Randomly Methylated Beta-cyclodextrin Research Articles

In vivo assessment of tumor targeting potential of 68Ga-labelled randomly methylated beta-cyclodextrin (RAMEB) and 2-hydroxypropyl-β-cyclodextrin (HPβCD) using positron emission tomography

Cyclodextrin derivates (CyDs) can form complexes with cyclooxygenase-2 induced tumor promoting prostaglandin E2 (PGE2). Based on our previous observations, 68Ga-labelled CyDs may represent promising radiopharmaceuticals in the positron emission tomography (PET) diagnostics of PGE2 positive tumors. We aimed at evaluating the tumor-targeting potential of 68Ga-NODAGA conjugated randomly methylated beta-cyclodextrin (68Ga-NODAGA-RAMEB) and 2-hydroxypropyl-β-cyclodextrin (68Ga-NODAGA-HPβCD) using in vivo PET imaging with experimental tumor models. Tumor radiopharmaceutical uptake was assessed applying PET and gamma counter in vivo and ex vivo respectively, following the administration of 18FDG, 68Ga-NODAGA-RAMEB or 68Ga-NODAGA-HPβCD via the lateral tail vein to the subsequent tumor-bearing animals: HT1080, A20, PancTu-1, BxPC3, B16-F10, Ne/De and He/De. All investigated tumors were identifiable with both 68Ga-labelled CyDs; however, in vivo results, in correlation with the ex vivo data, revealed that the PGE2 positive BxPC3, A20, Ne/De and He/De tumors presented the highest accumulation. In case of HT1080, A20, B16-F10 tumors significant differences were encountered between the accumulations of both 68Ga-labelled radiopharmaceuticals of the same tumor. Subcutaneously and the orthotopically transplanted Ne/De tumors differed significantly (p ≤ 0.01) regarding tracer uptake. 68Ga-labelled CyDs may open a novel field in the PET diagnostics of PGE2 positive primary tumors and metastases.

In vivo investigation of Gallium-68 and Bismuth-205/206 labeled beta cyclodextrin for targeted alpha therapy of prostaglandin E2 receptor-expressing tumors in mice

Prostaglandin E2 (PGE2) molecule and its receptors play an important role in the development of malignancies and metastases therefore PGE2 may play a crucial role in the diagnosis and a new therapeutic target in the field of radionuclide therapy of PGE2-positive tumors. PGE2 form complexes with RAMEB (randomly-methylated-beta-cyclodextrin) with high affinity therefore the aim of this present study was to synthesize a PGE2-specific DOTAGA-RAMEB, which can be labeled with diagnostic and therapeutic isotopes also and binds to PGE2-positive tumors. DOTAGA-RAMEB was labeled with 68Ga and 205/206Bi radionuclides and their radiochemical purity (RCP%), partition coefficient (logP values), and in vitro and in vivo stability were determined. For the assessment of the biological properties and the PGE2 specificity of [68Ga]Ga-DOTAGA-RAMEB and [205/206Bi]Bi-DOTAGA-RAMEB in vivo PET imaging and ex vivo biodistribution studies were performed using healthy control and PGE2-positive BxPC-3 tumor-bearing CB17 SCID mice. The RCP% of the newly synthesized [68Ga]Ga-DOTAGA-RAMEB and [205/206Bi]Bi-DOTAGA-RAMEB was higher than 98 %. In vivo studies showed that the tumor-to-background ratio of [68Ga]Ga-DOTAGA-RAMEB was 2.5 ± 0.2 as a result BxPC-3 tumors were clearly identified on PET images. Beside this the ex vivo biodistribution studies showed that the accumulation rate of [68Ga]Ga-DOTAGA-RAMEB and [205/206Bi]Bi-DOTAGA-RAMEB was similar in the PGE2-positive BxPC-3 tumors.

Simultaneously enhanced surfactant flushing of diesel contaminated soil column and qualified emission of effluent

Seven surfactants were selected as candidate agents for in situ soil column flushing. Column flushing lacks the interaction between surfactants and contaminants, so efficiency is not easy to improve. Microbubbles generated in situ may adhere to the contaminant diesel. Thereafter, the bubbles were mobilized to lift the multi-system oil to the top layer. This process must be attributed to the increased column flushing efficiency of diesel removal. Compared with a single solution, using randomly methylated beta-cyclodextrin (RAMEB) and microbubble enhancement, the diesel removal of column flushing increased by 30.7%. Compared with the existing conditions (5.25 × 10−4 cm s−1), the hydraulic conductivity of loam soil (3.74 × 10−3 cm s−1) increased by 7.1 times after the continued operation of the two processes. The oil layer was collected for further reuse. After three treatments, the effluent for the RAMEB was more than 85%. The collected effluent was treated with a synthetic absorbent and then qualifiedly discharged with a TOC value of only 2.6 mg L−1. By combining surfactant flushing with microbubbles and other equipment, not only can the reaction time be effectively saved, but organic pollutants could be concentrated and reused in the soil, so no additional treatment was required.

Characterization of olive pomace extract obtained by cyclodextrin-enhanced pulsed ultrasound assisted extraction

Cyclodextrin enhanced pulsed ultrasound assisted extraction procedure was developed for obtaining olive pomace extract rich in bioactive polyphenols, principally oleuropein, tyrosol, and hydroxytyrosol. 20-minute extraction using 12 mm probe at 100% output intensity was selected as optimal for the extraction of olive pomace polyphenols, using 60% ethanol at 1:40 solvent to solid ratio. Addition of cyclodextrins to extraction solvent (especially randomly-methylatedbeta cyclodextrin and hydroxypropyl-beta cyclodextrin) significantly affected extraction yields, stability and the appearance (colour and particle size distribution) of obtained extracts. Extracts obtained under optimized conditions contained 887 mgkg-1 of hydroxytyrosol, 1117 mgkg-1 of tyrosol and 1744 mgkg-1 of oleuropein. In comparison to conventional solvent extraction, application of ultrasound-assisted extraction resulted in significantly higher yields, reduced extraction time and solvent consumption.

Study of Cyclodextrin/Fluoroquinolone Inclusion Complexes by Capillary Electrophoresis

AbstractIntroduction: In the present work we evaluated the complexation role of cyclodextrins toward fluoroquinolones in an attempt to assess their potential as new formulation additives for more efficient fluoroquinolone delivery and as selectors in capillary electrophoresis.Material and method: Guest-host interactions of two second generation quinolones, ciprofloxacin and norfloxacin with four cyclodextrins, beta-cyclodextrin (β-CD), gamma-cyclodextrin (γ-CD) and two beta-cyclodextrin derivatives, 2-hydroxypropyl beta-cyclodextrin (HP-β-CD) and randomly methylated beta-cyclodextrin (RAMEB), were tested by capillary electrophoresis in borate running buffer. Experimental parameters like buffer concentration, pH, organic modifier, voltage and cyclodextrin concentration have been varied for a better resolution.Results: In capillary zone electrophoresis ciprofloxacin and norfloxacin are migrating together, a difference in their migration times and thus separation occured by the addition of cyclodextrins.Conclusion: Our results suggest formation of inclusion complexes between fluoroquinolones and cyclodextrins. Differences in their affinity to host molecules resulted in separation of the two fluoroquinolones

Enhancing effect of modified beta-cyclodextrins on in vitro skin permeation of estradiol

Estradiol, the most important hormone in females, was complexed with hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and randomly methylated beta-cyclodextrin (RM-b-CD). After obtaining the inclusion complexes, they were characterized by DSC, ¹H-NMR and solubility studies. The enhancing effect of CDs on estradiol skin permeation/retention was investigated in vitro using Franz diffusion cells. Both CDs increased estradiol aqueous solubility, but in different proportions. DSC and NMR-H¹ analyses showed that estradiol was complexed with both CDs and RM-beta-CD has stronger interactions with the hormone than HP-beta-CD. Moreover, complexes formation increased estradiol flux through the skin (P<0.01), but the hormone retention in the stratum corneum (SC) only increased after complexation with HP-beta-CD. On the other hand, only RM-b-CD was able to modify estradiol retention in the SC after skin pretreatment with CDs. The results suggest that the enhancing effect of CDs on estradiol flux through the skin may be mainly described as an increase in drug availability on the skin surface due to inclusion complexation. Furthermore, the formation of a significant reservoir of estradiol in the SC due to HP-beta-CD complexation makes it an interesting approach for estradiol transdermal delivery.

Evaluation of Buccal Methyl-β-Cyclodextrin Toxicity on Human Oral Epithelial Cell Culture Model

Cyclodextrins, especially methylated beta-cyclodextrins offer several advantages for drug delivery which include improved drug solubilization, protection against physicochemical and enzymatic degradation, as well as a potential for absorption improvement. However, little or no data are available for their use as drug penetration enhancer via the buccal route. This study focuses on the toxicity of randomly methylated beta-cyclodextrin (RAMEB) on buccal mucosa using a reconstituted human oral epithelium model composed of TR 146 cells. Toxicity of RAMEB on TR 146 cells was evaluated by measuring cell viability (MTT assay) and membrane damages followed by LDH release after single and repeated exposures to RAMEB solutions. Inflammatory effects of RAMEB are also considered by measuring expression of interleukin-1alpha and are supported by histological examination. The present results indicate that 10% RAMEB results in cytotoxic and inflammatory effects depending on time exposure, whereas 2% and 5% RAMEB do not induce tissue damages even after 5 days of repeated exposures. Therefore, the highly water-soluble RAMEB is thought to be a safe candidate as an excipient for buccal mucosal drug delivery.

Antioxidant activities of natural vitamin E formulations.

The antioxidant activities of natural d-alpha-tocopherol, mixed tocopherols and tocotrienols, and formulations comprising all forms of vitamin E, providing 400 IU, were determined employing an improved oxygen radical absorbance capacity (ORAC) assay using fluorescein (FL) as the fluorescent probe, randomly methylated beta-cyclodextrin (RMCD), 2,2'-azobis(2-amidino-propane)dihydrochloride (AAPH) as the peroxyl radical generator, and Trolox as the standard in 75 mM phosphate buffer. The antioxidant activities, expressed in micromol Trolox equivalent per gram, of d-alpha-tocopherol (87%), mixed tocopherols (70%), and tocotrienols (30%) were found to be 1,293, 1,948, and 1,229, respectively. Some of the vitamin E formulations showed antioxidant activities superior to d-alpha-tocopherol.

Development and validation of oxygen radical absorbance capacity assay for lipophilic antioxidants using randomly methylated beta-cyclodextrin as the solubility enhancer.

We recently reported the improved oxygen radical absorbance capacity (ORAC) assay using fluorescein (FL) as the fluorescent probe. The current ORAC(FL) assay is limited in hydrophilic antioxidant due to the aqueous environment of the assay. Lipophilic antioxidants mainly include the vitamin E family and carotenoids, which play a critical role in biological defense systems. In this paper, we expanded the current ORAC(FL) assay to lipophilic antioxidants. Randomly methylated beta-cyclodextrin (RMCD) was introduced as the water solubility enhancer for lipophilic antioxidants. Seven percent RMCD (w/v) in a 50% acetone-H(2)O mixture was found to sufficiently solubilize vitamin E compounds and other lipophilic phenolic antioxidants in 75 mM phosphate buffer (pH 7.4). This newly developed ORAC assay (abbbreviated ORAC(FL-LIPO)) was validated through linearity, precision, accuracy, and ruggedness. The validation results demonstrate that the ORAC(FL-LIPO) assay is reliable and robust. For the first time, by using 6-hydroxy-2,5,7,8-tetramethyl-2-carboxylic acid as a standard (1.0), the ORAC values of alpha-tocopherol, (+)-gamma-tocopherol, (+)-delta-tocopherol, alpha-tocopherol acetate, tocotrienols, 2,6-di-tert-butyl-4-methylphenol, and gamma-oryzanol were determined to be 0.5 +/- 0.02, 0.74 +/- 0.03, 1.36 +/- 0.14, 0.00, 0.91 +/- 0.04, 0.16 +/- 0.01, and 3.00 +/- 0.26, respectively. The structural information of oxidized alpha-tocopherol obtained by liquid chromatography/mass spectrometry reveals that the mechanism for the reaction between the vitamin E and the peroxyl radical follows the hydrogen atom transfer mechanism, which is in agreement with the notion that vitamin E is the chain-breaking antioxidant.

Effect of cyclodextrins on surface and pore properties of soil clay minerals.

Although cyclodextrins are increasingly used in soil decontamination, little is known about their effects on soil physicochemical properties. In this work, the surface and pore properties of randomly methylated beta-cyclodextrin (RAMEB) and three typical clay minerals were characterized, and the effects of RAMEB concentrations on clay minerals were studied using water vapor adsorption-desorption and mercury intrusion porosimetry techniques. As compared to clay minerals, for pure RAMEB very large surface area and volume of nanometer-size pores (micropores) were determined. Energy of interaction with water vapor, volume of micrometer-size pores (mesopores), and fractal dimensions in both pore size ranges of RAMEB were lower than those of the minerals. When increasing amounts of RAMEB were added to the minerals, the surface area and micropore volume decreased and adsorption energy increased. The volume of mesopores decreased after RAMEB treatments for bentonite and kaolin and increased for illite. As deduced from the fractal dimensions increase, the pore structure of the minerals became more complex with RAMEB addition. The observed changes were in general contrary to these expected when RAMEB and minerals coexist as separate, nonreactive phases and suggested strong interaction of RAMEB with clay minerals.