Drug delivery of 6-bromoindirubin-3’-glycerol-oxime ether employing poly(d,l-lactide-co-glycolide)-based nanoencapsulation techniques with sustainable solvents

Abstract

Background Insufficient solubility and stability of bioactive small molecules as well as poor biocompatibility may cause low bioavailability and are common obstacles in drug development. One example of such problematic molecules is 6-bromoindirubin-3'-glycerol-oxime ether (6BIGOE), a hydrophobic indirubin derivative. 6BIGOE potently modulates the release of inflammatory cytokines and lipid mediators from isolated human monocytes through inhibition of glycogen synthase kinase-3 in a favorable fashion. However, 6BIGOE suffers from poor solubility and short half-lives in biological aqueous environment and exerts cytotoxic effects in various mammalian cells. In order to overcome the poor water solubility, instability and cytotoxicity of 6BIGOE, we applied encapsulation into poly(d,l-lactide-co-glycolide) (PLGA)-based nanoparticles by employing formulation methods using the sustainable solvents Cyrene™ or 400 g/mol poly(ethylene glycol) as suitable technology for efficient drug delivery of 6BIGOE. Results For all preparation techniques the physicochemical characterization of 6BIGOE-loaded nanoparticles revealed comparable crystallinity, sizes of about 230 nm with low polydispersity, negative zeta potentials around − 15 to − 25 mV, and biphasic release profiles over up to 24 h. Nanoparticles with improved cellular uptake and the ability to mask cytotoxic effects of 6BIGOE were obtained as shown in human monocytes over 48 h as well as in a shell-less hen’s egg model. Intriguingly, encapsulation into these nanoparticles fully retains the anti-inflammatory properties of 6BIGOE, that is, favorable modulation of the release of inflammation-relevant cytokines and lipid mediators from human monocytes. Conclusions Our formulation method of PLGA-based nanoparticles by applying sustainable, non-toxic solvents is a feasible nanotechnology that circumvents the poor bioavailability and biocompatibility of the cargo 6BIGOE. This technology yields favorable drug delivery systems for efficient interference with inflammatory processes, with improved pharmacotherapeutic potential. Graphical Abstract

Modulation of Inflammation-Related Lipid Mediator Pathways by Celastrol During Human Macrophage Polarization

“…Indeed, drug delivery by nanofluids improved the efficacy of isoniazid 65 or of bromocriptine, 66 and encapsulation of a cytotoxic indirubin derivative into polymer-based nanoparticles reduced its detrimental impact on monocyte viability. 67 …”

Cyrene as Solvent for Metal Nanoparticles Synthesis

“…In all four conditions, however, the conversion yield is within the results reported for the synthesis of Ag NPs in ethylene glycol. 17 We want to emphasize that the conversion yields reported here were from digestion of only the Ag NPs and excludes the formation of the silver mirror. Therefore, we posit that these results represent the lower end of the conversion yield and the syntheses with PVP likely have higher values given the absence of the silver mirror under such reaction conditions.…”

“…[15,16] Due to its low toxicity, Cyrene has also been used in the formulation of polymer nanoparticles for drug delivery. [17,18] Furthermore, Cyrene's boiling point (203 ˚C) is comparable to that of ethylene glycol and thus, is suitable for analogous nanoparticles syntheses. However, there is limited information regarding the thermal and chemical stability of Cyrene at temperatures relevant to nanoparticles synthesis (> 100 ˚C).…”

Hydrogel-Assisted Microfluidic Wet Spinning of Poly(Lactic Acid) Fibers from a Green and Pro-Crystallization Spinning Dope

“…Although Cyrene TM has been claimed to have low mutagenicity, no acute oral toxicity, and low ecotoxicity, and often mentioned as a noncytotoxic solvent [57,82,83], its concentration dependent toxicity towards human cells was not reported so far. We had tested a range of Cyrene TM concentrations for revealing its toxicity on human dermal fibroblasts (HDF) with MTT assay (Fig.…”