Screening of Astec® CHIRALDEX™ G-PN and LIPODEX™ D gas chromatography columns for enantioseparation of amphetamine derivatives.

Among different substance classes, New Psychoactive Substances (NPS) comprise chiral amphetamines for stimulant and empathic effects. There is little knowledge in terms of clinical studies about possibly different effects of the two enantiomers of novel amphetamine derivatives. For this reason, there is a big demand for enantioseparation method development of this new substance class. Regarding gas chromatography, cyclodextrins proved to be effective for enantioseparation of NPS. In our attempt, an Astec® Chiraldex™ G-PN column containing 2,6-di-O-pentyl-3-propionyl-γ-cyclodextrin and a Lipodex™ D column containing heptakis-(2,6-di-O-pentyl-O-acetyl)-ß-cyclodextrin as chiral selector served as stationary phases in a Shimadzu GCMS-QP2010 SE system. Because of the special coating, maximum temperature is limited to 200 °C isothermal or 220 °C in programmed mode. To ensure detection, trifluoroacetic anhydride (TFAA) was used to increase sample volatility.1 As a result, 35 amphetamines were tested as their TFAA-derivatives. A screening method with a temperature gradient from 140 °C to 200 °C at a heating ramp of 1 °C per minute and final time of 5 min, showed baseline separation for seven and partial separations for 16 trifluoro acetylated amphetamines using the Chiraldex™ G-PN column. Six baseline and nine partial separations were observed with the Lipodex™ D column, respectively.

A non-lipid nucleic acid delivery vector with dendritic cell tropism and stimulation.

Rationale: Nucleic acid constructs are commonly used for vaccination, immune stimulation, and gene therapy, but their use in cancer still remains limited. One of the reasons is that systemic delivery to tumor-associated antigen-presenting cells (dendritic cells and macrophages) is often inefficient, while off-target nucleic acid-sensing immune pathways can stimulate systemic immune responses. Conversely, certain carbohydrate nanoparticles with small molecule payloads have been shown to target these cells efficiently in the tumor microenvironment. Yet, nucleic acid incorporation into such carbohydrate-based nanoparticles has proven challenging. Methods: We developed a novel approach using cross-linked bis succinyl-cyclodextrin (b-s-CD) nanoparticles to efficiently deliver nucleic acids and small-molecule immune enhancer to phagocytic cells in tumor environments and lymph nodes. Our study involved incorporating these components into the nanoparticles and assessing their efficacy in activating antigen-presenting cells. Results: The multi-modality immune stimulators effectively activated antigen-presenting cells and promoted anti-tumor immunity in vivo. This was evidenced by enhanced delivery to phagocytic cells and subsequent immune response activation in tumor environments and lymph nodes. Conclusion: Here, we describe a new approach to incorporating both nucleic acids and small-molecule immune enhancers into cross-linked bis succinyl-cyclodextrin (b-s-CD) nanoparticles for efficient delivery to phagocytic cells in tumor environments and lymph nodes in vivo. These multi-modality immune stimulators can activate antigen-presenting cells and foster anti-tumor immunity. We argue that this strategy can potentially be used to enhance anti-tumor efficacy.

Synthesis of cyclodextrin-based polyrotaxanes and polycatenanes for supramolecular pharmaceutical sciences.

Cyclodextrins (CDs) are essential in the pharmaceutical industry and have long been used as food and pharmaceutical additives. CD-based interlocked molecules, such as rotaxanes, polyrotaxanes, catenanes, and polycatenanes, have been synthesized and have attracted considerable attention in supramolecular chemistry. Among them, CD polyrotaxanes have been employed as slide-ring materials and biomaterials. CD polycatenanes are new materials; therefore, to date, no examples of applied research on CD polycatenanes have been reported. Consequently, we expect that applied research on CD polycatenanes will accelerate in the future. This review article summarizes the syntheses and structural analyses of CD polyrotaxanes and polycatenanes to facilitate their applications in the pharmaceutical industry. We believe that this review will promote further research on CD-based interlocked molecules.

Biocompatible hydrophobic cross-linked cyclodextrin-based metal-organic framework as quercetin nanocarrier for enhancing stability and controlled release.

Cyclodextrin-based metal-organic framework (CD-MOF) has been widely used in various delivery systems due to its excellent edibility and high drug loading capacity. However, its typically bulky size and high brittleness in aqueous solutions pose significant challenges for practical applications. Here, we proposed an ultrasonic-assisted method for rapid synthesis of uniformly-sized nanoscale CD-MOF, followed by its hydrophobic modification through ester bond cross-linking (Nano-CMOF). Proper ultrasound treatment effectively reduced particle size to nanoscale (393.14 nm). Notably, carbonate ester cross-linking method significantly improved water stability without altering its cubic shape and high porosity (1.3 cm3/g), resulting in a retention rate exceeding 90% in various media. Furthermore, the loading of quercetin did not disrupt cubic structure and showcased remarkable storage stability. Nano-CMOF achieved controlled release of quercetin in both aqueous environments and digestion. Additionally, Nano-CMOF demonstrated exceptional antioxidant (free radical scavenging 82.27%) and biocompatibility, indicating its significant potential as novel nutritional delivery systems in food and biomedical fields.

Simultaneous Rosiglitazone Release and Low-Density Lipoprotein Removal by Chondroitin Sodium Sulfate/Cyclodextrin/Poly(acrylic acid) Composite Adsorbents for Atherosclerosis Therapy.

Atherosclerosis (AS) is characterized by the accumulation of substantial low-density lipoprotein (LDL) and inflammatory response. Hemoperfusion is commonly employed for the selective removal of LDL from the body. However, conventional hemoperfusion merely focuses on LDL removal and does not address the symptom of plaque associated with AS. Based on the LDL binding properties of acrylated chondroitin sodium sulfate (CSA), acrylated beta-cyclodextrin (CD) and acrylic acid (AA), along with the anti-inflammatory property of rosiglitazone (R), the fabricated AA-CSA-CD-R microspheres could simultaneously release R and facilitate LDL removal for hemoperfusion. The AA and CSA offer electrostatic adsorption sites for LDL, while the CD provides hydrophobic adsorption sites for LDL and weak binding sites for R. According to the Sips model, the maximum static LDL adsorption capacity of AA-CSA-CD-R is determined to be 614.73 mg/g. In dynamic simulated perfusion experiments, AA-CSA-CD-R exhibits an initial cycle LDL adsorption capacity of 150.97 mg/g. The study suggests that the weakened inflammatory response favors plaque stabilization. The anti-inflammatory property of the microspheres is verified through an inflammation model, wherein the microsphere extracts are cocultured with mouse macrophages. Both qualitative analysis of iNOS\TNF-α and quantitative analysis of IL-6\TNF-α collectively demonstrate the remarkable anti-inflammatory effect of the microspheres. Therefore, the current study presents a novel blood purification treatment of eliminating pathogenic factors and introducing therapeutic factors to stabilize AS plaque.

Dynamic RGD ligands derived from highly mobile cyclodextrins regulate spreading and proliferation of endothelial cells to promote vasculogenesis.

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.

On Interactions of Sulfamerazine with Cyclodextrins from Coupled Diffusometry and Toxicity Tests.

This scientific study employs the Taylor dispersion technique for diffusion measurements to investigate the interaction between sulfamerazine (NaSMR) and macromolecular cyclodextrins (ß-CD and HP-ß-CD). The results reveal that the presence of ß-CD influences the diffusion of the solution component, NaSMR, indicating a counterflow of this drug due to solute interaction. However, diffusion data indicate no inclusion of NaSMR within the sterically hindered HP-ß-CD cavity. Additionally, toxicity tests were conducted, including pollen germination (Actinidia deliciosa) and growth curve assays in BY-2 cells. The pollen germination tests demonstrate a reduction in sulfamerazine toxicity, suggesting potential applications for this antimicrobial agent with diminished adverse effects. This comprehensive investigation contributes to a deeper understanding of sulfamerazine-cyclodextrin interactions and their implications for pharmaceutical and biological systems.

Transport Properties in Multicomponent Systems Containing Cyclodextrins and Nickel Ions.

In this work, we propose a comprehensive experimental study of the diffusion of nickel ions in combination with different cyclodextrins as carrier molecules for enhanced solubility and facilitated transport. For this, ternary mutual diffusion coefficients measured by Taylor dispersion method are reported for aqueous solutions containing nickel salts and different cyclodextrins (that is, α-CD, ß-CD, and γ-CD) at 298.15 K. A combination of Taylor dispersion and other methods, such as UV-vis spectroscopy, will be used to obtain complementary information on these systems. The determination of the physicochemical properties of these salts with CDs in aqueous solution provides information that allows us to understand solute-solvent interactions, and gives a significant contribution to understanding the mechanisms underlying diffusional transport in aqueous solutions, and, consequently, to mitigating the potential toxicity associated with these metal ions. For example, using mutual diffusion data, it is possible to estimate the number of moles of each ion transported per mole of the cyclodextrin driven by its own concentration gradient.

Cyclodextrins: Properties and Applications.

Cyclodextrins (CDs) are cyclic oligosaccharides that contain at least six d-(+)-glucopyranose units linked by α-(1, 4) glucosidic bonds [...].

Exploring Cyclodextrin-Based Nanosponges as Drug Delivery Systems: Understanding the Physicochemical Factors Influencing Drug Loading and Release Kinetics.

Cyclodextrin-based nanosponges (CDNSs) are complex macromolecular structures composed of individual cyclodextrins (CDs) and nanochannels created between cross-linked CD units and cross-linkers. Due to their unique structural and physicochemical properties, CDNSs can possess even more beneficial pharmaceutical features than single CDs. In this comprehensive review, various aspects related to CDNSs are summarized. Particular attention was paid to overviewing structural properties, methods of synthesis, and physicochemical analysis of CDNSs using various analytical methods, such as DLS, PXRD, TGA, DSC, FT-IR, NMR, and phase solubility studies. Also, due to the significant role of CDNSs in pharmaceutical research and industry, aspects such as drug loading, drug release studies, and kinetics profile evaluation of drug-CDNS complexes were carefully reviewed. The aim of this paper is to find the relationships between the physicochemical features and to identify crucial characteristics that are influential for using CDNSs as convenient drug delivery systems.

Synergistic applications of cyclodextrin-based systems and metal-organic frameworks in transdermal drug delivery for skin cancer therapy.

This review article explores the innovative field of eco-friendly cyclodextrin-based coordination polymers and metal-organic frameworks (MOFs) for transdermal drug delivery in the case of skin cancer therapy. We critically examine the significant advancements in developing these nanocarriers, with a focus on their unique properties such as biocompatibility, targeted drug release, and enhanced skin permeability. These attributes are instrumental in addressing the limitations inherent in traditional skin cancer treatments and represent a paradigm shift towards more effective and patient-friendly therapeutic approaches. Furthermore, we discuss the challenges faced in optimizing the synthesis process for large-scale production while ensuring environmental sustainability. The review also emphasizes the immense potential for clinical applications of these nanocarriers in skin cancer therapy, highlighting their role in facilitating targeted, controlled drug release which minimizes systemic side effects. Future clinical applications could see these nanocarriers being customized to individual patient profiles, potentially revolutionizing personalized medicine in oncology. With further research and clinical trials, these nanocarriers hold the promise of transforming the landscape of skin cancer treatment. With this study, we aim to provide a comprehensive overview of the current state of research in this field and outline future directions for advancing the development and clinical application of these innovative nanocarriers.

Covalent modification of γ-cyclodextrin with geraniol: An antibacterial agent with good thermal stability, solubility and biocompatibility.

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.

Multifunctionality of cyclodextrin-based polymeric nanoparticulate delivery systems for chemotherapeutics, combination therapy, and theranostics.

As cancer being the most difficult disease to treat, different kinds of medications and therapeutic approaches have been prominently developed by scientists. For certain families of drugs, such as immuno-therapeutics or antibody-drug conjugates, efficient delivery systems are required during administration to protect the drugs from chemical degradation or biological inactivation. Delivery systems with the ability to carry different therapeutics or diagnostic agents or both, hold promising potential to tackle the abnormalities behind cancer. In this context, this review provides updated insights on how cyclodextrin-based polymeric nanosystems have become an effective treatment approach against cancer. Cyclodextrins (CDs) are natural oligosaccharides that are famously exploited in pharmaceutical research due to their exceptional quality of entrapping water-insoluble molecules inside their hydrophobic core and providing enhanced solubility with the help of their hydrophilic exterior. Combining the properties of CDs with polymeric nanoparticles (PNPs) brings out excellent versatile and tunable profiles, thanks to the submicron-sized PNPs. By introducing the significance of CD as a delivery system, a collective discussion on different binding approaches and release mechanisms of CD-drug complexation, followed by their characterization studies has been done in this review. Further, in light of recent studies, the article majorly focuses on conveying how promoting CD to a polymeric and nanoscale elevates the multifunctional advantages against cancer that can be successfully applied in combination therapy and theranostics. Moreover, CD-based delivery systems including CALAA-01, CRLX101, and CRLX301, have demonstrated improved tumor targeting, reduced side effects, and prolonged drug release in preclinical studies and clinical trials.

Encapsulation of 4-terpineol with ß-cyclodextrin: Inclusion mechanism, characterization and relative humidity-triggered release.

4-Terpineol (4-TA), a typical monocyclic monoterpene essential oil compound with important biological activities, poor stability and solubility severely hamper its biological activities. To date, ß-cyclodextrin (ß-CD) encapsulating essential oil to form inclusion complexes (ICs) is considered as a satisfactory treatment. Nevertheless, the detailed inclusion mechanism of ß-CD for 4-TA especially the behavior of 4-TA during inclusion formation have not available yet. Herein, 4-TA/ß-CD ICs were successfully synthesized by the co-precipitation method, and hydrogen bonds and hydrophobic interactions played a key role in the formation of ICs, and the isopropyl of 4-TA entered the cavity through the wide rim of ß-CD. Moreover, the release profile demonstrated that high RH (85 % and 99 %) triggered the release of TA from ICs. This study suggests the great potential of cyclodextrin inclusion strategy for improving the stability and sustained release of 4-TA in food preservation application.

Application of sodium sulfobutylether-ß-cyclodextrin based on encapsulation.

Sodium Sulfobutylether-ß-cyclodextrin (SBE-ß-CD) is a derivative of ß-cyclodextrin, characterized by its stereo structure, which closely resembles a truncated cone with a hydrophobic internal cavity. The solubility of insoluble substances within the hydrophobic cavity is significantly enhanced, reducing contact between the guest and the environment. Consequently, SBE-ß-CD is frequently employed as a co-solvent and stabilizer. As the research progresses, it has been observed that the inclusion of SBE-ß-CD is reversible and competitive. Besides, some inclusion complexes undergo distinct physicochemical property alterations compared to the guests. Additionally, certain guests exhibit varying inclusions with SBE-ß-CD at different concentrations. These features have contributed to the expanding applications. SBE-ß-CD finds widespread application in pharmaceutics as a protective agent and pKa regulator, in pharmaceutical analysis as a chiral substance separator, and in biomedical engineering for encapsulating dyes and modifying sensors. The article will elaborate in detail on the physicochemical properties of SBE-ß-CD, encapsulation principles, and factors influencing the formation of inclusion complexes. Furthermore, the review focuses on the application of SBE-ß-CD through encapsulation in pharmaceutics, pharmaceutical analysis, and biomedical engineering. Finally, the prospects and potential applications of SBE-ß-CD are discussed.

Asiatic acid cyclodextrin inclusion micro-cocrystal for insoluble drug delivery and acute lung injury therapy enhancement.

BACKGROUND: Acute lung injury (ALI) is a fatal respiratory disease caused by overreactive immune reactions (e.g., SARS-CoV-2 infection), with a high mortality rate. Its treatment is often compromised by inefficient drug delivery barriers and insufficient potency of the currently used drugs. Therefore, developing a highly effective lung-targeted drug delivery strategy is a pressing clinical need. RESULTS: In this study, the micro-sized inclusion cocrystal of asiatic acid/γ-cyclodextrin (AA/γCD, with a stoichiometry molar ratio of 2:3 and a mean size of 1.8 µm) was prepared for ALI treatment. The dissolution behavior of the AA/γCD inclusion cocrystals followed a "spring-and-hover" model, which meaned that AA/γCD could dissolve from the cocrystal in an inclusion complex form, thereby promoting a significantly improved water solubility (nine times higher than free AA). This made the cyclodextrin-based inclusion cocrystals an effective solid form for enhanced drug absorption and delivery efficiency. The biodistribution experiments demonstrated AA/γCD accumulated predominantly in the lung (Cmax = 50 µg/g) after systemic administration due to the micron size-mediated passive targeting effect. The AA/γCD group showed an enhanced anti-inflammatory therapeutic effect, as evidenced by reduced levels of pro-inflammatory cytokines in the lung and bronchoalveolar lavage fluids (BALF). Histological examination confirmed that AA/γCD effectively inhibited inflammation reactions. CONCLUSION: The micro-sized inclusion cocrystals AA/γCD were successfully delivered into the lungs by pulmonary administration and had a significant therapeutic effect on ALI.

Comparative Analysis of the Structure and Pharmacological Properties of Some Piperidines and Host-Guest Complexes of ß-Cyclodextrin.

Pain and anesthesia are a problem for all physicians. Scientists from different countries are constantly searching for new anesthetic agents and methods of general anesthesia. In anesthesiology, the role and importance of local anesthesia always remain topical. In the present work, a comparative analysis of the results of pharmacological studies on models of the conduction and terminal anesthesia, as well as acute toxicity studies of the inclusion complex of 1-methyl-4-ethynyl-4-hydroxypiperidine (MEP) with ß-cyclodextrin, was carried out. A virtual screening and comparative analysis of pharmacological activity were also performed on a number of the prepared piperidine derivatives and their host-guest complexes of ß-cyclodextrin to identify the structure-activity relationship. Various programs were used to study biological activity in silico. For comparative analysis of chemical and pharmacological properties, data from previous works were used. For some piperidine derivatives, new dosage forms were prepared as beta-cyclodextrin host-guest complexes. Some compounds were recognized as promising local anesthetics. Pharmacological studies have shown that KFCD-7 is more active than reference drugs in terms of local anesthetic activity and acute toxicity but is less active than host-guest complexes, based on other piperidines. This fact is in good agreement with the predicted results of biological activity.

Enhancement of ß-Cyclodextrin Production Using a Glycogen Debranching Enzyme from Saccharolobus solfataricus STB09.

Efficient production of cyclodextrins (CDs) has always been challenging. CDs are primarily produced from starch via cyclodextrin glycosyltransferase (CGTase), which acts on α-1,4 glucosidic bonds; however, α-1,6 glucosidic bonds in starch suppress the enzymatic production of CDs. In this study, a glycogen debranching enzyme from Saccharolobus solfataricus STB09 (SsGDE) was utilized to promote the production of ß-CD by hydrolyzing α-1,6 glucosidic bonds. The addition of SsGDE (750 U/g of starch) at the liquefaction stage remarkably improved the ß-CD yield, with a 43.9% increase. Further mechanism exploration revealed that SsGDE addition could hydrolyze specific branches with less generation of byproducts, thereby promoting CD production. The chain segments of a degree of polymerization ≥13 produced by SsGDE debranching could also be utilized by ß-CGTase to convert into CDs. Overall, these findings proposed a new approach of combining SsGDE with ß-CGTase to enhance the CD yield.

Synthesis, characterization, molecular modeling, binding energies of ß-cyclodextrin-inclusion complexes of quercetin: Modification of photo physical behavior upon ß-CD complexation.

We prepared a naturally occurring flavanoid namely quercetin from tea leaves and analyzed by Absorption, Emission, FT-IR, 1H, 13C nmr spectra and ESI-MS analysis. The inclusion behavior of quercetin in cyclodextrins like α-, ß-, γ-, per-6-ABCD and mono-6-ABCD cavities were supported such as UV-vis., Emission, FT-IR and ICD spectra and energy minimization studies. From the absorption and emission results, the type of complexes formed were found to depend on stoichiometry of Host:Guest. FT-IR data of CD complexes of quercetin supported inclusion complex formation of the substrate with α-, ß- and γ-CDs. The inclusion of host-guest complexation of quercetin with α-, ß-, γ-CDs, per-6-ABCD and mono-6-ABCDs provides very valuable information about the CD:quercetin complexes, the study also shows that ß-CD complexation improves water solubility, chemical stability and bioavailability of quercetin. Besides, phase solubility studies also supported the formation of 1:1 drug-CD soluble complexes. All these spectral results provide insight into the binding behavior of substrate into CD cavity in the order per-6-ABCD > Mono-6-ABCD > γ-CD > ß-CD > α-CD. The proposed model also finds strong support from the fact with excess CD this exciton coupling disappears indicates the formation of only 1:1 complex.

Influence of degree of substitution on the hydroxypropyl-ß-cyclodextrin complexation with rifampicin in water solution: a molecular simulation.

CONTEXT: Hydroxypropyl-ß-cyclodextrin (HPßCD) is one of the derivatized cyclodextrins most widely used as an excipient in the pharmaceutical industry, for its capacity to improve certain drugs properties. Different configurations of HPßCD are possible depending on the number and location of the 2-hydroxypropyl groups substituted on the glucose rings. Rifampicin has become the most commonly clinically used antibiotic against tuberculosis in recent years, despite its low solubility and variable bioavailability. Different techniques and materials have been proposed to enhance the properties of rifampicin: cyclodextrin complexation is one of them. The van der Waals term was the main contribution to the interaction energy, which then decisively conditioned the complex configurations. The size of rifampicin did not allow the whole molecule to fit into the host. Moreover, interaction energy was much greater when the guest was located near each rim of HPßCD, where rifampicin was partially included in the cavity and formed inclusion complexes. The piperazine tail of rifampicin was included inside the host in minimum energy structures and the guest was situated near the primary rim of HPßCD in most cases, although the complex configurations depended on the degree of substitution. METHODS: A molecular mechanics simulation based on the GROMOS 53A6 force field was applied in this work to study the inclusion complexes formed by twelve configurations of HPßCD, with different degrees of substitution and rifampicin in water solution. We determined the penetration potential, the complex structures with minimum energies, the possibility of forming inclusion complexes other than those of minimum energies and potential energy surfaces.