Synthesis of ß-cyclodextrin-based nanosponges for remediation of 2,4-D polluted waters.

Two cyclodextrin-based nanosponges (CD-NSs) were synthesized using diamines with 6 and 12 methylene groups, CDHD6 and CDHD12, respectively, and used as adsorbents to remove 2,4-D from aqueous solutions. The physico-chemical characterization of the CD‒NSs demonstrated that, when using the linker with the longest chain length, the nanosponges show a more compact structure and higher thermal stability, probably due to hydrophobic interactions. SEM micrographs showed significant differences between the two nanosponges used. The adsorption of 2,4-D was assessed in terms of different parameters, including solid/liquid ratio, pH, kinetics and isotherms. Adsorption occurred preferentially at lower pH values and for short-chain crosslinked nanosponges; while the former is explained by the balance of acid-base characteristics of the adsorbent and adsorbate, the latter can be justified by the increase in the crosslinker-crosslinker interactions, predominantly hydrophobic, rather than adsorbent-adsorbate interactions. The maximum adsorption capacity at the equilibrium (qe) was 20,903 mmol/kg, obtained using CDHD12 with an initial 2,4-D concentration of 2 mmol/L. An environmentally friendly strategy, based on alkali desorption, was developed to recycle and reuse the adsorbents. On the basis of the results obtained, cyclodextrin-based nanosponges appear promising materials for an economically feasible removal of phenoxy herbicides, to be used as potential adsorbents for the sustainable management of agricultural wastewaters.

Complexing the Marine Sesquiterpene Euplotin C by Means of Cyclodextrin-Based Nanosponges: A Preliminary Investigation.

Euplotin C is a sesquiterpene of marine origin endowed with significant anti-microbial and anti-tumor properties. Despite the promising functional profile, its progress as a novel drug candidate has failed so far, due to its scarce solubility and poor stability in aqueous media, such as biological fluids. Therefore, overcoming these limits is an intriguing challenge for the scientific community. In this work, we synthesized ß-cyclodextrin-based nanosponges and investigated their use as colloidal carriers for stably complex euplotin C. Results obtained proved the ability of the carrier to include the natural compound, showing remarkable values of both loading efficiency and capacity. Moreover, it also allowed us to preserve the chemical structure of the loaded compound, which was recovered unaltered once extracted from the complex. Therefore, the use of ß-cyclodextrin-based nanosponges represents a viable option to vehiculate euplotin C, thus opening up its possible use as pharmacologically active compound.

Evaluation of EDTA Dianhydride Versus Diphenyl Carbonate Nanosponges for Curcumin.

Cyclodextrin-based nanosponges are widely investigated for several applications and are considered potential drug carriers. The method of nanosponges preparation involves the use of chemical cross-linking agents where the properties of Nanosponges can be affected. This study compared the resulting differences in the final nanosponges' properties using carbonate and dianhydride crosslinkers. Diphenyl carbonate and EDTA dianhydride were used for the synthesis of nanosponges. Both types of nanosponges were loaded with curcumin as a model drug. Physicochemical characterizations, including PXRD, DSC, FTIR, scanning electron microscopy, AFM, particle size, zeta potential, and surface area analysis, were carried out for the prepared nanosponges. Curcumin release and drug content were also evaluated. Nanosponges prepared by Diphenyl carbonate crosslinker resulted in an amorphous form compared to crystalline EDTA-nanosponges. This study reported the successful inclusion and complexation of curcumin inside carbonate cross-linked cyclodextrin-based nanosponges and suggested the physical entrapment of crystalline curcumin in EDTA dianhydride. These findings were further investigated and supported by computational modeling.

Oral supplementation of solvent-free kynurenic acid/cyclodextrin nanosponges complexes increased its bioavailability.

Many nutraceuticals present problems due to their poor water solubility or stability, which prevents the final bioactivity achievement. For that reason, the oral administration of KYNA complexed with HPß-CD and ßNS-CDI nanosponges was evaluated in mice. The solvent-free technology was used to prepare the complexes in a complete comparison between kneading in ball milling and classical inclusion complex preparation. The solvent-free ones showed higher strength and efficiency with ball milling, considerably reducing time. A 50 mg KYNA/kg/day dosage was orally administered in formulations showing a higher bioavailability when the nutraceutical was complexed with ßNS-CDI compared to HPß-CD and free KYNA, respectively. Several antioxidant statuses demonstrated a higher global antioxidant level perfectly related to bioavailability. Finally, the formulation of KYNA reduced the temporal oxidative stress damage in the kidney and liver, making ßNS-CDI the best formulation. These results suggest an important future application of cyclodextrin-based nanosponges for the oral delivery of nutraceuticals and their stabilization.

ß-Cyclodextrin Nanosponges Inclusion Compounds Associated with Silver Nanoparticles to Increase the Antimicrobial Activity of Quercetin.

This work aimed to synthesize and characterize a nanocarrier that consisted of a ternary system, namely ß-cyclodextrin-based nanosponge (NS) inclusion compounds (ICs) associated with silver nanoparticles (AgNPs) to increase the antimicrobial activity of quercetin (QRC). The nanosystem was developed to overcome the therapeutical limitations of QRC. The host-guest interaction between NSs and QRC was confirmed by field emission scanning electron microscopy (FE-SEM), X-ray powder diffraction (XRPD), thermogravimetric analysis (TGA), and proton nuclear magnetic resonance (1H-NMR). Moreover, the association of AgNPs with the NS-QRC was characterized using FE-SEM, energy-dispersive spectroscopy (EDS), transmission electron microscopy (TEM), dynamic light scattering (DLS), ζ-potential, and UV-Vis. Finally, the antimicrobial activity of the novel formulations was tested, which depicted that the complexation of QRC inside the supramolecular interstices of NSs increases the inhibitory effects against Escherichia coli ATCC25922, as compared to that observed in the free QRC. In addition, at the same concentrations used to generate an antibacterial effect, the NS-QRC system with AgNPs does not affect the metabolic activity of GES-1 cells. Therefore, these results suggest that the use of NSs associated with AgNPs resulted in an efficient strategy to improve the physicochemical features of QRC.

Nanosponges for Drug Delivery and Cancer Therapy: Recent Advances.

Nanosponges with three-dimensional (3D) porous structures, narrow size distribution, and high entrapment efficiency are widely engineered for cancer therapy and drug delivery purposes. They protect the molecular agents from degradation and help to improve the solubility of lipophilic therapeutic agents/drugs with targeted delivery options in addition to being magnetized to attain suitable magnetic features. Nanosponge-based delivery systems have been applied for cancer therapy with high specificity, biocompatibility, degradability, and prolonged release behavior. In this context, the drug loading within nanosponges is influenced by the crystallization degree. Notably, 3D printing technologies can be applied for the development of novel nanosponge-based systems for biomedical applications. The impacts of polymers, cross-linkers, type of drugs, temperature, loading and mechanism of drug release, fabrication methods, and substitution degree ought to be analytically evaluated. Eco-friendly techniques for the manufacturing of nanosponges still need to be uncovered in addition to the existing methods, such as solvent techniques, ultrasound-assisted preparation, melting strategies, and emulsion solvent diffusion methods. Herein, the recent advancements associated with the drug delivery and cancer therapy potential of nanosponges (chiefly, cyclodextrin-based, DNAzyme, and ethylcellulose nanosponges) are deliberated, focusing on the important challenges and future perspectives.

Weak complexation of 5-fluorouracil with ß-cyclodextrin, carbonate, and dianhydride crosslinked ß-cyclodextrin: in vitro and in silico studies.

Background and purpose: Several pharmaceutical formulations were investigated to improve the solubility of 5-fluorouracil to enhance bioavailability and therapeutic efficacy. This study aimed to examine the potential use of cyclodextrin-based nanosponges for the incorporation of 5-fluorouracil and to investigate the use of different crosslinking agents on the properties of the resulting drug carrier. 5-Fluorouracil complexation with ß-cyclodextrin was also studied to explain the unexpected results of weak 5-fluorouracil incorporation in nanosponge. Experimental approach: Nanosponges were synthesized by crosslinking ß-cyclodextrin with two different crosslinkers; diphenyl carbonate and ethylenediaminetetraacetic dianhydride. The incorporation of 5-fluorouracil into ß-cyclodextrin and the prepared nanosponges were assessed by NMR, FTIR, PXRD, DSC, and TGA. In addition, an in vitro release study was carried out to evaluate the potential use of ß-cyclodextrin- based nanosponges as pharmaceutical formulations for 5-fluorouracil. Findings / Results: Physicochemical characterization of the dried formulations indicated the complexation of 5-fluorouracil with the ß-cyclodextrin polymer. Despite that, no clear manifestation of 5-fluorouracil encapsulation in the prepared ß-cyclodextrin-based nanosponge was detected. Furthermore, no significant differences were observed in the release profiles of 5-fluorouracil, ß-cyclodextrin complex, and ß- cyclodextrin-based nanosponge, suggesting weak complexation and instability in aqueous solutions. EDTA- crosslinked ß-cyclodextrin-based nanosponge showed a slight improvement in 5-fluorouracil solubility with a faster initial rate of 5-fluorouracil release. Conclusion and implications: This study suggested weak complexation between 5-fluorouracil and the ß- cyclodextrin polymer or nanosponges. Crosslinking of ß-cyclodextrin with EDTA dianhydride crosslinker showed an enhancement in 5-fluorouracil saturation solubility combined with a faster initial rate of drug release.

Stabilization and Anticancer Enhancing Activity of the Peptide Nisin by Cyclodextrin-Based Nanosponges against Colon and Breast Cancer Cells.

The great variability of cancer types demands novel drugs with broad spectrum, this is the case of Nisin, a polycyclic antibacterial peptide that recently has been considered for prevention of cancer cells growth. As an accepted food additive, this drug would be very useful for intestinal cancers, but the peptide nature would make easier its degradation by digestion procedures. For that reason, the aim of present study to investigate the protective effect of two different ß-cyclodextrin-based nanosponges (carbonyl diimidazole and pyromellitic dianhydride) and their anti-cancer enhancement effect of Nisin-Z encapsulated with against colon cancer cells (HT-29). To extend its possible use, a comparison with breast (MCF-7) cancer cell was carried out. The physicochemical properties, loading efficiency, and release kinetics of Nisin complex with nanosponges were studied. Then, tricin-SDS-PAGE electrophoresis was used to understand the effect of NSs on stability of Nisin-Z in the presence of gastric peptidase pepsin. In addition, the cytotoxicity and cell membrane damage of Nisin Z were evaluated by using the MTT and LDH assay, which was complemented via Annexin-V/ Propidium Iodide (PI) by using flowcytometry. CD-NS are able to complex Nisin-Z with an encapsulation efficiency around 90%. A protective effect of Nisin-Z complexed with CD-NSs was observed in presence of pepsin. An increase in the percentage of apoptotic cells was observed when the cancer cells were exposed to Nisin Z complexed with nanosponges. Interestingly, Nisin Z free and loaded on PMDA/CDI-NSs is more selectively toxic towards HT-29 cells than MCF-7 cancer cells. These results indicated that nanosponges might be good candidates to protect peptides and deliver drugs against intestinal cancers.

ß-Cyclodextrin-Based Nanosponges Inclusion Compounds Associated with Gold Nanorods for Potential NIR-II Drug Delivery.

This article describes the synthesis and characterization of two nanocarriers consisting of ß-cyclodextrin-based nanosponges (NSs) inclusion compounds (ICs) and gold nanorods (AuNRs) for potential near-infrared II (NIR-II) drug-delivery systems. These nanosystems sought to improve the stability of two drugs, namely melphalan (MPH) and curcumin (CUR), and to trigger their photothermal release after a laser irradiation stimulus (1064 nm). The inclusion of MPH and CUR inside each NS was confirmed by field emission scanning electron microscopy (FE-SEM), Raman spectroscopy, Fourier transform infrared spectroscopy, (FT-IR) differential scanning calorimetry (DSC), transmission electron microscopy (TEM), and proton nuclear magnetic resonance (1H-NMR). Furthermore, the association of AuNRs with both ICs was confirmed by FE-SEM, energy-dispersive spectroscopy (EDS), TEM, dynamic light scattering (DLS), ζ-potential, and UV-Vis. Moreover, the irradiation assays demonstrated the feasibility of the controlled-photothermal drug release of both MPH and CUR in the second biological window (1000-1300 nm). Finally, MTS assays depicted that the inclusion of MPH and CUR inside the cavities of NSs reduces the effects on mitochondrial activity, as compared to that observed in the free drugs. Overall, these results suggest the use of NSs associated with AuNRs as a potential technology of controlled drug delivery in tumor therapy, since they are efficient and non-toxic materials.

Cyclodextrin Based Nanosponges: A Multidimensional Drug Delivery System and its Biomedical Applications.

Cyclodextrin based nanosponges are the designed nanocarriers for the projected delivery of complex drugs. They are multifunctional hypercrosslinked cyclodextrin polymers connected in a three-dimensional, mesh-like network. Their functional characteristics can be fabricated by using different crosslinkers or their different rations with polymer. They can encapsulate various hydrophilic, lipophilic, small-sized or large-sized drug molecules. They offer formulation flexibility and are primarily used for solubility, bioavailability and stability enhancement purposes. This system is also pliable for co-delivery of pharmaceutical entities, improving therapeutic efficacy and patient compliance. If the surface of nanosponge is coupled with an appropriate ligand, even a target specific drug delivery can be achieved. It has a variety of applications in the field of pharmacy for the delivery of tricky drug molecules, proteins, enzymes, natural moieties and gaseous compounds. The list of its applications further widens with the development of nanodiagnostics, nanosensors, biomimetics and scaffolds based on nanosponges. The sudden explosion of research in this working area signifies cyclodextrin nanosponge based products in the market soon.

Cyclodextrin-based sorbents for solid phase extraction.

Cyclodestrins (CDs) are cyclic oligosaccharides well-known for their ability to form host-guest inclusion complexes with properly sized compounds. They have been used for decades as chiral selectors as well as drug delivery systems within the frameworks of separation science and pharmaceutical science. More recently, their use has been extended to the field of extractive science under the stimulus of additional advantageous characteristics, such as low-price, negligible environmental impact, non-toxicity, as arising from the fact that natural CDs are starch degradation products. To abate their solubility in water and generate novel sorbents for solid phase extraction, the following approaches have been employed: (i) immobilization onto inert materials (silica, attapulgite, etc.); (ii) immobilization onto nanomaterials (magnetic nanoparticles, titanium oxide, carbon nanotubes, graphene oxide, etc.); (iii) polymerisation with specific cross-linkers to form the so-called CD-based nanosponges. Particularly promising are these last ones for their selectivity, mesoporous structure, insolubility in aqueous media and good dispersibility. This review offers a concise overview on the state of art and future prospects of CDs in this important sector of the analytical chemistry, offering a critical perspective of the most significant applications.

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

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 (KF) 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.

Cyclodextrin-based nanosponges: A critical review.

Cyclodextrin-based nanosponges (CD-NS) are innovative cross-linked cyclodextrin polymers nanostructured within three-dimensional network. CD-NS are highly porous nanoparticles characterized by crystalline or amorphous structure, spherical shape and swelling properties. Different cross-linkers provide variety of nanosponges. The polarity, dimension of the polymer mesh and release of entrapped molecule can be easily tuned by varying the type of cross-linker and degree of cross-linking. The site-specific targeting can be achieved by conjugating various ligands on the surface of nanosponge. They offer unique advantage of controlled release and are biologically safe and biodegradable material. Cyclodextrin-based nanosponges can form complexes with different types of lipophilic or hydrophilic molecules. The nanosponges could be used to improve the aqueous solubility of poorly water-soluble molecules, protect degradable substances and as innovative carrier in pharmaceuticals, cosmetics, protein/peptide delivery, diagnostics, enzyme-catalysed reactions, environmental control and agrochemistry.

Ester-Based Hydrophilic Cyclodextrin Nanosponges for Topical Ocular Drug Delivery.

BACKGROUND: Cyclodextrin-based nanosponges are hyper-cross-linked supramolecular architectures. Similar to the parent compound they are derived from, they have been shown to possess the ability to form inclusion and non-inclusion complexes with drugs of different polarities, enzymes, proteins, peptides and macromolecules. Cyclodextrins only form inclusion complexes with hydrophobic guest molecules, while nanosponges extend this function by forming inclusion and non-inclusion complexes with both hydrophobic and hydrophilic compounds. This host-guest interaction provides enhancement in stability, solubility and sometimes in membrane permeability. OBJECTIVE: The potential of ester-based hydrophilic nanosponges as drug carriers in topical ocular drug delivery was assessed by undertaking drug loading, drug release, phase solubility and ex vivo pig corneal drug permeation studies on the nanosponges. METHOD: The ester-based cyclodextrin-based nanosponges were synthesized through cross-linking ß-cyclodextrin by pyromellitic dianhydride. Various concentrations of pyromellitic dianhydride, the cross-linker, were initially tested for their effects on the drug loading capacity of the nanosponges. Thereafter, varying ratios of drug to nanosponge complexes were studied and analyzed for their drug release kinetics, and solubility and permeation effects. RESULTS: A cyclodextrin-based nanosponge drug delivery system with potential to improve corneal permeation and drug solubility was formulated. Their ability to improve pig corneal permeation was shown; where up to 75% permeation of the model drug was achieved in the presence of the nanosponges as compared to the 28% permeation of the pure drug. The nanosponges provided drug release for approximately an hour. This is a common behavior for hydrophilic complexes due to their high solubility in aqueous media. CONCLUSION: The ester-based hydrophilic cyclodextrin-based nanosponge derivative can be used as a drug delivery system in topical ocular drug delivery, to improve stability, solubility and corneal permeation.