Dexamethasone-loaded Nanoparticles Research Articles

Preparation of Dexamethasone-Loaded Nanoparticles and Therapeutic Adoption for Acute Lung Injury in Septic Mice Through the TLR9 Pathway

This research aimed to better exert the efficacy of dexamethasone (DEX) and fabricate an intercellular adhesion molecule A (ILDMA) monoclonal antibody (mAb)-modified nanostructured lipid carrier (NSLC). The anionic DEX NSLC was fabricated by the aqueous solvent diffusion methodology using DEX as the model drug and in combination with various types of lipids. Using N,N’-succinimidyl carbonate as the link, anti-ILDMA mAb-modified anion DEX NSLC (ILDM/DEX/NSLC) and anti-IgG mAb-modified cation DEX NSLC (IgG/DEX/NSLC) were prepared. The total lipid content was controlled unchanged, 3% mass ratio of glyceryl monostearate (MS) in the original prescription was replaced with 3% mass ratio of octadecylamine (ODA), and ILDM/DEX/ODA-NSLC and IgG/DEX/ODA-NSLC were fabricated in the same way. The four NSLCs prepared in the experiment were round in shape and uniform in size. The nanoparticles with a size of approximately 230 nm were similar, and the zeta potentials were (−29.8±21.5) mV, (−27.9±1.6) mV, (36.8±0.8) mV, and (33.7±2.9) mV, respectively. In vitro drug release demonstrated a cumulative release rate of more than 55% of DEX NSLC. The inhibitory rate of DEX NSLC on the activated human vascular endothelial cell line (EAhy926 cell) was dose dependent, and ILDM/DEX/NSLC could transport DEX to activated endothelial cells more efficiently, thus enhancing the intervention ability on diseased endothelium. For the establishment of a sepsis-induced acute lung injury (ALI) mouse model, ILDM/DEX/NSLC was highly distributed in the lung of the model, and its infiltration effect on inflammatory cells was superior to that of other drugs (P < 0.05). Meanwhile, ILDM/DEX/NSLC could more markedly repair the pathological features in the mouse model than other drugs did (P < 0.05). The nanodrug inhibited the protein level of TLR9 in mouse lung tissue to the maximum extent (P < 0.05), thereby enhancing the survival rate of the mice.

Nanomanipulation of Ligand Nanogeometry Modulates Integrin/Clathrin-Mediated Adhesion and Endocytosis of Stem Cells.

Nanosubstrate engineering can be a biomechanical approach for modulating stem cell differentiation in tissue engineering. However, the study of the effect of clathrin-mediated processes on manipulating this behavior is unexplored. Herein, we develop integrin-binding nanosubstrates with confined nanogeometries that regulate clathrin-mediated adhesion- or endocytosis-active signaling pathways for modulating stem fates. Isotropically presenting ligands on the nanoscale enhances the expression of clathrin in cells, thereby facilitating uptake of dexamethasone-loaded nanoparticles (NPs) to boost osteogenesis of stem cells. In contrast, anisotropic ligand nanogeometry suppresses this clathrin-mediated NP entry by strengthening the association between clathrin and adhesion spots to reinforce mechanotransduced signaling, which can be abrogated by the pharmacological inhibition of clathrin. Meanwhile, inhibiting focal adhesion formation hinders cell spreading and enables a higher endocytosis efficiency. Our findings reveal the crucial roles of clathrin in both endocytosis and mechanotransduction of stem cells and provide the parameter of ligand nanogeometry for the rational design of biomaterials for tissue engineering.

Increasing stiffness promotes pulmonary retention of ligand-directed dexamethasone-loaded nanoparticle for enhanced acute lung inflammation therapy.

Inhaled nanoparticles (NPs) need to penetrate the bronchial mucosa to deliver drug payloads deeply in the lung for amplified local therapy. However, the bronchial mucociliary barrier eliminates NPs rapidly, which considerably limits their mucosal penetration. In this study, we find that surface ligand modification and stiffness adjustment of NPs contribute to the significantly enhanced bronchial mucosal absorption and pulmonary retention of inhaled drugs. We utilize neonatal Fc receptor ligand (FcBP) to modify the rationally designed low stiffness NPs (Soft-NP) and high stiffness NPs (Stiff-NP) to target bronchial mucosa. In an acute lung inflammation rat model, after intranasal administration with dexamethasone-loaded NPs, Stiff-NP endowed with FcBP displays superior therapeutic effects. The in vitro data demonstrate that the promotion effect of FcBP to bronchial mucosal absorption of Stiff-NP dominates over Soft-NP. This could be attributed to the higher affinity between ligand-receptor when incorporating FcBP on the Stiff-NP surface. Meanwhile, high stiffness modulates more actin filaments aggregation to mediate endocytosis, along with strengthened Ca2+ signal to enhance exocytosis. Conclusively, we highlight that FcBP-modified NPs with higher stiffness would be a potential pulmonary drug delivery system.

Simultaneous Release of Aflibercept and Dexamethasone from an Ocular Drug Delivery System

Purpose Intravitreal injections of anti-vascular endothelial growth factors (anti-VEGF) are the current standard of care for patients with choroidal neovascularization (CNV) secondary to age-related macular degeneration (AMD). There is a growing subset of patients that does not respond to anti-VEGF monotherapy treatment. Some patients, however, do respond to combination therapy of corticosteroids and anti-VEGF. This treatment requires monthly/bimonthly injections of anti-VEGF and semi-annual injections of corticosteroid. A drug delivery system (DDS) that simultaneously releases multiple drugs could benefit these patients by reducing the number of injections. The purpose of this study was to characterize the simultaneous release of aflibercept and dexamethasone from a biodegradable microparticle- and nanoparticle-hydrogel DDS. Methods Dexamethasone-loaded nanoparticles and aflibercept-loaded microparticles were created using modified single- and double-emulsion techniques, respectively. Then, microparticles and nanoparticles were embedded into a thermoresponsive, biodegradable poly(ethylene glycol)-co-(L-lactic acid) diacrylate (PEG-PLLA-DA)-N-isopropylacrylamide (NIPAAm) hydrogel DDS. Drug release studies and characterization of DDS were conducted with varying doses of microparticles and nanoparticles. Results The combination aflibercept-loaded microparticle- and dexamethasone-loaded nanoparticle- hydrogel (Combo-DDS) achieved a total release time of 224 days. Small decreases were seen in swelling ratio and equilibrium water content for Combo-DDS compared to monotherapy aflibercept-loaded microparticle-hydrogel DDS (AFL-DDS) and monotherapy dexamethasone-loaded nanoparticle-hydrogel DDS (DEX-DDS). Bioactivity of aflibercept was maintained in Combo-DDS compared to AFL-DDS. Conclusions The Combo-DDS was able to extend and control the release of both aflibercept and dexamethasone simultaneously from a single DDS. This may eliminate the need for separate dosing regiments of anti-VEGF and corticosteroids for wet AMD patients.

Modulation of Inflammatory Mediators by Polymeric Nanoparticles Loaded with Anti-Inflammatory Drugs.

The first-line treatment of osteoarthritis is based on anti-inflammatory drugs, the most currently used being nonsteroidal anti-inflammatory drugs, selective cyclooxygenase 2 (COX-2) inhibitors and corticoids. Most of them present cytotoxicity and low bioavailability in physiological conditions, making necessary the administration of high drug concentrations causing several side effects. The goal of this work was to encapsulate three hydrophobic anti-inflammatory drugs of different natures (celecoxib, tenoxicam and dexamethasone) into core-shell terpolymer nanoparticles with potential applications in osteoarthritis. Nanoparticles presented hydrodynamic diameters between 110 and 130 nm and almost neutral surface charges (between −1 and −5 mV). Encapsulation efficiencies were highly dependent on the loaded drug and its water solubility, having higher values for celecoxib (39–72%) followed by tenoxicam (20–24%) and dexamethasone (14–26%). Nanoencapsulation reduced celecoxib and dexamethasone cytotoxicity in human articular chondrocytes and murine RAW264.7 macrophages. Moreover, the three loaded systems did not show cytotoxic effects in a wide range of concentrations. Celecoxib and dexamethasone-loaded nanoparticles reduced the release of different inflammatory mediators (NO, TNF-α, IL-1β, IL-6, PGE2 and IL-10) by lipopolysaccharide (LPS)-stimulated RAW264.7. Tenoxicam-loaded nanoparticles reduced NO and PGE2 production, although an overexpression of IL-1β, IL-6 and IL-10 was observed. Finally, all nanoparticles proved to be biocompatible in a subcutaneous injection model in rats. These findings suggest that these loaded nanoparticles could be suitable candidates for the treatment of inflammatory processes associated with osteoarthritis due to their demonstrated in vitro activity as regulators of inflammatory mediator production.

A simple coating method of PDMS microchip with PTFE for synthesis of dexamethasone-encapsulated PLGA nanoparticles.

Dexamethasone is a widely used drug in medical and biological applications. Since the systematic and controllable release of this drug is of significant importance, encapsulation of this anti-inflammatory drug in poly(lactic-co-glycolic acid) (PLGA) nanoparticles can minimize uncontrolled issues. As dexamethasone-encapsulated PLGA nanoparticles are synthesized in the presence of organic solvents, poly(dimethylsiloxane) (PDMS)-based microchannels collapse due to the swelling problem. In present study, PTFE nanoparticles were used for the surface modification of the microchannels to prevent absorption and adhesion of solvents into the microchannels' wall. The contact angle analysis of microchips after coating showed that the surface of microchannels bear the superhydrophobicity feature (140.30°) and SEM images revealed that PTFE covered the surface of PDMS, favorably. Then, the prepared microchip was tested for the synthesis of dexamethasone-loaded nanoparticles. SEM and atomic force microscopy (AFM) images of the synthesized nanoparticles represented that there was not any evidence of adhesion or absorption of nanoparticles. Furthermore, the monodispersity of nanoparticles was discernible. As AFM results revealed, the average diameters of 47, 63, and 82nm were achieved for flow ratios of 0.01, 0.05, and 0.1, respectively. To evaluate the drug efficiency, cumulative release and encapsulation efficiency were analyzed which showed much more efficiency than the synthesized nanoparticles in the bulk mode. In addition, MTT test revealed that nanoparticles could be considered as a non-toxic material. Since the synthesis of drug-loaded nanoparticles is ubiquitous in laboratory experiments, the approach presented in this study can render more versatility in this regard.

General and Facile Coating of Single Cells via Mild Reduction

Cell surface modification has been extensively studied to enhance the efficacy of cell therapy. Still, general accessibility and versatility are remaining challenges to meet the increasing demand for cell-based therapy. Herein, we present a facile and universal cell surface modification method that involves mild reduction of disulfide bonds in cell membrane protein to thiol groups. The reduced cells are successfully coated with biomolecules, polymers, and nanoparticles for an assortment of applications, including rapid cell assembly, in vivo cell monitoring, and localized cell-based drug delivery. No adverse effect on cellular morphology, viability, proliferation, and metabolism is observed. Furthermore, simultaneous coating with polyethylene glycol and dexamethasone-loaded nanoparticles facilitates enhanced cellular activities in mice, overcoming immune rejection.

Pharmacokinetics and tolerance study of intravitreal injection of dexamethasone-loaded nanoparticles in rabbits.

The aim of the study was to investigate the tolerance and pharmacokinetics of dexamethasone (DEX)-loaded poly(lactic acid-co-glycolic acid) nanoparticles (DEX-NPs) in rabbits after intravitreal injection. The DEX-NPs were prepared and characterized in terms of morphology, particle size and size distribution, encapsulation efficiency, and in vitro release. Ophthalmic investigations were performed, including fundus observation and photography, intraocular pressure measurement, and B-scan ocular ultrasonography. There were no abnormalities up to 50 days after administration of DEX-NPs in rabbits. The DEX concentrations in plasma and the ocular tissues such as the cornea, aqueous humor, lens, iris, vitreous humor, and chorioretina were determined by high-pressure liquid chromatography. The DEX-NPs maintained a sustained release of DEX for about 50 days in vitreous and provided relatively constant DEX levels for more than 30 days with a mean concentration of 3.85 mg/L(-1). Based on the areas under the curve, the bioavailability of DEX in the experimental group was significantly higher than that in the control group injected with regular DEX. These results suggest that intravitreal injection of DEX-NPs lead to a sustained release of DEX with a high bioavailability, providing a basis for a novel approach to the treatment of posterior segment diseases.

Polyketal Nanoparticles: A New pH-Sensitive Biodegradable Drug Delivery Vehicle

In this report, we present an acid-sensitive drug delivery vehicle, termed polyketal nanoparticles, which are designed to target therapeutics to the acidic environments of tumors, inflammatory tissues, and phagosomes. The polyketal nanoparticles are formulated from poly(1,4-phenyleneacetone dimethylene ketal) (PPADK), a new hydrophobic polymer which contains ketal linkages in its backbone. The polyketal nanoparticles undergo acid-catalyzed hydrolysis into low molecular weight hydrophilic compounds and should therefore release encapsulated therapeutics at an accelerated rate in acidic environments. Importantly, the polyketal nanoparticles do not generate acidic degradation products after hydrolysis, as with polyester-based biomaterials. Dexamethasone-loaded nanoparticles, 200-600 nm in diameter, were fabricated with PPADK via an emulsion procedure using chloroform and water. The hydrolysis half-life of PPADK was measured to be 102 h at pH 7.4 and 35 h at pH 5.0. PPADK was synthesized by a new polymerization strategy based on the acetal exchange reaction. This new delivery system should find numerous applications in the field of drug delivery because of its ease of synthesis and excellent degradation properties.