Online preconcentration and determination of five alkaloids in Yangxinshi tablet by large-volume sample stacking and micelle to solvent stacking in cyclodextrin-modified electrokinetic chromatography.

The two-step preconcentration technique consisting of large-volume sample stacking (LVSS) and micelle to solvent stacking (MSS) in cyclodextrin-modified electrokinetic chromatography (CDEKC) was developed for the analysis of five cationic alkaloids in complex Chinese herbal prescriptions. Relevant parameters affecting separation and stacking performance were optimized separately. Under the optimal LVSS-MSS-CDEKC conditions, less analysis time and organic solvent were required, and the enhancement factors of analytes ranged from 12 to 15 compared with the normal CDEKC separation mode. Further, all validation results demonstrated good applicability and multiple alkaloids (epiberberine, dehydrocorydaline, jatrorrhizine, coptisine and berberine) in Yangxinshi tablet (YXST) have been simultaneously determined. This approach presents powerful potential for the determination of multiple components in complex preparations of Chinese medicine.

The soybean lecithin-cyclodextrin-vitamin E complex nanoparticles stabilized Pickering emulsions for the delivery of ß-carotene: Physicochemical properties and in vitro digestion.

In this work, soybean lecithin (LC) was used to modify ß-cyclodextrin (ß-CD) with hydrophobic fat chains to become amphiphilic (LC-CD), and vitamin E (VE) was encapsulated in former modified ß-CD complexes (LC-CD-VE), the new Pickering emulsions stabilized by LC-CD-VE and LC-CD complexes for the delivery of ß-carotene (BC) were created. The surface tension, contact angle, zeta potential, and particle size were used to assess the changes in complexes nanoparticles at various pH values. Furthermore, LC-CD-VE has more promise as Pickering emulsion stabilizer than LC-CD because of the smaller particle size (271.11 nm), proper contact angle (58.02°), and lower surface tension (42.49 mN/m). The interactions between ß-cyclodextrin, soybean lecithin, and vitamin E were confirmed using Fourier transform infrared spectroscopy (FTIR), X-ray diffraction (XRD), nuclear magnetic resonance (NMR), and thermogravimetric analysis (TGA). The durability of Pickering emulsions was examined at various volume fractions of the oil phase and concentrations of nanoparticles. Compared to the emulsion stabilized by LC-CD, the one stabilized by LC-CD-VE showed superior storage stability. Moreover, for the delivery of BC, Pickering emulsions stabilized by LC-CD and LC-CD-VE can outperform bulk oil and Tween 80 stabilized emulsions in terms of UV light stability, storage stability, and bioaccessibility. This work could offer fresh perspectives on stabilizer alternatives for Pickering emulsion delivery systems.

Formulation Studies with Cyclodextrins for Novel Selenium NSAID Derivatives.

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.

Carboxymethyl potato starch hydrogels encapsulated cyclodextrin metal-organic frameworks for enantioselective loading of S-naproxen and its programmed release.

A natural polysaccharide-based vehicle is facilely prepared for enantioselective loading of S-naproxen (S-NPX) and its programmed release. Cyclodextrin metal-organic frameworks (CD-MOF) are synthesized through the coordination of K+ with γ-cyclodextrin (γ-CD). Compared with R-NPX, the CD-MOF preferably combines with S-NPX, which can be confirmed by the thermodynamic calculations. The S-NPX loaded CD-MOF (CD-MOF-S-NPX) is grafted with disulfide bond (-S-S-) to improve its hydrophobicity, and the loaded S-NPX is further encapsulated in the chiral cavity of γ-CD by carboxymethyl potato starch (CPS) hydrogels. The intermolecular hydrogen bonding of the CPS hydrogels is prone to be destroyed in mildly basic media (∼pH 8.0), resulting in the swelling of the hydrogels; the -S-S- linkage in the vehicle can be cleaved in the presence of glutathione (GSH), leading to the collapse of the CD-MOF. Therefore, the programmed release of S-NPX can be achieved. Also in this work, the release kinetics is investigated, and the results indicate that the release of S-NPX is controlled by the Higuchi model.

Microneedle-mediated nose-to-brain drug delivery for improved Alzheimer's disease treatment.

Conventional transnasal brain-targeted drug delivery strategies are limited by nasal cilia clearance and the nasal mucosal barrier. To address this challenge, we designed dissolving microneedles combined with nanocarriers for enhanced nose-to-brain drug delivery. To facilitate transnasal administration, a toothbrush-like microneedle patch was fabricated with hyaluronic acid-formed microneedles and tannic acid-crosslinked gelatin as the base, which completely dissolved in the nasal mucosa within seconds leaving only the base, thereby releasing the loaded cyclodextrin-based metal-organic frameworks (CD-MOFs) without affecting the nasal cilia and nasal microbial communities. As nanocarriers for high loading of huperzine A, these potassium-structured CD-MOFs, reinforced with stigmasterol and functionalized with lactoferrin, possessed improved physical stability and excellent biocompatibility, enabling efficient brain-targeted drug delivery. This delivery system substantially attenuated H2O2- and scopolamine-induced neurocyte damage. The efficacy of huperzine A on scopolamine- and D-galactose & AlCl3-induced memory deficits in rats was significantly improved, as evidenced by inhibiting acetylcholinesterase activity, alleviating oxidative stress damage in the brain, and improving learning function, meanwhile activating extracellular regulated protein kinases-cyclic AMP responsive element binding protein-brain derived neurotrophic factor pathway. Moreover, postsynaptic density protein PSD-95, which interacts with two important therapeutic targets Tau and ß-amyloid in Alzheimer's disease, was upregulated. This fruitful treatment was further shown to significantly ameliorate Tau hyperphosphorylation and decrease ß-amyloid by ways including modulating beta-site amyloid precursor protein cleaving enzyme 1 and a disintegrin and metalloproteinase 10. Collectively, such a newly developed strategy breaks the impasse for efficient drug delivery to the brain, and the potential therapeutic role of huperzine A for Alzheimer's disease is further illustrated.

Highly selective whole-cell 25-hydroxyvitamin D3 synthesis using molybdenum-dependent C25-steroid dehydrogenase and cyclodextrin recycling.

BACKGROUND: The global prevalence of vitamin D (VitD) deficiency associated with numerous acute and chronic diseases has led to strategies to improve the VitD status through dietary intake of VitD-fortified foods and VitD supplementation. In this context, the circulating form of VitD3 (cholecalciferol) in the human body, 25-hydroxy-VitD3 (calcifediol, 25OHVitD3), has a much higher efficacy in improving the VitD status, which has motivated researchers to develop methods for its effective and sustainable synthesis. Conventional monooxygenase-/peroxygenase-based biocatalytic platforms for the conversion of VitD3 to value-added 25OHVitD3 are generally limited by a low selectivity and yield, costly reliance on cyclodextrins and electron donor systems, or by the use of toxic co-substrates. RESULTS: In this study, we used a whole-cell approach for biocatalytic 25OHVitD3 synthesis, in which a molybdenum-dependent steroid C25 dehydrogenase was produced in the denitrifying bacterium Thauera aromatica under semi-aerobic conditions, where the activity of the enzyme remained stable. This enzyme uses water as a highly selective VitD3 hydroxylating agent and is independent of an electron donor system. High density suspensions of resting cells producing steroid C25 dehydrogenase catalysed the conversion of VitD3 to 25OHVitD3 using either O2 via the endogenous respiratory chain or externally added ferricyanide as low cost electron acceptor. The maximum 25OHVitD3 titer achieved was 1.85 g L-1 within 50 h with a yield of 99%, which is 2.2 times higher than the highest reported value obtained with previous biocatalytic systems. In addition, we developed a simple method for the recycling of the costly VitD3 solubiliser cyclodextrin, which could be reused for 10 reaction cycles without a significant loss of quality or quantity. CONCLUSIONS: The established steroid C25 dehydrogenase-based whole-cell system for the value-adding conversion of VitD3 to 25OHVitD3 offers a number of advantages in comparison to conventional oxygenase-/peroxygenase-based systems including its high selectivity, independence from an electron donor system, and the higher product titer and yield. Together with the established cyclodextrin recycling procedure, the established system provides an attractive platform for large-scale 25OHVitD3 synthesis.

Effective Treatment of Knee Osteoarthritis Using a Nano-Enabled Drug Acupuncture Technology in Mice.

A nano-enabled drug delivery acupuncture technology (nd-Acu) is developed that is based on traditional acupuncture needles where the stainless-steel surface is designed to deliver various payload molecules. To create the nd-Acu platform, an electrochemistry procedure is used to attach methyl salicylate-modified cyclodextrin in which the sugar rings allow the encapsulation of structurally defined single or multiple payload molecules via an inclusion complexation process. Drug loading and release profile are first studied using fluorescent dyes abiotically and at intact animal level. nd-Acu allows more efficient dye loading and time-dependent release compared to pristine needles without cyclodextrin modification. Subsequently, a proof-of-principle efficacy study is conducted using the platform to load a local anesthetic, lidocaine, for the treatment of knee osteoarthritis (KOA) in mice. It is demonstrated that lidocaine-laden nd-Acu can effectively alleviate pain, reduce inflammation, and slow down KOA development biochemically and histologically. Hypothesis-driven and proteomic approaches are utilized to investigate the working mechanisms of lidocaine nd-Acu, indicating that the therapeutic outcome is attributed to the in vivo modulation of the HMGB1/TLR4 signaling pathway. The study also obtained preliminary evidence suggesting the involvement of mitochondria as well as small GTPase such as cdc42 during the treatment by lidocaine nd-Acu.

Ex Vivo Drug Screening Assay with Artificial Membranes: Characterizing Cholesterol Desorbing Competencies of Beta-Cyclodextrins.

Despite advancements in contemporary therapies, cardiovascular disease from atherosclerosis remains a leading cause of mortality worldwide. Supported lipid bilayers (SLBs) are membrane interfaces that can be constructed with varying lipid compositions. Herein, we use a solvent-assisted lipid bilayer (SALB) construction method to build SLB membranes with varying cholesterol compositions to create a lipid-sterol interface atop a piezoelectric sensor. These cholesterol-laden SLBs were utilized to investigate the mechanisms of various cholesterol-lowering drug molecules. Within a flow-cell, membranes with varying cholesterol content were exposed to cyclodextrins 2-hydroxypropyl-beta-cyclodextrin (HPßCD) and methyl-beta-cyclodextrin (MßCD). Quartz-crystal microgravimetry with dissipation monitoring (QCM-D) enabled the collection of in vitro, real-time changes in relative areal mass and dissipation. We define the cholesterol desorbing competency of a cyclodextrin species via measures of the rate of cholesterol removal, the rate of the transfer of membrane-bound cholesterol to drug-complexed cholesterol, and the binding strength of the drug to the cholesterol-ladened membrane. Desorption data revealed distinct cholesterol removal kinetics for each cyclodextrin while also supporting a model for the lipid-cholesterol-drug interface. We report that MßCD removes a quantity of cholesterol 1.61 times greater, with a speed 2.12 times greater, binding affinity to DOPC lipid interfaces 1.97 times greater, and rate of internal cholesterol transfer 3.41 times greater than HPßCD.

Modification of Dispersin B with Cyclodextrin-Ciprofloxacin Derivatives for Treating Staphylococcal.

To address the high tolerance of biofilms to antibiotics, it is urgent to develop new strategies to fight against these bacterial consortia. An innovative antibiofilm nanovector drug delivery system, consisting of Dispersin B-permethylated-ß-cyclodextrin/ciprofloxacin adamantyl (DspB-ß-CD/CIP-Ad), is described here. For this purpose, complexation assays between CIP-Ad and (i) unmodified ß-CD and (ii) different derivatives of ß-CD, which are 2,3-O-dimethyl-ß-CD, 2,6-O-dimethyl-ß-CD, and 2,3,6-O-trimethyl-ß-CD, were tested. A stoichiometry of 1/1 was obtained for the ß-CD/CIP-Ad complex by NMR analysis. Isothermal Titration Calorimetry (ITC) experiments were carried out to determine Ka, ΔH, and ΔS thermodynamic parameters of the complex between ß-CD and its different derivatives in the presence of CIP-Ad. A stoichiometry of 1/1 for ß-CD/CIP-Ad complexes was confirmed with variable affinity according to the type of methylation. A phase solubility study showed increased CIP-Ad solubility with CD concentration, pointing out complex formation. The evaluation of the antibacterial activity of CIP-Ad and the 2,3-O-dimethyl-ß-CD/CIP-Ad or 2,3,6-O-trimethyl-ß-CD/CIP-Ad complexes was performed on Staphylococcus epidermidis (S. epidermidis) strains. The Minimum Inhibitory Concentration (MIC) studies showed that the complex of CIP-Ad and 2,3-O-dimethyl-ß-CD exhibited a similar antimicrobial activity to CIP-Ad alone, while the interaction with 2,3,6-O-trimethyl-ß-CD increased MIC values. Antimicrobial assays on S. epidermidis biofilms demonstrated that the synergistic effect observed with the DspB/CIP association was partly maintained with the 2,3-O-dimethyl-ß-CDs/CIP-Ad complex. To obtain this "all-in-one" drug delivery system, able to destroy the biofilm matrix and release the antibiotic simultaneously, we covalently grafted DspB on three carboxylic permethylated CD derivatives with different-length spacer arms. The strategy was validated by demonstrating that a DspB-permethylated-ß-CD/ciprofloxacin-Ad system exhibited efficient antibiofilm activity.

Soybean lecithin and cholesterol-loaded cyclodextrin in combination to enhances the cryosurvival of dairy goat semen.

The objective of the study was to examine the effect of soy lecithin (SL) and cholesterol loaded cryclodestrin (CLC) on cryo-survival of sperm cryopreserved in the presence or absence of seminal plasma in Saanen dairy goats. Tris-based dilutions containing various concentrations of SL (0, 0.5%, 1.0% or 2.0%) and CLC (0, 2.0 g/L, 4.0 g/L or 6.0 g/L CLC) were used to cryopreserve Saanen dairy goat sperm. The quality of frozen-thawed sperm, including progressive motility, viability, acrosome and plasma membrane integrity, as well as fertility were detected. Results found that the optimal combination of the two cryoprotectants was 1.0% SL+4.0 g/L CLC, which significantly increased progressive motility, viability, acrosome and plasma membrane integrity of frozen thawed sperm. The impact of the two cryoprotectants in combination was not affected by the presence of seminal plasma. The conception rates obtained after artificial insemination using sperm cryopreserved with and without seminal plasma were 88.89% and 91.67% (P > 0.05), respectively. The respective values for average number of litter sizes were 1.55 ± 0.17 and 1.56 ± 0.21 (P > 0.05). Therefore, this study improved the cryopreservation efficiency of goat semen, enhanced the sperm cryosurvival, and layed a foundation for the wide application of frozen goat semen.

Cyclodextrin regulated natural polysaccharide hydrogels for biomedical applications-a review.

Cyclodextrin and its derivative (CDs) are natural building blocks for linking with other components to afford functional biomaterials. Hydrogels are polymer network systems that can form hydrophilic three-dimensional network structures through different cross-linking methods and are developing as potential materials in biomedical applications. Natural polysaccharide hydrogels (NPHs) are widely adopted in biomedical field with good biocompatibility, biodegradability, low cytotoxicity, and versatility in emulating natural tissue properties. Compared with conventional NPHs, CD regulated natural polysaccharide hydrogels (CD-NPHs) maintain good biocompatibility, while improving poor mechanical qualities and unpredictable gelation times. Recently, there has been increasing and considerable usage of CD-NPHs while there is still no review comprehensively introducing their construction, classification, and application of these hydrogels from the material point of view regarding biomedical fields. To draw a complete picture of the current and future development of CD-NPHs, we systematically overview the classification of CD-NPHs, and provide a holistic view on the role of CD-NPHs in different biomedical fields, especially in drug delivery, wound dressing, cell encapsulation, and tissue engineering. Moreover, the current challenges and prospects of CD-NPHs are discussed rationally, providing an insight into developing vibrant fields of CD-NPHs-based biomedicine, and facilitating their translation from bench to clinical medicine.

The COVID-19 Illness: Addressing the Current Treatment Limitations and Care Gaps with a Novel Alternative and Complementary Agent-the Glutathione-Cyclodextrin Complex.

We are approaching the fourth year of the COVID-19 pandemic. Although great progress has been made in addressing the SARS-CoV-2 infection, there are significant treatment limitations and care gaps that need to be addressed in order to more effectively treat patients critically ill with COVID-19 and the large population of patients with post-COVID symptoms. We highlight the significance of the cytokine storm in the immunothrombotic process of COVID-19 illness. Finally, we present scientific evidence of the utility of a novel complementary therapeutic agent, the glutathione-cyclodextrin complex, that will likely address those limitations and close those gaps. If confirmed by rigorous clinical trials, the complex will have a significant impact on the treatment of the entire spectrum of COVID-19 illness and contribute to the control or resolution of the COVID-19 pandemic.

Developing New Cyclodextrin-Based Nanosponges Complexes to Improve Vitamin D Absorption in an In Vitro Study.

Vitamin D plays an important role in numerous cellular functions due to the ability to bind the Vitamin D receptor (VDR), which is present in different tissues. Several human diseases depend on low vitamin D3 (human isoform) serum level, and supplementation is necessary. However, vitamin D3 has poor bioavailability, and several strategies are tested to increase its absorption. In this work, the complexation of vitamin D3 in Cyclodextrin-based nanosponge (CD-NS, in particular, ßNS-CDI 1:4) was carried out to study the possible enhancement of bioactivity. The ßNS-CDI 1:4 was synthesized by mechanochemistry, and the complex was confirmed using FTIR-ATR and TGA. TGA demonstrated higher thermostability of the complexed form. Subsequently, in vitro experiments were performed to evaluate the biological activity of Vitamin D3 complexed in the nanosponges on intestinal cells and assess its bioavailability without cytotoxic effect. The Vitamin D3 complexes enhance cellular activity at the intestinal level and improve its bioavailability. In conclusion, this study demonstrates for the first time the ability of CD-NS complexes to improve the chemical and biological function of Vitamin D3.

Evaluation of 6-OxP-CD, an Oxime-based cyclodextrin as a viable medical countermeasure against nerve agent poisoning: Experimental and molecular dynamic simulation studies on its inclusion complexes with cyclosarin, soman and VX.

The ability of the cyclodextrin-oxime construct 6-OxP-CD to bind and degrade the nerve agents Cyclosarin (GF), Soman (GD) and S-[2-[Di(propan-2-yl)amino]ethyl] O-ethyl methylphosphonothioate (VX) has been studied using 31P-nuclear magnetic resonance (NMR) under physiological conditions. While 6-OxP-CD was found to degrade GF instantaneously under these conditions, it was found to form an inclusion complex with GD and significantly improve its degradation (t1/2 ~ 2 hrs) relative over background (t1/2 ~ 22 hrs). Consequently, effective formation of the 6-OxP-CD:GD inclusion complex results in the immediate neutralization of GD and thus preventing it from inhibiting its biological target. In contrast, NMR experiments did not find evidence for an inclusion complex between 6-OxP-CD and VX, and the agent's degradation profile was identical to that of background degradation (t1/2 ~ 24 hrs). As a complement to this experimental work, molecular dynamics (MD) simulations coupled with Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) calculations have been applied to the study of inclusion complexes between 6-OxP-CD and the three nerve agents. These studies provide data that informs the understanding of the different degradative interactions exhibited by 6-OxP-CD with each nerve agent as it is introduced in the CD cavity in two different orientations (up and down). For its complex with GF, it was found that the oxime in 6-OxP-CD lies in very close proximity (PGF⋯OOxime ~ 4-5 Å) to the phosphorus center of GF in the 'downGF' orientation for most of the simulation accurately describing the ability of 6-OxP-CD to degrade this nerve agent rapidly and efficiently. Further computational studies involving the center of masses (COMs) for both components (GF and 6-OxP-CD) also provided some insight on the nature of this inclusion complex. Distances between the COMs (ΔCOM) lie closer in space in the 'downGF' orientation than in the 'upGF' orientation; a correlation that seems to hold true not only for GF but also for its congener, GD. In the case of GD, calculations for the 'downGD' orientation showed that the oxime functional group in 6-OxP-CD although lying in close proximity (PGD⋯OOxime ~ 4-5 Å) to the phosphorus center of the nerve agent for most of the simulation, adopts another stable conformation that increase this distance to ~ 12-14 Å, thus explaining the ability of 6-OxP-CD to bind and degrade GD but with less efficiency as observed experimentally (t1/2 ~ 4 hr. vs. immediate). Lastly, studies on the VX:6-OxP-CD system demonstrated that VX does not form a stable inclusion complex with the oxime-bearing cyclodextrin and as such does not interact in a way that is conducive to an accelerated degradation scenario. Collectively, these studies serve as a basic platform from which the development of new cyclodextrin scaffolds based on 6-OxP-CD can be designed in the development of medical countermeasures against these highly toxic chemical warfare agents.

Evaluation of deodorization techniques using cyclodextrins on the headspace volatiles and antioxidant properties of onion.

Sulphur-containing volatiles in onion produce unpleasant odors and this limit their usage in foods. To expand its application, several additives including α-cyclodextrin (α-CD), ß-cyclodextrin (ß-CD), 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD), and chitosan were added to onion solution and evaluated for their effect on sulphur-containing volatiles. Also, antioxidant property using 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay and oxidative stabilities in an oil-in-water (O/W) emulsion were carried out. The total volatile contents were decreased in the order of α-CD (50.1%), ß-CD (49.3%), HP-ß-CD (46.2%), and chitosan (7%). Meanwhile, HP-ß-CD showed the highest DPPH radical scavenging ability followed by ß-CD, α-CD, and chitosan with decreasing order. The ß-CD significantly enhanced the oxidative stability of the O/W emulsion, whereas α-CD and ß-HP-CD showed prooxidative behavior. Overall, ß-CD might be used as a sulphur-containing volatile decreasing agent, which could keep the antioxidant properties of onion in the O/W emulsion.

Natural deep eutectic solvents combined with cyclodextrins: A novel strategy for chokeberry anthocyanins extraction.

Innovative eco-friendly methods based on natural deep eutectic solvents (NaDES) coupled with ultrasound-assisted extraction were employed for chokeberry anthocyanins extractions. Nine different NaDES composed of choline chloride as a hydrogen bond acceptor and organic acids (lactic, citric, malic), sugars (glucose, fructose), polyols (glycerol, 1,2-propanediol, sorbitol), and an amide (urea) as hydrogen bond donors were screened. Malic acid-containing NaDES was selected for optimization extraction conditions (time, temperature, water in NaDES) by response surface methodology. Optimal conditions for simultaneously maximizing the anthocyanins extraction (cyanidin-3-O-glucoside, cyanidin-3-O-galactoside, cyanidin-3-O-arabinoside, total anthocyanins) were 42.7 °C, 90 min, and 40 % (w/w) water in NaDES. In the next stage of this study, the possibility to improve anthocyanins extraction at elevated temperatures by incorporating different concentrations of hydroxypropyl-ß-cyclodextrin into selected NaDES was investigated. The extraction was improved at hydroxypropyl-ß-cyclodextrin concentrations up to 3 % (w/w). To clarify the interaction of NaDES components and anthocyanins, a molecular dynamic simulation was conducted.

Dynamic nitric oxide/drug codelivery system based on polyrotaxane architecture for effective treatment of Candida albicans infection.

The low permeability of antifungal agents to fungal biofilms, which allows the continued survival of the fungus inside, is a key issue that makes fungal infections difficult to cure. Inspired by the unique dynamic molecule motion properties of the polyrotaxane (PR) nanomedicine, herein, a dynamic delivery system Clo@mPRP/NONOate was fabricated by co-loading nitric oxide (NO) and the antifungal drug clotrimazole (Clo) onto the α-cyclodextrin (α-CD) PR modified mesoporous polydopamine (mPDA) nanoparticles, in which pentaethylenehexamine (PEHA) was grafted to α-CDs. The cationic α-CDs endowed this dynamic NO/Clo codelivery system with the ability to effectively attach to fungal biofilms through electrostatic interaction, while the introduction of PRs with flexible molecule motion (slide and rotation of CDs) enhanced the permeability of nanoparticles to biofilms. Meanwhile, NO could effectively inhibit the formation of fungal hyphae, showing an dissipating effect on mature biofilms, and could be further combined with Clo to completely eradicate fungi inside the biofilms. In addition, the dynamic system Clo@mPRP/NONOate could efficiently and synergistically eliminate planktonic Candida albicans (C. albicans) in a safe and no toxic side effect manner, and effectively cured C. albicans-induced vaginal infection in mice. Therefore, this dynamic NO/Clo codelivery system provided an effective solution to the clinical treatment of C. albicans-induced vaginal infection, and the application prospect could even be extended to other microbial infectious diseases. STATEMENT OF SIGNIFICANCE: A dynamic codelivery system based on cationized cyclodextrin polyrotaxane combining nitric oxide and antifungal drugs clotrimazole was prepared to deal with the issue of clinical fungal biofilm infection. This dynamic codelivery system could be attached to the Candida albicans biofilms and penetrate into biofilm via flexible molecular mobility to effectively eradicate the fungi. This dynamic codelivery system could synergistically and efficiently eliminate planktonic-state Candida albicans, but did not show significant cytotoxicity to normal somatic cells.

Design and Optimization of Rivaroxaban-Cyclodextrin-Polymer Triple Complex Formulation with Improved Solubility.

Purpose: This study aimed to ensure the convenience of administration and reproducibility of efficacy, regardless of the meal, by improving the solubility of rivaroxaban (RIV). Methods: RIV is a non-vitamin K antagonist oral anticoagulants that exhibits a coagulation effect by directly inhibiting coagulation factor Xa. However, RIV has a very low solubility; therefore, it must be administered with a meal at high doses. We used a drug- hydroxypropyl-beta-cyclodextrin (CD)-water-soluble polymer triple complex (R-C-P complex) to solubilize RIV. Using Minitab, we evaluated the effect of each factor on RIV solubility and developed an optimal R-C-P complex formulation. The amount of CD, amount of polymer, and polymer type were set as the independent variables X1, X2, and X3, respectively. RIV solubility (Y1) and dissolution rate for 45 min in pH 4.5 medium (Y2) and pH 1.2 medium (Y3) were set as response variables. Results: The most efficient RIV solubilization effect was obtained from the composition using CD and HPMC 2208, and physicochemical properties and dissolution parameters were analyzed. RIV in the R-C-P complex was present in an amorphous form and showed high solubility. Unlike commercial products, it showed a 100% dissolution rate. The R-C-P complex formulation secured high RIV solubility and 100% release regardless of pH. Conclusion: The results imply that high-dose RIV can be administered regardless of the meal, reducing the risk of changing the drug effect due to the patient's administration mistake.

Green Extraction of Forsythoside A, Phillyrin and Phillygenol from Forsythia suspensa Leaves Using a ß-Cyclodextrin-Assisted Method.

In this study, a green process of ß-cyclodextrin (ß-CD)-assisted extraction of active ingredients from Forsythia suspensa leaves was developed. Firstly, the optimal process of extraction was as follows: the ratio between Forsythia suspensa leaves and ß-CD was 3.61:5, the solid-liquid ratio was 1:36.3, the temperature was 75.25 °C and the pH was 3.94. The yields of forsythoside A, phillyrin and phillygenol were 11.80 ± 0.141%, 5.49 ± 0.078% and 0.319 ± 0.004%, respectively. Then, the structure characteristics of the ß-CD-assisted extract of Forsythia suspensa leaves (FSE-ß-CD) were analyzed using powder X-ray diffraction (PXRD), Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and molecular docking to demonstrate that the natural active products from Forsythia suspensa leaves had significant interactions with the ß-CD. Additionally, the loss of forsythoside A from aqueous FSE-CD at 80 °C was only 12%, compared with Forsythia suspensa leaf extract (FSE) which decreased by 13%. In addition, the aqueous solubility of FSE-CD was significantly increased to 70.2 g/L. The EC50 for scavenging DPPH and ABTS radicals decreased to 28.98 ug/mL and 25.54 ug/mL, respectively. The results showed that the ß-CD-assisted extraction process would be a promising technology for bioactive compounds extracted from plants.

Is It Possible to Improve the Bioavailability of Resveratrol and Polydatin Derived from Polygoni cuspidati Radix as a Result of Preparing Electrospun Nanofibers Based on Polyvinylpyrrolidone/Cyclodextrin?

The low bioavailability of resveratrol and polydatin obtained from Polygoni cuspidati extract limits the application of their pro-health properties. While nanofibers have attracted increasing attention in nutrition delivery due to their special properties, including an increase in the dissolution and permeability, which affects the bioavailability. Therefore, it is justified to obtain nanofibers from Polygoni cuspidati extract, which showed antioxidant and anti-inflammatory properties as a result of a presence of stilbene analogs in the Polygoni cuspidati extract (especially resveratrol and polydatin). In the first stage of the work, using the Design of Experiment (DoE) approach, the Polygoni cuspidati extract (70% of methanol, temperature 70 °C and 4 cycles) was obtained, which showed the best antioxidant and anti-inflammatory properties. Using the Polygoni cuspidati extract as a substrate, nanofibers were obtained by electrospinning. The identification of nanofibers was confirmed on the basis of the analysis of changes in XRPD diffractograms, SEM picture and FTIR-ATR spectra. Obtaining nanofibers from the Polygoni cuspidati extract significantly improved the solubility of resveratrol and polydatin (approx. 6-fold comparing to pure substance). As a consequence, the penetration coefficients of both tested resveratrol and polydatin also increased. The proposed strategy for the preparation of nanofibers from the Polygoni cuspidati extract is an innovative approach to better use the synergy of biological action of active compounds present in extracts. It is especially during the development of nutraceuticals based on the use of selected stilbenes.