Abstract
Water-soluble formulations of the pyrazole derivative 3-(4-chlorophenyl)-5-(4-nitrophenylamino)-1H-pyrazole-4-carbonitrile (CR232), which were proven to have in vitro antiproliferative effects on different cancer cell lines, were prepared by two diverse nanotechnological approaches. Importantly, without using harmful organic solvents or additives potentially toxic to humans, CR232 was firstly entrapped in a biodegradable fifth-generation dendrimer containing lysine (G5K). CR232-G5K nanoparticles (CR232-G5K NPs) were obtained with high loading (DL%) and encapsulation efficiency (EE%), which showed a complex but quantitative release profile governed by Weibull kinetics. Secondly, starting from hydrogenated soy phosphatidylcholine and cholesterol, we prepared biocompatible CR232-loaded liposomes (CR232-SUVs), which displayed DL% and EE% values increasing with the increase in the lipids/CR232 ratio initially adopted and showed a constant prolonged release profile ruled by zero-order kinetics. When relevant, attenuated total reflectance Fourier transformed infrared spectroscopy (ATR-FTIR) and nuclear magnetic resonance (NMR) spectroscopy, scanning electron microscopy (SEM) and dynamic light scattering (DLS) experiments, as well as potentiometric titrations completed the characterization of the prepared NPs. CR232-G5K NPs were 2311-fold more water-soluble than the pristine CR232, and the CR232-SUVs with the highest DL% were 1764-fold more soluble than the untreated CR232, thus establishing the success of both our strategies.
Highlights
The diazole five-membered ring of pyrazole and its derivatives represent versatile template structures for designing new potent bioactive agents [1,2,3]
The proper number of butoxy carbonyl (Boc)-protected lysine equivalents was directly grafted onto G5OH by an esterification reaction utilizing the coupled 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) and 4-dimethylaminopyridine (DMAP) as a coupling agent and catalyst, respectively, in dimethylformamide (DMF) as a solvent, for 24 h at room temperature (Scheme 1)
The release profiles obtained by the two measurement ways were very similar, we considered the profile obtained by the UV-Vis analysis, which is one of the most reported techniques to quantify the drugs released from polymeric scaffold, including pyrazole derivatives [36]
Summary
The diazole five-membered ring of pyrazole and its derivatives represent versatile template structures for designing new potent bioactive agents [1,2,3]. Molecules belonging to the pyrazole family have numerous pharmacological activities, mainly attributable to the planar structure of the aromatic heterocycle [1,2,3]. According to Scopus, anti-inflammatory, analgesic, anticonvulsant, anthelmintic, antioxidant, and herbicidal effects of pyrazole have been reported since the year 1944 [4]. Several 3,5-diphenylpyrazole derivatives showed analgesic, hypotensive, anti-inflammatory, local anaesthetic, and motor activity inhibition effects in mice and rats, while mild platelet antiaggregating action in vitro [5]. The first studies reporting the antimicrobial effects and the cytotoxic action of pyrazole derivatives have been published more recently [6,7]. The naturally occurring amino acid L-α-amino-β-(pyrazolyl-N)-propanoic acid [(S)-β-pyrazolyl alanine], isolated in 1957 from the Citrullus vulgarisin juice of watermelon, was the first example of the pyrazole-containing natural product endowed with anti-diabetic activity [8]
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