Thiolated α-cyclodextrin: The likely smallest drug carrier providing enhanced cellular uptake and endosomal escape.

This study aimed to evaluate the effect of thiolated α-cyclodextrin (α-CD-SH) on the cellular uptake of its payload. For this purpose, α-CD was thiolated using phosphorous pentasulfide. Thiolated α-CD was characterized by FT-IR and 1H NMR spectroscopy, differential scanning calorimetry (DSC), and powder X-ray diffractometry (PXRD). Cytotoxicity of α-CD-SH was evaluated on Caco-2, HEK 293, and MC3T3 cells. Dilauryl fluorescein (DLF) and coumarin-6 (Cou) serving as surrogates for a pharmaceutical payload were incorporated in α-CD-SH, and cellular uptake was analyzed by flow cytometry and confocal microscopy. Endosomal escape was investigated by confocal microscopy and hemolysis assay. Results showed no cytotoxic effect within 3 h, while dose-dependent cytotoxicity was observed within 24 h. The cellular uptake of DLF and Cou was up to 20- and 11-fold enhanced by α-CD-SH compared to native α-CD, respectively. Furthermore, α-CD-SH provided an endosomal escape. According to these results, α-CD-SH is a promising carrier to shuttle drugs into the cytoplasm of target cells.

Glucocorticoid-loaded pH/ROS dual-responsive nanoparticles alleviate joint destruction by downregulating the NF-κB signaling pathway.

Rheumatoid arthritis (RA) is an autoimmune disease causing severe symptoms that are difficult to treat. Nano-drug delivery system is recognized as a promising strategy for management of RA. However, how to thoroughly release payloads from nanoformulations and synergistic therapy of RA needs to be further investigated. To address this issue, a pH and reactive oxygen species (ROS) dual-responsive, methylprednisolone (MPS)-loaded and arginine-glycine-aspartic acid (RGD)-modified nanoparticles (NPs) was fabricated using phytochemical and ROS-responsive moiety co-modified α-cyclodextrin (α-CD) as a carrier. In vitro and in vivo experiments verified that the pH/ROS dual-responsive nanomedicine could be efficiently internalized by activated macrophages and synovial cells, and the released MPS could promote transformation of M1-type macrophages into M2 phenotype, thereby down-regulating pro-inflammatory cytokines. In vivo experiments demonstrated that the pH/ROS dual-responsive nanomedicine was remarkably accumulated in the inflamed joints of mice with collagen-induced arthritis (CIA). The accumulated nanomedicine could obviously relieve joint swelling and cartilage destruction without obvious adverse effects. Importantly, the expression of interleukin-6 and tumor necrosis factor-α in the joints of CIA mice were significantly inhibited by the pH/ROS dual-responsive nanomedicine in comparison with free drug and non-targeted counterparts. In addition, the expression of the NF-κB signaling pathway molecule P65 was also significantly decreased by nanomedicine-treatment. Our results reveal that MPS-loaded pH/ROS dual-responsive NPs can effectively alleviate joint destruction via down-regulation of the NF-κB signaling pathway. STATEMENT OF SIGNIFICANCE: Nanomedicine is recognized as an attractive method for the targeting treatment of rheumatoid arthritis (RA). To thorough release of payloads from nanoformulations and synergistic therapy of RA, herein, a phytochemical and ROS-responsive moiety co-modified α-cyclodextrin was used as a pH/ROS dual-responsive carrier to encapsulate methylprednisolone to manage RA. The fabricated nanomedicine can effectively release its payloads under pH and/or ROS microenvironment, and the released drugs dramatically promote transformation of M1-type macrophages into M2 phenotype to reduce the release of pro-inflammatory cytokines. The prepared nanomedicine also obviously decreased the NF-κB signaling pathway molecule P65 expression in the joints, thereby down-regulating pro-inflammatory cytokines expression to alleviate joint swelling and cartilage destruction. We provided a candidate for the targeting treatment of RA.

Positive postprandial glycaemic and appetite-related effects of wheat breads enriched with either α-cyclodextrin or hydroxytyrosol/α-cyclodextrin inclusion complex.

PURPOSE: Enrichment of wheat bread with either α-cyclodextrin (α-CD) or an inclusion complex of hydroxytyrosol (HT) and α-CD was performed to examine potential postprandial benefits. METHODS: Ten healthy normoglycaemic adults were provided with either a glucose solution (reference food, GS), white wheat bread (WB), wheat bread enriched with α-CD (α-CDB) or wheat bread enriched with HT/α-CD complex ((HT + α-CD)B), with 1-week intervals in amounts that yielded 50 g of available carbohydrates. Venous blood samples were collected before consumption and at 15, 30, 45, 60, 90, 120 and 180 min, postprandially. Glycaemic, insulinaemic and appetite hormone responses as well as glycaemic index (GI) and subjective appetite ratings were evaluated. RESULTS: Both enriched breads were characterized as low GI foods (α-CDB:49.7, (HT + α-CD)B:40.0) and presented similar reduction in glucose, insulin and GLP-1 responses. Significant differences were found in glucose values 45 min after (HT + α-CD)B consumption compared to α-CDB (P < 0.05) as well as in serum ghrelin, 120 min postprandially, between (HT + α-CD)B and WB in (- 90.55 ± 29.17 and 16.53 ± 21.78 pg/dL, respectively, P < 0.05). Neither of the enriched breads prevailed regarding the induced self-reported satiety. However, their consumption led to a lower desire for the next meal compared to WB. CONCLUSION: Enrichment of bread with α-CD resulted in positive effects on postprandial glycaemia and induced satiety. Incorporation of encapsulated HT offered similar overall acceptability, due to the bitter taste-masking effect provided by α-CD, and a slightly additional positive effect in postprandial glycaemia and satiety. The development of foods with favorable metabolic effects is of great importance for the prevention of chronic diseases. The study was prospectively registered in clinicaltrials.gov (NCT04725955, date: 27th January 2021).

In vitro and clinical studies on the efficacy of α-cyclodextrin and hydroxytyrosol against SARS-CoV-2 infection.

OBJECTIVE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a new coronavirus responsible for the current pandemic of coronavirus disease 2019 (COVID-19). This virus attacks cells of the airway epithelium by binding transmembrane angiotensin-converting enzyme 2 (ACE2). Hydroxytyrosol has anti-viral properties. Alpha-cyclodextrin can deplete sphingolipids and phospholipids from cell membranes. The aim of the present experimental study was to evaluate the efficacy of α-cyclodextrin and hydroxytyrosol in improving defenses against SARS-CoV-2 infection in in vitro cell models and humans. PATIENTS AND METHODS: For in vitro experiments on Vero E6 cells, RNA for RT-qPCR analysis was extracted from Caco2 and human fibroblast cell lines. For study in humans, the treatment group consisted of 149 healthy volunteers in Northern Cyprus, considered at higher risk of SARS-CoV-2 infection than the general population. The volunteers used nasal spray containing α-cyclodextrin and hydroxytyrosol for 4 weeks. The control group consisted of 76 healthy volunteers who did not use the spray. RESULTS: RT-qPCR experiments on targeted genes involved in endocytosis showed a reduction in gene expression, whereas cytotoxicity and cytoprotective tests showed that the compounds exerted a protective effect against SARS-CoV-2 infection at non-cytotoxic concentrations. None of the volunteers became positive to SARS-CoV-2 RT-qPCR assay during the 30 days of treatment. CONCLUSIONS: Treatment with α-cyclodextrin and hydroxytyrosol nasal spray improved defenses against SARS-CoV-2 infection and reduced synthesis of viral particles.

Scoping review on the role and interactions of hydroxytyrosol and alpha-cyclodextrin in lipid-raft-mediated endocytosis of SARS-CoV-2 and bioinformatic molecular docking studies.

OBJECTIVE: The aim of the study was to show the effect that two naturally occurring compounds, a cyclodextrin and hydroxytyrosol, can have on the entry of SARS-CoV-2 into human cells. MATERIALS AND METHODS: The PubMed database was searched to retrieve studies published from 2000 to 2020, satisfying the inclusion criteria. The search keywords were: SARS-CoV, SARS-CoV-2, coronavirus, lipid raft, endocytosis, hydroxytyrosol, cyclodextrin. Modeling of alpha-cyclodextrin and hydroxytyrosol were done using UCSF Chimera 1.14. RESULTS: The search results indicated that cyclodextrins can reduce the efficiency of viral endocytosis and that hydroxytyrosol has antiviral properties. Bioinformatic docking studies showed that alpha-cyclodextrin and hydroxytyrosol, alone or in combination, interact with the viral spike protein and its host cell receptor ACE2, thereby potentially influencing the endocytosis process. CONCLUSIONS: Hydroxytyrosol and alpha-cyclodextrin can be useful against the spread of SARS-CoV-2.

Lecithin Inclusion by α-Cyclodextrin Activates SREBP2 Signaling in the Gut and Ameliorates Postprandial Hyperglycemia.

BACKGROUND: α-cyclodextrin (α-CD) is one of the dietary fibers that may have a beneficial effect on cholesterol and/or glucose metabolism, but its efficacy and mode of action remain unclear. METHODS: In the present study, we examined the anti-hyperglycemic effect of α-CD after oral loading of glucose and liquid meal in mice. RESULTS: Administration of 2 g/kg α-CD suppressed hyperglycemia after glucose loading, which was associated with increased glucagon-like peptide 1 (GLP-1) secretion and enhanced hepatic glucose sequestration. By contrast, 1 g/kg α-CD similarly suppressed hyperglycemia, but without increasing secretions of GLP-1 and insulin. Furthermore, oral α-CD administration disrupts lipid micelle formation through its inclusion of lecithin in the gut luminal fluid. Importantly, prior inclusion of α-CD with lecithin in vitro nullified the anti-hyperglycemic effect of α-CD in vivo, which was associated with increased intestinal mRNA expressions of SREBP2-target genes (Ldlr, Hmgcr, Pcsk9, and Srebp2). CONCLUSIONS: α-CD elicits its anti-hyperglycemic effect after glucose loading by inducing lecithin inclusion in the gut lumen and activating SREBP2, which is known to induce cholecystokinin secretion to suppress hepatic glucose production via a gut/brain/liver axis.

Effects of alpha-cyclodextrin on water transport, cell hydration and longevity.

Among parent cyclodextrins (CDs), alpha-CD (a-CD) has been utilized in a number of nutraceutical products, and approved as a dietary fiber to affect glycemic response and reduce dietary fat absorption. To extend our current knowledge on the biology of this natural carbohydrate, here we investigated its potential effects on cellular water uptake and aging. Two independent in vivo biological test systems were used, a single cell Xenopus oocyte with expressed human aquaporin for cell hydration studies and the nematode Caenorhabditis elegans for testing life span in the treated animals. a-CD was found to enhance water uptake through aquaporins of oocytes. Furthermore, the compound promoted longevity in C. elegans. Together, these results raise a rational for assaying a-CD as a potent drug candidate in treating various age-related diseases.

Effects of α-Cyclodextrin on Cholesterol Control and Hydrolyzed Ginseng Extract on Glycemic Control in People With Prediabetes: A Randomized Clinical Trial.

Importance: Effective strategies for preventing type 2 diabetes are needed. Many people turn to complementary medicines, but there is little well-conducted scientific evidence to support their use. Objective: To assess the efficacy of α-cyclodextrin for cholesterol control and that of hydrolyzed ginseng for glycemic control in people with prediabetes and overweight or obesity. Design, Setting, and Participants: This 6-month double-blind, placebo-controlled, randomized clinical trial, with a 2 × 2 factorial design, was conducted between July 2015 and October 2018 at 2 locations in Sydney, Australia. Eligible participants were aged 18 years or older, had a body mass index (weight in kilograms divided by height in meters squared) of 25 or higher, and had prediabetes within 6 months of study entry according to the American Diabetes Association guidelines. Data analysis was performed from May to August 2019. Interventions: Participants were randomized to 1 of 4 groups to take active or placebo versions of each supplement (α-cyclodextrin plus hydrolyzed ginseng, α-cyclodextrin plus placebo, placebo plus hydrolyzed ginseng, or placebo plus placebo) for 6 months. All participants received dietetic advice for weight loss. Main Outcomes and Measures: The primary outcomes were the differences in total cholesterol and fasting plasma glucose between groups after 6 months. The primary analysis used the intention-to-treat principle. Multiple predetermined subsample analyses were conducted. Results: A total of 401 participants were eligible for the study (248 women [62%]; mean [SD] age, 53.5 [10.2] years; mean [SD] body mass index, 34.6 [6.2]). One hundred one patients were randomized to receive α-cyclodextrin plus hydrolyzed ginseng, 99 were randomized to receive α-cyclodextrin plus placebo, 101 were randomized to receive placebo plus hydrolyzed ginseng, and 100 were randomized to receive placebo plus placebo. For 200 participants taking α-cyclodextrin compared with 201 participants taking placebo, there was no difference in total cholesterol after 6 months (-1.5 mg/dL; 95% CI, -6.6 to 3.5 mg/dL; P = .51). For 202 participants taking hydrolyzed ginseng compared with 199 participants taking placebo, there was no difference in fasting plasma glucose after 6 months (0.0 mg/dL; 95% CI, -1.6 to 1.8 mg/dL; P = .95). Use of α-cyclodextrin was associated with constipation (16 participants vs 4 participants; P = .006) and cough (8 participants vs 1 participant; P = .02). Use of hydrolyzed ginseng was associated with rash and pruritus (13 participants vs 2 participants; P = .006). Only 37 of 401 participants (9.2%) experienced these adverse events. Conclusions and Relevance: Although they are safe for use, there was no benefit found for either α-cyclodextrin for cholesterol control or hydrolyzed ginseng for glycemic control in people with prediabetes and overweight or obesity. Trial Registration: Australian New Zealand Clinical Trials Registry Identifier: ACTRN12614001302640.

A pH-responsive citric-acid/α-cyclodextrin-functionalized Fe3O4 nanoparticles as a nanocarrier for quercetin: An experimental and DFT study.

Developing new nanocarriers and understanding the interactions between the drug and host molecules in the nanocarrier at the molecular level is of importance for future of nanomedicine. In this work, we synthesized and characterized a series of iron oxide nanoparticles (IONPs) functionalized with different organic molecules (citric acid, α-cyclodextrin, and citric acid/α-cyclodextrin composite). It was found that incorporation of citric acid into the α-cyclodextrin had negligible effect on the adsorption efficiency (<5%) of citric acid/α-cyclodextrin functionalized IONPs, while the isotherm adsorption data were well described by the Langmuir isotherm model (qmax = 2.92 mg/g at T = 25 °C and pH = 7). In addition, the developed nanocarrier showed pH-responsive behavior for releasing the quercetin molecules as drug model, where the Korsmeyer-Peppas model could describe the release profile with Fickian diffusion (n < 0.45 for at all pH and temperatures). Then, Density functional theory was applied to calculate the absolute binding energies (ΔEb) of the complexation of quercetin with different host molecules in the developed nanocarriers. The calculated energies are as follow: 1) quercetin and citric acid: ΔEb = -16.58 kcal/mol, 2) quercetin and α-cyclodextrin: ΔEb = -46.98 kcal/mol, and 3) quercetin and citric acid/α-cyclodextrin composite: ΔEb = -40.15 kcal/mol. It was found that quercetin tends to interact with all hosts via formation of hydrogen bonds and van der Waals interactions. Finally, the cytotoxicity of the as-developed nanocarriers was evaluated using MTT assay and both normal NIH-3T3 and cancereous HeLa cells. The cell viability results showed that the quercetin could be delivered effectively to the HeLa cells due to the acidic environment inside the cells with minimum effect on the viability of NIH-3T3 cells. These results might open a new window to design of stimuli-responsive nanocarriers for drug delivery applications.

AIE Supramolecular Assembly with FRET Effect for Visualizing Drug Delivery.

Here, we constructed a nanostructured pH/redox dual-responsive supramolecular drug carrier with both aggregation-induced emission (AIE) and Forster resonance energy transfer (FRET) effects, which enabled selective drug release and monitoring drug delivery and release processes. Taking the hyperbranched polyamide amine (H-PAMAM) with intrinsic AIE effects as the core, poly(ethylene glycol) (PEG) was bridged on its periphery by dithiodipropionic acid. Then, through the host-guest interaction of PEG and α-cyclodextrin, the supramolecular nanoparticles with AIE effects were constructed to load the anticancer drug doxorubicin (DOX). The supramolecular assembly has sufficiently large DOX loading due to the abundant cavities formed by branched structures. The hyperbranched core H-PAMAM has strong fluorescence, and the dynamic track of drug carriers and the dynamic drug release process can be monitored by the AIE and FRET effects between H-PAMAM and DOX, respectively. Furthermore, the introduction of disulfide bonds and the pH sensitivity of H-PAMAM enable the achievement of rapid selective release of loaded DOX at the tumor while remaining stable under normal physiological conditions. In vitro cytotoxicity indicates that the drug-loaded supramolecular assembly has a good therapeutic effect on cancer. In addition, the H-PAMAM core is different from the traditional AIE functional group, which has no conjugated structure, such as a benzene ring, thereby providing better biocompatibility. This technology will have broad applications as a new drug delivery system.

Mucoadhesive S-protected thiolated cyclodextrin-iodine complexes: a promising strategy to prolong mucosal residence time of iodine.

AIM: The purpose of this study was to develop S-protected thiolated α-cyclodextrin-iodine complexes providing prolonged mucosal residence time and sustained release of the antimicrobial agent. MATERIALS & METHODS: First, L-cysteine was conjugated with 2-mercaptonicotinic acid to generate cysteine-2-mercaptonicotinic acid (Cys-MNA). Subsequently, α-CD was oxidized with NaIO4 and Cys-MNA was bound to the resulting aldehyde groups via reductive amination. Finally, iodine was incorporated into complex. RESULT: S-protected thiolated α-CD displayed 3804 µmol/g MNA groups. The inclusion constant (KC) between iodine and S-protected thiolated α-CD was 5.37 × 104 M-1. In vitro release of iodine was around 15% per hour, whereas mucoadhesive properties showed 38-fold improvement in mucoadhesion. The complex did not show cytotoxicity at a concentration of 0.5% (m/v). In addition, complexes exhibited pronounced antimicrobial activity against Staphylococcus aureus and Escherichia coli. CONCLUSION: According to these results, S-protected thiolated α-CD-iodine complex might be a promising novel formulation for the mucosal use of iodine.

Alpha-cyclodextrin inhibits cholesterol crystal-induced complement-mediated inflammation: A potential new compound for treatment of atherosclerosis.

BACKGROUND AND AIMS: Cholesterol crystal (CC)-induced inflammation is a critical step in the development of atherosclerosis. CCs activate the complement system and induce an inflammatory response resulting in phagocytosis of the CCs, production of reactive oxygen species (ROS) and release of cytokines. The cyclodextrin 2-hydroxypropyl-ß-cyclodextrin has been found to reduce CC-induced complement activation and induce regression of established atherosclerotic plaques in a mouse model of atherosclerosis, thus inhibition of complement with cyclodextrins is a potential new strategy for treatment of inflammation during atherosclerosis. We hypothesized that other cyclodextrins, like α-cyclodextrin, may have related functions. METHODS: The effect of cyclodextrins on CC-induced complement activation, phagocytosis, and production of ROS from granulocytes and monocytes was investigated by flow cytometry and ELISA. RESULTS: We showed that α-cyclodextrin strongly inhibited CC-induced complement activation by inhibiting binding of the pattern recognition molecules C1q (via IgM) and ficolin-2. The reduced CC-induced complement activation mediated by α-cyclodextrin resulted in reduced phagocytosis and reduced ROS production in monocytes and granulocytes. Alpha-cyclodextrin was the most effective inhibitor of CC-induced complement activation, with the reduction in deposition of complement activation products being significantly different from the reduction induced by 2-hydroxypropyl-ß-cyclodextrin. We also found that α-cyclodextrin was able to dissolve CCs. CONCLUSIONS: This study identified α-cyclodextrin as a potential candidate in the search for therapeutics to prevent CC-induced inflammation in atherosclerosis.

Study to Probe Subsistence of Host-Guest Inclusion Complexes of α and ß-Cyclodextrins with Biologically Potent Drugs for Safety Regulatory Dischargement.

Host-guest interaction of two significant drugs, phenylephrine hydrochloride and synephrine with α and ß-cyclodextrins were studied systematically. Initially two simple but reliable physicochemical techniques namely conductance and surface tension were employed to find out saturation concentration for the inclusion and its stoichiometry. The obtained 1:1 stoichiometry was further confirmed by two spectrometric methods, UV-Vis study and spectrofluorimetry. Significant shifts in IR stretching frequency also support the inclusion process. Relative stabilities of the inclusion complexes were established by the association constants obtained from UV-Vis spectroscopic measurements, program based mathematical calculation of conductivity data. Calculations of the thermodynamic parameters dictates thermodynamic feasibility of the inclusion process. Spectrofluorometric measurement scaffolds the UV-Vis spectroscopic measurement validating stability of the ICs once again. Mass spectroscopic measurement gives the molecular ion peaks corresponding to the inclusion complex of 1:1 molar ratio of host and guest molecules. The mechanism of inclusion was drawn by 1H-NMR and 2D ROESY spectroscopic analysis. Surface texture of the inclusion complexes was studied by SEM. Finally, the cytotoxic activities of the inclusion complexes were analyzed and found, Cell viability also balances for non-toxic behavior of the ICs. Moreover, all the studies reveal the formation of inclusion complexes of two ephedra free, alternatively emerging drugs (after their banned product having ephedra) SNP, PEH with α and ß-CD which enriches the drug delivery system with their regulatory release without any chemical modification.

A Combined Approach of NMR and Mass Spectrometry Techniques Applied to the α-Cyclodextrin/Moringin Complex for a Novel Bioactive Formulation †.

Moringin, obtained via enzymatic conversion of the glucosinolate precursor glucomoringin, is an uncommon member of the isothiocyanate class, and has been proven to possess a broad range of biological activities such as antitumor activity, protection against neurodegenerative disorders and bactericidal effects. Since moringin is weakly soluble in water and unstable in aqueous medium, cyclodextrins (CDs) were considered for the development of a new moringin formulation, with a view to improving its solubility and stability in aqueous solution for use as an anti-inflammatory. A combined structural study using proton nuclear magnetic resonance (¹H-NMR), diffusion-ordered spectroscopy (DOSY) and ion mobility mass spectrometry (IM-MS) is reported, highlighting the formation of a 1:1 α-CD/moringin inclusion complex. The association constant K was determined (1300 M-1 at 300 K). Completion of the structural characterization was performed by T-ROESY and MS/MS experiments, which evidenced the mode of penetration of moringin into α-CD. Finally, the "chaperone-like" properties of α-CD with respect to the stability of moringin have been highlighted.

Inhibitory effects of alpha-cyclodextrin and its derivative against sucrose-induced hyperglycemia in an in vivo evaluation system.

Cyclodextrins (CyDs) are cyclic oligosaccharides consisting of six to eight glucose residues. Administration of α-CyD (six glucose residues) inhibits sucrose-induced hyperglycemia in humans. Here we show that oral administration of α-CyD and dimethyl α-CyD suppresses sucrose-induced hyperglycemia in an in vivo evaluation system using silkworms. On the other hand, ß-CyD (seven glucose residues), γ-CyD (eight glucose residues), and their derivatives did not show the suppressive effect. These findings suggest that dimethyl α-CyD is a new inhibitor against sucrose-induced hyperglycemia and the silkworm system is useful for evaluation of suppressive activities of α-CyD derivatives against postprandial hyperglycemia.

Reduction-active polymeric prodrug micelles based on α-cyclodextrin polyrotaxanes for triggered drug release and enhanced cancer therapy.

As one of the medical polymers approved by US Food and Drug Administration (FDA), poly(ethylene glycol) has low toxicity, high stability, good biocompatibility, unique physical and chemical properties. Cyclodextrin is an ideal candidate as a drug carrier due to its special structures and characteristics. These two materials were successfully assembled through chemosynthesis in combination with the hydrophilic poly(ethylene glycol) methyl ether methacrylate (OEGMA) chain and hydrophobic polymeric camptothecin (CPT) chain by atom transfer radical polymerization (ATRP). The introduction of disulfide bond of monomer was aimed to realize reduction agent-triggered release of active CPT. The obtained amphipathic prodrug [(Denoted as PC-PCPT-b-POEGMA (PCCO)] could form nano-sized polymeric micelles, which could release more than 85% of the loaded CPT via triggered cleavage of the disulfide linker. The cellular co-localization study revealed the potential pathway of drug internalization. Moreover, the PCCO micelles showed good biocompatibility in vivo after intravenous injection on a mouse model. This new CPT-loaded prodrug system could be prepared with low cost, and showed efficient and controlled drug release and favorable biocompatibility, demonstrating a promising potential as a stimuli-responsive polymeric prodrug for future clinical applications.

Enhancement of iodinin solubility by encapsulation into cyclodextrin nanoparticles.

Phenazine is known to regroup planar nitrogen-containing heterocyclic compounds. It was used here to enhance the bioavailability of the biologically important compound iodinin, which is near insoluble in aqueous solutions. Its water solubility has led to the development of new formulations using diverse amphiphilic α-cyclodextrins (CDs). With the per-[6-desoxy-6-(3-perfluorohexylpropanethio)-2,3-di-O-methyl]-α-CD, we succeeded to get iodinin-loaded nanoformulations with good parameters such as a size of 97.9 nm, 62% encapsulation efficiency and efficient control release. The study presents an interesting alternative to optimizing the water solubility of iodinin by chemical modifications of iodinin.

Evaluation of the antibacterial and modulatory potential of α-bisabolol, ß-cyclodextrin and α-bisabolol/ß-cyclodextrin complex.

The present study aimed to evaluate the antibacterial and modulatory potential of α-bisabolol, ß-cyclodextrin and α-bisabolol/ß-cyclodextrin complex. The minimum inhibitory concentration was determined through the broth microdilution technique using the bacterial strains: Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa. The drugs norfloxacin, imipenem and gentamicin were used in the tests, and the compounds α-bisabolol and ß-cyclodextrin; all the compounds were diluted in DMSO. To obtain the minimum inhibitory concentration (MIC) a serial microdilution of the substances in volumes corresponding to the sub-inhibitory concentration (MIC/8), and microdilution with the antibiotic until the penultimate well were performed. The results showed that ß-cyclodextrin did not present synergistic effects when combined with the antibiotics. It was found that α-bisabolol presented a synergistic effect against S. aureus, when combined with the antibiotic norfloxacin. Moreover, α-bisabolol presented synergism against E. coli when combined with gentamicin. The results of this study show that α-bisabolol presents a modulatory synergistic effect for some antibiotics, as gentamicin, and this is an interesting result against multidrug resistant bacteria (MDR). By other side, the complexation of α-bisabolol with ß-cyclodextrin apparently reduces the modulatory effect, maybe due the polarity enhancement of the polarity of α-bisabolol, affecting the interaction of this compound with the cell membrane bilayer. However, more studies are necessary to demonstrate or not these interactions.

The α-cyclodextrin complex of the Moringa isothiocyanate suppresses lipopolysaccharide-induced inflammation in RAW 264.7 macrophage cells through Akt and p38 inhibition.

In the last decades, a growing need to discover new compounds for the prevention and treatment of inflammatory diseases has led researchers to consider drugs derived from natural products as a valid option in the treatment of inflammation-associated disorders. The purpose of the present study was to investigate the anti-inflammatory effects of a new formulation of Moringa oleifera-derived 4-(α-L-rhamnopyranosyloxy)benzyl isothiocyanate as a complex with alpha-cyclodextrin (moringin + α-CD) on lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells, a common model used for inflammation studies. In buffered/aqueous solution, the moringin + α-CD complex has enhanced the water solubility and stability of this isothiocyanate by forming a stable inclusion system. Our results showed that moringin + α-CD inhibits the production of inflammatory mediators in LPS-stimulated macrophages by down-regulation of pro-inflammatory cytokines (TNF-α and IL-1ß), by preventing IκB-α phosphorylation, translocation of the nuclear factor-κB (NF-κB), and also via the suppression of Akt and p38 phosphorylation. In addition, as a consequence of upstream inhibition of the inflammatory pathway following treatment with moringin + α-CD, the modulation of the oxidative stress (results focused on the expression of iNOS and nitrotyrosine) and apoptotic pathway (Bax and Bcl-2) was demonstrated. Therefore, moringin + α-CD appears to be a new relevant helpful tool to use in clinical practice for inflammation-associated disorders.

Dietary α-cyclodextrin reduces atherosclerosis and modifies gut flora in apolipoprotein E-deficient mice.

SCOPE: α-Cyclodextrin (α-CD), a cyclic polymer of glucose, has been shown to lower plasma cholesterol in animals and humans; however, its effect on atherosclerosis has not been previously described. METHODS AND RESULTS: apoE-knockout mice were fed either low-fat diet (LFD; 5.2% fat, w/w), or Western high fat diet (21.2% fat) containing either no additions (WD), 1.5% α-CD (WDA); 1.5% ß-CD (WDB); or 1.5% oligofructose-enriched inulin (WDI). Although plasma lipids were similar after 11 weeks on the WD vs. WDA diets, aortic atherosclerotic lesions were 65% less in mice on WDA compared to WD (P < 0.05), and similar to mice fed the LFD. No effect on atherosclerosis was observed for the other WD supplemented diets. By RNA-seq analysis of 16S rRNA, addition of α-CD to the WD resulted in significantly decreased cecal bacterial counts in genera Clostridium and Turicibacterium, and significantly increased Dehalobacteriaceae. At family level, Comamonadaceae significantly increased and Peptostreptococcaceae showed a negative trend. Several of these bacterial count changes correlated negatively with % atherosclerotic lesion and were associated with increased cecum weight and decreased plasma cholesterol levels. CONCLUSION: Addition of α-CD to the diet of apoE-knockout mice decreases atherosclerosis and is associated with changes in the gut flora.