RESUMEN

KLEPTOSE® CRYSMEB methylated cyclodextrin derivative displays less methylated group substitution than randomly methylated cyclodextrin. It has demonstrated an impact on atherosclerosis and neurological diseases, linked in part to cholesterol complexation and immune response, however, its impact on inflammatory cascade pathways is not clear. Thus, the impact of KLEPTOSE® CRYSMEB on various pharmacological targets was assessed using human umbilical vein endothelial cells under physiological and inflammatory conditions, followed by screening against twelve human primary cell-based systems designed to model complex human tissue and disease biology of the vasculature, skin, lung, and inflammatory tissues using the BioMAP® Diversity PLUS® panel. Finally, its anti-inflammatory mechanism was investigated on peripheral blood mononuclear cells to evaluate anti-inflammatory or pro-resolving properties. The results showed that KLEPTOSE® CRYSMEB can modulate the immune system in vitro and potentially manage vascular issues by stimulating the expression of molecules involved in the crosstalk between immune cells and other cell types. It showed anti-inflammatory effects that were driven by the inhibition of pro-inflammatory cytokine secretion and could have different impacts on different tissue types. Moreover, this cyclodextrin showed no clear impact on pro-resolving lipid mediators. Additionally, it appeared that the mechanism of action of KLEPTOSE® CRYSMEB seems to not be shared by other well-known anti-inflammatory molecules. Finally, KLEPTOSE® CRYSMEB may have an anti-inflammatory impact, which could be due to its effect on receptors such as TLR or direct complexation with LPS or PGE2, and conversely, this methylated cyclodextrin could stimulate a pro-inflammatory response involving lipid mediators and on proteins involved in communication with immune cells, probably via interaction with membrane cholesterol.

Asunto(s)

Antiinflamatorios , Ciclodextrinas , Células Endoteliales de la Vena Umbilical Humana , Inflamación , Humanos , Inflamación/metabolismo , Ciclodextrinas/química , Ciclodextrinas/farmacología , Antiinflamatorios/farmacología , Antiinflamatorios/química , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Leucocitos Mononucleares/metabolismo , Leucocitos Mononucleares/efectos de los fármacos , Citocinas/metabolismo , Metilación , Células Cultivadas

RESUMEN

The antimicrobial and pro-healing properties remain critical clinical objectives for skin wound management. However, the escalating problem of antibiotic overuse and the corresponding rise in bacterial resistance necessitates an urgent shift towards an antibiotic-free approach to antibacterial treatment. The quest for antimicrobial efficacy while accelerating wound healing without antibiotic treatment have emerged as innovative strategies in skin wound treatment. Here, a dual-function hydrogel with antimicrobial and enhanced tissue-healing properties was developed by utilizing cyclodextrin, ferrocene, polyethyleneimine (PEI), and Bletilla striata polysaccharide (BSP), through multiple non-covalent interactions, which can intelligently release BSP by recognizing the wound inflammatory microenvironment through the cyclodextrin-ferrocene unit. Moreover, the porosity (65 % - 85 %), Young's modulus (400 KPa - 140 KPa), and DPPH scavenge rate (18 % - 40 %) of the hydrogel are modulated by varying the BSP content. The hydrogel exhibits outstanding antibacterial properties (98.3 % reduction of Escherichia coli observed after exposure to HTFC@BSP-20 for 24 h) and favorable biocompatibility. Furthermore, in a rat full-thickness skin wound model, the dual-function hydrogel significantly accelerates wound healing, increased CD31 expression promotes vascular regeneration, reduced TNF-α express and inhibited the inflammation. This multifunctional ROS responsive hydrogel provides a new perspective for antibiotics-free treatment of skin injuries.

Asunto(s)

Antibacterianos , Vendajes , Hidrogeles , Polisacáridos , Especies Reactivas de Oxígeno , Cicatrización de Heridas , Cicatrización de Heridas/efectos de los fármacos , Hidrogeles/química , Hidrogeles/farmacología , Animales , Polisacáridos/química , Polisacáridos/farmacología , Ratas , Especies Reactivas de Oxígeno/metabolismo , Antibacterianos/farmacología , Antibacterianos/química , Inflamación/tratamiento farmacológico , Orchidaceae/química , Escherichia coli/efectos de los fármacos , Humanos , Piel/efectos de los fármacos , Ciclodextrinas/química , Ciclodextrinas/farmacología , Ratas Sprague-Dawley , Masculino , Compuestos Ferrosos/química , Compuestos Ferrosos/farmacología , Metalocenos

RESUMEN

Immunoglobulin A (IgA) is a major gut antibody that coats commensal gut bacteria and contributes to shaping a stable gut bacterial composition. Although previous studies have shown that cyclic oligosaccharides, including cyclic nigerosyl-1,6-nigerose (CNN) and cyclodextrins (CDs, including αCD, ßCD, and γCD), alter the gut bacterial composition, it remains unclear whether cyclic oligosaccharides modify the IgA coating of gut bacteria, which relates to cyclic oligosaccharide-induced alteration of the gut bacterial composition. To address this issue, mice were maintained for 12 weeks on diets containing CNN, αCD, ßCD, or γCD; the animals' feces were evaluated for their bacterial composition and the IgA coating index (ICI), a measure of the degree of IgA coating of bacteria. We observed that the intake of each cyclic oligosaccharide altered the gut bacterial composition, with changes in the ICI found at both the phylum and genus levels. The ICI for Bacillota, Lachnospiraceae NK4A136 group, UC Lachnospiraceae, and Tuzzerella were significantly and positively correlated with the relative abundance (RA) in total bacteria for these bacteria; in contrast, significant correlations were not seen for other phyla and genera. Our observations suggest that cyclic oligosaccharide-induced modulation of the IgA coating of gut bacteria may partly relate to changes in the community structure of the gut bacteria.

Asunto(s)

Heces , Microbioma Gastrointestinal , Inmunoglobulina A , Oligosacáridos , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Oligosacáridos/farmacología , Ratones , Heces/microbiología , Bacterias/efectos de los fármacos , Masculino , Ciclodextrinas/farmacología , Ratones Endogámicos C57BL

RESUMEN

Aiming to improve the retrieval rate of retrievable vena cava filters (RVCF) and extend its dwelling time in vivo, a novel hydrogel coating loaded with 10 mg/mL heparin and 30 mg/mL cyclodextrin/paclitaxel (PTX) inclusion complex (IC) was prepared. The drug-release behavior in the phosphate buffer solution demonstrated both heparin and PTX could be sustainably released over approximately two weeks. Furthermore, it was shown that the hydrogel-coated RVCF (HRVCF) with 10 mg/mL heparin and 30 mg/mL PTX IC effectively extended the blood clotting time to above the detection limit and inhibited EA.hy926 and CCC-SMC-1 cells' proliferation in vitro compared to the commercially available bare RVCF. Both the HRVCF and the bare RVCF were implanted into the vena cava of sheep and retrieved at at 2nd and 4th week after implantation, revealing that the HRVCF had a significantly higher retrieval rate of 67 % than the bare RVCF (0 %) at 4th week. Comprehensive analyses, including histological, immunohistological, and immunofluorescent assessments of the explanted veins demonstrated the HRVCF exhibited anti-hyperplasia and anticoagulation properties in vivo, attributable to the hydrogel coating, thereby improving the retrieval rate in sheep. Consequently, the as-prepared HRVCF shows promising potential for clinical application to enhance the retrieval rates of RVCFs.

Asunto(s)

Ciclodextrinas , Heparina , Hidrogeles , Paclitaxel , Filtros de Vena Cava , Ciclodextrinas/química , Ciclodextrinas/farmacología , Paclitaxel/farmacología , Paclitaxel/química , Heparina/química , Heparina/farmacología , Animales , Hidrogeles/química , Hidrogeles/farmacología , Humanos , Ovinos , Materiales Biocompatibles Revestidos/química , Materiales Biocompatibles Revestidos/farmacología , Coagulación Sanguínea/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Liberación de Fármacos

RESUMEN

This work aimed to explore an alternative to the use of antibiotics for prevention and treatment of wounds infection caused by two common bacterial pathogens Staphylococcus aureus and Pseudomonas aeruginosa. For this purpose, three different essential oil components (EOCs), namely carvacrol, citronellol and cinnamic acid, were loaded into electrospun fibers of poly-ε-caprolactone (PCL) aided by alpha-cyclodextrin (αCD) and hydroxypropyl-ß-cyclodextrin (HPßCD). Electrospun-fibers prepared with each EOC and their mixtures were screened for antimicrobial capability and characterized regarding morphological, mechanical, thermal, surface polarity, antibiofilm and antioxidant properties. αCD formed poly(pseudo)rotaxanes with PCL and weakly interacted with EOCs, while HPßCD facilitated EOC encapsulation and formation of homogeneous fibers (500-1000 nm diameter) without beads. PCL/HPßCD fibers with high concentration of EOCs (mainly carvacrol and cinnamic acid) showed strong antibiofilm (>3 log CFU reduction) and antioxidant activity (10-50% DPPH scavenging effects). Different performances were recorded for the EOCs and their mixtures; cinnamic acid migrated to fiber surface and was released faster. Fibers biocompatibility was verified using hemolysis tests and in ovo tissue integration and angiogenesis assays. Overall, HPßCD facilitates complete release of EOCs from the fibers to the aqueous medium, being an environment-friendly and cost-effective strategy for the treatment of infected wounds.

Asunto(s)

Monoterpenos Acíclicos , Antioxidantes , Cinamatos , Cimenos , Monoterpenos , Cicatrización de Heridas , Cicatrización de Heridas/efectos de los fármacos , Cimenos/farmacología , Cimenos/química , Cinamatos/química , Cinamatos/farmacología , Monoterpenos Acíclicos/farmacología , Monoterpenos Acíclicos/química , Antioxidantes/farmacología , Antioxidantes/química , Monoterpenos/farmacología , Monoterpenos/química , Antiinfecciosos/farmacología , Antiinfecciosos/química , Staphylococcus aureus/efectos de los fármacos , Ciclodextrinas/química , Ciclodextrinas/farmacología , Biopelículas/efectos de los fármacos , Nanofibras/química , Pruebas de Sensibilidad Microbiana , Antibacterianos/farmacología , Antibacterianos/química , Poliésteres/química , Aceites Volátiles/farmacología , Aceites Volátiles/química , Pseudomonas aeruginosa/efectos de los fármacos

RESUMEN

This study evaluates the antiproliferative potential of flavanones, chromanones and their spiro-1-pyrazoline derivatives as well as their inclusion complexes. The main goal was to determine the biological basis of molecular pro-apoptotic activities and the participation of reactive oxygen species (ROS) in shaping the cytotoxic properties of the tested conjugates. For this purpose, changes in mitochondrial potential and the necrotic/apoptotic cell fraction were analyzed. Testing with specific fluorescent probes found that ROS generation had a significant contribution to the biological anticancer activity of complexes of flavanone analogues. TT (thrombin time), PT (prothrombin time) and APTT (activated partial tromboplastin time) were used to evaluate the influence of the compounds on the extrinsic and intrinsic coagulation pathway. Hemolysis assays and microscopy studies were conducted to determine the effect of the compounds on RBCs.

Asunto(s)

Antineoplásicos , Apoptosis , Ciclodextrinas , Flavanonas , Especies Reactivas de Oxígeno , Humanos , Flavanonas/farmacología , Flavanonas/química , Apoptosis/efectos de los fármacos , Antineoplásicos/farmacología , Antineoplásicos/química , Especies Reactivas de Oxígeno/metabolismo , Ciclodextrinas/química , Ciclodextrinas/farmacología , Línea Celular Tumoral , Hemólisis/efectos de los fármacos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Proliferación Celular/efectos de los fármacos

RESUMEN

Quercetin, recognized for its antioxidant, anti-inflammatory, and antibacterial properties, faces limited biomedical application due to its low solubility. Cotton, a preferred wound dressing material over synthetic ones, lacks inherent antibacterial and wound-healing attributes and can benefit from quercetin features. This study explores the potential of overcoming these challenges through the inclusion complexation of quercetin with cyclodextrins (CDs) and the development of a nanofibrous coating on a cotton nonwoven textile. Hydroxypropyl-beta-cyclodextrin (HP-ß-CD) and hydroxypropyl-gamma-cyclodextrin (HP-γ-CD) formed inclusion complexes of quercetin, with chitosan added to enhance antibacterial properties. Phase solubility results showed that inclusion complexation can enhance quercetin solubility up to 20 times, with HP-γ-CD forming a more stable inclusion complexation compared with HP-ß-CD. Electrospinning of the nanofibers from HP-ß-CD/Quercetin and HP-γ-CD/Quercetin aqueous solutions without the use of a polymeric matrix yielded a uniform, smooth fiber morphology. The structural and thermal analyses of the HP-ß-CD/Quercetin and HP-γ-CD/Quercetin nanofibers confirmed the presence of inclusion complexes between quercetin and each of the CDs (HP-ß-CD and HP-γ-CD). Moreover, HP-ß-CD/Quercetin and HP-γ-CD/Quercetin nanofibers showed a near-complete loading efficiency of quercetin and followed a fast-releasing profile of quercetin. Both HP-ß-CD/Quercetin and HP-γ-CD/Quercetin nanofibers showed significantly higher antioxidant activity compared to pristine quercetin. The HP-ß-CD/Quercetin and HP-γ-CD/Quercetin nanofibers also showed antibacterial activity, and with the addition of chitosan in the HP-γ-CD/Quercetin system, the Chitosan/HP-γ-CD/Quercetin nanofibers completely eliminated the investigated bacteria species. The nanofibers were nontoxic and well-tolerated by cells, and exploiting the quercetin and chitosan anti-inflammatory activities resulted in the downregulation of IL-6 and NO secretion in both immune as well as regenerative cells. Overall, CD inclusion complexation markedly enhances quercetin solubility, resulting in a biofunctional antioxidant, antibacterial, and anti-inflammatory wound dressing through a nanofibrous coating on cotton textiles.

Asunto(s)

Antibacterianos , Antiinflamatorios , Antioxidantes , Vendajes , Quitosano , Ciclodextrinas , Ensayo de Materiales , Nanofibras , Quercetina , Quercetina/farmacología , Quercetina/química , Antioxidantes/farmacología , Antioxidantes/química , Nanofibras/química , Quitosano/química , Quitosano/farmacología , Antibacterianos/farmacología , Antibacterianos/química , Antiinflamatorios/farmacología , Antiinflamatorios/química , Ciclodextrinas/química , Ciclodextrinas/farmacología , Tamaño de la Partícula , Materiales Biocompatibles/química , Materiales Biocompatibles/farmacología , Pruebas de Sensibilidad Microbiana , Fibra de Algodón , Cicatrización de Heridas/efectos de los fármacos , Humanos , Picratos/antagonistas & inhibidores , Supervivencia Celular/efectos de los fármacos , Compuestos de Bifenilo

RESUMEN

Purpose: Conventional oral formulations for inflammatory bowel disease (IBD) treatment are less than satisfactory, due to the poor controllability of drug release and lack of specificity to the inflammation sites in the gastrointestinal (GI) tract. To overcome these limitations, we developed a multiple carbohydrate-based nanosystem with pH/ROS dual responsibility and charge-mediated targeting ability for IBD-specific drug delivery. Methods: In view of the overproduction of ROS and overexpression of cationic proteins in the inflammatory colon, the designed nanosystem was composed of oxidation-sensitive cyclodextrin (OX-CD), chitosan (CS) and pectin (AHP). OX-CD was utilized to load dexamethasone (DM) by the solvent evaporation method. CS and AHP with opposite charges were sequentially coated onto OX-CD to generate the nanosystems by the electrostatic self-assembly method. The physicochemical properties, stability, dual-sensitive drug release behavior, cytotoxicity, cellular uptake and anti-inflammatory activity were investigated in vitro. In vivo bio-distribution and therapeutic efficacy of the nanosystem were further evaluated in the ulcerative colitis (UC) mice. Results: The obtained AHP/CS/OX-CD-DM nanosystem (ACOC-DM) could maintain stability under the GI pH environments, and release drug in the inflammatory colon with pH/ROS sensitivity. Dual polysaccharide-coated ACOC-DM exhibited higher cellular uptake and anti-inflammatory efficacy in macrophages than single polysaccharide-coated CS/OX-CD-DM nanosystem (COC-DM). Orally administrated ACOC-DM could enhance inflammation targeting ability and therapeutic efficacy of DM in the UC mice. Conclusion: This carbohydrate-based nanosystem with pH/ROS dual sensitivity and inflammation targeting capacity may serve as a safe and versatile nanoplatform for IBD therapy.

Asunto(s)

Antiinflamatorios , Quitosano , Colitis Ulcerosa , Dexametasona , Pectinas , Animales , Colitis Ulcerosa/tratamiento farmacológico , Ratones , Quitosano/química , Dexametasona/química , Dexametasona/administración & dosificación , Dexametasona/farmacocinética , Dexametasona/farmacología , Pectinas/química , Antiinflamatorios/química , Antiinflamatorios/administración & dosificación , Antiinflamatorios/farmacología , Antiinflamatorios/farmacocinética , Ciclodextrinas/química , Ciclodextrinas/farmacología , Sistemas de Liberación de Medicamentos/métodos , Liberación de Fármacos , Células RAW 264.7 , Concentración de Iones de Hidrógeno , Humanos , Especies Reactivas de Oxígeno/metabolismo , Colon/efectos de los fármacos , Colon/metabolismo , Portadores de Fármacos/química , Masculino , Nanopartículas/química

RESUMEN

Cyclodextrins, commonly used as excipients in antifungal formulations to improve the physicochemical properties and availability of the host molecules, have not been systematically studied for their effects and bioactivity without a complex active substance. This paper evaluates the effects of various cyclodextrins on the physiology of the test organism Candida boidinii. The research examines their impact on yeast growth, viability, biofilm formation and morphological changes. Native ACD, BCD, randomly methylated α- and ß-CD and quaternary ammonium α-CD and ß-CD were investigated in the 0.5-12.5 mM concentration range in both static and dynamic systems. The study revealed that certain cyclodextrins exhibited notable antifungal effects (up to ~69%) in dynamic systems; however, the biofilm formation was enhanced in static systems. The magnitude of these effects was influenced by several variables, including the size of the internal cavity, the concentration and structure of the cyclodextrins, and the contact time. Furthermore, the study found that CDs exhibited distinct effects in both static and dynamic systems, potentially related to their tendency to form aggregates. The findings suggest that cyclodextrins may have the potential to act as antifungal agents or growth promoters, depending on their structure and surrounding environments.

Asunto(s)

Antifúngicos , Biopelículas , Candida , Ciclodextrinas , Candida/efectos de los fármacos , Ciclodextrinas/química , Ciclodextrinas/farmacología , Antifúngicos/farmacología , Antifúngicos/química , Biopelículas/efectos de los fármacos , Biopelículas/crecimiento & desarrollo , Pruebas de Sensibilidad Microbiana

RESUMEN

There is an urgent need to develop safer and more effective modalities for the treatment of numerous pathologies due to the increasing rates of drug resistance, undesired side effects, poor clinical outcomes, etc. Over the past decades, cyclodextrins (CDs) have gathered great attention as potential drug carriers due to their ability to enhance their bioactivities and properties. Likewise, selenium (Se) and tellurium (Te) have been extensively studied during the last decades due to their possible therapeutical applications. Although there is limited research on the relationship between Se and Te and CDs, herein, we highlight different representative examples of the advances related to this topic as well as give our view on the future directions of this emerging area of research. This review encompasses three different aspects of this relationship: (1) modification of the structure of the different CDs; (2) formation of host-guest interaction complexes of naïve CDs with Se and Te derivatives in order to overcome specific limitations of the latter; and (3) the use of CDs as catalysts to achieve novel Se and Te compounds.

Asunto(s)

Ciclodextrinas , Selenio , Telurio , Telurio/química , Ciclodextrinas/química , Ciclodextrinas/farmacología , Selenio/química , Humanos , Portadores de Fármacos/química , Animales

RESUMEN

Quorum sensing (QS) allows bacteria to coordinate their activities by producing and detecting low-molecular-weight signal molecules based on population density, thereby controlling the infectivity of bacteria through various virulence factors. Quorum-sensing inhibition is a promising approach to tackle bacterial communication. Cyclodextrins (CDs) are a class of cyclic oligosaccharides that reversibly encapsulate the acyl chain of the signal molecules, thereby preventing their binding to receptors and interrupting bacterial communication. This results in the inhibition of the expression of various properties, including different virulence factors. To examine the potential quorum-quenching (QQ) ability of newly prepared cyclodextrin derivatives, we conducted short-term tests using Aliivibrio fischeri, a heterotrophic marine bacterium capable of bioluminescence controlled by quorum sensing. α- and ß-cyclodextrins monosubstituted with alkylthio moieties and further derivatized with quaternary ammonium groups were used as the test agents. The effect of these cyclodextrins on the quorum-sensing system of A. fischeri was investigated by adding them to an exponential growth phase of the culture and then measuring bioluminescence intensity, population growth, and cell viability. Our results demonstrate that the tested cyclodextrins have an inhibitory effect on the quorum-sensing system of A. fischeri. The inhibitory effect varies based on the length of the alkyl chain, with alkylthio substitution enhancing it and the presence of quaternary ammonium groups decreasing it. Our findings suggest that cyclodextrins can be a promising therapeutic agent for the treatment of bacterial infections.

Asunto(s)

Aliivibrio fischeri , Ciclodextrinas , Percepción de Quorum , Aliivibrio fischeri/efectos de los fármacos , Percepción de Quorum/efectos de los fármacos , Ciclodextrinas/farmacología , Ciclodextrinas/química , Mediciones Luminiscentes/métodos , Luminiscencia

RESUMEN

Atherosclerotic plaques exhibit high cholesterol deposition and oxidative stress resulting from high reactive oxygen species (ROS). These are the major components in plaques and the main pro-inflammatory factor. Therefore, it is crucial to develop an effective therapeutic strategy that can simultaneously address the multiple pro-inflammatory factors via removing cholesterol and inhibiting the overaccumulated ROS. In this study, we constructed macrophage membrane-encapsulated biomimetic nanoparticles (MM@DA-pCD@MTX), which not only alleviate cholesterol deposition at the plaque lesion via reverse cholesterol transport but also scavenge the overaccumulated ROS. ß-Cyclodextrin (ß-CD) and the loaded methotrexate (MTX) act synergistically to induce cholesterol efflux for inhibiting the formation of foam cells. Among them, MTX up-regulated the expression of ABCA1, CYP27A1, and SR-B1. ß-CD increased the solubility of cholesterol crystals. In addition, the ROS scavenging property of dopamine (DA) was perfectly preserved in MM@DA-pCD@MTX, which could scavenge the overaccumulated ROS to alleviate the oxidative stress at the plaque lesion. Last but not least, MM-functionalized "homing" targeting of atherosclerotic plaques not only enables the targeted drug delivery but also prolongs in vivo circulation time and drug half-life. In summary, MM@DA-pCD@MTX emerges as a potent, multifunctional therapeutic platform for AS treatment, offering a high degree of biosafety and efficacy in addressing the complex pathophysiology of atherosclerosis.

Asunto(s)

Aterosclerosis , Materiales Biomiméticos , Colesterol , Dopamina , Macrófagos , Metotrexato , Nanopartículas , Dopamina/química , Dopamina/farmacología , Nanopartículas/química , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/metabolismo , Aterosclerosis/patología , Ratones , Animales , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Metotrexato/química , Metotrexato/farmacología , Colesterol/química , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Humanos , Ciclodextrinas/química , Ciclodextrinas/farmacología , Células RAW 264.7 , Estrés Oxidativo/efectos de los fármacos , Portadores de Fármacos/química , beta-Ciclodextrinas

RESUMEN

Drug repositioning is a high-priority and feasible strategy in the field of oncology research, where the unmet medical needs are continuously unbalanced. Disulfiram is a potential non-chemotherapeutic, adjuvant anticancer agent. However, the clinical translation is limited by the drug's poor bioavailability. Therefore, the molecular encapsulation of disulfiram with cyclodextrins is evaluated to enhance the solubility and stability of the drug. The present work describes for the first time the complexation of disulfiram with randomly methylated-ß-cyclodextrin. A parallel analytical andin vitrobiological comparison of disulfiram inclusion complexes with hydroxypropyl-ß-cyclodextrin, randomly methylated-ß-cyclodextrin and sulfobutylether-ß-cyclodextrin is conducted. A significant drug solubility enhancement by about 1000-folds and fast dissolution in 1 min is demonstrated. Thein vitrodissolution-permeation studies and proliferation assays demonstrate the solubility-dependent efficacy of the drug. Throughout the different cancer cell lines' characteristics and disulfiram unspecific antitumoral activity, the inhibitory efficacy of the cyclodextrin encapsulated drug on melanoma (IC50 about 100 nM) and on glioblastoma (IC50 about 7000 nM) cell lines differ by a magnitude. This pre-formulation screening experiment serves as a proof of concept of using cyclodextrin encapsulation as a platform tool for further drug delivery development in repositioning areas.

Asunto(s)

Antineoplásicos , Disulfiram , Reposicionamiento de Medicamentos , Solubilidad , beta-Ciclodextrinas , Disulfiram/farmacología , Disulfiram/química , Disulfiram/administración & dosificación , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/administración & dosificación , Línea Celular Tumoral , beta-Ciclodextrinas/química , 2-Hidroxipropil-beta-Ciclodextrina/química , Ciclodextrinas/química , Ciclodextrinas/farmacología , Proliferación Celular/efectos de los fármacos , Composición de Medicamentos/métodos , Glioblastoma/tratamiento farmacológico

RESUMEN

1,8-Cineole is a bicyclic monoterpene widely distributed in the essential oils of various medicinal plants, and it exhibits significant anti-inflammatory and antioxidant activities. We aimed to investigate the therapeutic effect of 1,8-cineole on anti-Alzheimer's disease by using transgenic Caenorhabditis elegans models. Our studies demonstrated that 1,8-cineole significantly relieved Aß1-42-induced paralysis and exhibited remarkable antioxidant and anti-Aß1-42 aggregation activities in transgenic nematodes CL4176, CL2006 and CL2355. We developed a 1,8-cineole/cyclodextrin inclusion complex, displaying enhanced anti-paralysis, anti-Aß aggregation and antioxidant activities compared to 1,8-cineole. In addition, we found 1,8-cineole treatment activated the SKN-1/Nrf-2 pathway and induced autophagy in nematodes. Our results demonstrated the antioxidant and anti-Alzheimer's disease activities of 1,8-cineole, which provide a potential therapeutic approach for Alzheimer's disease.

Asunto(s)

Enfermedad de Alzheimer , Péptidos beta-Amiloides , Animales Modificados Genéticamente , Antioxidantes , Caenorhabditis elegans , Eucaliptol , Eucaliptol/farmacología , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/metabolismo , Animales , Caenorhabditis elegans/efectos de los fármacos , Antioxidantes/farmacología , Péptidos beta-Amiloides/metabolismo , Ciclodextrinas/farmacología , Ciclodextrinas/química , Fragmentos de Péptidos/farmacología , Autofagia/efectos de los fármacos , Modelos Animales de Enfermedad

RESUMEN

A thiolated RGD was incorporated into the threaded allyl-ß-cyclodextrins (Allyl-ß-CDs) of the polyrotaxane (PR) through a thiol-ene click reaction, resulting in the formation of dynamic RGD ligands on the PR surface (dRGD-PR). When maintaining consistent RGD density and other physical properties, endothelial cells (ECs) cultured on dRGD-PR exhibited significantly increased cell proliferation and a larger cell spreading area compared to those on the non-dynamic RGD (nRGD-PCL). Furthermore, ECs on dRGD-PR demonstrated elevated expression levels of FAK, p-FAK, and p-AKT, along with a larger population of cells in the G2/M stage during cell cycle analysis, in contrast to cells on nRGD-PCL. These findings suggest that the movement of the RGD ligands may exert additional beneficial effects in promoting EC spreading and proliferation, beyond their essential adhesion and proliferation-promoting capabilities, possibly mediated by the RGD-integrin-FAK-AKT pathway. Moreover, in vitro vasculogenesis tests were conducted using two methods, revealing that ECs cultured on dRGD-PR exhibited much better vasculogenesis than nRGD-PCL in vitro. In vivo testing further demonstrated an increased presence of CD31-positive tissues on dRGD-PR. In conclusion, the enhanced EC spreading and proliferation resulting from the dynamic RGD ligands may contribute to improved in vitro vasculogenesis and in vivo vascularization.

Asunto(s)

Proliferación Celular , Ciclodextrinas , Oligopéptidos , Humanos , Adhesión Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Ciclodextrinas/química , Ciclodextrinas/farmacología , Células Endoteliales/metabolismo , Células Endoteliales/efectos de los fármacos , Células Endoteliales/citología , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Ligandos , Neovascularización Fisiológica/efectos de los fármacos , Oligopéptidos/farmacología , Oligopéptidos/química , Poloxámero/química , Poloxámero/farmacología , Proteínas Proto-Oncogénicas c-akt/metabolismo , Rotaxanos

RESUMEN

Geraniol (Ger) is an essential oil molecule with excellent biological activity. High hydrophobicity and volatility limit its practical application. Cyclodextrins (CDs) are water-soluble cyclic oligosaccharides with hydrophobic cavities. Physical encapsulation of CDs to improve the solubility and stability of essential oil molecules is not satisfactory. Therefore, this study synthesized the γ-CD derivative (γ-CD-Ger) by grafting Ger onto γ-CD using a bromide-mediated method. Compared to the inclusion complexes (γ-CD/Ger) formed by both, the derivatives exhibit better solubility and thermal stability. The derivative has better antibacterial activity when the ratio of γ-CD to Ger was 1:2. In addition, the derivatives did not exhibit cytotoxic and hemolytic properties. These results indicate that this research provides a water-soluble antibacterial agent with a wide range of promising applications and offers new ideas for the application of alcohol hydrophobic molecules in aqueous systems.

Asunto(s)

Monoterpenos Acíclicos , Ciclodextrinas , Aceites Volátiles , gamma-Ciclodextrinas , gamma-Ciclodextrinas/farmacología , gamma-Ciclodextrinas/química , Solubilidad , Antibacterianos/farmacología , Ciclodextrinas/farmacología , Ciclodextrinas/química , Agua/química

RESUMEN

The experiment evaluated the effect of adding cholesterol-loaded cyclodextrin (CLC) to Prochilodus lineatus fish (Curimata) semen on post-thaw sperm quality. Twelve adult fish were used for sperm collection after induced spermiation with carp pituitary gland. The semen was diluted and treated with CLC in concentrations of 0 (control), 0.5, 1.0, 2.0, 3.0, and 4.0 mg for 120 × 106 spermatozoa/ml, loaded in 0.5 ml straws, packaged and placed in dry vapor vessel cylinders for 24 h before being submerged in liquid nitrogen for storage. The samples were thawed in a water bath at 60 °C for 8 s, and the sperm parameters evaluated were motility, activation duration, longevity, plasma membrane integrity, and morphology. Data were tested for normal distribution and ANOVA, followed by Friedman test (P < 0.05). Spermatozoa treated with CLC displayed higher motility than the control (P < 0.05). The duration of sperm activation was longer in sperm treated with 0.5, 1.0, and 2.0 mg of CLC than in control (P < 0.05). The membrane integrity was higher in sperm treated with 0.5, 1.0, 2.0, and 3.0 mg of CLC than in control and four mg-treated samples (P < 0.05). The sperm longevity and morphology alterations did not differ between treatments (P > 0.05). Adding 0.5, 1.0, or 2.0 mg of CLC in Prochilodus lineatus semen before cryopreservation improves sperm motility and membrane integrity.

Asunto(s)

Colesterol , Criopreservación , Crioprotectores , Ciclodextrinas , Preservación de Semen , Motilidad Espermática , Espermatozoides , Animales , Masculino , Criopreservación/métodos , Criopreservación/veterinaria , Preservación de Semen/métodos , Preservación de Semen/veterinaria , Motilidad Espermática/efectos de los fármacos , Ciclodextrinas/farmacología , Ciclodextrinas/química , Espermatozoides/efectos de los fármacos , Colesterol/farmacología , Crioprotectores/farmacología , Membrana Celular/efectos de los fármacos , Characiformes , Análisis de Semen

RESUMEN

The influenza BM2 transmembrane domain (BM2TM), an acid-activated proton channel, is an attractive antiviral target due to its essential roles during influenza virus replication, whereas no effective inhibitors have been reported for BM2. In this study, we draw inspiration from the properties of cyclodextrins (CDs) and hypothesize that CDs of appropriate sizes may possess the potential to act as inhibitors of the BM2TM proton channel. To explore this possibility, molecular dynamics simulations were employed to assess their inhibitory capabilities. Our findings reveal that CD4, CD5, and CD6 are capable of binding to the BM2TM proton channel, resulting in disrupted water networks and reduced hydrogen bond occupancy between H19 and the solvent within the BM2TM channel necessary for proton conduction. Notably, CD4 completely obstructs the BM2TM water channel. Based on these observations, we propose that CD4, CD5, and CD6 individually contribute to diminishing the proton transfer efficiency of the BM2 protein, and CD4 demonstrates promising potential as an inhibitor for the BM2 proton channel.

Asunto(s)

Ciclodextrinas , Gripe Humana , Humanos , Protones , Ciclodextrinas/farmacología , Ciclodextrinas/metabolismo , Virus de la Influenza B/química , Virus de la Influenza B/metabolismo , Simulación de Dinámica Molecular , Proteínas de la Matriz Viral/química

RESUMEN

Commercial cyclodextrins (CDs) are commonly used to form inclusion complexes (ICs) with different molecules in order to enhance their water solubility, stability, and bioavailability. Nowadays, there is strong, convincing evidence of the anticancer effect of selenium (Se)-containing compounds. However, pharmaceutical limitations, such as an unpleasant taste or poor aqueous solubility, impede their further evaluation and clinical use. In this work, we study the enhancement of solubility with CD complexes for a set of different nonsteroidal anti-inflammatory drug (NSAID) derivatives with Se as selenoester or diacyl diselenide chemical forms, with demonstrated antitumoral activity. The CD complexes were analyzed via nuclear magnetic resonance (NMR) spectroscopic techniques. In order to obtain additional data that could help explain the experimental results obtained, 3D models of the theoretical CD-compound complexes were constructed using molecular modeling techniques. Among all the compounds, I.3e and II.5 showed a remarkable increase in their water solubility, which could be ascribed to the formation of the most stable interactions with the CDs used, in agreement with the in silico studies performed. Thus, the preliminary results obtained in this work led us to confirm the selection of ß and γ-CD as the most suitable for overcoming the pharmaceutical drawbacks of these Se derivatives.

Asunto(s)

Ciclodextrinas , Selenio , Ciclodextrinas/farmacología , Ciclodextrinas/química , Solubilidad , Agua/química , Preparaciones Farmacéuticas , Antiinflamatorios no Esteroideos/farmacología

RESUMEN

Overcoming P-glycoprotein (P-gp)-mediated efflux poses a significant challenge for the pharmaceutical industry. This study investigates the potential of thiolated ß-cyclodextrins (ß-CD-SHs) as inhibitors of P-gp-mediated efflux in Caco-2 cells. Through a series of transport assays, intracellular accumulation, and efflux of the P-gp substrates Rhodamine 123 (Rh123) and Calcein-AM with and without co-administration of ß-CD-SHs were assessed. The results revealed that the cellular uptake of Rh123 and Calcein-AM were enhanced up to 7- and 3-fold, compared to the control, respectively. In efflux studies an up to 2.5-fold reduction of the Rh123 efflux was reached compared the control, indicating a substantial decrease of Rh123 efflux by ß-CD-SHs. Furthermore, it was observed that ß-CD-SHs led to a decrease in the reactivity of fluorescence-labeled anti-P-gp, suggesting additional effects on the conformation of P-gp. Overall, this study demonstrates the potential of ß-CD-SHs as effective modulator of P-gp-mediated drug efflux in Caco-2 cells.

Asunto(s)

Miembro 1 de la Subfamilia B de Casetes de Unión a ATP , Ciclodextrinas , Humanos , Células CACO-2 , Ciclodextrinas/farmacología , Rodamina 123