Optimizing the therapeutic index of liposomal glucocorticoids in experimental arthritis

Hoven, Jolanda M. van den; Hofkens, Wouter; Wauben, Marca H. M.; Wagenaar-Hilbers, Josée P A; Beijnen, Jos H.; Nuijen, Bastiaan; Metselaar, Josbert M.; Storm, Gert

doi:10.1016/j.ijpharm.2011.03.025

Cited by 50 publications

(44 citation statements)

References 21 publications

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“…[15][16][17][18][19] In this study, authors identified that DEX-PEG-coated CNTs were taken up by TNF-α-stimulated RA FLS via upregulated caveolin-mediated endocytosis, induced greater nanodrug uptake, and quickly released therapeutic agents in the EE compartments. Meanwhile, released therapeutic agents accumulated in the mitochondria, which in turn successfully suppressed TNF-α-induced ROS production and recovered mitochondrial membrane disruption at very low doses of DEX-PEG-coated CNTs.…”

Section: Resultsmentioning

confidence: 95%

“…To this date, most studies for nanodrug harboring GC have shown only in vivo anti-inflammatory efficacy without understanding the mechanism of intracellular drug delivery. [15][16][17][18][19] Thus, there was a need to unveil a mechanism related to the inhibition of inflammation on synovial fibroblasts and FLS. TNF-α usually causes mitochondrial transmembrane disruption and induces subsequent oxidative stress signaling through the activation of ROS.…”

Section: Intracellular Nanodrug Delivery and Changes In Mitochondrialmentioning

confidence: 99%

“…15 However, previous studies did not emphasize on the outstanding intracellular mechanism used by GC liposomes and PCL-PEG. [15][16][17][18][19] Carbon nanotubes (CNTs), primarily employed for applications in cancer treatment, are easily functionalized by surface alterations through non-covalent and covalent functionalization and, thus, are widely used as molecular carriers in both in vitro and in vivo drug delivery. 20,21 Soluble CNTs functionalized by surface oxidization and coated by surfactants or amphiphilic polymers are able to be engulfed by cells via the energy-dependent endocytosis pathway.…”

Section: Introductionmentioning

confidence: 99%

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Suppression of human arthritis synovial fibroblasts inflammation using dexamethasone-carbon nanotubes via increasing caveolin-dependent endocytosis and recovering mitochondrial membrane potential

Lee¹,

Kim²,

Park³

et al. 2017

IJN

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Dexamethasone (DEX), a non-particulate glucocorticoid (GC) to inhibit anti-inflammatory response, has been widely used for the treatment of various diseases such as arthritis, cancer, asthma, chronic obstructive pulmonary disease, cerebral edema, and multiple sclerosis. However, prolonged and/or high-dose GC therapy can cause various serious adverse effects (adrenal insufficiency, hyperglycemia, Cushing’s syndrome, osteoporosis, Charcot arthropathy, etc). In this study, developed DEX-carbon nanotube (CNT) conjugates improved intracellular drug delivery via increased caveolin-dependent endocytosis and ultimately suppressed the expression of major pro-inflammatory cytokines in tumor necrosis factor-α (TNF-α)-stimulated human fibroblast-like synoviocytes (FLS) at low drug concentrations. Specifically, DEX on polyethylene-glycol (PEG)-coated CNTs induced caveolin uptake, recovered mitochondrial disruption, and inhibited reactive oxygen species production by targeting mitochondria that was released from the early endosome in TNF-α-stimulated FLS. The obtained results clearly demonstrated that DEX-PEG-coated CNTs significantly inhibited the inflammation by FLS in rheumatoid arthritis (RA) by achieving greater drug uptake and efficient intracellular drug release from the endosome, thus suggesting a mechanism of effective low-dose GC therapy to treat inflammatory diseases, including RA and osteoarthritis.

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Section: Resultsmentioning

confidence: 95%

Section: Intracellular Nanodrug Delivery and Changes In Mitochondrialmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Suppression of human arthritis synovial fibroblasts inflammation using dexamethasone-carbon nanotubes via increasing caveolin-dependent endocytosis and recovering mitochondrial membrane potential

Lee¹,

Kim²,

Park³

et al. 2017

IJN

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“…7,8) However, as glucocorticoids can cause severe toxic side effects when used with frequent dosing or at high doses, their use is often limited. 9) Toxic side effects of glucocorticoids, including diabetes, hypertension and osteoporosis, are caused by systemic absorption of the drug. In order to improve such side effects, it is known to be useful to deliver the drug specifically to the target site and suppress the drug level in the systemic circulation.…”

mentioning

confidence: 99%

Chondroitin Sulfate–Glycyl-Prednisolone Conjugate as Arthritis Targeting System: Localization and Drug Release in Inflammatory Joints

Onishi

Yoshida

Matsuyama

2014

Biological & Pharmaceutical Bulletin

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Chondroitin sulfate-glycyl-prednisolone conjugate (CS-GP) was previously demonstrated to exhibit superior anti-arthritic effects compared to prednisolone (PD) alone. In this study, CS-GP was examined for its pharmacokinetic features and tropism for inflammatory joints using rats with adjuvant-induced arthritis in order to identify the mechanism of the potential enhancement. After intravenous injection (2.5 mg PD eq./ kg), CS-GP yielded an area under the curve (AUC) of the total (free conjugated) drug much higher than that of PD alone. After intravenous administration at the same dose, the drug distribution to the hind paw inflammatory joints was investigated. For PD alone, the PD concentration was 1.2-1.7 µg/g at 1 h and fell to 0.12-0.14 µg/g at 24 h. In contrast, CS-GP maintained the total concentration in the range of 0.55-0.97 µg/g for 1-24 h, and maintained the free PD concentration at 0.06-0.16 µg/g for 1-24 h. Furthermore, at 24 h after intravenous administration (2.5 mg PD eq./kg), CS-GP exhibited a higher total drug concentration in arthritic rats than in healthy rats. These findings suggested that CS-GP may have the ability to target inflammatory joints. As the apparent molecular weight of CS-GP became greater in plasma, it might interact with blood components and cause high plasma retention and good tropism to the inflammatory sites. Enhancement of the anti-inflammatory potential of CS-GP was found to be due to good maintenance of drug levels in the inflamed area.

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“…However, chronic use of these drugs often leads to severe systemic side effects like immunosuppression, thinning of the skin, osteoporosis, induction of diabetes and adrenal failure, thus decreasing patient's quality of life (Saag, 2002;Schiffelers et al, 2006;van den Hoven et al, 2011;Leroy et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Preparation and in vitro/pharmacokinetic/pharmacodynamic evaluation of a slow-release nano-liposomal form of prednisolone

et al. 2016

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A nano-liposomal carrier was prepared for the anti-inflammatory drug prednisolone acetate (PA). The drug showed remarkable loading in the nano-carriers. The drug-loaded nano-liposmes with average sizes of about 186 nm and zeta potentials of À20 mV were obtained. Our drug release studies showed an apparently zero-order trend with only 18% of the drug released in the first 120 h. Fourier transform infrared (FT-IR) spectroscopy and differential scanning calorimetry (DSC) analyses showed no chemical interaction between the drug and carrier. Transmission electron microscopy (TEM) imaging showed near-spherical drug-containing nanocarriers. The intramuscular (IM) trial of the nanoformulation compared with the free drug showed both pharmacokinetic (lower C max , higher area under the curve (AUC)) and pharmacodynamic (higher and longer lasting anti-inflammatory effect, both macroscopically and biochemically) superiority for the nano-liposomal drug above the free prednisolone in rats.

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Optimizing the therapeutic index of liposomal glucocorticoids in experimental arthritis

Cited by 50 publications

References 21 publications

Suppression of human arthritis synovial fibroblasts inflammation using dexamethasone-carbon nanotubes via increasing caveolin-dependent endocytosis and recovering mitochondrial membrane potential

Suppression of human arthritis synovial fibroblasts inflammation using dexamethasone-carbon nanotubes via increasing caveolin-dependent endocytosis and recovering mitochondrial membrane potential

Chondroitin Sulfate–Glycyl-Prednisolone Conjugate as Arthritis Targeting System: Localization and Drug Release in Inflammatory Joints

Preparation and in vitro/pharmacokinetic/pharmacodynamic evaluation of a slow-release nano-liposomal form of prednisolone

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