Nanosized drug crystals have been reported with enhanced apparent solubility, bioavailability, and therapeutic efficacy compared to microcrystal materials, which are not suitable for parenteral administration. However, nanocrystal design and development by bottom-up approaches are challenging, especially considering the non-standardized process parameters in the injection step. This work aims to present a systematic step-by-step approach through Quality-by-Design (QbD) and Design of Experiments (DoE) for synthesizing drug nanocrystals by a semi-automated nanoprecipitation method. Curcumin is used as a drug model due to its well-known poor water solubility (0.6 µg mL-1, 25 °C). Formal and informal risk assessment tools allow identifying the critical factors. A fractional factorial 24-1 screening design evaluates their impact on the average size and polydispersity of nanocrystals. The optimization of significant factors is done by a Central Composite Design. This response surface methodology supports the rational design of the nanocrystals, identifying and exploring the design space. The proposed joint approach leads to a reproducible, robust, and stable nanocrystalline preparation of 316 nm with a PdI of 0.217 in compliance with the quality profile. An orthogonal approach for particle size and polydispersity characterization allows discarding the formation of aggregates. Overall, the synergy between advanced data analysis and semi-automated standardized nanocrystallization of drugs is highlighted.
- Klíčová slova
- design space, nanocrystals, orthogonal characterization, response surface methodology, solvent–antisolvent precipitation,
- MeSH
- automatizace MeSH
- krystalizace MeSH
- kurkumin chemie MeSH
- léčivé přípravky chemie MeSH
- nanočástice * chemie MeSH
- velikost částic MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- kurkumin MeSH
- léčivé přípravky MeSH
Gram-positive bacteria are responsible for a wide range of infections in humans. In most Gram-positive bacteria, sortase A plays a significant role in attaching virulence factors to the bacteria's cell wall. These cell surface proteins play a significant role in virulence and pathogenesis. Even though antibiotics are available to treat these infections, there is a continuous search for an alternative strategy due to an increase in antibiotic resistance. Thus, using anti-sortase drugs to combat these bacterial infections may be a promising approach. Here, we describe a method for targeting Gram-positive bacterial infection by combining curcumin and trans-chalcone as sortase A inhibitors. We have used curcumin and trans-chalcone alone and in combination as a sortase A inhibitor. We have seen ~78%, ~43%, and ~94% inhibition when treated with curcumin, trans-chalcone, and a combination of both compounds, respectively. The compounds have also shown a significant effect on biofilm formation, IgG binding, protein A recruitment, and IgG deposition. We discovered that combining curcumin and trans-chalcone is more effective against Gram-positive bacteria than either compound alone. The present work demonstrated that a combination of these natural compounds could be used as an antivirulence therapy against Gram-positive bacterial infection.
- Klíčová slova
- E. faecalis, S. aureus, Biofilm, Infection, Protein A, Sortase A,
- MeSH
- aminoacyltransferasy * antagonisté a inhibitory metabolismus MeSH
- antibakteriální látky * farmakologie chemie MeSH
- bakteriální proteiny * metabolismus antagonisté a inhibitory MeSH
- biofilmy * účinky léků MeSH
- chalkon * farmakologie chemie MeSH
- cysteinové endopeptidasy * účinky léků metabolismus MeSH
- faktory virulence metabolismus MeSH
- grampozitivní bakteriální infekce farmakoterapie mikrobiologie MeSH
- grampozitivní bakterie účinky léků MeSH
- kurkumin * farmakologie chemie MeSH
- mikrobiální testy citlivosti MeSH
- virulence účinky léků MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- aminoacyltransferasy * MeSH
- antibakteriální látky * MeSH
- bakteriální proteiny * MeSH
- chalkon * MeSH
- cysteinové endopeptidasy * MeSH
- faktory virulence MeSH
- kurkumin * MeSH
- sortase A MeSH Prohlížeč
Lipid nanocarriers are among the most employed systems for drug delivery purposes in several research and industrial sectors, since their favorable properties ensure broad applicability. The design and characterization of these nanosystems are of paramount importance to obtain controlled outcome, since the supramolecular structure and molecular interactions deeply impact the functionality of the resulting aggregates. The choice of the most appropriate formulation for the target of interest relies on in-depth physico-chemical characterization in order to optimize stability, loading rates and sustained release. Several supramolecular architectures suited for carrier development can be obtained from lipid building blocks, by varying lipid composition and packing parameter. In particular, cubosome and liposome aggregates are often used as drug vectors thanks to their high cargo capability and biocompatibility. Moreover, the possibility to employ lipids from natural sources i.e. biomasses to prepare nanosystems makes them especially attractive. In this work, two aggregate types were characterized and compared as drug vectors for poorly water-soluble antioxidants, particularly curcumin and two adjuvants (i.e. tocopherol and piperine). The nanovectors were obtained by extracting lipids from algal biomasses with different lipid composition, and characterized by advanced structural (DLS, SAXS, Cryo-TEM) techniques, spectroscopy (NMR) and calorimetry (ITC). Finally, the structural stability of both aggregate types was evaluated.
- Klíčová slova
- Algal lipids, Molecular interactions, Morphology, Nanocarriers, Structure,
- MeSH
- difrakce rentgenového záření MeSH
- kurkumin * chemie MeSH
- lipidy * chemie MeSH
- liposomy MeSH
- maloúhlový rozptyl MeSH
- nosiče léků chemie MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- kurkumin * MeSH
- lipidy * MeSH
- liposomy MeSH
- nosiče léků MeSH
Pharmaceutical nanocrystals represent a promising new formulation that combines the benefits of bulk crystalline materials and colloidal nanoparticles. To be applied in vivo, nanocrystals must meet several criteria, namely colloidal stability in physiological media, non-toxicity to healthy cells, avoidance of macrophage clearance, and bioactivity in the target tissue. In the present work, curcumin, a naturally occurring poorly water-soluble molecule with a broad spectrum of bioactivity has been considered a candidate substance for preparing pharmaceutical nanocrystals. Curcumin nanocrystals in the size range of 40-90 nm were prepared by wet milling using the following combination of steric and ionic stabilizers: Tween 80, sodium dodecyl sulfate, Poloxamer 188, hydroxypropyl methylcellulose, phospholipids (with and without polyethylene glycol), and their combination. Nanocrystals stabilized by a combination of phospholipids enriched with polyethylene glycol proved to be the most successful in all evaluated criteria; they were colloidally stable in all media, exhibited low macrophage clearance, and proved non-toxic to healthy cells. This curcumin nanoformulation also exhibited outstanding anticancer potential comparable to commercially used cytostatics (IC50 = 73 µM; 24 h, HT-29 colorectal carcinoma cell line) which represents an improvement of several orders of magnitude when compared to previously studied curcumin formulations. This work shows that the preparation of phospholipid-stabilized nanocrystals allows for the conversion of poorly soluble compounds into a highly effective "solution-like" drug delivery system at pharmaceutically relevant drug concentrations.
- MeSH
- deriváty hypromelózy MeSH
- dodecylsíran sodný chemie MeSH
- fosfolipidy MeSH
- kurkumin * chemie farmakologie MeSH
- léčivé přípravky MeSH
- makrofágy MeSH
- nanočástice * chemie MeSH
- poloxamer chemie MeSH
- polyethylenglykoly chemie MeSH
- polysorbáty MeSH
- rozpustnost MeSH
- velikost částic MeSH
- voda MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- deriváty hypromelózy MeSH
- dodecylsíran sodný MeSH
- fosfolipidy MeSH
- kurkumin * MeSH
- léčivé přípravky MeSH
- poloxamer MeSH
- polyethylenglykoly MeSH
- polysorbáty MeSH
- voda MeSH
Curcumin and its congeners exist in an equilibrium between diketo and ketoenol tautomers, which have different potencies to bind biomolecules. This work describes procedures for the preparation of 4-alkylated curcumin derivatives and the separation of their two tautomeric forms. Comprehensive NMR studies of the tautomer equilibria in various solvents have been accomplished. Additionally, a pure ketoenol tautomeric form of the active pharmaceutical ingredient (API) ASC-JM17 has been unequivocally determined by X-ray crystallography. Two different polymorphs of this API have been microscopically identified in the X-ray sample and manually separated, and a solid-state NMR study of the two polymorphs has also been performed. This work reports on the slow kinetics of diketo-ketoenol tautomerization in particular solvents that allow the separation and full characterization of both curcuminoids' tautomers.
- MeSH
- diarylheptanoidy * MeSH
- isomerie MeSH
- kinetika MeSH
- kurkumin * chemie MeSH
- rozpouštědla chemie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- diarylheptanoidy * MeSH
- kurkumin * MeSH
- rozpouštědla MeSH
Amphiphilic gradient copolymers represent a promising alternative to extensively used block copolymers due to their facile one-step synthesis by statistical copolymerization of monomers of different reactivity. Herein, an in-depth analysis is provided of micelles based on amphiphilic gradient poly(2-oxazoline)s with different chain lengths to evaluate their potential for micellar drug delivery systems and compare them to the analogous diblock copolymer micelles. Size, morphology, and stability of self-assembled nanoparticles, loading of hydrophobic drug curcumin, as well as cytotoxicities of the prepared nanoformulations are examined using copoly(2-oxazoline)s with varying chain lengths and comonomer ratios. In addition to several interesting differences between the two copolymer architecture classes, such as more compact self-assembled structures with faster exchange dynamics for the gradient copolymers, it is concluded that gradient copolymers provide stable curcumin nanoformulations with comparable drug loadings to block copolymer systems and benefit from more straightforward copolymer synthesis. The study demonstrates the potential of amphiphilic gradient copolymers as a versatile platform for the synthesis of new polymer therapeutics.
- Klíčová slova
- gradient copolymers, nanomedicine, poly(2-oxazoline)s, self-assembly,
- MeSH
- hydrofobní a hydrofilní interakce MeSH
- kurkumin * chemie MeSH
- micely * MeSH
- nosiče léků chemie MeSH
- polymery chemie MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- kurkumin * MeSH
- micely * MeSH
- nosiče léků MeSH
- polymery MeSH
Pterygium is a progressive disease of the human eye arising from sub-conjunctival tissue and extending onto the cornea. Due to its invasive growth, pterygium can reach the pupil compromising visual function. Currently available medical treatments have limited success in suppressing efficiently the disease. Previous studies have demonstrated that curcumin, polyphenol isolated from the rhizome of Curcuma longa, induces apoptosis of human pterygium fibroblasts in a dose- and time-dependent manner showing promising activity in the treatment of this ophthalmic disease. However, this molecule is not very soluble in water in either neutral or acidic pH and is only slightly more soluble in alkaline conditions, while its dissolving in organic solvents drastically reduces its potential use for biomedical applications. A nanoformulation of curcumin stabilized silver nanoparticles (Cur-AgNPs) seems an effective strategy to increase the bioavailability of curcumin without inducing toxic effects. In fact, silver nitrates have been used safely for the treatment of many ophthalmic conditions and diseases for a long time and the concentration of AgNPs in this formulation is quite low. The synthesis of this new compound was achieved through a modified Bettini's method adapted to improve the quality of the product intended for human use. Indeed, the pH of the reaction was changed to 9, the temperature of the reaction was increased from 90 °C to 100 °C and after the synthesis the Cur-AgNPs were dispersed in Borax buffer using a dialysis step to improve the biocompatibility of the formulation. This new compound will be able to deliver both components (curcumin and silver) at the same time to the affected tissue, representing an alternative and a more sophisticated strategy for the treatment of human pterygium. Further in vitro and in vivo assays will be required to validate this formulation.
- Klíčová slova
- curcumin, green synthesis, keratinocytes, nanoparticles, pterygium, silver,
- MeSH
- keratinocyty metabolismus MeSH
- kovové nanočástice * chemie terapeutické užití MeSH
- kurkumin * chemie farmakologie MeSH
- lidé MeSH
- pterygium * farmakoterapie metabolismus MeSH
- stříbro * chemie farmakologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- kurkumin * MeSH
- stříbro * MeSH
Yeast glucan particles are porous polysaccharide cell walls extracted from Saccharomyces cerevisiae. Being mildly immunogenic, they are efficiently phagocytosed and have therefore been proposed as possible vehicles for drug delivery. Using curcumin as a model poorly water-soluble drug, a systematic comparison of three different physical loading methods - incipient wetness impregnation, slurry evaporation, and spray drying - was carried out and their influence on the particle morphology, encapsulation efficiency, amorphous drug content and release kinetics was evaluated. It was found that yeast glucan particles can contain up to 30% wt. of curcumin in the amorphous form when prepared by slurry evaporation. The dissolution of curcumin from glucan particles lead to a supersaturated solution in asimilar way as amorphous solid dispersions do, despite the fact that glucan particles themselves do not dissolve. Bi-phasic dissolution tests revealed up to 4-fold acceleration of curcumin dissolution rate from amorphous glucan particles compared to its crystalline form. Crucially, glucan particles were shown to retain the ability to be recognised and phagocytosed even after drug encapsulation.
- Klíčová slova
- Amorphous solid dispersion, Incipient wetness impregnation, Slurry evaporation, Spray drying, Two-phase dissolution test, β-glucan,
- MeSH
- beta-glukany chemie MeSH
- chemie farmaceutická metody MeSH
- kinetika MeSH
- krystalizace MeSH
- kurkumin aplikace a dávkování chemie MeSH
- nosiče léků chemie MeSH
- příprava léků metody MeSH
- rozpustnost MeSH
- systémy cílené aplikace léků * MeSH
- uvolňování léčiv MeSH
- voda chemie MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- beta-glukany MeSH
- kurkumin MeSH
- nosiče léků MeSH
- voda MeSH
Glucan particles (GPs) from Saccharomyces cerevisiae consist mainly of β-1,3-d-glucan. Curcumin is a phenolic compound of plant origin. A 24 h incubation with a mixture of GPs and curcumin increased the expression of the Nrf2 protein and increased the activation of the Nrf2-ARE system significantly.
- MeSH
- antioxidancia * chemie metabolismus farmakologie MeSH
- buňky Hep G2 MeSH
- faktor 2 související s NF-E2 metabolismus MeSH
- glukany chemie MeSH
- kurkumin * chemie farmakologie MeSH
- lidé MeSH
- oxidační stres účinky léků MeSH
- příprava léků MeSH
- Saccharomyces cerevisiae chemie MeSH
- THP-1 buňky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antioxidancia * MeSH
- faktor 2 související s NF-E2 MeSH
- glukany MeSH
- kurkumin * MeSH
- NFE2L2 protein, human MeSH Prohlížeč
In recent years, a great deal of attention has been paid to the combined use of multiple antitumor drugs for better cancer treatment. The aims of the study are to construct a nanoparticle drug delivery system for the co-delivery of irinotecan hydrochloride and curcumin and to develop an analytical method for simultaneously quantifying these molecules, which is essential for further studies of the co-delivered nano system. The irinotecan hydrochloride and curcumin co-delivered nanoparticle (ICN) were prepared by combinatorially entrapping them into polyethylene glycol-poly lactic acid-co-glycolic acid (PEG-PLGA) polymeric nanoparticles. A simple, sensitive and rapid high-performance liquid chromatography method was developed and validated to simultaneously quantify the compounds in the co-delivered nanoparticle system. Acetonitrile and ultrapure water containing sodium dodecyl sulfate (0.08 mol/L), disodium phosphate (Na2HPO4, 0.002 mol/L) and acetic acid (4%, v/v) were used as the mobile phase and their ratio was set at 50:50. The flow rate was set to 1.0 mL/min, and the temperature in the column oven was maintained at 40°C. The analysis was carried out at 256 and 424 nm to assess irinotecan hydrochloride and curcumin, respectively. Detectors with only one channel can also visualize both analytes in one chromatogram at 379 nm and still demonstrate acceptable sensitivity. The retention times for irinotecan hydrochloride and curium were 3.317 and 5.560 min, respectively. The method developed was confirmed to be sensitive, accurate (recovery, 100 ± 2%), precise (relative standard deviation, RSD ≤ 1%), robust and linear (R2 ≥ 0.9996) in the range from 2.05 to 1050 μg/mL. The presented method has been used to quantify irinotecan hydrochloride and curcumin in the co-delivered ICN nano system to assess the drug delivery quality of the nanoparticles and can also be used for routine analysis because of its simplicity and accuracy.
- MeSH
- irinotekan analýza chemie MeSH
- kurkumin analýza chemie MeSH
- limita detekce MeSH
- lineární modely MeSH
- nanočástice chemie MeSH
- polyestery chemie MeSH
- polyethylenglykoly chemie MeSH
- reprodukovatelnost výsledků MeSH
- systémy cílené aplikace léků MeSH
- vysokoúčinná kapalinová chromatografie metody MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- irinotekan MeSH
- kurkumin MeSH
- polyestery MeSH
- polyethylene glycol-poly(lactide-co-glycolide) MeSH Prohlížeč
- polyethylenglykoly MeSH
