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

Journal of Nanobiotechnology

Karl Scheuer¹  Klaus D. Jandt²  Anna Czapka³  Vivien Bachmann³  Patrick Schädel³  Oliver Werz⁴  Alexios-Leandros Skaltsounis⁵  Michael Dirauf⁶  Ulrich S. Schubert⁶  Christine Weber⁶  Christian Grune⁷  Dagmar Fischer⁸ 

[1] Chair of Materials Science (CMS), Faculty of Physics and Astronomy, Otto Schott Institute of Materials Research, Friedrich Schiller University Jena, Löbdergraben 32, 07743, Jena, Germany;Chair of Materials Science (CMS), Faculty of Physics and Astronomy, Otto Schott Institute of Materials Research, Friedrich Schiller University Jena, Löbdergraben 32, 07743, Jena, Germany;Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, 07743, Jena, Germany;Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Philosophenweg 14, 07743, Jena, Germany;Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Philosophenweg 14, 07743, Jena, Germany;Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, 07743, Jena, Germany;Department of Pharmacy, Division of Pharmacognosy and Natural Products Chemistry, University of Athens, Panepistimiopolis Zografou, 15771, Athens, Greece;Laboratory of Organic and Macromolecular Chemistry (IOMC), Friedrich Schiller University Jena, Humboldtstraße 10, 07743, Jena, Germany;Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, 07743, Jena, Germany;Pharmaceutical Technology and Biopharmacy, Institute of Pharmacy, Friedrich Schiller University Jena, Lessingstraße 8, 07743, Jena, Germany;Pharmaceutical Technology and Biopharmacy, Institute of Pharmacy, Friedrich Schiller University Jena, Lessingstraße 8, 07743, Jena, Germany;Jena Center for Soft Matter (JCSM), Friedrich Schiller University Jena, Philosophenweg 7, 07743, Jena, Germany;Division of Pharmaceutical Technology, Department for Chemistry and Pharmacy, Friedrich-Alexander-University Erlangen-Nürnberg, Cauerstrasse 4, 91058, Erlangen, Germany;

关键词: Nanoparticles;    Drug delivery;    PLGA;    Sustainable solvents;    Inflammation;    Indirubin;   

DOI  :  10.1186/s12951-021-01179-7

来源: Springer

【 摘 要 】

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 Abstract

【 授权许可】

CC BY