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The present contribution describes the application of three single-isomeric cyclodextrin derivatives for the first time - Sugammadex, Subetadex and Sualphadex as chiral selectors. Their recognition ability was investigated by means of chiral capillary electrophoresis, on a pool of cathinone and amphetamine derivatives. The selectors differ in cavity sizes and in the number of ionizable groups which evidently influenced their enantioselectivity performance. Their common feature is their high isomeric purity that enabled the detailed study of the molecular association between the cathinone guest and the cyclodextrin host at the atomic level. With the aid of enantiopure cathinone derivatives, the migration order could also be determined in capillary electrophoresis. As the result of the capillary electrophoresis screening, partial or baseline chiral separation of 19 cathinones and an amphetamine derivative could be achieved, and the systematic study was performed focusing on three different pH conditions pH = 7.0, pH = 5.0 and pH = 2.5 and several different selector concentrations. Among the tested derivatives Subetadex is the best performing chiral selector, especially under acidic pH values for separating enantiomers, proven not only by capillary electrophoresis but also by 1D and 2D NMR measurements., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Mitragynine (MTR), the main indole alkaloid of the well-known plant kratom ( Mitragyna speciosa ), is one of the most studied natural products nowadays, due to its remarkable biological effects. It is a partial agonist on the opioid receptors, and as such relieves pain without the well-known side-effects of the opioids applied in the clinical practice. MTR and its derivatives therefore became novel candidates for drug development. The poor aqueous solubility and low bioavailability of drugs are often improved by cyclodextrins (CyDs) as excipients through host-guest type complex formation. Among the wide variety of CyDs, sulfobutylether-beta-cyclodextrin (SBEβCyD) is frequently used and official in the European and U.S. Pharmacopoeia. Herein, the host-guest complexation of MTR with βCyD and SBEβCyD was studied using chiroptical and NMR spectroscopy. It was found by NMR measurements that MTR forms a rather weak (log β 11 = 0.8) 1:1 host-guest complex with βCyD, while the co-existence of the 2MTR∙SBEβCyD and MTR∙SBEβCyD species was deducted from 1 H NMR titrations in the millimolar MTR concentration range. Sulfobutylation of βCyD significantly enhanced the affinity towards MTR. The structure of the formed inclusion complex was extensively studied by circular dichroism spectroscopy and 2D ROESY NMR. The insertion of the indole moiety was confirmed by both techniques.

In this contribution, we report a strategy to enhance the therapeutic action of the chemotherapeutic Sorafenib (SRB) through its combination with a multifunctional β-cyclodextrin-based polymer able to deliver nitric oxide (NO) and emit green fluorescence upon visible light excitation (PolyCDNO). The basically water-insoluble SRB is effectively encapsulated in the polymeric host (1 mg mL -1 ) up to a concentration of 18 μg mL -1 . The resulting host-guest supramolecular complex is able to release SRB in sink conditions and to preserve very well the photophysical and photochemical properties of the free PolyCDNO, as demonstrated by the similar values of the NO release and fluorescence emission quantum efficiencies found. The complex PolyCDNO/SRB internalizes in HEP-G2 hepatocarcinoma, MCF-7 breast cancer and ACHN kidney adenocarcinoma cells, localizing in all cases mainly at the cytoplasmic level. Biological experiments have been performed at SRB concentrations below the IC 50 and with light doses producing NO at nontoxic concentrations. The results demonstrate exceptional mortality levels for PolyCDNO/SRB upon visible light irradiation in all the different cell lines tested, indicating a clear synergistic action between the chemotherapeutic drug and the NO. These findings can open up exciting avenues to potentiate the anticancer action of SRB and, in principle, to reduce its side effects through its use at low dosages when in combination with the photo-regulated release of NO.

Supramolecular organization and self-assembly are the pillars of functionality of many nanosystems. The covalent conjugate (6-spirolactam rhodamine B-6-monodeoxy)-β-cyclodextrin (Rho-βCD) is assembled as a self-included, rigid nanostructure, identical in the crystal and in aqueous solution, as revealed by detailed X-ray and NMR analyses. Rho-βCD self-assembly is the result of an interesting reaction pathway, which partially de-aggregates Rho and disturbs the zwitterion↔spirolactone equilibrium. Rho-βCD is stable at pH 4.6, but displays controllable photoswitching between the colored, fluorescent, zwitterionic and the colorless, non-fluorescent closed structures, during several iterative cycles. After an initial drop in absorbance, the on-off process continues without further changes under our irradiation conditions, a consequence of the specific self-locked arrangement of Rho in the cavity. Rho-βCD exemplifies a water soluble photoresponsive nanosystem with improved photostability suggesting promising applications in super resolution bioimaging., (© 2021 Wiley-VCH GmbH.)

The highly anionic synthetic pentasaccharide fondaparinux (FDPX) - representing the antithrombin binding sequence of heparin - is in clinical use as a potent anticoagulant. Contrary to the unfractionated heparin, FDPX lacks potent antidote completely reversing its anticoagulant activity, therefore it is of great importance to identify new structures exhibiting strong intermolecular interactions towards FDPX. The polycationic heptakis(6-amino-6-deoxy)-beta-cyclodextrin (NH 2 -β-CD) can serve as an excellent model compound to mimic these interactions between the oppositely charged oligosaccharides. Herein, extensive NMR spectroscopic and nano-electrospray ionization mass spectrometric (nESI-MS) studies were conducted to understand the molecular-level interactions in the FDPX - NH 2 -β-CD systems. NMR experiments were performed at pD 7.4 and 2.0. Job's method of continuous variation and 1 H NMR titration experiments suggested the formation of FDPX∙NH 2 -β-CD complex at pD 7.4, while the presence of multiple complexes was assumed at pD 2.0. Stability constants were determined by separate 1 H NMR titrations, yielding log β 11 =3.65 ± 0.02 at pD 7.4, while log β 11 ≥ 4.9 value suggested a high-affinity system at pD 2.0. 2D NOESY NMR studies indicated spatial proximities between the anomeric resonance α-l-iduronic acid residue and the cyclodextrin's methylene unit in the proximity of the cationic amino function. Acidic degradation of FDPX was investigated by NMR and MS for the first time in detail confirming that desulfation occurs involving one to two sulfate moieties. The desulfation of FDPX was inhibited by the cationic cyclodextrin in the case of equimolar ratio at pD 2.0. This is the first report on the stabilizing effect of cyclodextrin complexation on heparin degradation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

The cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2) pathway plays an important role in tumor development and formation of metastases. It was earlier reported that cyclodextrin derivatives have a high affinity to form complexes with PGE2. Based on these results radiolabeled cyclodextrins - as new radiopharmaceuticals - may open a new pathway in the in vivo imaging and diagnosis of PGE2 positive tumors. The aims of this study were to synthetize the PGE2 specific 68 Ga-labeled NODAGA-randomly methylated beta-cyclodextrin ( 68 Ga-NODAGA-RAMEB) and investigate its tumor-targeting properties. NODAGA-RAMEB was labeled with Gallium-68 ( 68 Ga), and the radiochemical purity (RCP%), partition coefficient (logP values), and in vitro-in vivo stability of 68 Ga-NODAGA-RAMEB were determined. After intravenous injection of 68 Ga-NODAGA-RAMEB the accumulation in organs and tissues was monitored in vivo by positron emission tomography (PET) and ex vivo by gamma counter in BxPC-3 and PancTu-1 tumor-bearing CB17 SCID mice. The RCP% of the newly synthesized 68 Ga-NODAGA-RAMEB was higher than 98%. The molar activity was 15.34 ± 1.93 GBq/μmol. The logP of 68 Ga labeled NODAGA-RAMEB was - 3.63 ± 0.04. Biodistribution studies showed high accumulation of 68 Ga-NODAGA-RAMEB in PGE2 positive BxPC-3 tumors; approximately 15-20-fold higher radiotracer uptake was observed, than that of the background. 68 Ga-labeled RAMEB is a promising radiotracer in PET diagnostics of PGE2 positive tumors., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The chiral separation ability of the full library of methylated-β-cyclodextrins towards pharmacologically significant racemic drugs including basic compounds was studied by chiral CE. The syntheses of all the methylated, single isomer β-cyclodextrins were revised and optimized and the aqueous solubility of the derivatives was unambiguously established. The three most relevant commercially available methylated isomeric mixtures were also included in the screening, so a total of ten various methylated CDs were investigated. The effects of the selector concentration on the enantiorecognition properties at acidic pH were investigated. Among the dimethylated β-cyclodextrins, the heptakis (2,6-di-O-methyl)-β-cyclodextrin isomer (2,6-DIMEB) resulted to be the most versatile chiral selector. Terbutaline was selected as a model compound for the in-depth investigation of host-guest enantiodiscrimination ability. The association constants between the two terbutaline enantiomers and 2,6-DIMEB were determined in order to support that the enantioseparation is driven by differences is host-guest binding. The migration order of the enantiomers was confirmed by performing spiking experiments with the pure enantiomers. 1D and 2D NMR spectroscopy was applied to the 2,3-, and 2,6-DIMEB/terbutaline systems to rationalize at molecular level the different enantioseparation ability of the dimethylated β-cyclodextrin selectors., (© 2019 The Authors. Electrophoresis published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The exhaustive primary-side alkylation of cyclodextrins has never been achieved directly. The undesired and simultaneous derivatization of the secondary hydroxyl moieties generates intricate isomeric mixtures that are challenging to purify, analyse and characterize. The aim of this study was to develop a chromatography-free and up-scalable strategy towards the preparation of per-6-O-methylated cyclodextrin and to test the compound as potential chiral selector. The target molecule was prepared according to a five-step synthesis by using methyltriphenylphosphonium bromide as catalyst under heterogeneous conditions. The removal of benzyl moieties, used as temporary secondary-side protecting groups, was attained by applying hydrazine-carbonate in the presence of Pd/C. All the intermediates were obtained in high yields, thoroughly characterized and their purity was assessed by ad-hoc developed HPLC methods. The per-6-O-methylated β-cyclodextrin showed promising chiral recognition ability as background electrolyte additive in cyclodextrin-modified capillary electrophoresis using the recreational drug methylene-dioxypyrovalerone as model compound. Additionally, a model for the inclusion geometry between the single isomer host and the selected drug was developed based on the extensive 2D NMR analysis. The versatility of the proposed synthetic strategy opens the way to the industrial production of homogeneously primary-alkylated cyclodextrins and to their wide application in chiral separation of various drugs., (© 2019 The Authors. Electrophoresis published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

We report herein on a novel water-soluble β-cyclodextrin-branched polymer covalently integrating a fluorescein moiety and a nitric oxide (NO) photodonor within its macromolecular skeleton. Photoexcitation with visible light induces the parallel activation of the two chromophores, which results in the green fluorescence emission suitable for imaging accompanied by NO release for therapy. In fact, this polymer internalizes in squamous carcinoma cancer cells in vitro, visualized by fluorescence microscopy, and induces cell mortality as result of the NO photo-decaging. The non-covalent drug delivery capability of this new material is also demonstrated using a hydrophobic photosensitizer for photodynamic therapy as a probe.

Two β-cyclodextrin derivatives randomly appended on the primary face with both the nitric oxide (NO) photodonor 4-nitro-3-(trifluoromethyl)aniline and a mannose or α(1→2)mannobioside residue are reported to construct targeted NO photoreleasing nanocarriers. 2D ROESY and PGSE NMR suggested supramolecular homodimerization in water by inclusion of the nitroaniline group into the facing macrocycle cavities. Isothermal titration calorimetry on their concanavalin A lectin binding showed an exothermic binding event to the lectin and an endothermic process during the dilution of the conjugates. Both α(1→2)mannobioside and the nitroaniline moieties significantly enhanced the binding to the lectin. These effects might arise from a better fit within the carbohydrate-recognition site in the former case and a multivalent effect caused by homodimerization in the latter. Direct detection of NO by amperometric technique shows that both β-cyclodextrin derivatives release this radical upon excitation with visible light with higher efficiency than the unfunctionalized NO photodonor., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Clofazimine (CLZ) is an antibiotic with a promising behavior against Gram-positive bacteria; however, the drug is completely insoluble in water and accumulates in fat tissues. We explored nanocarriers, labeled and not labeled with rhodamine, consisting of negatively charged sulfobutylether-β-cyclodextrins for CLZ loading. A new oligomeric carrier was obtained cross-linking βCyD with epichlorohydrin followed by sulfonation in a strongly alkaline aqueous medium. The oligomeric carrier has a MW of 53 kDa and forms small nanoparticles of a few tens of nm. With aqueous solutions containing a 25 mg/mL oligomeric carrier, we loaded up to 0.5 mg/mL of drug. The oligomers exhibited a 10-fold better loading capacity compared to monomers and formed nanoparticles with a size in the 20-60 nm range after drug loading. Circular dichroism confirmed encapsulation of the CLZ in the nanocarriers. All carriers with or without CLZ are not cytotoxic up to 1 μM, while CLZ alone is highly cytotoxic at the same concentration. The drug has IC 50 values below 100 nM against S. epidermidis. The same holds true also for clinical isolates of S. epidermidis, some displaying MDR. So, the selectivity index significantly increased for CLZ/carrier systems compared to the drug alone. Taken all together, our results open new avenues for the clinical application of this antibiotic.

Ethionamide (ETH) is a second line antitubercular drug suffering from poor solubility in water and strong tendency to crystallize. These drawbacks were addressed by loading ETH in β-cyclodextrin (βCyD)-based carriers. The drug was incorporated in a molecular state avoiding crystallization even for long-term storage and obtaining a tenfold increased solubility up to 25mM. The binding of ETH to polymeric βCyD nanoparticles (pβCyD NPs) was investigated in neutral aqueous medium by means of solubility phase diagrams, circular dichroism (CD) and UV-vis absorption and compared with the corresponding βCyD monomer. The binding constants and the absolute CD spectra of the drug complexes were determined by global analysis of multiwavelength data from spectroscopic titrations. The spectroscopic and photophysical properties of the complexes evidenced an alcohol-like environment for ETH included in the cavity. Additionally, ETH was found to be located not only in βCyD cavities, but also in confined microdomains inside the crosslinked NPs. This double modality of complexation together with a slightly higher binding constant makes the utilization of pβCyD NPs preferable over the monomeric βCyDs. In order to pave the way to future in vitro experiments, fluorescein labeled pβCyDs were synthesized. Interestingly the FITC labeling did not hamper the encapsulation of ETH and the drug improved the fluorescent signal of FITC molecules. The βCyD-based carriers appeared as versatile "green" systems for efficient incorporation and future delivery of ETH., (Copyright © 2017 Elsevier B.V. All rights reserved.)

This contribution reports the design, synthesis and photochemical properties of a novel cationic, water soluble, β-cyclodextrin (βCD) conjugate integrating an anthracene moiety and a nitroaniline derivative within the primary side of the βCD scaffold. Photoinduced energy transfer between the anthracene and the nitroaniline chromophores effectively suppresses the fluorescence of the anthracene unit. Excitation with visible light triggers the release of nitric oxide (NO) from the nitroaniline chromophore, accompanied to the concomitant revival of the anthracene fluorescence, which acts as an optical reporter for detecting the amount of the NO released. Furthermore, the anthracene moiety photogenerates singlet oxygen ( 1 O 2 ) sequentially to NO release. The conjugate is also able to accommodate hydrophobic guests within the βCD cavity, as proven by using naphthalene as a model compound. In view of the key role NO and 1 O 2 play as anticancer and antibacterial species, the present βCD derivative represents an intriguing candidate for further studies in biopharmaceutical research addressed to multimodal therapeutic applications., (Copyright © 2017 Elsevier B.V. All rights reserved.)

This contribution reports the synthesis, characterization and capillary electrophoretic application of heptakis-(6-O-sulfobutyl-ether)-β-cyclodextrin sodium salt, (6-(SB) 7 -β-CD). The compound was obtained through a five-steps synthesis and it represents the first example of single-isomer sulfobutylated cyclodextrin that carries the negatively charged functions exclusively on its primary side and it is unmodified on the lower rim. The purity of each intermediate was determined by appropriate liquid chromatographic methods, while the isomeric purity of the final product was established by an ad-hoc developed HPLC method based on a CD-Screen-IEC column. The structural identification of 6-(SB) 7 -β-CD was carried out by 1D, 2D NMR spectroscopy and ESI-MS. The chiral separation ability of 6-(SB) 7 -β-CD was studied by chiral capillary electrophoresis using the single-isomer host as a background electrolyte additive to separate the enantiomers of a representative set of pharmacologically significant model compounds such as verapamil, dapoxetine, ondansetron, propranolol, atenolol, metoprolol, carvedilol, terbutaline, amlodipine and tadalafil. The enantiomer migration order and the effects of the selector concentration on the enantiorecognition properties were investigated. NMR spectroscopy was applied to deepen and further confirm the host-guest interactions and in the case of the model compound dapoxetine a potential representation for the supramolecular assembly was developed based on the dataset collected by the extensive 2D NMR analysis. This single-isomer chiral selector offers a new alternative to the widely applied randomly sulfobutylated- and sulfated-beta-cylodextrins as well as to the single-isomer sulfated and carboxymethylated derivatives in chiral separations., (Copyright © 2017 Elsevier B.V. All rights reserved.)

In this work, the synthesis, characterization, and chiral capillary electrophoretic study of heptakis-(2,3-di-O-methyl-6-O-carboxymethyl)-β-CD (HDMCM), a single-isomer carboxymethylated CD, are presented. The pH-dependent and selector concentration-dependent enantiorecognition properties of HDMCM were investigated and discussed herein. The enantioseparation was assessed applying a structurally diverse set of noncharged, basic, and zwitterionic racemates. The increase in the selector concentration and gross negative charge of HDMCM improved the enantioseparation that could be observed in the majority of the cases. HDMCM was also successfully applied as BGE additive in NACE using a methanol-based system in order to prove the separation selectivity features and to highlight the broad applicability of HDMCM. Over 25 racemates showed partial or baseline separation with HDMCM under the conditions investigated, among which optimal enantiomer migration order was found for the four stereoisomers of tadalafil, tapentadol, and dapoxetine, offering the possibility of a chiral CE method development for chiral purity profiling of these drugs., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: Metal-organic framework nanoparticles (nanoMOFs) are biodegradable highly porous materials with a remarkable ability to load therapeutic agents with a wide range of physico-chemical properties. Engineering the nanoMOFs surface may provide nanoparticles with higher stability, controlled release, and targeting abilities. Designing postsynthetic, non-covalent self-assembling shells for nanoMOFs is especially appealing due to their simplicity, versatility, absence of toxic byproducts and minimum impact on the original host-guest ability., Methods: In this study, several β-cyclodextrin-based monomers and polymers appended with mannose or rhodamine were randomly phosphorylated, and tested as self-assembling coating building blocks for iron trimesate MIL-100(Fe) nanoMOFs. The shell formation and stability were studied by isothermal titration calorimetry (ITC), spectrofluorometry and confocal imaging. The effect of the coating on tritium-labeled AZT-PT drug release was estimated by scintillation counting., Results: Shell formation was conveniently achieved by soaking the nanoparticles in self-assembling agent aqueous solutions. The grafted phosphate moieties enabled a firm anchorage of the coating to the nanoMOFs. Coating stability was directly related to the density of grafted phosphate groups, and did not alter nanoMOFs morphology or drug release kinetics., Conclusion: An easy, fast and reproducible non-covalent functionalization of MIL-100(Fe) nanoMOFs surface based on the interaction between phosphate groups appended to β-cyclodextrin derivatives and iron(III) atoms is presented., General Significance: This study proved that discrete and polymeric phosphate β-cyclodextrin derivatives can conform non-covalent shells on iron(III)-based nanoMOFs. The flexibility of the β-cyclodextrin to be decorated with different motifs open the way towards nanoMOFs modifications for drug delivery, catalysis, separation, imaging and sensing. This article is part of a Special Issue entitled "Recent Advances in Bionanomaterials" Guest Editors: Dr. Marie-Louise Saboungi and Dr. Samuel D. Bader., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The enantioselectivity of neutral single-isomer synthetic precursors of sulfated-β-cyclodextrins was studied. Four neutral single-isomer cyclodextrins substituted on the secondary side with acetyl and/or methyl functional groups, heptakis(2-O-methyl-3,6-dihydroxy)-β-cyclodextrin (HM-β-CD), heptakis(2,3-di-O-acetyl-6-hydroxy)-β-cyclodextrin (HDA-β-CD), heptakis(2,3-di-O-methyl-6-hydroxy)-β-cyclodextrin (HDM-β-CD), heptakis(2-O-methyl-3-O-acetyl-6-hydroxy)-β-cyclodextrin (HMA-β-CD), and their sulfated analogs the negatively charged heptakis(2,3-di-O-methyl-6-sulfato)-β-cyclodextrin (HDMS-β-CD) and heptakis(2,3-di-O-acetyl-6-sulfato)-β-cyclodextrin (HDAS-β-CD) were investigated by non-aqueous capillary electrophoresis in the view of enantiodiscrimination for various drugs and related pharmaceutical compounds. The focus of the present work was on the chiral selectivity studies of the neutral derivatives, which are the synthesis intermediates of the sulfated products. The chiral recognition experiments proved that among the neutral compounds the HMA-β-CD shows remarkable enantioselectivity towards chiral guests in non-aqueous capillary electrophoresis, while HM-β-CD, HDA-β-CD and HDM-β-CD failed to resolve any of the 25 studied racemates under the applied experimental conditions. In order to get deeper insight into the molecular interactions between the studied single-isomer cyclodextrin and chiral fluoroquinolones (ofloxacin, gatifloxacin and lomefloxacin) and β-blockers (propranolol), 1 H and ROESY NMR experiments were performed. The 2-O-methylation in combination with the 3-O-acetylation of the host was evidenced to exclusively carry the essential spatial arrangement for chiral recognition., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Methylated cyclodextrins (CDs) are effective solubilizers of poorly soluble organic compounds. In this work, we compared various methylated β-CDs concerning their structure characterized by nuclear magnetic resonance spectroscopy, composition analyzed by HPLC and solubilizing capability by using model compounds such as cholesterol, fatty acids, furosemide, tamoxifen, and amiodarone. All the commercially available methylated β-CDs are mixtures of various isomers and homologues except trimethyl β-CD. The effects of the degree of methylation, the composition, as well as the influence of further derivatization with ionic groups were studied. The number of methyl groups in a CD ring should be around 14 to get the highest solubility for the included guest molecules. Although the distribution of isomers and related compounds has hardly any effect at constant degree of substitution, the introduction of amino and succinyl moieties on the CD ring adds ionic interactions to the hydrophobic interactions of the inclusion complex formation, which might result in synergic effect in solubilization., (© 2014 Wiley Periodicals, Inc. and the American Pharmacists Association.)

Cyclodextrins are widely used excipients for increasing the bioavailability of poorly water-soluble drugs. Their effect on drug absorption in the gastrointestinal tract is explained by their solubility- and permeability-enhancement. The aims of this study were to investigate penetration properties of fluorescently labeled randomly methylated-beta-cyclodextrin (FITC-RAMEB) on Caco-2 cell layer and examine the cellular entry of cyclodextrins on intestinal cells. The permeability of FITC-RAMEB through Caco-2 monolayers was very limited. Using this compound in 0.05 mM concentration the permeability coefficient was 3.35±1.29×10(-8) cm/s and its permeability did not change in the presence of 5 mM randomly methylated-beta-cyclodextrin. Despite of the low permeability, cellular accumulation of FITC-RAMEB in cytoplasmic vesicles was significant and showed strong time and concentration dependence, similar to the characteristics of the macropinocytosis marker Lucifer Yellow. The internalization process was fully inhibited at 0°C and it was drastically reduced at 37°C applying rottlerin, an inhibitor of macropinocytosis. Notably, FITC-RAMEB colocalized with the early endosome organizer Rab5a. These results have revealed that FITC-RAMEB is able to enter intestinal epithelial cells by fluid-phase endocytosis from the apical side. This mechanism can be an additional process which helps to overcome the intestinal barrier and contributes to the bioavailability enhancement of cyclodextrins.

Herein we report the design, preparation, and properties of a supramolecular system based on a tailored nitric oxide (NO) photodonor and a rhodamine-labeled β-cyclodextrin conjugate. The combination of spectroscopic and photochemical experiments shows the absence of significant interchromophoric interactions between the host and the guest in the excited states. As a result, the complex is able to release NO under the exclusive control of visible light, as unambiguously demonstrated by direct detection of this transient species through an amperometric technique, and exhibits the typical red fluorescence of the rhodamine appendage. The supramolecular complex effectively internalizes in HeLa cancer cells as proven by fluorescence microscopy, shows a satisfactory biocompatibility in the dark, and induces about 50% of cell mortality upon irradiation with visible light. The convergence of all these properties in one single complex makes the present host-guest ensemble an appealing candidate for further delevopment of photoactivatable nanoscaled systems addressed to photostimulated NO-based therapy., (Copyright © 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)