Abstract
BackgroundInsufficient 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.ResultsFor 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.ConclusionsOur 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
Highlights
Insufficient solubility and stability of bioactive small molecules as well as poor biocompatibility may cause low bioavailability and are common obstacles in drug development
Indirubin and its synthetic analogues are well-established inhibitors of cyclin-dependent kinases, dual-specificity tyrosine-regulated kinases, aurora kinases, and glycogen synthase kinase (GSK)-3 [2,3,4], and offer a broad therapeutic potential for the treatment of various disorders ranging from inflammatory [5, 6], autoimmune [7], metabolic [8] and neurodegenerative diseases [9] to cancer [10]
Application of bioactive small molecules is often impeded by their poor aqueous solubility [16] and the requirement of potentially harmful organic solvents which demands the use of suitable drug delivery systems [17]
Summary
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 mol‐ ecules is 6-bromoindirubin-3’-glycerol-oxime ether (6BIGOE), a hydrophobic indirubin derivative. Indirubin and its synthetic analogues are well-established inhibitors of cyclin-dependent kinases, dual-specificity tyrosine-regulated kinases, aurora kinases, and glycogen synthase kinase (GSK)-3 [2,3,4], and offer a broad therapeutic potential for the treatment of various disorders ranging from inflammatory [5, 6], autoimmune [7], metabolic [8] and neurodegenerative diseases [9] to cancer [10] Among these indirubins, 6-bromoindirubin3’-glycerol-oxime ether (6BIGOE) was identified as a highly potent and favorable modulator of inflammatory cytokines and lipid mediators (LMs) in human monocytes and represents an interesting candidate for the treatment of inflammation-related diseases [11]. Drug encapsulation can avoid unintended off-target interactions and distribution in vivo, and increase circulation time [21]
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