Anti-Inflammatory Polymeric Nanoparticles Based on Ketoprofen and Dexamethasone

Abstract

Polymeric nanoparticles that combine dexamethasone and naproxen reduce inflammation and synergistically inhibit Interleukin-12b (Il12b) transcription in macrophages. This effect can be the result of a cyclooxygenase-dependent or a cyclooxygenase-independent mechanism. The aim of this work is to obtain potent anti-inflammatory polymeric nanoparticles by the combination of dexamethasone and ketoprofen, one of the most efficient cyclooxygenase-inhibitors among non-steroidal anti-inflammatory drugs, with appropriate hydrodynamic properties to facilitate accumulation and co-release of drugs in inflamed tissue. Nanoparticles are spherical with hydrodynamic diameter (117 ± 1 nm), polydispersity (0.139 ± 0.004), and surface charge (+30 ± 1 mV), which confer them with high stability and facilitate both macrophage uptake and internalization pathways to favor their retention at the inflamed areas and lysosomal degradation and drug release, respectively. In vitro biological studies concluded that the dexamethasone-loaded ketoprofen-bearing system is non-cytotoxic and efficiently reduces lipopolysaccharide-induced nitric oxide release. The RT-qPCR analysis shows that the ketoprofen nanoparticles were able to reduce to almost basal levels the expression of tested pro-inflammatory markers and increase the gene expression of anti-inflammatory cytokines under inflammatory conditions. However, the synergistic inhibition of Il12b observed in nanoparticles that combine dexamethasone and naproxen was not observed in nanoparticles that combine dexamethasone and ketoprofen, suggesting that the synergistic trans-repression of Il12b observed in the first case was not mediated by cyclooxygenase-dependent pathways.

Preparation of Electrospun Small Intestinal Submucosa/Poly(caprolactone-co-Lactide-co-glycolide) Nanofiber Sheet as a Potential Drug Carrier

“…The Dex-S/P(5:1)-NS showed a gradual decrease in macrophage infiltration, but AgS-S/P(5:1)-NS suppressed macrophage infiltration at 2 weeks and then slightly increased at 3 weeks. This result indicates that sustained drug release is required to suppress macrophage infiltration because Dex and AgS display potent inflammatory suppressive properties [ 30 , 31 , 32 ].…”

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

“…Among these factors, NO overproduction plays a major regulatory role in tissue damage associated with chronic inflammation presented in OA. Different polymeric NPs have demonstrated a reduction of NO in LPS-stimulated RAW264.7 encapsulating CLX [ 28 ] and DEX [ 23 , 63 , 64 ]. Unloaded NPs were deeply studied in a previous work and the reduction in NO production was not observed in LPS-stimulated RAW264.7 macrophages [ 40 ].…”

“…In particular, considerable work trying to combine DEX with nanotechnology has been developed, since DEX possesses powerful anti-inflammatory activity, even at low doses [ 19 ]. It has been recently encapsulated alone [ 20 , 21 , 22 ], or in combination with other factors, such as other anti-inflammatory molecules like ketoprofen [ 23 ] or small interfering RNA [ 24 ], and covalently conjugated, for example, with the avidin protein [ 25 ] with positive effects both in vitro and in vivo. In the case of CLX, CLX poly(1-vinyl-2-pyrrolidone) solid dispersion NPs [ 26 ], or CLX-loaded hyaluronan NPs [ 27 ], were prepared to improve this drug bioavailability.…”

Nanomaterials for the Diagnosis and Treatment of Inflammatory Arthritis

“…Liposomes MTX, Dex, SIN Improved controlled release, reduced RA signs, decreased side effects [128] Polymeric NPs Ket, Dex, TFC, MTX Decreased inflammation [134] Niosomes PC, thiocolchicoside, ibuprofen Increased drug retention [143] Silver NPs FA-AgNPs Enhanced anti-inflammatory activities [148] Gold NPs Triam Enhanced anti-inflammatory activities [150] Iron NPs MTX Suppression of joint edema and inflammation [152] Quantum dots celecoxib Localized activity in sites of inflammation [153] Solid lipid NPs CUR, Pi, CIP Enhanced anti-inflammatory activities [154] Polymeric micelles Dex, indomethacin Decreased side effects [159] Abbreviations: NPs, nanoparticles; MTX, methotrexate; Dex, dexamethasone; SIN, sinomenine hydrochloride; Ket, Ketoprofen; TFC, tofacitinib; PC, piroxicam; FA-AgNPs, folic acid modified with silver nanoparticles; Triam, triamcinolone; CUR, curcumin; Pi, piperine; CIP, ciprofloxacin; RA, rheumatoid arthritis; COX-2, cyclooxygenase 2.…”

“…Espinosa-Cano et al [ 134 ] demonstrated the benefits of using polymeric NPs conjugated with naproxen and Dex to decrease inflammation and prevent IL-12 expression in macrophages. Note that IL-12 and IL-23 recently appeared as therapeutic targets in the therapy of long-lasting inflammatory disorders in which T cells are the primary dysfunctional immune cells, via either COX-dependent or COX-independent regulation mechanisms.…”