Ethoxy acetalated dextran-based nanocarriers accomplish efficient inhibition of leukotriene formation by a novel FLAP antagonist in human leukocytes and blood

Abstract

Leukotrienes are pro-inflammatory lipid mediators generated by 5-lipoxygenase aided by the 5-lipoxygenase-activating protein (FLAP). BRP-201, a novel benzimidazole-based FLAP antagonist, inhibits leukotriene biosynthesis in isolated leukocytes. However, like other FLAP antagonists, BRP-201 fails to effectively suppress leukotriene formation in blood, which limits its therapeutic value. Here, we describe the encapsulation of BRP-201 into poly(lactide-co-glycolide) (PLGA) and ethoxy acetalated dextran (Ace-DEX) nanoparticles (NPs), aiming to overcome these detrimental pharmacokinetic limitations and to enhance the bioactivity of BRP-201. NPs loaded with BRP-201 were produced via nanoprecipitation and the physicochemical properties of the NPs were analyzed in-depth using dynamic light scattering (size, dispersity, degradation), electrophoretic light scattering (effective charge), NP tracking analysis (size, dispersity), scanning electron microscopy (size and morphology), UV–VIS spectroscopy (drug loading), an analytical ultracentrifuge (drug release, degradation kinetics), and Raman spectroscopy (chemical attributes). Biological assays were performed to study cytotoxicity, cellular uptake, and efficiency of BRP-201-loaded NPs versus free BRP-201 to suppress leukotriene formation in primary human leukocytes and whole blood. Both PLGA- and Ace-DEX-based NPs were significantly more efficient to inhibit leukotriene formation in neutrophils versus free drug. Whole blood experiments revealed that encapsulation of BRP-201 into Ace-DEX NPs strongly increases its potency, especially upon pro-longed (≥ 5 h) incubations and upon lipopolysaccharide-challenge of blood. Finally, intravenous injection of BRP-201-loaded NPs significantly suppressed leukotriene levels in blood of mice in vivo. These results reveal the feasibility of our pharmacological approach using a novel FLAP antagonist encapsulated into Ace-DEX-based NPs with improved efficiency in blood to suppress leukotriene biosynthesis.

Diversity of Rationally Modified Polysaccharides for Pharmaceutical Applications

“…Encapsulation of BRP‐201 into Ac Dex NPs significantly improved its activity in whole blood especially when incubation duration was longer than 5 hours. These findings demonstrate that encapsulating the FLAP antagonist into Ac Dex based NPs can reduce inflammation in a plausible pharmacological manner [91] …”

“…These findings demonstrate that encapsulating the FLAP antagonist into Ac Dex based NPs can reduce inflammation in a plausible pharmacological manner. [91] Moreover, Ac-DEX microparticles encapsulating Rapa and the disease-associated antigen ovalbumin (commonly found in egg white) was found to produce antigen-specific immunity in multiple sclerosis of the central nervous system. The novel Dex.…”

Developing Next‐Generation Protein‐Based Vaccines Using High‐Affinity Glycan Ligand‐Decorated Glyconanoparticles

“…The reaction of commonly used dextran (Dex) from Leuconostoc mesenteroides (molecular weight: 9−11 kDa) [ 8 , 9 , 12 ] with imidazole‐1‐carboxylic acid 2‐[2‐(2‐azido‐ethoxy)‐ethoxy]‐ethyl ester (CDI‐TEG‐azide) [ 13 ] in the presence of 4‐dimethylaminopyridine (DMAP) led to dextran‐azide (Dex‐Az). Oxidation of Dex‐Az with sodium periodate yielded partially oxidized azide‐bearing dextran (Oxi‐Dex‐Az).…”

“…Compared with Ac‐Dex, ethoxy‐derivatized acetalated dextran (Ace‐Dex) is more biocompatible because Ace‐Dex produces ethanol. [ 9 ] Accordingly, we investigated whether partially oxidized Ace‐Dex NPs can be used to deliver protein antigens (PAs). In the reported studies, [ 8 , 10 ] the uptake of Ac‐Dex NPs by immune cells occurred through passive transport; however, delivering antigens to antigen‐presenting cells (APCs) through an actively targeted delivery can be a more effective strategy to enhance adaptive immunity.…”

PEG–Lipid–PLGA Hybrid Particles for Targeted Delivery of Anti-Inflammatory Drugs

“…It belongs to a new class of anti-inflammatory drugs with superior properties compared to the current anti-inflammatory therapies available [ 26 , 27 , 28 ]. However, BRP-201 is a lipophilic drug with a very low water solubility and hence low bioavailability, which is why it relies on an encapsulation into a suitable DDS [ 29 ].…”