Malaria is one of the major life-threatening health problems worldwide. Artesunate is the most potent antimalarial drug to combat severe malaria. However, development of drug resistance, short plasma half-life, and poor bioavailability limit the efficacy of this drug. Here, we applied the dimerization concept to synthesize dimeric artesunate glycerol monocaprylate conjugate (D-AS-GC) by conjugating artesunate (AS) with glycerol monocaprylate (GC) via esterification reaction. D-AS-GC conjugate, AS, and GC were well characterized by 1H NMR, attached proton test (APT) 13C NMR and 2D NMR spectroscopy. D-AS-GC conjugate was further analyzed by ESI-TOF MS. Finally, a series of nanoemulsion preconcentrate (F1–F6) of D-AS-GC was prepared by mixing different ratios of oil and surfactant/cosurfactant and evaluated after dilution with an aqueous phase. The optimized formulation (F6) exhibits a clear nanoemulsion and the hydrodynamic diameter of the dispersed phase was determined by DLS and DOSY NMR spectroscopy. The morphology of the nanoemulsion droplets of F6 was investigated by AFM, which revealed the formation of tiny nanoemulsion droplets on a hydrophilic mica substrate. Moreover, using a less polar silicon wafer led to the formation of larger droplets with a spherical core shell-like structure. Overall, the rational design of the dimeric artesunate-based nanoemulsion preconcentrate could potentially be used in more efficient drug delivery systems.
Microbial transglutaminases (mTGases) or protein-glutamine 𝜸-glutamyltransferases are a family of enzymes that catalyze the transamidation of glutamine (Gln) residues of proteins or peptides with various primary amines. mTGase is suitable for site-specific enzymatic modification of therapeutic proteins. Here, the enzymatic conjugation of recombinant human erythropoietin (rHuEPO) with the semisynthetic starch derivative, hydroxyethyl starch (HES), is studied, using a thermoresistant variant mTGase TG 16 . An amine-modified HES (HES-g-NH 2 ) is synthesized to act as an acyl acceptor substrate for TG 16 and characterized by 1 H NMR, 2D NMR, and Fourier transform infrared (FTIR) spectroscopy. Subsequently, HES-g-NH 2 is labeled with rhodamine B-isothiocyanate resulting in rhodamine B-labeled HES-g-NH 2 (HES-g-NH 2 -R). Finally, amine-modified HES before and after labeling is applied for the conjugation reaction with rHuEPO at its transition temperature T m . Using SDS-PAGE, high molar mass conjugates as well as aggregates are observed, thus, demonstrating the efficient conjugation of HES with the acyl donor rHuEPO. Importantly, it is shown that this enzymatic method gives easy access to the preparation of rHuEPO-HES conjugates.
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