Leflunomide biodegradable microspheres intended for intra-articular administration: Development, anti-inflammatory activity and histopathological studies

El-Setouhy, Doaa Ahmed; Abdelmalak, Nevine Shawky; Anis, Shady E.; Louis, Dina

doi:10.1016/j.ijpharm.2015.09.040

Cited by 18 publications

(7 citation statements)

References 28 publications

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“…The amount of LEF encapsulated in the prepared cubosomes was determined by a reported (El-Setouhy et al., 2015 ; Zewail et al., 2019 ; Zewail, 2021 ) indirect method. Briefly, a 1-mL aliquot LEF loaded cubosomal suspension was transferred into a centrifuge tube fitted with an ultrafilter (Vivaspin 6VR, Sartorius, MWCO 10 kDa) and then centrifuged at 4000 rpm for 1 h at 4 °C (Sigma Laboratory Refrigerated Centrifuge, Model 3 K-3o, Germany).…”

Section: Methodsmentioning

confidence: 99%

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Lipidic cubic-phase leflunomide nanoparticles (cubosomes) as a potential tool for breast cancer management

et al. 2022

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Despite the fact of availability of several treatments for breast cancer, most of them fail to attain the desired therapeutic response due to their poor bioavailability, high doses, non-selectivity and as a result systemic toxicity. Here in an attempt made to study the transdermal effect of leflunomide (LEF) against breast cancer. In order to improve the poor physicochemical properties of LEF, it was loaded into cubosomes. Cubosomes were prepared by the emulsification method. Colloidal characteristics of cubosomes including particle size, ζ-potential, entrapment efficiency, in-vitro release profile and ex-vivo permeation were studied. In addition, morphology, stability, cytotoxicity and cell uptake in MDA-MB-231 cell line were carried out for the selected cubosomal formulation. The selected LEF loaded cubosomal formulation showed a small particle size (168 ± 1.08) with narrow size distribution (PI 0.186 ± 0.125) and negative ζ potential (–25.5 ± 0.98). Its Entrapment efficiency (EE%) was 93.2% and showed sustained release profile that extended for 24 h. The selected formulation showed stability when stored at 25 °C for three months in terms of size and EE%. TEM images illustrated the cubic structure of the cubosome. Cell culture results revealed the superiority of LEF cubosomes compared to LEF suspension in their cytotoxic effects with an IC50 close to that of doxorubicin. Furthermore, LEF cell uptake was significantly higher for LEF cubosomes. This may be attributed to the effect of nano-encapsulation on enhancing drug pharmacological effects and uptake indicating the potential usefulness of LEF cubosomes for breast cancer management.

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Section: Methodsmentioning

confidence: 99%

“…Unfortunately, LEF possess several gastrointestinal side effects including stomatitis, diarrhea, colitis and esophagitis, besides to its systemic side effects on the skin, liver and lungs (El-Setouhy et al., 2015 ; Zewail et al., 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Lipidic cubic-phase leflunomide nanoparticles (cubosomes) as a potential tool for breast cancer management

et al. 2022

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“…Microspheres can act as a vehicle for the controlled release of encapsulated growth factors due to their small dimensions and the corresponding high surface area, high loading capacity and their ability to protect the growth factors from degradation in vivo [23,24]. As such, microspheres have been investigated for use in various cartilage tissue engineering approaches [24][25][26][27][28]. For example, Eswaramoorthy et al showed that sustained release of PTH from poly(lactideco-glycolide) (PLGA) microspheres suppresses osteoarthritis progression in rats [25].…”

Section: Introductionmentioning

confidence: 99%

Microspheres containing decellularized cartilage induce chondrogenesis in vitro and remain functional after incorporation within a poly(caprolactone) filament useful for fabricating a 3D scaffold

et al. 2018

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In this study, articular cartilage was decellularized preserving a majority of the inherent proteins, cytokines, growth factors and sGAGs. The decellularized cartilage matrix (dCM) was then encapsulated in poly(lactic acid) microspheres (MS+dCM) via double emulsion. Blank microspheres without dCM, MS(-), were also produced. The microspheres were spherical in shape and protein encapsulation efficiency within MS+dCM was 63.4%. The sustained release of proteins from MS+dCM was observed over 4 weeks in vitro. Both MS+dCM and MS(-) were cytocompatible. The sustained delivery of retained growth factors and cytokines from MS+dCM promoted cell migration in contrast to MS(-). Subsequently, chondrogenesis of hMSCs was upregulated in presence of MS+dCM as evidenced from immunohistochemistry, biochemical quantification and qPCR studies. Specifically, collagen II, aggrecan and SOX 9 gene expression were increased in the presence of MS+dCM by an order or more in magnitude compared to MS(-) with concomitant downregulation of hypertrophic genes (COL X) despite being cultured in the absence of chondrogenic media, (p<0.05). Lastly, microspheres containing alkaline phosphatase (MS+ALP), a surrogate to assess the thermal stability of dCM proteins, incorporated within poly(caprolactone) filaments showed that the enzyme remained functional after filament production by melt extrusion. The establishment of a novel, thermally stable process for producing filaments containing chondroinductive microspheres provides evidence supporting subsequent development of a clinically-relevant, 3D scaffold fabricated from them for osteochondral regeneration and repair.

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“…In brief, a 1 mL aliquot of LEF EML suspension was centrifuged (Sigma Laboratory Refrigerated Centrifuge, Model 3K-3o, Osterode am Harz, Germany) at 4000 rpm at 4 °C for 1 h using a centrifuge tube fitted with an ultrafilter (Vivaspin 6VR, Sartorius, MWCO 10 kDa, Littleton, MA, USA). The amount of free LEF was measured spectrophotometrically at 263 nm [ 21 , 22 , 24 ], and EE % was quantified according to the following equation: EE % = (Total amount of LEF − amount of unencapsulated LEF)/(Total amount of LEF) × 100 …”

Section: Methodsmentioning

confidence: 99%

“…Unfortunately, systemic LEF administration is associated with side effects, such as diarrhea, esophagitis, and colitis. Moreover, prolonged LEF administration may cause more serious side effects on the liver, lungs, and nerves [ 22 , 23 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

Development and Evaluation of Novel Leflunomide SPION Bioemulsomes for the Intra-Articular Treatment of Arthritis

et al. 2022

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Systemic treatments for rheumatoid arthritis are associated with many side effects. This study aimed to minimize the side effects associated with the systemic administration of leflunomide (LEF) by formulating LEF-loaded emulsomes (EMLs) for intra-articular administration. Additionally, EMLs were loaded with supramagnetic nanoparticles (SPIONs) to enhance joint localization, where a magnet was placed on the joint area after intra-articular administration. Full in vitro characterization, including colloidal characteristics, entrapment efficiency, and in vitro release were conducted besides the in vivo evaluation in rats with adjuvant-induced arthritis. In vivo study included joint diameter measurement, X-ray radiographic analysis, RT-PCR analysis, Western blotting, ELISA for inflammatory markers, and histopathological examination of dissected joints. The particle size and entrapment efficiency of the selected LEF SPION EMLs were 198.2 nm and 83.7%, respectively. The EMLs exhibited sustained release for 24 h. Moreover, in vivo evaluation revealed LEF SPION EMLs to be superior to the LEF suspension, likely due to the increase in LEF solubility by nanoencapsulation that improved the pharmacological effects and the use of SPION that ensured the localization of EMLs in the intra-articular cavity upon administration.

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Leflunomide biodegradable microspheres intended for intra-articular administration: Development, anti-inflammatory activity and histopathological studies

Cited by 18 publications

References 28 publications

Lipidic cubic-phase leflunomide nanoparticles (cubosomes) as a potential tool for breast cancer management

Lipidic cubic-phase leflunomide nanoparticles (cubosomes) as a potential tool for breast cancer management

Microspheres containing decellularized cartilage induce chondrogenesis in vitro and remain functional after incorporation within a poly(caprolactone) filament useful for fabricating a 3D scaffold

Development and Evaluation of Novel Leflunomide SPION Bioemulsomes for the Intra-Articular Treatment of Arthritis

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