scholarly journals Pyrazole-Based Water-Soluble Dendrimer Nanoparticles as a Potential New Agent against Staphylococci

Biomedicines ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 17
Author(s):  
Silvana Alfei ◽  
Chiara Brullo ◽  
Debora Caviglia ◽  
Gabriella Piatti ◽  
Alessia Zorzoli ◽  
...  
Keyword(s):  
Antimicrobial Agents ◽  
Water Solubility ◽  
Therapeutic Option ◽  
Human Keratinocytes ◽  
Biological Properties ◽  
Water Soluble ◽  
Skin Infections ◽  
Resistance Patterns ◽  
Staphylococcal Skin Infections

Although the antimicrobial potency of the pyrazole nucleus is widely reported, the antimicrobial effects of the 2-(4-bromo-3,5-diphenyl-pyrazol-1-yl)-ethanol (BBB4), found to be active against several other conditions, have never been investigated. Considering the worldwide need for new antimicrobial agents, we thought it noteworthy to assess the minimum inhibitory concentration (MICs) of BBB4 but, due to its scarce water-solubility, unequivocal determinations were tricky. To obtain more reliable MICs and to obtain a substance also potentially applicable in vivo, we recently prepared water-soluble, BBB4-loaded dendrimer nanoparticles (BBB4-G4K NPs), which proved to have physicochemical properties suitable for clinical application. Here, with the aim of developing a new antibacterial agent based on BBB4, the BBB4-G4K NPs were tested on several strains of different species of the Staphylococcus genus. Very low MICs (1.5–3.0 µM), 15.5–124.3-fold lower than those of the free BBB4, were observed against several isolates of S. aureus and S. epidermidis, the most pathogenic species of this genus, regardless of their resistance patterns to antibiotics. Aiming at hypothesizing a clinical use of BBB4-G4K NPs for staphylococcal skin infections, cytotoxicity experiments on human keratinocytes were performed; it was found that the nano-manipulated BBB4 released from BBB4-G4K NPs (LD50 138.6 µM) was 2.5-fold less cytotoxic than the untreated BBB4 (55.9 µM). Due to its physicochemical and biological properties, BBB4-G4K NPs could be considered as a promising novel therapeutic option against the very frequent staphylococcal skin infections.

scholarly journals Efficacy of Ursolic Acid-Enriched Water-Soluble and Not Cytotoxic Nanoparticles against Enterococci

Pharmaceutics ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 1976
Author(s):  
Anna Maria Schito ◽  
Debora Caviglia ◽  
Gabriella Piatti ◽  
Alessia Zorzoli ◽  
Danilo Marimpietri ◽  
...  
Keyword(s):  
Ursolic Acid ◽  
Therapeutic Option ◽  
Human Keratinocytes ◽  
Biological Properties ◽  
Water Soluble ◽  
Pentacyclic Triterpenoid ◽  
Different Strains ◽  
Time Kill

Ursolic acid (UA), a pentacyclic triterpenoid acid found in many medicinal plants and aromas, is known for its antibacterial effects against multi-drug-resistant (MDR) Gram-positive bacteria, which seriously threaten human health. Unfortunately, UA water-insolubility, low bioavailability, and systemic toxicity limit the possibilities of its application in vivo. Consequently, the beneficial activities of UA observed in vitro lose their potential clinical relevance unless water-soluble, not cytotoxic UA formulations are developed. With a nano-technologic approach, we have recently prepared water-soluble UA-loaded dendrimer nanoparticles (UA-G4K NPs) non-cytotoxic on HeLa cells, with promising physicochemical properties for their clinical applications. In this work, with the aim of developing a new antibacterial agent based on UA, UA-G4K has been tested on different strains of the Enterococcus genus, including marine isolates, toward which UA-G4K has shown minimum inhibitory concentrations (MICs) very low (0.5–4.3 µM), regardless of their resistance to antibiotics. Time-kill experiments, in addition to confirming the previously reported bactericidal activity of UA against E. faecium, also established it for UA-G4K. Furthermore, cytotoxicity experiments on human keratinocytes revealed that nanomanipulation of UA significantly reduced the cytotoxicity of UA, providing UA-G4K NPs with very high LD50 (96.4 µM) and selectivity indices, which were in the range 22.4–192.8, depending on the enterococcal strain tested. Due to its physicochemical and biological properties, UA-G4K could be seriously evaluated as a novel oral-administrable therapeutic option for tackling difficult-to-treat enterococcal infections.

scholarly journals Synthesis, Characterization and Bactericidal Activity of a 4-Ammoniumbuthylstyrene-Based Random Copolymer

Polymers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1140
Author(s):  
Silvana Alfei ◽  
Gabriella Piatti ◽  
Debora Caviglia ◽  
Anna Maria Schito
Keyword(s):  
Antibacterial Activity ◽  
Bactericidal Activity ◽  
Antimicrobial Agents ◽  
Water Solubility ◽  
Physicochemical Characterization ◽  
Random Copolymer ◽  
Water Soluble ◽  
Cationic Polymers ◽  
Severe Infections

The growing resistance of bacteria to current chemotherapy is a global concern that urgently requires new and effective antimicrobial agents, aimed at curing untreatable infection, reducing unacceptable healthcare costs and human mortality. Cationic polymers, that mimic antimicrobial cationic peptides, represent promising broad-spectrum agents, being less susceptible to develop resistance than low molecular weight antibiotics. We, thus, designed, and herein report, the synthesis and physicochemical characterization of a water-soluble cationic copolymer (P5), obtained by copolymerizing the laboratory-made monomer 4-ammoniumbuthylstyrene hydrochloride with di-methyl-acrylamide as uncharged diluent. The antibacterial activity of P5 was assessed against several multi-drug-resistant clinical isolates of both Gram-positive and Gram-negative species. Except for strains characterized by modifications of the membrane charge, most of the tested isolates were sensible to the new molecule. P5 showed remarkable antibacterial activity against several isolates of genera Enterococcus, Staphylococcus, Pseudomonas, Klebsiella, and against Escherichia coli, Acinetobacter baumannii and Stenotrophomonas maltophilia, displaying a minimum MIC value of 3.15 µM. In time-killing and turbidimetric studies, P5 displayed a rapid non-lytic bactericidal activity. Due to its water-solubility and wide bactericidal spectrum, P5 could represent a promising novel agent capable of overcoming severe infections sustained by bacteria resistant the presently available antibiotics.

scholarly journals Considerable Improvement of Ursolic Acid Water Solubility by Its Encapsulation in Dendrimer Nanoparticles: Design, Synthesis and Physicochemical Characterization

Nanomaterials ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 2196 ◽  
Author(s):  
Silvana Alfei ◽  
Anna Maria Schito ◽  
Guendalina Zuccari
Keyword(s):  
Ursolic Acid ◽  
Water Solubility ◽  
Drug Loading ◽  
Physicochemical Characterization ◽  
Systemic Toxicity ◽  
Water Soluble ◽  
Design Synthesis ◽  
Pentacyclic Triterpenoid

Ursolic acid (UA) is a pentacyclic triterpenoid found in many medicinal plants and aromas endowed with numerous in vitro pharmacological activities, including antibacterial effects. Unfortunately, UA is poorly administered in vivo, due to its water insolubility, low bioavailability, and residual systemic toxicity, thus making urgent the development of water-soluble UA formulations. Dendrimers are nonpareil macromolecules possessing highly controlled size, shape, and architecture. In dendrimers with cationic surface, the contemporary presence of inner cavities and of hydrophilic peripheral functions, allows to encapsulate hydrophobic non-water-soluble drugs as UA, to enhance their water-solubility and stability, and to promote their protracted release, thus decreasing their systemic toxicity. In this paper, aiming at developing a new UA-based antibacterial agent administrable in vivo, we reported the physical entrapment of UA in a biodegradable not cytotoxic cationic dendrimer (G4K). UA-loaded dendrimer nanoparticles (UA-G4K) were obtained, which showed a drug loading (DL%) much higher than those previously reported, a protracted release profile governed by diffusion mechanisms, and no cytotoxicity. Also, UA-G4K was characterized by principal components analysis (PCA)-processed FTIR spectroscopy, by NMR and elemental analyses, and by dynamic light scattering experiments (DLS). The water solubility of UA-G4K was found to be 1868-fold times higher than that of pristine UA, thus making its clinical application feasible.

scholarly journals Albendazole solid dispersions against alveolar echinococcosis: a pharmacotechnical strategy to improve the efficacy of the drug

Parasitology ◽  
2020 ◽  
Vol 147 (9) ◽  
pp. 1026-1031
Author(s):  
Julia Fabbri ◽  
Patricia Eugenia Pensel ◽  
Clara María Albani ◽  
Lurdes Milagros Lopez ◽  
Analia Simonazzi ◽  
...  
Keyword(s):  
Alveolar Echinococcosis ◽  
Water Solubility ◽  
Solid Dispersions ◽  
Water Soluble ◽  
Poloxamer 407 ◽  
Infection Model ◽  
Efficacy Study ◽  
Dissolution Profile ◽  
Germinal Layer

AbstractAlveolar echinococcosis is a neglected parasitic zoonosis caused by Echinococcus multilocularis. The pharmacological treatment is based on albendazole (ABZ). However, the low water solubility of the drug produces a limited dissolution rate, with the consequent failure in the treatment of the disease. Solid dispersions are a successful pharmacotechnical strategy to improve the dissolution profile of poorly water-soluble drugs. The aim of this work was to determine the in vivo efficacy of ABZ solid dispersions using poloxamer 407 as a carrier (ABZ:P407 solid dispersions (SDs)) in the murine intraperitoneal infection model for secondary alveolar echinococcosis. In the chemoprophylactic efficacy study, the ABZ suspension, the ABZ:P407 SDs and the physical mixture of ABZ and poloxamer 407 showed a tendency to decrease the development of murine cysts, causing damage to the germinal layer. In the clinical efficacy study, the ABZ:P407 SDs produced a significant decrease in the weight of murine cysts. In addition, the SDs produced extensive damage to the germinal layer. The increase in the efficacy of ABZ could be due to the improvement of water solubility and wettability of the drug due to the surfactant nature of poloxamer 407. In conclusion, this study is the basis for further research. This pharmacotechnical strategy might in the future offer novel treatment alternatives for human alveolar echinococcosis.

scholarly journals Nanoparticle-Mediated Dual Targeting: An Approach for Enhanced Baicalin Delivery to the Liver

Pharmaceutics ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 107 ◽  
Author(s):  
Iman Saad Ahmed ◽  
Hassan Medhat Rashed ◽  
Hend Fayez ◽  
Faten Farouk ◽  
Rehab Nabil Shamma
Keyword(s):  
Oral Administration ◽  
Water Solubility ◽  
Area Under The Curve ◽  
Oral Solution ◽  
Water Soluble ◽  
Spherical Particles ◽  
Therapeutic Molecules ◽  
Ph Dependent ◽  
Full Factorial

In this study, water-soluble chitosan lactate (CL) was reacted with lactobionic acid (LA), a disaccharide with remarkable affinity to hepatic asialoglycoprotein (ASGP) receptors, to form dual liver-targeting LA-modified-CL polymer for site-specific drug delivery to the liver. The synthesized polymer was used to encapsulate baicalin (BA), a promising bioactive flavonoid with pH-dependent solubility, into ultrahigh drug-loaded nanoparticles (NPs) via the ionic gelation method. The successful chemical conjugation of LA with CL was tested and the formulated drug-loaded LA-modified-CL-NPs were assessed in terms of particle size (PS), encapsulation efficiency (EE) and zeta potential (ZP) using full factorial design. The in vivo biodistribution and pharmacokinetics of the designed NPs were assessed using 99mTc-radiolabeled BA following oral administration to mice and results were compared to 99mTc-BA-loaded-LA-free-NPs and 99mTc-BA solution as controls. Results showed that the chemical modification of CL with LA was successfully achieved and the method of preparation of the optimized NPs was very efficient in encapsulating BA into nearly spherical particles with an extremely high EE exceeding 90%. The optimized BA-loaded-LA-modified-CL-NPs showed an average PS of 490 nm, EE of 93.7% and ZP of 48.1 mV. Oral administration of 99mTc-BA-loaded-LA-modified-CL-NPs showed a remarkable increase in BA delivery to the liver over 99mTc-BA-loaded-LA-free-CL-NPs and 99mTc-BA oral solution. The mean area under the curve (AUC0–24) estimates from liver data were determined to be 11-fold and 26-fold higher from 99mTc-BA-loaded-LA-modified-CL-NPs relative to 99mTc-BA-loaded-LA-free-CL-NPs and 99mTc-BA solution respectively. In conclusion, the outcome of this study highlights the great potential of using LA-modified-CL-NPs for the ultrahigh encapsulation of therapeutic molecules with pH-dependent/poor water-solubility and for targeting the liver.

Development and Characterization of the Neuroregenerative Xanthohumol C/Hydroxypropyl-β-cyclodextrin Complex Suitable for Parenteral Administration

Planta Medica ◽  
2019 ◽  
Vol 85 (16) ◽  
pp. 1233-1241
Author(s):  
Michael Kirchinger ◽  
Lara Bieler ◽  
Julia Tevini ◽  
Michael Vogl ◽  
Elisabeth Haschke-Becher ◽  
...  
Keyword(s):  
Water Solubility ◽  
Pharmaceutical Research ◽  
Water Soluble ◽  
Complexing Agents ◽  
Cyclodextrin Complex ◽  
Scanning Calorimetry ◽  
In Vivo Experiments ◽  
Strong Candidate

AbstractThe chroman-like chalcone Xanthohumol C, originally found in hops, was demonstrated to be a potent neuroregenerative and neuroprotective natural product and therefore constitutes a strong candidate for further pharmaceutical research. The bottleneck for in vivo experiments is the low water solubility of this chalcone. Consequently, we developed and validated a suitable formulation enabling in vivo administration. Cyclodextrins were used as water-soluble and nontoxic complexing agents, and the complex of Xanthohumol C and 2-hydroxypropyl-β-cyclodextrin was characterized using HPLC, HPLC-MS, NMR, and differential scanning calorimetry. The water solubility of Xanthohumol C increases with increasing concentrations of cyclodextrin. Using 50 mM 2-hydroxypropyl-β-cyclodextrin, solubility was increased 650-fold. Furthermore, in vitro bioactivity of Xanthohumol C in free and complexed form did not significantly differ, suggesting the release of Xanthohumol C from 2-hydroxypropyl-β-cyclodextrin. Finally, a small-scaled in vivo experiment in a rat model showed that after i. p. administration of the complex, Xanthohumol C can be detected in serum, the brain, and the cerebrospinal fluid at 1 and 6 h post-administration. Mean (± SD) Xanthohumol C serum concentrations after 1, 6, and 12 h were determined as 463.5 (± 120.9), 61.9 (± 13.4), and 9.3 (± 0.8) ng/mL upon i. v., and 294.3 (± 22.4), 45.5 (± 0.7), and 13 (± 1.0) ng/mL after i. p. application, respectively. Accordingly, the formulation of Xanthohumol C/2-hydroxypropyl-β-cyclodextrin is suitable for further in vivo experiments and further pharmaceutical research aiming for the determination of its neuroregenerative potential in animal disease models.

Exploration on the adsorption mechanism of aminopyrimidines and quinazoline compounds on graphene oxide: Hydrophobicity and structure-controlled release process

2019 ◽  
Vol 9 (5) ◽  
pp. 419-428
Author(s):  
Li Li ◽  
Chunjiao Pan ◽  
Zhongqiu Guo ◽  
Bingmi Liu ◽  
Hao Pan ◽  
...  
Keyword(s):  
Graphene Oxide ◽  
Computer Simulations ◽  
Water Solubility ◽  
High Water ◽  
Water Soluble ◽  
Release Process ◽  
Adsorption Mechanisms ◽  
Mechanical Stirring

In this study, graphene oxide was synthesized using the Hummers method, and stable and homogeneous graphene oxide aqueous solutions were obtained through mechanical stirring and ultrasonic stripping. In conjunction with our previous studies, graphene oxide-loaded insoluble compound delivery systems were prepared to verify the in vivo release profiles of the graphene oxide delivery system. Several insoluble compounds including imatinib, nilotinib, erlotinib, gefitinib, and afatinib were selected for loading and in vitro graphene oxide release assays to study the non-covalent adsorption mechanisms. Computer simulations were employed for validation processes. For in vivo release assays, the T1/2 values of the poorly water soluble groups were 1.104 ± 0.18 h and the Cmax was 2.600 ± 2.06 mg/L. In previous assays, compounds with high water solubility supported by graphene oxide were released and detected in vivo. The solubility of the compound and its binding force with the carrier played a crucial role in release. The results of graphene oxide loading experiments showed that the maximum loading and entrapment efficiencies of the insoluble model compounds with similar aromatic rings were comparable. Under basic conditions, the in vitro release rates and maximum release levels of amino pyrimidine were elevated. In contrast, quinazoline release declined. Combined with computer simulations, π–π stacking was identified as the dominant mechanism for adsorption onto graphene oxide. Both hydrogen bonding and cation-π bonds played an auxiliary reinforcing role, and the two were regarded as antagonistic.

Silver Sulphadiazine- xanthan gum- hyaluronic Acid Composite Hydrogel for Wound Healing: Formulation Development and in vivo Evaluation

2020 ◽  
Vol 16 (1) ◽  
pp. 21-29 ◽  
Author(s):  
M.O. Ilomuanya ◽  
Z.A. Seriki ◽  
U.N. Ubani-Ukoma ◽  
B.A. Oseni ◽  
B.O. Silva
Keyword(s):  
Wound Healing ◽  
Hyaluronic Acid ◽  
Xanthan Gum ◽  
Wound Closure ◽  
Antimicrobial Agents ◽  
Biological Properties ◽  
Formulation Development ◽  
Hybrid Hydrogels ◽  
Silver Sulphadiazine

Background: Development and modifications of hybrid hydrogels have been done to improve biological properties or to decrease the disadvantages of biomaterials.Objectives: The efficacy of hyaluronic acid in combination with silver sulphadiazine in wound healing was investigated. The retaining properties of xanthan gum to aid re- epithelialization was also explored.Materials and Method: Four hybrid hydrogels comprising of different concentrations of xanthan gum, eugenol and antimicrobial agents – hyaluronic acid and silver sulphadiazine were formulated. The physicochemical properties of the gels were assessed, and the antimicrobial effectiveness of the different hydrogel were determined using the extent of wound closure as an index.Results: The hydrogel samples had approximately 90% moisture content with rate of evaporation between 26- 32% for a 5 h period at 37oC. The pH of all formulations was between 7.59 - 8.05 considering that the formulation would be applied to underlying tissues of the skin. The swelling index after a 12 h period in distilled water was 10% for HX 1, 27% for HX 2, 29% for HX 3 and 30% for HX 4. There was no new peak observed in the FTIR analysis to indicate formation of new bonds.Conclusion: Incorporation of silver sulphadiazine at 0.1% and hyaluronic acid at 1.5% in the formulation yielded the best results with regards to least presence of inflammatory cell infiltrates and excellent wound closure at 14 days compared to the control and other formulations. Further investigation may be required for clinical use as an effective wound dressing material. Keywords: Silver sulphadiazine, Xanthan gum, Hyaluronic acid, Hydrogels, Wound healing.

scholarly journals SULFATION PATHWAYS: Potential benefits of a sulfated resveratrol derivative for topical application

2018 ◽  
Vol 61 (2) ◽  
pp. M27-M39 ◽  
Author(s):  
Marta Correia-da-Silva ◽  
Verónica Rocha ◽  
Cláudia Marques ◽  
Cláudia M Deus ◽  
Adriana Marques-Carvalho ◽  
...  
Keyword(s):  
Protein Content ◽  
Topical Application ◽  
In Silico ◽  
Water Solubility ◽  
Hacat Cell ◽  
Binding Free Energy ◽  
Water Soluble ◽  
Sirtuin 1 ◽  
Trypan Blue Exclusion

Resveratrol (RSV) is a polyphenolic compound with antioxidant, anti-inflammatory and anti-aging properties partly associated with sirtuin 1 (SIRT1)-activation in the skin. However, poor water solubility may limit RSV efficacy. This work aimed to clarify the interest of a new synthetic water-soluble RSV derivative (resveratrol glucoside sulfate, RSV-GS) for topical application. Resveratrol glucoside sulfate was synthesized using microwave-assisted sulfation. Cytotoxicity assays were performed with the keratinocyte HaCaT cell line, using MTT reduction, neutral red uptake, Alamar Blue/resazurin reduction, trypan blue exclusion and measurement of ATP concentration. Western blotting was used to evaluate SIRT1 protein content. Regarding SIRT1 binding, an in silico docking study was performed, using AutoDock Vina. Our results showed that the synthetic derivative RSV-GS was 1000 times more soluble in water than RSV and its non-sulfated glucoside. No relevant decrease in HaCaT cell viability was observed for concentrations up to 5 mM for RSV-GS, and up to 500 μM for resveratrol glucoside, while a significant decrease in HaCaT viability occurred from 100 μM for RSV. RSV-GS and RSV showed a similar behavior regarding protective effect against oxidative stress-induced cytotoxicity. SIRT1 protein content increased after treatment with 500 μM of RSV-GS and 100 μM of RSV. Moreover, in silico studies predicted that RSV-GS binds more stably to SIRT1 with a lower binding free energy than RSV. Although these results support the possible use of RSV-GS in topical formulations, in vivo safety and efficacy studies are needed before considering the use of RSV-GS in commercial products.

Water soluble multiarm-polyethylene glycol–betulinic acid prodrugs: design, synthesis, and in vivo effectiveness

2014 ◽  
Vol 5 (19) ◽  
pp. 5775-5783 ◽  
Author(s):  
Lin Dai ◽  
Dan Li ◽  
Jing Cheng ◽  
Jing Liu ◽  
Li-Hong Deng ◽  
...  
Keyword(s):  
Polyethylene Glycol ◽  
Betulinic Acid ◽  
Water Solubility ◽  
Drug Loading ◽  
Water Soluble ◽  
Loading Capacity ◽  
Design Synthesis ◽  
High Drug ◽  
High Drug Loading

Multiarm-polyethylene glycol–betulinic acid prodrugs were prepared by using multiarm-polyethylene glycol linkers and betulinic acid, which exhibited high drug loading capacity, good water solubility, and excellent anticancer activity.

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