pH-Responsive Polymersome Microparticles as Smart Cyclodextrin-Releasing Agents.

Cyclodextrins (CDs) are increasingly drawing attention as potential therapeutic tools in the treatment of cholesterol-associated diseases. However, bioavailability and delivery of CDs in the monomeric form still remain challenging. CD-based macromolecular systems seem to display a promising capacity in overcoming some of these limitations. Therefore, smart, stimuli-responsive nanosystems are currently being investigated in order to provide improved CD-releasing agents. Herein, we present a novel class of CD-based polymersome microparticles (CD-PMs) designed for potential therapeutic use. A new synthetic route to obtain a CD-appended, pH-sensitive polymer that self-assembles into a stable polymersome microparticle is reported. Through an easy-to-use approach, a benzoic imine bond is incorporated into a poly(ε-caprolactone) backbone and employed as a building block in the construction of the nanoarchitecture. The CD-PMs show cellular uptake representing a promising potential therapeutic tool in the treatment of cholesterol-associated conditions such as neurodegenerative diseases.

Cyclodextrin-Based Macromolecular Systems as Cholesterol-Mopping Therapeutic Agents in Niemann-Pick Disease Type C.

Over the last decade, cyclodextrins (CDs) have gained considerable attention as a potential therapeutic intervention in the treatment of the rare genetic condition Niemann-Pick type C disease (NPC). However, the oligosaccharide in its monomeric form suffers from serious side effects, especially from a pharmacokinetic and biodistribution standpoint. CD-based macromolecular systems hold great promise to overcome such limitations and might provide an improved therapeutic approach in reducing cholesterol accumulation in NPC. In the present article, the latest developments and synthetic strategies in the preparation of CD-containing polymers as cholesterol-mopping therapeutic agents in NPC are summarized.

Multifunctional 8-hydroxyquinoline-appended cyclodextrins as new inhibitors of metal-induced protein aggregation.

Mounting evidence suggests a pivotal role of metal imbalances in protein misfolding and amyloid diseases. As such, metal ions represent a promising therapeutic target. In this context, the synthesis of chelators that also contain complementary functionalities to combat the multifactorial nature of neurodegenerative diseases is a highly topical issue. We report two new 8-hydroxyquinoline-appended cyclodextrins and highlight their multifunctional properties, including their Cu(II) and Zn(II) binding abilities, and capacity to act as antioxidants and metal-induced antiaggregants. In particular, the latter property has been applied in the development of an effective assay that exploits the formation of amyloid fibrils when ß-lactoglobulin A is heated in the presence of metal ions.

New cyclodextrin-bearing 8-hydroxyquinoline ligands as multifunctional molecules.

Recent investigations have rekindled interest in 8-hydroxyquinolines as therapeutic agents for cancer, Alzheimer's disease, and other neurodegenerative disorders. Three new ß-cyclodextrin conjugates of 8-hydroxyquinolines and their copper(II) and zinc(II) complexes have been synthesized and characterized spectroscopically. In addition to improving aqueous solubility, due to the presence of the cyclodextrin moiety, the hybrid systems have interesting characteristics including antioxidant activity, and their copper(II) complexes are efficient superoxide dismutase (SOD) mimics. The ligands and their copper(II) complexes show low cytotoxicity, attributed to the presence of the cyclodextrin moiety. These compounds have potential as therapeutic agents in diseases related both to metal dyshomeostasis and oxidative stress.

A cyclodextrin-capped histone deacetylase inhibitor.

We have synthesized a ß-cyclodextrin (ßCD)-capped histone deacetylase (HDAC) inhibitor 3 containing an alkyl linker and a zinc-binding hydroxamic acid motif. Biological evaluation (HDAC inhibition studies) of 3 enabled us to establish the effect of replacing an aryl cap (in SAHA (vorinostat,)) 1 by a large saccharidic scaffold "cap". HDAC inhibition was observed for 3, to a lesser extent than SAHA, and rationalized by molecular docking into the active site of HDAC8. However, compound 3 displayed no cellular activity.

Grafting of Cyclodextrin to Theranostic Nanoparticles Improves Blood-Brain Barrier Model Crossing.

Core-shell superparamagnetic iron oxide nanoparticles hold great promise as a theranostic platform in biological systems. Herein, we report the biological effect of multifunctional cyclodextrin-appended SPIONs (CySPION) in mutant Npc1-deficient CHO cells compared to their wild type counterparts. CySPIONs show negligible cytotoxicity while they are strongly endocytosed and localized in the lysosomal compartment. Through their bespoke pH-sensitive chemistry, these nanoparticles release appended monomeric cyclodextrins to mobilize over-accumulated cholesterol and eject it outside the cells. CySPIONs show a high rate of transport across blood-brain barrier models, indicating their promise as a therapeutic approach for cholesterol-impaired diseases affecting the brain.

Cyclodextrin-Appended Superparamagnetic Iron Oxide Nanoparticles as Cholesterol-Mopping Agents.

Cholesterol plays a crucial role in major cardiovascular and neurodegenerative diseases, including Alzheimer's disease and rare genetic disorders showing altered cholesterol metabolism. Cyclodextrins (CDs) have shown promising therapeutic efficacy based on their capacity to sequester and mobilise cholesterol. However, the administration of monomeric CDs suffers from several drawbacks due to their lack of specificity and poor pharmacokinetics. We present core-shell superparamagnetic iron oxide nanoparticles (SPIONs) functionalised with CDs appended to poly (2-methyl-2-oxazoline) polymers grafted in a dense brush to the iron oxide core. The CD-decorated nanoparticles (CySPIONs) are designed so that the macrocycle is specifically cleaved off the nanoparticle's shell at a slightly acidic pH. In the intended use, free monomeric CDs will then mobilise cholesterol out of the lysosome to the cytosol and beyond through the formation of an inclusion complex. Hence, its suitability as a therapeutic platform to remove cholesterol in the lysosomal compartment. Synthesis and full characterization of the polymer as well as of the core-shell SPION are presented. Cholesterol-binding activity is shown through an enzymatic assay.

The 6-derivative of beta-cyclodextrin with succinic acid: a new chiral selector for CD-EKC.

6-O-Succinil-beta-cyclodextrin (CDsuc6) was synthesized with very good yield by one pot synthesis and characterized by NMR spectroscopy and ESI-MS. It was used as a chiral selector in capillary electrophoresis to resolve catecholamine racemates, namely norepinephrine, epinephrine, terbutaline and norphenilephrine. The CE experiments at pH 5.6 show very promising selector ability by 6-O-succinil-beta-cyclodextrin for the chiral recognition of all the catecholamines tested, while at pH 9.2, only racemic terbutaline was successfully separated.

Bioconjugates of cyclodextrins of manganese salen-type ligand with superoxide dismutase activity.

6A,6B-Dideoxy-6A,6B-di[(N-salicylidene)amino]-beta-cyclodextrin was synthesized and characterized by NMR, UV and CD spectroscopy in order to prepare a N,N(')-bis-(salicylidene)ethane-1,2-diamine (SalenH(2)) type ligand. The manganese(III) complex was synthesized and characterized by UV and cyclic voltammetry and compared to EUK-8. The superoxide dismutase (SOD)-like and catalase-like activities were tested by indirect assay. The cyclodextrin complex shows a larger solubility than EUK-8 and good SOD-like activity. Catalase activity is also shown.

3-Amino derivative of beta-cyclodextrin: thermodynamics of copper(II) complexes and exploitation of its enantioselectivity in the separation of amino acid racemates by ligand exchange capillary electrophoresis.

The systems that the 3-amino derivative of beta-cyclodextrin (CD3NH2) forms with the proton, the copper(II) ion and each of the enantiomers of certain amino acids (alanine, phenylalanine, tyrosine and tryptophan) were investigated. The enantioselectivity shown by the potentiometric measurements carried out on the phenylalanine ternary systems was exploited in capillary electrophoresis by ligand exchange capillary electrophoresis (LECE) to obtain the separation of phenylalanine racemate. The tyrosine racemate was also separated by LECE. The comparison between thermodynamic and capillary electrophoresis (CE) results is discussed, in order to get a better insight into the separation mechanism.

Synthesis, physicochemical properties and antioxidant activity of deferiprone-cyclodextrin conjugates and their iron(III) complexes.

3-Hydroxy-1,2-dimethylpyridin-4(1H)-one (deferiprone) is a successful iron chelator, which has been widely investigated for its activity in mitigating iron overload and in protecting against oxidative stress due to Reactive Oxygen Species (ROS). Herein, we present the synthesis, characterisation, physicochemical properties and antioxidant activity of two novel bioconjugates of ß-cyclodextrin bearing the deferiprone moiety either on the upper rim (1) or on the lower rim (2) of the cyclodextrin and their iron(III) complexes. Protonation and iron stability constants were measured by spectrophotometric titration for the two systems and antioxidant activity studied for both the ligands and the iron(III) complexes.

New conjugates of ß-cyclodextrin with manganese(III) salophen and porphyrin complexes as antioxidant systems.

Oxidative stress is the hallmark of several pathologies like arthritis, hypertension and many neurodegenerative disorders such as Parkinson's and Alzheimer's diseases. In this scenario, antioxidant compounds can play a pivotal role in treating these severe pathologies. The synthesis of molecules able to mimic physiologically-relevant proteins is nowadays of particular interest. Several transition metal complexes, especially manganese(III) complexes with porphyrin and salen-type ligands, have been reported to be superoxide scavengers. Here we report the synthesis and spectroscopic characterization of manganese(III) complexes of 5[4-(6-O-ß-cyclodextrin)-phenyl],10,15,20-tri(4-hydroxyphenyl)-porphyrin and of 6(A)-deoxy-6(A)[(S-cysteamidobenzoyl(3,4-diamino)-N,N'-bis(salicylidene))]-ß-cyclodextrin. The superoxide dismutase activity of the metal complexes was investigated by indirect methods. The catalase and peroxidase activities were tested using ABTS assays.

Crystal and molecular structure of beta-cyclodextrins functionalized with the anti-inflammatory drug Etodolac.

The conjugates of beta-cyclodextrins with R- or with S-Etodolac were characterized by NMR spectroscopy, and S-Etodolac alone was characterized by X-ray diffraction analysis. In solution, the R-Etodolac conjugate is soluble in water; the other epimer shows a very low solubility. The NMR characterization of the R-Etodolac conjugate in D(2)O shows that, in aqueous solution, the Edotolac moiety is self-included in the cavity, while the NMR characterization in MeOH of both conjugates underlines that, in this solvent, the Etodolac moiety is not included in the CD cavity. The X-ray structure determination of the S-Etodolac conjugate reveals a "sleeping swan"-like shape, with the covalently bonded Etodolac moiety being folded with the 8-ethyl group inserted inside the hydrophobic cavity of the beta-CD ring. The terminal methyl group of the 8-ethyl group enters the centre of cavity from the side of the primary hydroxyl groups and is buried inside the beta-CD macrocycle. The terminal methyl group is positioned at a distance of 1.06 A from the O(4) plane in the side of the primary hydroxyl groups. In addition to van der Waals interactions between the hydrophobic ethyl group and the beta-CD cavity, the folded conformation is further stabilized by one intramolecular H-bond involving the indole N-H group and the primary hydroxyl group of the glucose unit 7. Along the b axis, the beta-CD molecules are arranged in columns; the macrocycles form a herring bone pattern, so that the cavity of each beta-CD molecule is closed at each end by neighboring molecules. Within the layers, the beta-CD macrocycles are held together by a complicated intermolecular hydrogen bond network, in which numerous water molecules and hydroxyl groups are involved.

Synthesis and NMR characterization of beta-alanine-bridged hemispherodextrin, a very efficient chiral selector in EKC.

A capped derivative of beta-CD (THALAH) was synthesized and characterized by NMR spectroscopy at different pH values. A trehalose moiety, bonded through beta-alanine bridges to the CD cavity, is included in the capping unit, giving peculiar properties to this molecule. The hemispherodextrin thus obtained was tested as a chiral selector in EKC. At neutral pH, the monocationic species of THALAH behaves as a very efficient selector separating successfully all the 11 tested enantiomeric pairs of dansyl-derivatives of amino acids, some of them even at concentrations as low as 0.15 mM. The differences observed in the migration order among the different systems give suggestions about the mechanism of molecular recognition between the selector and the analytes.

Coordination properties of 3-functionalized beta-cyclodextrins. Thermodynamic stereoselectivity of copper(II) complexes of the A,B-diamino derivative and its exploitation in LECE.

The bis-amino AB derivative of beta-cyclodextrin on the secondary rim was synthesised and spectroscopically characterised by different techniques. Its binary systems both with protons and copper(II) were thermodynamically characterised by pH-metric potentiometry. In addition the ternary systems with each of the enantiomers of tryptophan and alanine were investigated. A thermodynamic stereoselectivity was observed for the tryptophan enantiomers and this was exploited to separate them by capillary electrophoresis through a ligand exchange mechanism (LECE). LECE separation of racemates of phenylalanine and tyrosine was also obtained.