Poly(ε-caprolactone) Scaffolds Doped with c-Jun N-terminal Kinase Inhibitors Modulate Phagocyte Activation

Abstract

The modulation of phagocyte responses is essential for successful performance of biomaterials in order to prevent negative outcomes associated with inflammation. Herein, we developed electrospun poly­(ε-caprolactone) (PCL) scaffolds doped with the novel potent c-Jun N-terminal kinase (JNK) inhibitors 11H-indeno­[1,2-b]­quinoxalin-11-one oxime (IQ-1) and 11H-indeno­[1,2-b]­quinoxalin-11-one O-(O-ethylcarboxymethyl) oxime­(IQ-1E) as a promising approach for modulating phagocyte activation. Optimized electrospinning parameters allowed us to produce microfiber composite materials with suitable mechanical properties. We found that embedded compounds were bound to the polymer matrix via hydrophobic interactions and released in two steps, with release mostly controlled by Fickian diffusion. The fabricated scaffolds doped with active compounds IQ-1 and IQ-1E effectively inhibited phagocyte inflammatory responses. For example, they suppressed human neutrophil activation by the biomaterials, as indicated by decreased neutrophil reactive oxygen species (ROS) production and Ca2+ mobilization. In addition, they inhibited lipopolysaccharide (LPS)-induced NF-κB/AP-1 reporter activity in THP-1Blue cells and interleukin (IL)-6 production in MonoMac-6 cells without affecting cell viability. These effects were attributed to the released compounds rather than cell–surface interactions. Therefore, our study demonstrates that doping tissue engineering scaffolds with novel JNK inhibitors represents a powerful tool for preventing adverse immune responses to biomaterials as well as serves as a platform for drug delivery.

Arene–Ruthenium(II) Complexes Containing 11H-Indeno[1,2-b]quinoxalin-11-one Derivatives and Tryptanthrin-6-oxime: Synthesis, Characterization, Cytotoxicity, and Catalytic Transfer Hydrogenation of Aryl Ketones

“…Our group is involved in the research of polycyclic N-containing ligandsoximes of 11 H -indeno­[1,2- b ]­quinoxalin-11-one and its structural analogues . 11 H -Indeno­[1,2- b ]­quinoxalin-11-one oxime, often denoted in the literature as IQ1, and its sodium salt, IQ1S, were reported as potent c-Jun N-terminal kinase (JNK3) inhibitors, , anti-inflammatory agents, − neuroprotectors, , and antitumor agents. − Tryptanthrin demonstrates a wide range of bioactivities, , including antibacterial, , antiviral, anticancer, , and anti-inflammatory activity. However, the coordination chemistry of such compounds is insufficiently explored.…”

Enhanced properties of poly(ε‐caprolactone)/polyvinylpyrrolidone electrospun scaffolds fabricated using 1,1,1,3,3,3‐hexafluoro‐2‐propanol

“…Due to unique mechanical properties, biocompatibility and biodegradability, poly(ε‐caprolactone) (PCL)‐based materials found numerous biomedical applications serving as delivery systems, coating materials, and matrixes for the tissue regeneration 1,2 . In particular, PCL‐based electrospun scaffolds are intensively used for the delivery of therapeutic agents, protein molecules, and other biologically active substances 3–7 …”

“…While the convenient solvents for the preparation of PCL‐based materials are mainly presented by chlorinated hydrocarbons (e.g., chlorophorm, dichloromethane), 1,1,1,3,3,3‐hexafluoro‐2‐propanol (HFIP) is a rarely utilized solvent for the preparation of various composite materials 11 . In spite of such drawbacks of that solvent as high toxicity and possible degradation of protein molecules, 12,13 HFIP allows fabricating PCL‐based materials with enhanced properties by the inclusion of proteins, drugs, and other biologically active compounds 7,11,14 . Despite the amount of research available, the PVP dissolution (and subsequently, preparation of PCL/PVP materials) in HFIP has not been reported yet.…”

“…1,2 In particular, PCL-based electrospun scaffolds are intensively used for the delivery of therapeutic agents, protein molecules, and other biologically active substances. [3][4][5][6][7] The other polymer being widely applied in biomaterial field is polyvinylpyrrolidone (PVP), which is characterized by low toxicity, biocompatibility, and stability as well as solubility in both water and organic solvents. 8 Due to the unique set of properties as well as polycationic nature, it was utilized for the preparation of multiple coatings, membranes, and filter materials.…”

“…11 In spite of such drawbacks of that solvent as high toxicity and possible degradation of protein molecules, 12,13 HFIP allows fabricating PCL-based materials with enhanced properties by the inclusion of proteins, drugs, and other biologically active compounds. 7,11,14 Despite the amount of research available, the PVP dissolution (and subsequently, preparation of PCL/PVP materials) in HFIP has not been reported yet.…”