Unveiling the synergy: a combined experimental and theoretical study of ß-cyclodextrin with melatonin.

Melatonin (MT) is a vital hormone controlling biorhythms, and optimizing its release in the human body is crucial. To address MT's unfavorable pharmacokinetics, we explored the inclusion complexes of MT with ß-cyclodextrin (ß-CD). Nano spray drying was applied to efficiently synthesize these complexes in three molar ratios (MT : ß-CD = 1 : 1, 2 : 1, and 1 : 2), reducing reagent use and expediting inclusion. The complex powders were characterized through thermal analyses (TGA and DSC), Fourier transform infrared spectroscopy (FTIR), and in vitro MT release measurements via high-performance liquid chromatography (HPLC). In parallel, computational studies were conducted, examining the stability of MT : ß-CD complexes by means of unbiased semi-empirical conformational searches refined by DFT, which produced a distribution of MT : ß-CD binding enthalpies. Computational findings highlighted that these complexes are stabilized by specific hydrogen bonds and non-specific dispersive forces, with stronger binding in the 1 : 1 complex, which was corroborated by in vitro release data. Furthermore, the alignment between simulated and experimental FTIR spectra demonstrated the quality of both the structural model and computational methodology, which was crucial to enhance our comprehension of optimizing MT's release for therapeutic applications.

Influence of size, volume concentration and aggregation state on magnetic nanoparticle hyperthermia properties versus excitation conditions.

Treatment planning in magnetic hyperthermia requires a thorough knowledge of specific loss power of magnetic nanoparticles as a function of size and excitation conditions. Moreover, in biological tissues the magnetic nanoparticles can aggregate into clusters, making the evaluation of their heating performance more challenging because of the magnetostatic dipole-dipole interactions. In this paper, we present a comprehensive modelling analysis of 10-40 nm sized spherical magnetite (Fe3O4) nanoparticles, investigating how their heating properties are influenced by magnetic field parameters (peak amplitude and frequency), and by volume concentration and aggregation state. The analysis is performed by means of an in-house micromagnetic numerical model, which solves the Landau-Lifshitz-Gilbert equation under the assumption of single-domain nanoparticles, including thermal effects via a Langevin approach. The obtained results provide insight into how to tune hyperthermia properties by varying magnetic nanoparticle size, under different excitation magnetic fields fulfilling the Hergt-Dutz limit (frequency between 50 kHz and 1 MHz, and peak amplitude between 1 kA m-1 and 50 kA m-1). Special attention is finally paid to the role of volume concentration and aggregation order, putting in evidence the need for models able to account for stochasticity and clustering in spatial distribution, to accurately simulate the contribution of magnetostatic dipole-dipole interactions in real applications.

Exploration of the Conformational Scenario for α-, ß-, and γ-Cyclodextrins in Dry and Wet Conditions, from Monomers to Crystal Structures: A Quantum-Mechanical Study.

Cyclodextrins (CDs) constitute a class of cyclic oligosaccharides that are well recognized and largely applied in the drug delivery field, thanks to their biocompatibility, low cost, and the possibility to be derivatized in order to tune and optimize the complexation/release of the specific drug. The conformational flexibility of these systems is one of their key properties and requires a cost-effective methodology to be studied by combining the accuracy of results with the possibility of exploring a large set of conformations. In the present paper, we have explored the conformational potential energy surface of the monomers and dimers of α-, ß-, and γ-cyclodextrins (i.e., 6, 7, and 8 monomeric units, respectively) by means of fast but accurate semiempirical methods, which are then refined by state-of-the-art DFT functionals. Moreover, the crystal structure is considered for a more suitable comparison with the IR spectrum experimentally recorded. Calculations are carried out in the gas phase and in water environments, applying both implicit and explicit treatments. We show that the conformation of the studied molecules changes from the gas phase to the water, even if treated implicitly, thus modifying their complexation capability.

Cyclodextrins for Lithium Batteries Applications.

Due to their high energy and power density, lithium-ion batteries (LIBs) have gained popularity in response to the demand for effective energy storage solutions. The importance of the electrode architecture in determining battery performance highlights the demand for optimization. By developing useful organic polymers, cyclodextrin architectures have been investigated to improve the performance of Li-based batteries. The macrocyclic oligosaccharides known as cyclodextrins (CDs) have relatively hydrophobic cavities that can enclose other molecules. There are many industries where this "host-guest" relationship has been found useful. The hydrogen bonding and suitable inner cavity diameter of CD have led to its selection as a lithium-ion diffusion channel. CDs have also been used as solid electrolytes for solid-state batteries and as separators and binders to ensure adhesion between electrode components. This review gives a general overview of CD-based materials and how they are used in battery components, highlighting their advantages.

Design and Validation of Experimental Setup for Cell Spheroid Radiofrequency-Induced Heating.

While hyperthermia has been shown to induce a variety of cytotoxic and sensitizing effects on cancer tissues, the thermal dose-effect relationship is still not well quantified, and it is still unclear how it can be optimally combined with other treatment modalities. Additionally, it is speculated that different methods of applying hyperthermia, such as water bath heating or electromagnetic energy, may have an effect on the resulting biological mechanisms involved in cell death or in sensitizing tumor cells to other oncological treatments. In order to further quantify and characterize hyperthermia treatments on a cellular level, in vitro experiments shifted towards the use of 3D cell spheroids. These are in fact considered a more representative model of the cell environment when compared to 2D cell cultures. In order to perform radiofrequency (RF)-induced heating in vitro, we have recently developed a dedicated electromagnetic field applicator. In this study, using this applicator, we designed and validated an experimental setup which can heat 3D cell spheroids in a conical polypropylene vial, thus providing a reliable instrument for investigating hyperthermia effects at the cellular scale.

A Comparison between the Molecularly Imprinted and Non-Molecularly Imprinted Cyclodextrin-Based Nanosponges for the Transdermal Delivery of Melatonin.

Melatonin is a neurohormone that ameliorates many health conditions when it is administered as a drug, but its drawbacks are its oral and intravenous fast release. To overcome the limitations associated with melatonin release, cyclodextrin-based nanosponges (CD-based NSs) can be used. Under their attractive properties, CD-based NSs are well-known to provide the sustained release of the drug. Green cyclodextrin (CD)-based molecularly imprinted nanosponges (MIP-NSs) are successfully synthesized by reacting ß-Cyclodextrin (ß-CD) or Methyl-ß Cyclodextrin (M-ßCD) with citric acid as a cross-linking agent at a 1:8 molar ratio, and melatonin is introduced as a template molecule. In addition, CD-based non-molecularly imprinted nanosponges (NIP-NSs) are synthesized following the same procedure as MIP-NSs without the presence of melatonin. The resulting polymers are characterized by CHNS-O Elemental, Fourier Transform Infrared Spectroscopy (FTIR), Thermogravimetric (TGA), Differential Scanning Calorimetry (DSC), Zeta Potential, and High-Performance Liquid Chromatography (HPLC-UV) analyses, etc. The encapsulation efficiencies are 60-90% for MIP-NSs and 20-40% for NIP-NSs, whereas melatonin loading capacities are 1-1.5% for MIP-NSs and 4-7% for NIP-NSs. A better-controlled drug release performance (pH = 7.4) for 24 h is displayed by the in vitro release study of MIP-NSs (30-50% released melatonin) than NIP-NSs (50-70% released melatonin) due to the different associations within the polymeric structure. Furthermore, a computational study, through the static simulations in the gas phase at a Geometry Frequency Non-covalent interactions (GFN2 level), is performed to support the inclusion complex between ßCD and melatonin with the automatic energy exploration performed by Conformer-Rotamer Ensemble Sampling Tool (CREST). A total of 58% of the CD/melatonin interactions are dominated by weak forces. CD-based MIP-NSs and CD-based NIP-NSs are mixed with cream formulations for enhancing and sustaining the melatonin delivery into the skin. The efficiency of cream formulations is determined by stability, spreadability, viscosity, and pH. This development of a new skin formulation, based on an imprinting approach, will be of the utmost importance in future research at improving skin permeation through transdermal delivery, associated with narrow therapeutic windows or low bioavailability of drugs with various health benefits.

Improvement of Hyperthermia Properties of Iron Oxide Nanoparticles by Surface Coating.

Magnetic hyperthermia is an oncological therapy that exploits magnetic nanoparticles activated by radiofrequency magnetic fields to produce a controlled temperature increase in a diseased tissue. The specific loss power (SLP) of magnetic nanoparticles or the capability to release heat can be improved using surface treatments, which can reduce agglomeration effects, thus impacting on local magnetostatic interactions. In this work, Fe3O4 nanoparticles are synthesized via a coprecipitation reaction and fully characterized in terms of structural, morphological, dimensional, magnetic, and hyperthermia properties (under the Hergt-Dutz limit). Different types of surface coatings are tested, comparing their impact on the heating efficacy and colloidal stability, resulting that sodium citrate leads to a doubling of the SLP with a substantial improvement in dispersion and stability in solution over time; an SLP value of around 170 W/g is obtained in this case for a 100 kHz and 48 kA/m magnetic field.

Application of Magnonic Crystals in Magnetic Bead Detection.

This paper aims at studying a sensor concept for possible integration in magnetic field-based lab-on-chip devices that exploit ferromagnetic resonance (FMR) phenomena in magnonic crystals. The focus is on 2D magnetic antidot arrays, i.e., magnetic thin films with periodic non-magnetic inclusions (holes), recently proposed as magnetic field sensor elements operating in the gigahertz (GHz) range. The sensing mechanism is here demonstrated for magnetic nano/microbeads adsorbed on the surface of permalloy (Ni80Fe20) antidot arrays with a rhomboid lattice structure and variable hole size. Through extensive micromagnetic modelling analysis, it is shown that the antidot arrays can be used as both bead traps and high-sensitivity detectors, with performance that can be tuned as a function of bead size and magnetic moment. A key parameter for the detection mechanism is the antidot array hole size, which affects the FMR frequency shifts associated with the interaction between the magnetization configuration in the nanostructured film and the bead stray field. Possible applications of the proposed device concept include magnetic immunoassays, using magnetic nano/microbeads as probes for biomarker detection, and biomaterial manipulation.

In silico evaluation of adverse eddy current effects in preclinical tests of magnetic hyperthermia.

BACKGROUND AND OBJECTIVE: Magnetic hyperthermia is an oncological therapy that employs magnetic nanoparticles activated by alternating current (AC) magnetic fields with frequencies between 50 kHz and 1 MHz, to release heat in a diseased tissue and produce a local temperature increase of about 5 °C. To assess the treatment efficacy, in vivo tests on murine models (mice and rats) are typically performed. However, these are often carried out without satisfying the biophysical constraints on the electromagnetic (EM) field exposure, with consequent generation of hot spots and undesirable heating of healthy tissues. Here, we investigate possible adverse eddy current effects, to estimate AC magnetic field parameters (frequency and amplitude) that can potentially guarantee safe animal tests of magnetic hyperthermia. METHODS: The analysis is performed through in silico modelling by means of finite element simulation tools, specifically developed to study eddy current effects in computational animal models, during magnetic hyperthermia treatments. The numerical tools enable us to locally evaluate the specific absorption rate (SAR) and the produced temperature increase, under different field exposure conditions. RESULTS: The simulation outcomes demonstrate that in mice with weight lower than 30 g the thermal effects induced by AC magnetic fields are very weak, also when slightly overcoming the Hergt-Dutz limit, that is the product of the magnetic field amplitude and frequency should be lower than 5·109 A/(m·s). Conversely, we observe significant temperature increases in 500 g rats, amplified when the field is applied transversally to the body longitudinal axis. A strong mitigation of side-effects can be achieved by introducing water boluses or by applying focused fields. CONCLUSIONS: The developed physics-based modelling approach has proved to be a useful predictive tool for the optimization of preclinical tests of magnetic hyperthermia, allowing the identification of proper EM field conditions and the design of setups that guarantee safe levels of field exposure during animal treatments. In such contest, the obtained results can be considered as valid indicators to assess reference levels for animal testing of biomedical techniques that involve EM fields, like magnetic hyperthermia, thus complying with the Directive 2010/63/EU on the protection of animals used for scientific purposes.

Design and Characterization of an RF Applicator for In Vitro Tests of Electromagnetic Hyperthermia.

The evaluation of the biological effects of therapeutic hyperthermia in oncology and the precise quantification of thermal dose, when heating is coupled with radiotherapy or chemotherapy, are active fields of research. The reliable measurement of hyperthermia effects on cells and tissues requires a strong control of the delivered power and of the induced temperature rise. To this aim, we have developed a radiofrequency (RF) electromagnetic applicator operating at 434 MHz, specifically engineered for in vitro tests on 3D cell cultures. The applicator has been designed with the aid of an extensive modelling analysis, which combines electromagnetic and thermal simulations. The heating performance of the built prototype has been validated by means of temperature measurements carried out on tissue-mimicking phantoms and aimed at monitoring both spatial and temporal temperature variations. The experimental results demonstrate the capability of the RF applicator to produce a well-focused heating, with the possibility of modulating the duration of the heating transient and controlling the temperature rise in a specific target region, by simply tuning the effectively supplied power.

On the Interactions of Melatonin/ß-Cyclodextrin Inclusion Complex: A Novel Approach Combining Efficient Semiempirical Extended Tight-Binding (xTB) Results with Ab Initio Methods.

Melatonin (MT) is a molecule of paramount importance in all living organisms, due to its presence in many biological activities, such as circadian (sleep-wake cycle) and seasonal rhythms (reproduction, fattening, molting, etc.). Unfortunately, it suffers from poor solubility and, to be used as a drug, an appropriate transport vehicle has to be developed, in order to optimize its release in the human tissues. As a possible drug-delivery system, ß-cyclodextrin (ßCD) represents a promising scaffold which can encapsulate the melatonin, releasing when needed. In this work, we present a computational study supported by experimental IR spectra on inclusion MT/ßCD complexes. The aim is to provide a robust, accurate and, at the same time, low-cost methodology to investigate these inclusion complexes both with static and dynamic simulations, in order to study the main actors that drive the interactions of melatonin with ß-cyclodextrin and, therefore, to understand its release mechanism.

Experimental and Modelling Analysis of the Hyperthermia Properties of Iron Oxide Nanocubes.

The ability of magnetic nanoparticles (MNPs) to transform electromagnetic energy into heat is widely exploited in well-known thermal cancer therapies, such as magnetic hyperthermia, which proves useful in enhancing the radio- and chemo-sensitivity of human tumor cells. Since the heat release is ruled by the complex magnetic behavior of MNPs, a careful investigation is needed to understand the role of their intrinsic (composition, size and shape) and collective (aggregation state) properties. Here, the influence of geometrical parameters and aggregation on the specific loss power (SLP) is analyzed through in-depth structural, morphological, magnetic and thermometric characterizations supported by micromagnetic and heat transfer simulations. To this aim, different samples of cubic Fe3O4 NPs with an average size between 15 nm and 160 nm are prepared via hydrothermal route. For the analyzed samples, the magnetic behavior and heating properties result to be basically determined by the magnetic single- or multi-domain configuration and by the competition between magnetocrystalline and shape anisotropies. This is clarified by micromagnetic simulations, which enable us to also elucidate the role of magnetostatic interactions associated with locally strong aggregation.

Influence of shape, size and magnetostatic interactions on the hyperthermia properties of permalloy nanostructures.

We present a detailed study of permalloy (Ni80Fe20) nanostructures with variable shape (disk, cylinder and sphere) for magnetic hyperthermia application, exploiting hysteresis losses for heat release. The study is performed modifying nanostructure aspect ratio and size (up to some hundreds of nanometres), to find the optimal conditions for the maximization of specific heating capabilities. The parameters are also tuned to guarantee negligible magnetic remanence and fulfilment of biophysical limits on applied field amplitude and frequency product, to avoid aggregation phenomena and intolerable resistive heating, respectively. The attention is first focused on disk-shaped nanostructures, with a comparison between micromagnetic simulations and experimental results, obtained on nanodisks still attached on the lithography substrate (2D array form) as well as dispersed in ethanol solution (free-standing). This analysis enables us to investigate the role of magnetostatic interactions between nanodisks and to individuate an optimal concentration for the maximization of heating capabilities. Finally, we study magnetization reversal process and hysteresis properties of nanocylinders (diameter between 150 nm and 600 nm, thickness from 30 nm up to 150 nm) and nanospheres (size between 100 nm and 300 nm), to give instructions on the best combination of geometrical parameters for the design of novel hyperthermia mediators.