作者: Dahlke, Philipp ; Schubert, Stephanie ; Czaplewska, Justyna Anna ; Shkodra, Blerina ; Stumpf, Steffi ; Hoeppener, Stephanie ; Jordan, Paul M ; Werz, Oliver ; Schubert, Ulrich S ; Vollrath, Antje ; Klemm, Paul ; Behnke, Mira ; Beringer-Siemers, Baerbel

Dextran-based polymers, such as ethoxy acetalated dextran (Ace-DEX), are increasingly becoming the focus of research as they offer great potential for the development of polymer-based nanoparticles as drug delivery vehicles. Their major advantages are the facile synthesis, straightforward particle preparation and the pH-dependent degradation of the particles that can be fine-tuned by the degree of acetalation of the polymer. In this study we have shown that Ace-DEX can not only compete against the commonly used and FDA-approved polymer poly(lactic-co-glycolic acid) (PLGA), but even has the potential to outperform it in its encapsulation properties, e.g., for the herein used anti-inflammatory leukotriene biosynthesis inhibitor BRP-187. We used three different methods (microfluidics, batch nanoprecipitation and emulsion solvent evaporation) for the preparation of BRP-187-loaded Ace-DEX nanoparticles to investigate the influence of the formulation technique on the physicochemical properties of the particles. Finally, we evaluated which production method offers the greatest potential for achieving the demands for a successful translation from research into pharmaceutical production by fulfilling the basic requirements, such as reaching a high loading capacity of the particles and excellent reproducibility while being simple and affordable.

2022-04-01·Journal of Colloid and Interface Science2区 · 化学

Miniemulsion polymerization at low temperature: A strategy for one-pot encapsulation of hydrophobic anti-inflammatory drugs into polyester-containing nanoparticles

2区 · 化学

Article

作者: Schubert, Stephanie ; Kleinsteuber, Maximilian ; De San Luis, Alicia ; Schuett, Timo ; Schubert, Ulrich S

HYPOTHESISConventional synthesis methods of polymeric nanoparticles as drug delivery systems are based on the use of large amounts of organic solvents, hence requiring several steps for the obtaining of waterborne dispersions. In view of the need for new environmentally friendly methods, emulsion polymerization and their related techniques are a good alternative for the production of monodispersed waterborne dispersions of biodegradable nanoparticles in a cleaner, reproducible and faster manner.EXPERIMENTSHerein, the miniemulsion polymerization technique at low temperature using poly(2-ethyl-2-oxazoline) as surfactant has been developed for poly(hydroxyethyl methacrylate-lactic acid) and poly(hydroxyethyl methacrylate-lactic-co-glycolic acid) nanoparticles. Additionally, the anti-inflammatory drug BRP-187 was used to proof the potential of this technique in the encapsulation of hydrophobic drugs. The effect of the oligomer composition on the miniemulsion and the final dispersion stability, the final oligomer conversion, the polymer particle size and the drug encapsulation efficiency has been studied.FINDINGSMonodisperse spherical particles ranging between 170 and 250 nm in diameter in long term non-toxic stable waterborne dispersions were obtained with drug encapsulation efficiencies up to 66%. In contrast with conventional synthesis techniques, residual organic solvents are completely removed and, thus, the potential of redox initiated miniemulsion polymerization to obtain stable drug loaded poly(hydroxyethyl methacrylate-lactic acid) and poly(hydroxyethyl methacrylate-lactic-co-glycolic acid) nanoparticles in an efficient and fast manner is shown.

2016-11-01·Biochemical Pharmacology2区 · 医学

BRP-187: A potent inhibitor of leukotriene biosynthesis that acts through impeding the dynamic 5-lipoxygenase/5-lipoxygenase-activating protein (FLAP) complex assembly

2区 · 医学

Article

作者: Çelikoğlu, Erşan ; Çalışkan, Burcu ; Gerstmeier, Jana ; Rummler, Silke ; Liening, Stefanie ; Scriba, Gerhard K E ; Werz, Oliver ; Banoglu, Erden ; Emini, Besa ; Sautebin, Lidia ; Pace, Simona ; Schubert, Ulrich S ; Rossi, Antonietta ; Weinigel, Christina ; Voelker, Susanna ; Garscha, Ulrike

The pro-inflammatory leukotrienes (LTs) are formed from arachidonic acid (AA) in activated leukocytes, where 5-lipoxygenase (5-LO) translocates to the nuclear envelope to assemble a functional complex with the integral nuclear membrane protein 5-LO-activating protein (FLAP). FLAP, a MAPEG family member, facilitates AA transfer to 5-LO for efficient conversion, and LT biosynthesis critically depends on FLAP. Here we show that the novel LT biosynthesis inhibitor BRP-187 prevents the 5-LO/FLAP interaction at the nuclear envelope of human leukocytes without blocking 5-LO nuclear redistribution. BRP-187 inhibited 5-LO product formation in human monocytes and polymorphonuclear leukocytes stimulated by lipopolysaccharide plus N-formyl-methionyl-leucyl-phenylalanine (IC₅₀=7-10nM), and upon activation by ionophore A23187 (IC₅₀=10-60nM). Excess of exogenous AA markedly impaired the potency of BRP-187. Direct 5-LO inhibition in cell-free assays was evident only at >35-fold higher concentrations, which was reversible and not improved under reducing conditions. BRP-187 prevented A23187-induced 5-LO/FLAP complex assembly in leukocytes but failed to block 5-LO nuclear translocation, features that were shared with the FLAP inhibitor MK886. Whereas AA release, cyclooxygenases and related LOs were unaffected, BRP-187 also potently inhibited microsomal prostaglandin E₂ synthase-1 (IC₅₀=0.2μM), another MAPEG member. In vivo, BRP-187 (10mg/kg) exhibited significant effectiveness in zymosan-induced murine peritonitis, suppressing LT levels in peritoneal exudates as well as vascular permeability and neutrophil infiltration. Together, BRP-187 potently inhibits LT biosynthesis in vitro and in vivo, which seemingly is caused by preventing the 5-LO/FLAP complex assembly and warrants further preclinical evaluation.

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适应症	最高研发状态	国家/地区	公司	日期
哮喘	临床前	意大利	Università degli Studi di Perugia	-
哮喘	临床前	德国	Friedrich Schiller University of Jena	-
动脉粥样硬化	临床前	德国	Friedrich Schiller University of Jena	-
动脉粥样硬化	临床前	意大利	Università degli Studi di Perugia	-