular cartilage; PCFMN could effectively delay the progression of osteoarthritis and showed a longer joint placement time and better anti-inflammatory effect than FMN, suggesting that the cartilage targeted nanosheets have a certain therapeutic effect on osteoarthritis. |
[163] |
| XG/PSBMA/collagen II-binding peptide | - | Cartilage targeting; Lubrication |
In vitro | - | The nanoparticles possess antioxidation verified by DPPH assay and exhibits synergistically enhanced ROS (OH, O2− and H2O2) scavenging. | [165] |
| PEG-SWCNTs | - | Cartilage targeting | In vitro & vivo | Chondrocytes; Mice | PEG-SWCNTs were capable to persist in the joint cavity for a prolonged time, entered the cartilage matrix, and delivered gene inhibitors into chondrocytes of both healthy and OA mice. | [44] |
| PLGA-PS | - | Cartilage targeting | In vitro | Synoviocytes; Chondrocyte | PLGA NPs surface-modified with a quaternary ammonium cation had the greatest retention within cartilage explants. | [167] |
| PEG/PLGA/WYRGRL | MK-8722 | Cartilage targeting | In vitro & vivo | Chondrocytes; Cartilage tissues; Mice | The novel delivery system binds very specifically to cartilage tissue in vitro and ex vivo because of WYRGRL; When injected into the knee joints of the mice with collagenase‐induced OA, the drug‐loaded nanoparticles can effectively reduce cartilage damage and alleviate the disease severity. |
[164,166] |
| DS | TA | Macrophage targeting | In vitro & vivo | RAW 264.7; Mice | DS-TA nanoparticles with the excellent targeting specificity to scavenger receptor class A; DS-TA nanoparticles could effectively reduce the activity of activated macrophages and the expression of proinflammatory cytokines. Intra-articular injection of DS-TA nanoparticles could effectively reduce the structural damage of articular cartilage. In addition, DS-TA nanoparticles reduced the expression of pro-inflammatory cytokines, including IL-1β, IL-6 and tumor necrosis factor-α in cartilage. |
[168] |
| PEG-4MAL/HAP-1/ WYR | - | Synovial targeting; Cartilage targeting |
In vitro & vivo | Rats | The drug could be released in the carrier for 16 days, near to zero-order release; The microgel display was retained in the joint space for at least 3 weeks. |
[169] |
| O-HTCC | SOD | Slow release | In vitro & vivo | Chondrocytes; Rats | O-HTCC-SOD was nontoxic to chondrocytes and had more long-acting and intracellular protection effects on chondrocytes against MIA-induced oxidative damage; O-HTCC-conjugated SOD significantly prolonged half-life and residence in rat joint cavity, and improved bioavailability compared with unmodified SOD; Intra-articular injection of O-HTCC-SOD significantly attenuated mechanical allodynia in MIA-induced osteoarthritis rats, dramatically suppressed gross morphological and histological lesions of articular cartilage, and greatly enhanced in vivo antioxidant capacity and anti-inflammatory effect. |
[170] |
| PPNP | Dex | ROS-responsive | In vitro & vivo | RAW264.7; Mice | The drug could efficiently inhibit the ROS and nitric oxide production in lipopolysaccharide-activated RAW264.7 macrophages and modulate macrophages M2 polarization at a much lower concentration than free drug dexamethasone; The monosodium iodoacetate-induced OA mice treated with this drug was very similar with the normal mice with the evaluation of body weight and scores including clinical arthritis scores, claw circumference, and kinematics scores. |
[171] |
| PAMAM/ C11 peptide/ CH6 aptamer | - | Bone targeting | In vitro & vivo | Osteoblastic; Rats | Nano-carrier could successfully accumulate in the targeted cells, mineralized areas and tissues. | [172] |
| Exosomes | ||||||
| SMSCs | CircRNA3503 | Improve drug stability | In vitro | Chondrocytes | Alleviating inflammation-induced apoptosis and the imbalance between ECM synthesis and ECM degradation; Promoting chondrocyte renewal to alleviate the progressive loss of chondrocytes. |
[82] |
| Dendritic cells | MicroRNA-140 | Cartilage targeting | In vitro & vivo | Chondrocytes; Rats | By fusing CAP with lysosomal membrane glycoprotein 2b protein on the surface of the exocrine body, the CAP- exosome could specifically enter and transport the goods to chondrocytes; CAP-exosomes also delivered miR-140 to deep cartilage regions through the dense mesochondrium, inhibit cartilage-degrading proteases, and alleviated OA progression in a rat model. |
[176] |
| SF-MSCs | KGN | Increase the effective concentration of the drug in the cell. | In vitro & vivo | Chondrocytes; Rats | The MSC-binding peptide E7 was fused with the extracellular membrane protein Lamp2b to obtain the exosome with SF-MSC targeting ability. The KGN carried by E7-Exo could effectively enter SF-MSCs and induce cartilage differentiation more effectively than KGN alone or KGN transported without E7; E7-Exo-KGN could effectively enter SF-MSCs and induce a higher degree of cartilage differentiation. The combined use of SF-MSCs and E7-Exo/KGN through intra-articular injection in the knee joint also showed a more significant therapeutic effect in rat OA model. |
[177] |
Abbreviations: LIPUS, low-intensity pulsed ultrasound; HOACs, human chondrocytes – osteoarthritis; HUVEC, human umbilical vein endothelial cell; sPLA, secretory phospholipase A2 enzyme; HUVECs, human umbilical vein endothelial cells; Raw264.7, murine macrophages; HIG-82, rabbit synovial cells; KGN, kartogenin; ATDC 5, chondrogenic ATDC 5 cell line; THP-1, human monocytic cell line; c-FMS, cell-cat McDonough strain sarcoma virus oncogene homology; FMN, formononetin; PCFMN, formononetin-poly(ethylene glycol); SWCNTs, single-walled carbon nanotubes; PEG, poly(ethylene glycol); DSPC, 1,2-dioctadecanoyl-sn-glycero-3-phosphocholine; OCT, octadecylamine; DPPC, dipalmitoyl phosphatidylcholine; BMPR2, bone morphogenetic protein 2; DOPC, 1,2-dioleoyl-sn-glycero-3-phosphocholine; DOPE, 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine; DSPE-PEG2000, 1,2-distearoyl-sn-glycero-3- 140 phosphoethanolamine-N-[methoxy(polyethylene glycol)-2000]; DSPE-PEG2000-maleimide, 1,2-distearoyl-sn-glycero-3-142 phosphoethanolamine-N-[maleimide (polyethylene glycol) 2000]; PCL, polycaprolactone; PEI, polyethylenimine; PEPS, poly(ethylene glycol)-block-poly(propylene sulphide); FA, folic acid; PSA, polysialic acid; PLGA-SeSe-mPEG, the coupling of poly (lactic-co-glycolic acid), methoxy polyethylene glycol and Se; CDMP-1, cartilage-derivedmor-phogeneticprotein-1; LMWH-TOS, the coupling of low molecular weight heparin and d-α-tocopheryl succinate; mPEG-PPF, amphiphilic methoxy polyethylene glycol-polypropylene fumarate; CAP, chondrocyte affinity peptide; Abs, anti-TNF α antibodies; ABP, azabisphosphonate; MSNs, mesoporous silica; pSBMA, photopolymerization of 3-[dimethyl-[2-(2-methylprop-2-enoyloxy) ethyl] azaniumyl] propane-1-sulfonate polymer; SNF, silk fibroin nanoparticles; PN, polyurethane nanoparticles; PNIPAM-PMPC, poly[N-isopropylacrylamide-2-methacryloyloxyethyl phosphorylcholine]; MK-8722, an activator of 5’-adenosine monophosphate-activated protein kinase (AMPK); XG, xanthan gum; SWCNTs, single-walled carbon nanotubes; PS, polystyrene; DS, dextran sulfate; PEG-4MAL, 4-arm-poly(ethylene glycol)-maleimide; HAP-1, SFHQFARATLAS sequence peptide; WYR, peptide WYRGRL; SOD, superoxide dismutase; O-HTCC, O-(2-hydroxyl) propyl-3- trimethyl ammonium chitosan chloride; sPL, super-activated platelet lysate; Dex, dexamethasone; TA, triamcinolone acetonide; PPNP, polyphenol–poloxamer assembled nanoparticle; CAP, chondrocyte-affinity peptide; SF-MSCs, synovial fluid-derived mesenchymal stem cells; PAMAM, poly- (amidoamine); HCL, hydrochloride; CS, chitosan.