Publications by authors named "Fabrizio Caldera"

46 Publications

Nanosponge-Based Composite Gel Polymer Electrolyte for Safer Li-O Batteries.

Polymers (Basel) 2021 May 17;13(10). Epub 2021 May 17.

Electrochemistry Group, Department of Applied Science and Technology, Politecnico di Torino, C.so D.ca degli Abruzzi 24, 10128 Torino, Italy.

Li-O batteries represent a promising rechargeable battery candidate to answer the energy challenges our world is facing, thanks to their ultrahigh theoretical energy density. However, the poor cycling stability of the Li-O system and, overall, important safety issues due to the formation of Li dendrites, combined with the use of organic liquid electrolytes and O cross-over, inhibit their practical applications. As a solution to these various issues, we propose a composite gel polymer electrolyte consisting of a highly cross-linked polymer matrix, containing a dextrin-based nanosponge and activated with a liquid electrolyte. The polymer matrix, easily obtained by thermally activated one pot free radical polymerization in bulk, allows to limit dendrite nucleation and growth thanks to its cross-linked structure. At the same time, the nanosponge limits the O cross-over and avoids the formation of crystalline domains in the polymer matrix, which, combined with the liquid electrolyte, allows a good ionic conductivity at room temperature. Such a composite gel polymer electrolyte, tested in a cell containing Li metal as anode and a simple commercial gas diffusion layer, without any catalyst, as cathode demonstrates a full capacity of 5.05 mAh cm as well as improved reversibility upon cycling, compared to a cell containing liquid electrolyte.
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http://dx.doi.org/10.3390/polym13101625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156716PMC
May 2021

Cyclodextrin Monomers and Polymers for Drug Activity Enhancement.

Polymers (Basel) 2021 May 21;13(11). Epub 2021 May 21.

Dip. Di Chimica, Università di Torino, Via P. Giuria 7, 10125 Torino, Italy.

Cyclodextrins (CDs) and cyclodextrin (CD)-based polymers are well-known complexing agents. One of their distinctive features is to increase the quantity of a drug in a solution or improve its delivery. However, in certain instances, the activity of the solutions is increased not only due to the increase of the drug dose but also due to the drug complexation. Based on numerous studies reviewed, the drug appeared more active in a complex form. This review aims to summarize the performance of CDs and CD-based polymers as activity enhancers. Accordingly, the review is divided into two parts, i.e., the effect of CDs as active drugs and as enhancers in antimicrobials, antivirals, cardiovascular diseases, cancer, neuroprotective agents, and antioxidants.
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http://dx.doi.org/10.3390/polym13111684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196804PMC
May 2021

Cyclic Nigerosyl-Nigerose as Oxygen Nanocarrier to Protect Cellular Models from Hypoxia/Reoxygenation Injury: Implications from an In Vitro Model.

Int J Mol Sci 2021 Apr 19;22(8). Epub 2021 Apr 19.

Department of Drug Science and Technology, University of Turin, 10125 Turin, Italy.

Heart failure (HF) prevalence is increasing among the aging population, and the mortality rate remains unacceptably high despite improvements in therapy. Myocardial ischemia (MI) and, consequently, ischemia/reperfusion injury (IRI), are frequently the basis of HF development. Therefore, cardioprotective strategies to limit IRI are mandatory. Nanocarriers have been proposed as alternative therapy for cardiovascular disease. Controlled reoxygenation may be a promising strategy. Novel nanocarriers, such as cyclic nigerosyl-nigerose (CNN), can be innovative tools for oxygen delivery in a controlled manner. In this study we analyzed new CNN-based formulations as oxygen nanocarriers (O-CNN), and compared them with nitrogen CNN (N-CNN). These different CNN-based formulations were tested using two cellular models, namely, cardiomyoblasts (H9c2), and endothelial (HMEC) cell lines, at different concentrations. The effects on the growth curve during normoxia (21% O, 5% CO and 74% N) and their protective effects during hypoxia (1% O, 5% CO and 94% N) and reoxygenation (21% O, 5% CO and 74% N) were studied. Neither O-CNN nor N-CNN has any effect on the growth curve during normoxia. However, O-CNN applied before hypoxia induces a 15-30% reduction in cell mortality after hypoxia/re-oxygenation when compared to N-CNN. O-CNN showed a marked efficacy in controlled oxygenation, which suggests an interesting potential for the future medical application of soluble nanocarrier systems for MI treatment.
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http://dx.doi.org/10.3390/ijms22084208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8073687PMC
April 2021

A physicochemical, thermodynamical, structural and computational evaluation of kynurenic acid/cyclodextrin complexes.

Food Chem 2021 Sep 23;356:129639. Epub 2021 Mar 23.

Dip. Di Chimica, Università di Torino, via P. Giuria 7, 10125 Torino, Italy.

In this work, the interaction between Kynurenic acid (KYNA) and several natural and modified cyclodextrins (CDs) is carried out. Among all the CD tested, HPβ-CD showed the strongest complexation constant (K), with a value of 270.94 ± 29.80 M. Between natural (α- and β-) CDs, the complex of KYNA with β-CD was the most efficient. The inclusion complex of KYNA with CDs showed a strong influence of pH and temperature. The K value decreased at high pH values, when the pK was passed. Moreover, an increase of the temperature caused a decrease in the K values. The thermodynamic parameters of the complexation (ΔH°, ΔS° and ΔG°) were studied with negative entropy, enthalpy and spontaneity of the process at 25 °C. Moreover, the inclusion complex was also characterized using FTIR and TGA. Finally, molecular docking calculations provided different interactions and their influence in the complexation constant.
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http://dx.doi.org/10.1016/j.foodchem.2021.129639DOI Listing
September 2021

Cyclodextrin nanosponge for the GSH-mediated delivery of Resveratrol in human cancer cells.

Nanotheranostics 2021 21;5(2):197-212. Epub 2021 Jan 21.

Laboratory of Molecular Pathology, Department of Health Sciences, Università del Piemonte Orientale "A. Avogadro", Novara, Italy.

Smart drug delivery systems are required for the site-specific drug targeting to enhance the therapeutic efficiency of a drug. Resveratrol (RV) is a polyphenolic compound with anti-cancer activity. However, its poor aqueous solubility and non-selectivity are the major challenges for its employment in cancer therapy. In this work, we present the synthesis of RV-loaded glutathione responsive cyclodextrin nanosponges (RV-GSH-NSs) to improve the therapeutic efficiency and selective delivery of RV. The drug loading and encapsulation efficiency were 16.12% and 80.64%, respectively. The release profile confirmed that RV release was enhanced in response to external glutathione (GSH). Nude NSs were not toxic to human fibroblasts when administered for up to 72 h at the highest dose. Cell internalization studies confirmed that RV-GSH-NSs were preferentially up-taken by tumor cells compared to non-tumorigenic cells. Accordingly, RV showed selective toxicity to cancer cells compared to normal cells. GSH depletion by buthionine sulfoximine, a potent inhibitor of its synthesis, reflected in a significant decrease of the NSs accumulation, and consequently resulted in a drastic reduction of RV-mediated toxic effects in cancer cells. These findings demonstrate that GSH- responsive NSs represent an effective delivery system for targeting cancer cells by harnessing the differential tumor characteristics in terms of redox status in parallel with the limitation of side effects toward normal cells.
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http://dx.doi.org/10.7150/ntno.53888DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868003PMC
June 2021

Effect of the Cross-Linking Density on the Swelling and Rheological Behavior of Ester-Bridged β-Cyclodextrin Nanosponges.

Materials (Basel) 2021 Jan 20;14(3). Epub 2021 Jan 20.

Department of Chemistry, University of Torino, Via P. Giuria 7, 10125 Torino, Italy.

The cross-linking density influences the physicochemical properties of cyclodextrin-based nanosponges (CD-NSs). Although the effect of the cross-linker type and content on the NSs performance has been investigated, a detailed study of the cross-linking density has never been performed. In this contribution, nine ester-bridged NSs based on β-cyclodextrin (β-CD) and different quantities of pyromellitic dianhydride (PMDA), used as a cross-linking agent in stoichiometric proportions of 2, 3, 4, 5, 6, 7, 8, 9, and 10 moles of PMDA for each mole of CD, were synthesized and characterized in terms of swelling and rheological properties. The results, from the swelling experiments, exploiting Flory-Rehner theory, and rheology, strongly showed a cross-linker content-dependent behavior. The study of cross-linking density allowed to shed light on the efficiency of the synthesis reaction methods. Overall, our study demonstrates that by varying the amount of cross-linking agent, the cross-linked structure of the NSs matrix can be controlled effectively. As PMDA βCD-NSs have emerged over the years as a highly versatile class of materials with potential applications in various fields, this study represents the first step towards a full understanding of the correlation between their structure and properties, which is a key requirement to effectively tune their synthesis reaction in view of any specific future application or industrial scale-up.
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http://dx.doi.org/10.3390/ma14030478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864023PMC
January 2021

Drug-Encapsulated Cyclodextrin Nanosponges.

Methods Mol Biol 2021 ;2207:247-283

Dipartimento di Chimica, Università di Torino, Torino, Italy.

To date, a number of nanocarriers, either inorganic or organic, have been developed to improve the delivery and therapeutic efficacy of various drugs. Drug delivery systems have attempted to overcome the undesirable pharmacokinetic problems encountered. Among the various nanomaterials that have been designed as potential nanocarriers, cyclodextrin-based polymers are of particular interest in this review.Cyclodextrins (CD) are a class of cyclic glucopyranose oligomers, obtained from starch by enzymatic action, with a characteristic toroidal shape that forms a truncated cone-shaped lipophilic cavity. The main common native cyclodextrins are named α, β, and γ which comprise six, seven, and eight glucopyranose units, respectively. Cyclodextrins have the capability to include compounds whose size and polarity are compatible with those of their cavity.Cyclodextrin-based cross-linked polymers, often referred to as "cyclodextrin nanosponges" (CDNSs), attract great attention from researchers for solving major bioavailability problems such as inadequate solubility, poor dissolution rate, and limited stability of some agents, as well as increasing their effectiveness and decreasing unwanted side effects.Registered patents about this novel system in various fields, different pharmaceutical applications, and classes of drugs encapsulated by CDNSs are detailed. The features outlined make CDNSs a promising platform for the development of innovative and advanced delivery systems.
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http://dx.doi.org/10.1007/978-1-0716-0920-0_19DOI Listing
March 2021

Cyclic Oligosaccharides as Active Drugs, an Updated Review.

Pharmaceuticals (Basel) 2020 Sep 29;13(10). Epub 2020 Sep 29.

Dipartimento di Chimica, Università di Torino, via P. Giuria 7, 10125 Torino, Italy.

There have been many reviews of the cyclic oligosaccharide cyclodextrin (CD) and CD-based materials used for drug delivery, but the capacity of CDs to complex different agents and their own intrinsic properties suggest they might also be considered for use as active drugs, not only as carriers. The aim of this review is to summarize the direct use of CDs as drugs, without using its complexing potential with other substances. The direct application of another oligosaccharide called cyclic nigerosyl-1,6-nigerose (CNN) is also described. The review is divided into lipid-related diseases, aggregation diseases, antiviral and antiparasitic activities, anti-anesthetic agent, function in diet, removal of organic toxins, CDs and collagen, cell differentiation, and finally, their use in contact lenses in which no drug other than CDs are involved. In the case of CNN, its application as a dietary supplement and immunological modulator is explained. Finally, a critical structure-activity explanation is provided.
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http://dx.doi.org/10.3390/ph13100281DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7601923PMC
September 2020

Nanosponges as protein delivery systems: Insulin, a case study.

Int J Pharm 2020 Nov 18;590:119888. Epub 2020 Sep 18.

Department of Drug Science and Technology, University of Turin, via P. Giuria 9, 10125 Turin, Italy. Electronic address:

Cyclodextrin-based nanosponges have been found to bepromising drug delivery systems. This paper investigates an application that still needs to be studied in depth, that is, the oral delivery of peptides and proteins, choosing insulin as a case study. The nanospongewas synthesized by crosslinkingβ-cyclodextrins withpyromellitic dianhydride, adopting a top-down approach for its subsequent formulation. Aphysicochemical characterization, in-vitro andin-vivo tests were carried out on the formulation developed. It was nanometric (around 250 nm) with high negative zeta potential, mucoadhesion and swelling properties, good loading capability (about 14%) and encapsulation efficiency (above 90%). The in-vitro release of insulin was negligible at a gastric pH (below 2%) while sustained at an intestinal pH, thus showing a pH-sensitive behaviour of the nanosponge. The Caco-2 cell permeability assay proved that the intestinal permeation of insulin was enhanced when loaded inside the nanosponge. The in-vivo studies confirmed the presence of insulin in rat plasma and a marked hypoglycemic effect in diabetic mice after duodenal and oral administrations, respectively. These preliminary results are encouraging with a view to continuing to study this β-cyclodextrin nanosponge technology for the oral administration of insulin and extending this approach to other proteins of pharmaceutical interest.
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http://dx.doi.org/10.1016/j.ijpharm.2020.119888DOI Listing
November 2020

Lifespan extension in Caenorhabditis elegans by oxyresveratrol supplementation in hyper-branched cyclodextrin-based nanosponges.

Int J Pharm 2020 Nov 8;589:119862. Epub 2020 Sep 8.

Departamento de Bioquímica y Biología Molecular A, Unidad Docente de Biología, Facultad de Veterinaria, Regional Campus of International Excellence "Campus Mare Nostrum", Universidad de Murcia, Murcia, Spain. Electronic address:

In this work, the increase of the Caenorhabditis elegans (C. elegans) lifespan extension using hyper-branched cyclodextrin-based nanosponges (CD-NS) complexing oxyresveratrol (OXY), and the possible inhibition of C. elegans phosphodiesterase type 4 (PDE4) were evaluated. The titration displacement of fluorescein was used to calculate the apparent complexation constant (K) between CD-NS and OXY. Moreover, PDE4 was expressed in E. coli, purified and refolded in presence of cyclodextrins (CDs) to study its possible inhibition as pharmacological target of OXY. The apparent activity was characterized and the inhibitory effect of OXY on PDE4 displayed a competitive in vitro inhibition corroborated in silico. A maximum increase of the in vivo life expectancy of about 9.6% of using OXY/CD-NS complexes in comparison with the control was obtained, in contrast to the 6.5% obtained with free OXY. No effect on lifespan or toxicity with CD-NS alone was found. These results as a whole represent new opportunities to use OXY and CD-NS in lifespan products.
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http://dx.doi.org/10.1016/j.ijpharm.2020.119862DOI Listing
November 2020

Preparation and characterization of cyclodextrin nanosponges for bortezomib delivery.

Expert Opin Drug Deliv 2020 12 9;17(12):1807-1816. Epub 2020 Nov 9.

Liver and Gastrointestinal Diseases Research Center and Faculty of Pharmacy, Tabriz University of Medical Sciences , Tabriz, Iran.

Background: Bortezomib (BTZ) as an anticancer drug has been used through the injection pathway.

Research Design And Methods: Two types of Cyclodextrin nanosponges (CDNSs) were synthesized and studied by DLS, TEM, FTIR, and DSC instruments for BTZ delivery. Both carriers were analyzed for loading efficiencies and release. Cell studies and intestinal permeability of selected CDNS were determined using MTT and SPIP method, respectively.

Results: Both types of CDNSs, encapsulated BTZ in their nano-porous structure, but better loading was shown in CDNS 1:4. FTIR and DSC results proved considerable encapsulation of BTZ into CDNSs. The slow and prolonged release profile was observed for CDNS 1:4 in comparison with CDNS 1:2. Based on results, BTZ-CDNS 1:4 was chosen as a selected nanosystem for further analysis. This nontoxic carrier revealed considerable uptake (93.9% in 3 h) against the MCF-7 cell line but indicated higher IC in comparison with the plain drug. This carrier also could improve the rat intestinal permeability of BTZ almost 5.8 times.

Conclusion: CDNS 1:4 has the ability to be introduced as a nontoxic carrier for BTZ delivery with its high loading, controlled release manner, high cellular uptake, and permeability improvement characteristics.
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http://dx.doi.org/10.1080/17425247.2020.1800637DOI Listing
December 2020

Mechanochemical green synthesis of hyper-crosslinked cyclodextrin polymers.

Beilstein J Org Chem 2020 29;16:1554-1563. Epub 2020 Jun 29.

Dipartimento di Chimica, Università degli Studi di Torino, Via Giuria 7, Torino 10125, Italy.

Cyclodextrin nanosponges (CD-NS) are nanostructured crosslinked polymers made up of cyclodextrins. The reactive hydroxy groups of CDs allow them to act as multifunctional monomers capable of crosslinking to bi- or multifunctional chemicals. The most common NS synthetic pathway consists in dissolving the chosen CD and an appropriate crosslinker in organic polar aprotic liquids (e.g., ,-dimethylformamide or dimethyl sulfoxide), which affect the final result, especially for potential biomedical applications. This article describes a new, green synthetic pathway through mechanochemistry, in particular via ball milling and using 1,1-carbonyldiimidazole as the crosslinker. The polymer obtained exhibited the same characteristics as a CD-based carbonate NS synthesized in a solvent. Moreover, after the synthesis, the polymer was easily functionalized through the reaction of the nucleophilic carboxylic group with three different organic dyes (fluorescein, methyl red, and rhodamine B) and the still reactive imidazoyl carbonyl group of the NS.
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http://dx.doi.org/10.3762/bjoc.16.127DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356557PMC
June 2020

Preparation of Microspheres and Monolithic Microporous Carbons from the Pyrolysis of Template-Free Hyper-Crosslinked Oligosaccharides Polymer.

Molecules 2020 Jul 2;25(13). Epub 2020 Jul 2.

Department of Chemistry, NIS and INSTM Reference Centres, University of Torino, Via P. Giuria 7, 10125 Torino, Italy.

Carbon-based materials with different morphologies have special properties suitable for application in adsorption, catalysis, energy storage, and so on. Carbon spheres and carbon monoliths are also nanostructured materials showing promising results. However, the preparation of these materials often require the use of a template, which aggravates their costs, making the operations for their removal complex. In this work, hollow carbon microspheres and carbon monolith were successfully prepared via carbonization of hyper-crosslinked polymer based on either cyclodextrins or amylose, in a template-free way. The carbons obtained are of the microporous type, showing a surface area up to 610 m/g, and a narrow pore distribution, typically between 5 and 15 Å.
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http://dx.doi.org/10.3390/molecules25133034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7411619PMC
July 2020

Biological Effect Evaluation of Glutathione-Responsive Cyclodextrin-Based Nanosponges: 2D and 3D Studies.

Molecules 2020 Jun 16;25(12). Epub 2020 Jun 16.

Department of Drug Science and Technology, University of Torino, Via Pietro Giuria 9, 10125 Torino, Italy.

This study aims to evaluate the bioeffects of glutathione-responsive β-cyclodextrin-based nanosponges (GSH-NSs) on two- (2D) and three-dimensional (3D) cell cultures. The bioeffects of two types of GSH-NS formulations, with low (GSH-NS B) and high (GSH-NS D) disulfide-bond content, were evaluated on 2D colorectal (HCT116 and HT-29) and prostatic (DU-145 and PC3) cancer cell cultures. In particular, the cellular uptake of GSH-NS was evaluated, as their effects on cell growth, mitochondrial activity, membrane integrity, cell cycle distribution, mRNA expression, and reactive oxygen species production. The effect of GSH-NSs on cell growth was also evaluated on multicellular spheroids (MCS) and a comparison of the GSH-NS cell growth inhibitory activity, in terms of inhibition concentration (IC) values, was performed between 2D and 3D cell cultures. A significant decrease in 2D cell growth was observed at high GSH-NS concentrations, with the formulation with a low disulfide-bond content, GSH-NS B, being more cytotoxic than the formulation with a high disulfide-bond content, GSH-NS D. The cell growth decrease induced by GSH-NS was owing to G cell cycle arrest. Moreover, a significant down-regulation of mRNA expression of the cyclin genes , , and and up-regulation of mRNA expression of the cyclin inhibitor genes and were observed. On the other hand, a significant decrease in MCS growth was also observed at high GSH-NS concentrations, but not influenced by the nanosponge disulfide-bond content, with the MCS IC values being significantly higher than those obtained on 2D cell cultures. GSH-NSs are suitable nanocarries as they provoke limited cellular effects, as cell cycle arrest only occurred at concentrations significantly higher than those used for drug delivery.
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http://dx.doi.org/10.3390/molecules25122775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355809PMC
June 2020

History of Cyclodextrin Nanosponges.

Polymers (Basel) 2020 May 14;12(5). Epub 2020 May 14.

Department of Chemistry, University of Torino, via P. Giuria 7, 10125 Torino, Italy.

Nowadays, research in the field of nanotechnology and nanomedicine has become increasingly predominant, focusing on the manipulation and development of materials on a nanometer scale. Polysaccharides have often been used as they are safe, non-toxic, hydrophilic, biodegradable and are low cost. Among them, starch derivatives and, in particular, cyclodextrin-based nanosponges (CD NSs) have recently emerged due to the outstanding properties attributable to their peculiar structure. In fact, alongside the common polysaccharide features, such as the presence of tunable functional groups and their ability to interact with biological tissues, thus giving rise to bioadhesion, which is particularly useful in drug delivery, what makes CD NSs unique is their three-dimensional network made up of crosslinked cyclodextrin units. The name "nanosponge" appeared for the first time in the 1990s due to their nanoporous, sponge-like structure and responded to the need to overcome the limitations of native cyclodextrins (CDs), particularly their water solubility and inability to encapsulate charged and large molecules efficiently. Since CD NSs were introduced, efforts have been made over the years to understand their mechanism of action and their capability to host molecules with low or high molecular weight, charged, hydrophobic or hydrophilic by changing the type of cyclodextrin, crosslinker and degree of crosslinking used. They enabled great advances to be made in various fields such as agroscience, pharmaceutical, biomedical and biotechnological sectors, and NS research is far from reaching its conclusion. This review gives an overview of CD NS research, focusing on the origin and key points of the historical development in the last 50 years, progressing from relatively simple crosslinked networks in the 1960s to today's multifunctional polymers. The approach adopted in writing the present study consisted in exploring the historical evolution of NSs in order to understand their role today, and imagine their future.
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http://dx.doi.org/10.3390/polym12051122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7285114PMC
May 2020

New Poly(β-Cyclodextrin)/Poly(Vinyl Alcohol) Electrospun Sub-Micrometric Fibers and their Potential Application for Wastewater Treatments.

Nanomaterials (Basel) 2020 Mar 7;10(3). Epub 2020 Mar 7.

Department of Chemistry and NIS Centre, University of Turin, Via P. Giuria 7, 10125 Torino, Italy.

Cyclodextrin (CD)-based polymers are known to efficiently form molecular inclusion complexes with various organic and inorganic guest compounds. In addition, they also have a great potential as metal complexes because deprotonated hydroxyls can strongly bind metal ions under alkaline conditions. The range of environmental conditions for polycyclodextrin/metal ion complexation can be extended by the polymerization of CDs with polyacids. This article describes the preparation and characterization of a new type of poly(β-cyclodextrin) (Poly-βCD) sub-micrometric fibers and explores their potential as metal ion sorbents. A water-soluble hyper-branched β-cyclodextrin polymer was blended with poly(vinyl alcohol) (PVA) and here used to improve the mechanical and morphological features of the fibers. Solutions with a different Poly-βCD/PVA ratio were electrospun, and the fibers were cross-linked by a post-spinning thermal treatment at 160 °C to ensure non-solubility in water. The fiber morphology was analyzed by scanning electron microscopy (SEM) before and after the curing process, and physical-chemical properties were studied by Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). The capability of the insoluble cyclodextrin-based fibers to remove heavy metals from wastewaters was investigated by testing the adsorption of Cu and Cd using inductively coupled plasma-optical emission spectroscopy (ICP-OES). The results suggest that the poly(β-cyclodextrin)/poly(vinyl alcohol) sub-micrometric fibers can complex metal ions and are especially effective Cu sorbents, thus opening new perspectives to the development of fibers and membranes capable of removing both metal ions and organic pollutants.
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http://dx.doi.org/10.3390/nano10030482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7153712PMC
March 2020

Glutathione-responsive cyclodextrin-nanosponges as drug delivery systems for doxorubicin: Evaluation of toxicity and transport mechanisms in the liver.

Toxicol In Vitro 2020 Jun 19;65:104800. Epub 2020 Feb 19.

Department of Clinical and Biological Sciences, University of Turin, Turin, Italy. Electronic address:

The potential mammalian hepatotoxicity of a new class of GSH-responsive cyclodextrin-based nanosponges loaded with the anticancer drug doxorubicin (Dox-GSH-NS) was investigated. Previous studies showed that these nanosponges can release medicaments preferentially in cells having high GSH content, a common feature of chemoresistant cells, and showed enhanced anti-tumoral activity compared to free Dox in vitro and in vivo in cells with high GSH content. Following these promising results, we investigated here the Dox-GSH-NS hepatotoxicity in human HepG2 cells (in vitro) and in the organotypic cultures of rat precision-cut liver slices (PCLS, ex vivo), while their accumulation in rat liver was assessed in vivo. Moreover, the transport in Dox uptake, as well as its efflux, was studied in vitro. Overall, benefiting of the integration of different investigational models, a good safety profile of Dox-GSH-NSs was evidenced, and their hepatotoxicity resulted to be comparable with respect to free Dox both in vitro and ex vivo. Furthermore, in vivo studies showed that the hepatic accumulation of the Dox loaded in the NS is comparable with respect to the free drug. In addition, Dox-GSH-NSs are taken up by active mechanisms, and can escape the efflux drug pump, thus, contributing to overcoming drug resistance.
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http://dx.doi.org/10.1016/j.tiv.2020.104800DOI Listing
June 2020

Immunotherapy of experimental melanoma with ICOS-Fc loaded in biocompatible and biodegradable nanoparticles.

J Control Release 2020 04 18;320:112-124. Epub 2020 Jan 18.

Department of Health Sciences, Inter Interdisciplinary Research Center of Autoimmune Diseases, UPO, 28100 Novara, Italy; Center for Translational Research on Autoimmune and Allergic Disease-CAAD, Università del Piemonte Orientale, 28100 Novara, Italy.

Inducible T-cell costimulator (ICOS) upon binding to its ligand (ICOSL) mediates adaptive immunity and antitumor response. Thus, antitumor therapies targeting the ICOS/ICOSL pathway hold great promise for cancer treatment. In this regard, ICOSL triggering by a soluble recombinant form of ICOS (ICOS-Fc) hampered adhesiveness and migration of dendritic, endothelial, and tumor cells in vitro. Furthermore, in vivo treatment with ICOS-Fc previously showed the capability to inhibit lung metastatization of ICOSL B16-F10 melanoma cells when injected intravenously in mice, but it failed to block the growth of established subcutaneous B16-F10 murine tumors. Thus, we asked whether passive targeting of solid tumors with ICOS-Fc-loaded biocompatible and biodegradable nanoparticles (NPs) could instead prove effectiveness in reducing tumor growth. Here, ICOS-Fc was loaded in two types of polymer nanoparticles, i.e. cross-linked β-cyclodextrin nanosponges (CDNS) and poly(lactic-co-glycolic acid) (PLGA) NPs and in vitro characterized. In vivo experiments showed that treatment of C57BL6/J mice with ICOS-Fc loaded into the two nanoformulations inhibits the growth of established subcutaneous B16-F10 tumors. This anticancer activity appears to involve both anti-angiogenic and immunoregulatory effects, as shown by decreased tumor vascularization and downmodulation of IL-10 and Foxp3, two markers of regulatory T cells (Tregs). Overall, the substantial in vivo anticancer activity of ICOS-Fc-loaded CDNS and PLGA NPs against different components of the tumor microenvironment makes these nanoformulations attractive candidates for future combination cancer therapy.
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http://dx.doi.org/10.1016/j.jconrel.2020.01.030DOI Listing
April 2020

In Situ Synthesis of MIL-100(Fe) at the Surface of [email protected] as Highly Efficient Dye Adsorbing Nanocomposite.

Int J Mol Sci 2019 Nov 9;20(22). Epub 2019 Nov 9.

Department of Chemistry, Faculty of Science, Yazd Branch, Islamic Azad University, Yazd 8915813135, Iran.

A new magnetic nanocomposite called MIL-100(Fe) @[email protected] was synthesized by the hydrothermal method as a stable adsorbent for the removal of Rhodamine B (RhB) dye from aqueous medium. In this work, in order to increase the carbon uptake capacity, magnetic carbon was first synthesized and then the FeO was used as the iron (III) supplier to synthesize MIL-100(Fe). The size of these nanocomposite is about 30-50 nm. Compared with activated charcoal (AC) and magnetic activated charcoal ([email protected]) nanoparticles, the surface area of MIL-100(Fe) @[email protected] were eminently increased while the magnetic property of this adsorbent was decreased. The surface area of AC, [email protected], and MIL-100(Fe) @[email protected] was 121, 351, and 620 m/g, respectively. The magnetic and thermal property, chemical structure, and morphology of the MIL-100(Fe) @[email protected] were considered by vibrating sample magnetometer (VSM), thermogravimetric analysis (TGA), zeta potential, X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), Brunner-Emmet-Teller (BET), and transmission electron microscopy (TEM) analyses. The relatively high adsorption capacity was obtained at about 769.23 mg/g compared to other adsorbents to eliminate RhB dye from the aqueous solution within 40 min. Studies of adsorption kinetics and isotherms showed that RhB adsorption conformed the Langmuir isotherm model and the pseudo second-order kinetic model. Thermodynamic amounts depicted that the RhB adsorption was spontaneous and exothermic process. In addition, the obtained nanocomposite exhibited good reusability after several cycles. All experimental results showed that MIL-100(Fe) @[email protected] could be a prospective sorbent for the treatment of dye wastewater.
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http://dx.doi.org/10.3390/ijms20225612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888277PMC
November 2019

Comparative Evaluation of Solubility, Cytotoxicity and Photostability Studies of Resveratrol and Oxyresveratrol Loaded Nanosponges.

Pharmaceutics 2019 Oct 20;11(10). Epub 2019 Oct 20.

Department of Chemistry, University of Torino, via P. Giuria 7, 10125 Torino, Italy.

Resveratrol and oxyresveratrol are natural polyphenolic stilbenes with several important pharmacological activities. However, low solubility and aqueous instability are the major limitations in their drug delivery applications. In the present work, we demonstrated the encapsulation of resveratrol and oxyresveratrol with nanosponge to improve solubility and stability. Several characterization techniques were used to confirm the encapsulation of both drug molecules within the nanosponges. The high encapsulation efficiency of resveratrol (77.73%) and oxyresveratrol (80.33%) was achieved within the nanosponges. Transmission electron microscopy suggested uniform spherical size particles of resveratrol and oxyresveratrol loaded nanosponges. Compared to free drugs, better protection against UV degradation was observed for resveratrol-loaded nanosponge (2-fold) and oxyresveratrol-loaded nanosponge (3-fold). Moreover, a higher solubilization of resveratrol- and oxyresveratrol-loaded nanosponges lead to a better antioxidant activity compared to drug molecules alone. Cytotoxicity studies against DU-145 prostate cancer cell lines further suggested improved activity of both resveratrol and oxyresveratrol-loaded nanosponges without any significant toxicity of blank nanosponges.
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http://dx.doi.org/10.3390/pharmaceutics11100545DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6836080PMC
October 2019

Eco-Friendly β-cyclodextrin and Linecaps Polymers for the Removal of Heavy Metals.

Polymers (Basel) 2019 Oct 11;11(10). Epub 2019 Oct 11.

Department of Chemistry, University of Torino, via P. Giuria 7, 10125 Torino, Italy.

Environment-friendly nanosponges, having a high content of carboxyl groups, were synthesized by crosslinking β-cyclodextrin and linecaps, a highly soluble pea starch derivative, with citric acid in water. Additionally, pyromellitic nanosponges were prepared by reacting β-cyclodextrin and linecaps with pyromellitic dianhydride in dimethyl sulfoxide and used in comparison with the citric nanosponges. After ion-exchange of the carboxyl groups H with sodium ions, the ability of the nanosponges to sequester heavy metal cations was investigated. At a metal concentration of 500 ppm, the pyromellitate nanosponges exhibited a higher retention capacity than the citrate nanosponges. At lower metal concentrations (≤50 ppm) both the citrate and the pyromellitate nanosponges showed high retention capacities (up to 94% of the total amount of metal), while, in the presence of interfering sea water salts, the citrate nanosponges were able to selectively adsorb a significantly higher amount of heavy metals than the pyromellitate nanosponges, almost double in the case of Cu.
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http://dx.doi.org/10.3390/polym11101658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6835710PMC
October 2019

Pyromellitic dianhydride crosslinked cyclodextrin nanosponges for curcumin controlled release; formulation, physicochemical characterization and cytotoxicity investigations.

J Microencapsul 2019 Dec 27;36(8):715-727. Epub 2019 Sep 27.

Department of Mechanical Engineering, Sharif University of Technology, Tehran, Iran.

In this study, a nanosponge structure was synthesised with capability of encapsulating curcumin as a model polyphenolic compound and one of the herbal remedies that have widely been considered due to its ability to treat cancer. FTIR, DSC and XRD techniques were performed to confirm the formation of the inclusion complex of the nanosponge-drug. DSC and XRD patterns showed an increasing stability and a decreasing crystallinity of curcumin after formation of inclusion complex. Encapsulation efficiency was 98% (w/w) and a significant increase was observed in loading capacity (184% w/w). The results of cytotoxicity assessments demonstrated no cell toxicity on the healthy cell line, while being toxic against cancer cells. Haemolysis test was performed to evaluate the blood-compatibility characteristic of nanosponge and complex and the results showed 0.54% haemolysis in the lowest complex concentration (50μgml) and 5.09% at the highest concentration (200μgml).: Thus, the introduced system could be widely considered in cancer treatment as a drug delivery system.
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http://dx.doi.org/10.1080/02652048.2019.1669728DOI Listing
December 2019

Evaluation of solubility enhancement, antioxidant activity, and cytotoxicity studies of kynurenic acid loaded cyclodextrin nanosponge.

Carbohydr Polym 2019 Nov 5;224:115168. Epub 2019 Aug 5.

Department of Chemistry, University of Torino, via P. Giuria 7, 10125, Torino, Italy. Electronic address:

Kynurenic acid demonstrates antioxidant, neuroprotective and free radical scavenging properties. However, low aqueous solubility of kynurenic acid limits its therapeutic activity. In the present study, cyclodextrin nanosponges were used to improve the solubility and therapeutic activity of kynurenic acid. The formation of kynurenic acid loaded nanosponge was confirmed by different characterization techniques. The solubility of kynurenic acid was significantly increased with nanosponge (111.1 μg/ml) compared to free kynurenic acid (16.4 μg/ml) and β-cyclodextrin (28.6 μg/ml). High drug loading (19.06%) and encapsulation efficiency (95.31%) were achieved with NS. The particle size and zeta potential of kynurenic acid loaded nanosponge was around 255.8 nm and -23 mV respectively. Moreover, higher solubilization of kynurenic acid loaded nanosponge produced better antioxidant activity compared to free kynurenic acid. The kynurenic acid loaded nanosponge and blank nanosponge were found nontoxic in the cytotoxicity assay. Thus, these studies demonstrated that nanosponges can be used as a carrier for the delivery of kynurenic acid.
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http://dx.doi.org/10.1016/j.carbpol.2019.115168DOI Listing
November 2019

Paclitaxel-Loaded Nanosponges Inhibit Growth and Angiogenesis in Melanoma Cell Models.

Front Pharmacol 2019 12;10:776. Epub 2019 Jul 12.

Dipartimento di Scienza e Tecnologia del Farmaco, University of Torino, Torino, Italy.

This study investigated the effects of free paclitaxel (PTX) and PTX-loaded in pyromellitic nanosponges (PTX-PNS) in reducing and melanoma cell growth and invasivity, and in inhibiting angiogenesis. To test the response of cells to the two PTX formulations, the cell viability was evaluated by MTT assay in seven continuous cell lines, in primary melanoma cells, both in 2D and 3D cultures, and in human umbilical vein endothelial cells (HUVECs) after exposure to different concentrations of PTX or PTX-PNS. Cell motility was assessed by a scratch assay or Boyden chamber assay, evaluating cell migration in presence or absence of diverse concentrations of PTX or PTX-PNS. The effect of PTX and PTX-PNS on angiogenesis was evaluated as endothelial tube formation assay, a test able to estimate the formation of three-dimensional vessels . To assess the anticancer effect of PTX and PTX-PNS in experiments, the two drug formulations were tested in a melanoma mouse model obtained by B16-BL6 cell implantation in C57/BL6 mice. Results obtained were as follows: 1) MTT analysis revealed that cell proliferation was more affected by PTX-PNS than by PTX in all tested cell lines, in both 2D and 3D cultures; 2) the analysis of the cell migration showed that PTX-PNS acted at very lower concentrations than PTX; 3) tube formation assay showed that PTX-PNS were more effective in inhibiting tube formation than free PTX; and 4) experiments demonstrated that tumor weights, volumes, and growth were significantly reduced by PTX-PNS treatment with respect to PTX; the angiogenesis and the cell proliferation, detected in the tumor samples with CD31 and Ki-67 antibodies, respectively, indicated that, in the PTX-PNS-treated tumors, the tube formation was inhibited, and a low amount of proliferating cells was present. Taken together, our data demonstrated that our new PTX nanoformulation can respond to some important issues related to PTX treatment, lowering the anti-tumor effective doses and increasing the effectiveness in inhibiting melanoma growth .
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http://dx.doi.org/10.3389/fphar.2019.00776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639435PMC
July 2019

In Vitro Enhanced Skin Permeation and Retention of Imiquimod Loaded in β-Cyclodextrin Nanosponge Hydrogel.

Pharmaceutics 2019 Mar 20;11(3). Epub 2019 Mar 20.

Department of Drug Science and Technology, University of Turin, via P. Giuria 9, 10125 Turin, Italy.

Imiquimod (IMQ) is an immune response modifier clinically used for the treatment of various topical diseases. However, its poor aqueous solubility and skin penetration capability make the topical delivery of IMQ a challenging task. This work aims at developing a nanomedicine-based topical formulation, carrying IMQ to control the scarring process for the treatment of aberrant wounds. For this purpose, IMQ was loaded in β-cyclodextrin-based nanosponges and dispersed in a hydrogel suitable for dermal application. The formulation was characterized in vitro and compared with IMQ inclusion complexes, with (2-hydroxy)propyl β-cyclodextrin(HPβCD) and carboxymethyl β-cyclodextrin (CMβCD) showing enhanced penetration properties. The hydrogel containing IMQ-loaded nanosponges could act as a drug reservoir and guarantee the sustained release of IMQ through the skin. A greater inhibitory effect on fibroblast proliferation was observed for IMQ loaded in nanosponges compared to the other formulations.
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http://dx.doi.org/10.3390/pharmaceutics11030138DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6471382PMC
March 2019

Glutathione/pH-responsive nanosponges enhance strigolactone delivery to prostate cancer cells.

Oncotarget 2018 Nov 9;9(88):35813-35829. Epub 2018 Nov 9.

Department of Drug Science and Technology, University of Turin, Turin, Italy.

Strigolactones (SLs) are carotenoid-derived plant hormones that exhibit anti-cancer activities. We previously demonstrated that two SL analogues, MEB55 and ST362, inhibit the growth and survival of various cancer cell lines. However, these compounds have low aqueous solubility and stability at physiological pH. Here, we generated SL-loaded glutathione/pH-responsive nanosponges (GSH/pH-NS) to selectively deliver SLs to prostate cancer cells and enhance their therapeutic efficacy. The SLs were readily incorporated into the GSH/pH-NS. The drug loading efficiency was 13.9% for MEB55 and 15.4% for ST362, and the encapsulation efficiency was 88.7% and 96.5%, respectively. Kinetic analysis revealed that release of MEB55 and ST362 from the GSH/pH-NS was accelerated at acidic pH and in the presence of a high GSH concentration. Evaluation of the effects of MEB55- and ST362-loaded GSH/pH-NS on the growth of DU145 (high GSH) and PC-3 (low GSH) prostate cancer cells revealed that the GSH/pH-NS inhibited the proliferation of DU145 cells to a greater extent than free MEB55 or ST362 over a range of concentrations. These findings indicate GSH/pH-NS are efficient tools for controlled delivery of SLs to prostate cancer cells and may enhance the therapeutic efficacy of these compounds.
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http://dx.doi.org/10.18632/oncotarget.26287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6254672PMC
November 2018

Controlled Release of DEET Loaded on Fibrous Mats from Electrospun PMDA/Cyclodextrin Polymer.

Molecules 2018 07 11;23(7). Epub 2018 Jul 11.

Department of Chemistry and NIS Centre, University of Turin, Via P. Giuria 7, 10125 Torino, Italy.

Electrospun beta-cyclodextrin (βCD)-based polymers can combine a high surface-to-volume ratio and a high loading/controlled-release-system potential. In this work, pyromellitic dianhydride (PMDA)/βCD-based nanosponge microfibers were used to study the capability to host a common insect repellent (,-diethyl-3-toluamide (DEET)) and to monitor its release over time. Fibrous samples characterized by an average fibrous diameter of 2.8 ± 0.8 µm were obtained and subsequently loaded with DEET, starting from a 10 g/L diethyl ether (DEET) solution. The loading capacity of the system was assessed via HPLC/UV⁻Vis analysis and resulted in 130 mg/g. The releasing behavior was followed by leaving fibrous DEET-loaded nanosponge samples in air at room temperature for a period of between 24 h and 2 weeks. The releasing rate and the amount were calculated by thermogravimetric analysis (TGA), and the release of the repellent was found to last for over 2 weeks. Eventually, both the chemical composition and sample morphology were proven to play a key role for the high sample loading capacity, determining the microfibers' capability to be applied as an effective controlled-release system.
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http://dx.doi.org/10.3390/molecules23071694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6100364PMC
July 2018

Investigation of Cyclodextrin-Based Nanosponges for Solubility and Bioavailability Enhancement of Rilpivirine.

AAPS PharmSciTech 2018 Jul 4;19(5):2358-2369. Epub 2018 Jun 4.

Department of Chemistry, University of Torino, Torino, Italy.

Rilpivrine is BCS class II drug used for treatment of HIV infection. The drug has low aqueous solubility (0.0166 mg/ml) and dissolution rate leading to low bioavailability (32%). Aim of this work was to enhance solubility and dissolution of rilpivirine using beta-cyclodextrin-based nanosponges. These nanosponges are biocompatible nanoporous particles having high loading capacity to form supramolecular inclusion and non-inclusion complexes with hydrophilic and lipophilic drugs for solubility enhancement. Beta-cyclodextrin was crosslinked with carbonyl diimidazole and pyromellitic dianhydride to prepare nanosponges. The nanosponges were loaded with rilpivirine by solvent evaporation method. Binary and ternary complexes of drug with β-CD, HP-β-CD, nanosponges, and tocopherol polyethylene glycol succinate were prepared and characterized by phase solubility, saturation solubility in different media, in vitro dissolution, and in vivo pharmacokinetics. Spectral analysis by Fourier transform infrared spectroscopy, powder X-ray diffraction, and differential scanning calorimetry was performed. Results obtained from spectral characterization confirmed inclusion complexation. Phase solubility studies indicated stable complex formation. Saturation solubility was found to be 10-13-folds higher with ternary complexes in distilled water and 12-14-fold higher in 0.1 N HCl. Solubility enhancement was evident in biorelevant media. Molecular modeling studies revealed possible mode of entrapment of rilpivirine within β-CD cavities. A 3-fold increase in dissolution with ternary complexes was observed. Animal studies revealed nearly 2-fold increase in oral bioavailability of rilpivirine. It was inferred that electronic interactions, hydrogen bonding, and van der Waals forces are involved in the supramolecular interactions.
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http://dx.doi.org/10.1208/s12249-018-1064-6DOI Listing
July 2018

α-Cyclodextrin and α-Cyclodextrin Polymers as Oxygen Nanocarriers to Limit Hypoxia/Reoxygenation Injury: Implications from an In Vitro Model.

Polymers (Basel) 2018 Feb 22;10(2). Epub 2018 Feb 22.

Department of Chemistry, University of Turin, 10125 Turin, Italy.

The incidence of heart failure (HF) is increasing worldwide and myocardial infarction (MI), which follows ischemia and reperfusion (I/R), is often at the basis of HF development. Nanocarriers are interesting particles for their potential application in cardiovascular disease. Impaired drug delivery in ischemic disease is challenging. Cyclodextrin nanosponges (NS) can be considered innovative tools for improving oxygen delivery in a controlled manner. This study has developed new α-cyclodextrin-based formulations as oxygen nanocarriers such as native α-cyclodextrin (α-CD), branched α-cyclodextrin polymer (α-CD POLY), and α-cyclodextrin nanosponges (α-CD NS). The three different α-CD-based formulations were tested at 0.2, 2, and 20 µg/mL to ascertain their capability to reduce cell mortality during hypoxia and reoxygenation (H/R) in vitro protocols. H9c2, a cardiomyoblast cell line, was exposed to normoxia (20% oxygen) or hypoxia (5% CO₂ and 95% N₂). The different formulations, applied before hypoxia, induced a significant reduction in cell mortality (in a range of 15% to 30%) when compared to samples devoid of oxygen. Moreover, their application at the beginning of reoxygenation induced a considerable reduction in cell death (12% to 20%). α-CD NS showed a marked efficacy in controlled oxygenation, which suggests an interesting potential for future medical application of polymer systems for MI treatment.
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http://dx.doi.org/10.3390/polym10020211DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6414891PMC
February 2018

Evolution of Cyclodextrin Nanosponges.

Int J Pharm 2017 Oct 20;531(2):470-479. Epub 2017 Jun 20.

Department of Chemistry, University of Torino, via P. Giuria 7, 10125, Torino, Italy.

Cyclodextrin-based nanosponges (CD-NSs) are insoluble, highly cross-linked 3D network polymers used in several scientific and technological fields, the main area of investigation concerns the pharmaceutical applications, in which CD-NSs have been mostly employed as drug delivery systems. CD-NSs can be generally grouped into four consecutive generations, taking into account their chemical composition and properties. The 1st generation of NSs are plain nanosponges, subdivided into four main types: urethane, carbonate, ester and ether NSs, depending on the chemical nature of the functional group connecting the CD to the cross-linker. The 2nd generation of NSs are modified nanosponges characterized by specific properties, such as fluorescence and electric charge. The 3rd generation of NSs is represented by stimuli-responsive CD polymers, which are able to modulate their behavior according to external variations in the environment, such as pH and temperature gradients, oxidative/reducing conditions, and finally the 4th generation of NSs, a new family of molecularly imprinted CD polymers (MIPs), exhibiting a high selectivity towards specific molecules. The following review focuses on the evolution of cyclodextrin nanosponges, listing some examples of each generation.
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http://dx.doi.org/10.1016/j.ijpharm.2017.06.072DOI Listing
October 2017
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