Molecular dynamics study of Sorafenib anti-cancer drug

Sorafenib (SOR) is an oral multikinase inhibitor which impedes proliferation, angiogenesis and invasion of cancer cells with low water-solubility. Amphiphilic cyclodextrins (aCD) have been investigated as a possible nanocarrier for systemic administration of SOR increasing its bio-availability [1]. A theoretical study about inclusion complexes of SOR drug and a model of aCD system using a simulation protocol based on Molecular Mechanics (MM) and Molecular Dynamics (MD) methods [2] is here reported. In this work we have studied at first the single model aCD (SC6OH, heptakis(2-O-oligo(ethylene oxide)-6-hexylthio)-β-CD bearing 14 units of ethylene-oxide at the CD secondary rim ) and the single molecule of SOR, then the formation of the complex in the dielectric environment [3]. The results data of final most stable geometry of the inclusion complex anticancer-cyclodextrin which showed the lowest potential and interaction energy were reported. The most stable host-guest geometry shows that the fluorine atoms of SOR drug are directed toward the hydrophobic primary rim of the aCD, while the part of the SOR rich in oxygen atoms is directed towards the hydrophilic secondary rim. References [1] M. L. Bondì, A. Scala, G. Sortino, E. Amore, C. Botto, A. Azzolina, D. Balasus, M. Cervello and A. Mazzaglia, Biomacromolecules, 2015, 16, 3784-3791. [2] G. Raffaini, F. Ganazzoli, L. Malpezzi, C. Fuganti, G. Fronza, W. Panzeri and A. Mele J. Phys. Chem B., 2009,113, 9110-9122

Aggregation behaviour of amphiphilic cyclodextrins: The nucleation stage by atomistic molecular dynamics simulations

Amphiphilically modified cyclodextrins may form various supramolecular aggregates. Here we report a theoretical study of the aggregation of a few amphiphilic cyclodextrins carrying hydrophobic thioalkyl groups and hydrophilic ethylene glycol moieties at opposite rims, focusing on the initial nucleation stage in an apolar solvent and in water. The study is based on atomistic molecular dynamics methods with a “bottom up” approach that can provide important information about the initial aggregates of few molecules. The focus is on the interaction pattern of amphiphilic cyclodextrin (aCD), which may interact by mutual inclusion of the substituent groups in the hydrophobic cavity of neighbouring molecules or by dispersion interactions at their lateral surface. We suggest that these aggregates can also form the nucleation stage of larger systems as well as the building blocks of micelles, vesicle, membranes, or generally nanoparticles thus opening new perspectives in the design of aggregates correlating their structures with the pharmaceutical properties

Aggregation behavior of amphiphilic cyclodextrins in a nonpolar solvent: Evidence of large-scale structures by atomistic molecular dynamics simulations and solution studies

Chemically modified cyclodextrins carrying both hydrophobic and hydrophilic substituents may form supramolecular aggregates or nanostructures of great interest. These systems have been usually investigated and characterized in water for their potential use as nanocarriers for drug delivery, but they can also aggregate in apolar solvents, as shown in the present paper through atomistic molecular dynamics simulations and dynamic light scattering measurements. The simulations, carried out with a large number of molecules in vacuo adopting an unbiased bottom-up approach, suggest the formation of bidimensional structures with characteristic length scales of the order of 10 nm, although some of these sizes are possibly affected by the assumed periodicity of the simulation cell, in particular at longer lengths. In any case, these nanostructures are stable at least from the kinetic viewpoint for relatively long times thanks to the large number of intermolecular interactions of dipolar and dispersive nature. The dynamic light scattering experiments indicate the presence of aggregates with a hydrodynamic radius of the order of 80 nm and a relatively modest polydispersity, even though smaller nanometer-sized aggregates cannot be fully ruled out. Taken together, these simulation and experimental results indicate that amphiphilic ally modified cyclodextrins do also form large-scale nanoaggregates even in apolar solvents

Electrical release of dopamine and levodopa mediated by amphiphilic \u3b2-cyclodextrins immobilized on polycrystalline gold

Vesicles of cationic amphiphilic \u3b2-cyclodextrins have been immobilized on polycrystalline gold by exploiting the chemical affinity between their amino groups and Au atoms. The presence of cyclodextrins has been widely investigated by means of AFM, XPS, kelvin probe and electrochemical measurements. This multi-functional coating confers distinct electrochemical features such as pH-dependent behavior and partial/total blocking properties towards electro-active species. The host-guest properties of \u3b2-cyclodextrins have been successfully exploited in order to trap drugs, like dopamine and levodopa. The further release of these drugs was successfully achieved by providing specific electrical stimuli. This proof-of-concept led us to fabricate an electronic device (i.e. an organic transistor) capable of dispensing both dopamine and levodopa in aqueous solution

Synthesis and Characterization of a Colloidal Novel Folic Acid–β-cyclodextrin Conjugate for Targeted Drug Delivery

A novel folic acid–b-cyclodextrin (b-CD) conjugate was synthesized and preliminarily characterized by 1H NMR, ESI-MS, and MALDI-MS. 1H NMR shows the presence of a- and c-conjugates which are generated by b-CD linkage in turn with both carboxylic functions of folic acid. Moreover ROESY evidences supramolecular interactions between the benzene ring of the folic acid and the b-CD cavity. DOSY suggests that ethylenediamine derived b-CD–folic acid forms a colloidal dispersion difficult to purify from free folic acid. An analysis of self-diffusion coefficient (Ds) of the three species (a-, c-conjugates, and free folic acid) and relaxation times (T1 and T2) is reported to tentatively explain the colloidal behaviour of the new species in an aqueous solution

New data about the Cathedral of Catania by geophysical investigations

The town of Catania, located in the southern part of the Sicily region, Italy, holds the remains of an ancient settlement in the city centre. One of the most important buildings is the Cathedral and the buried Achillean Baths. The Cathedral was repeatedly destroyed and rebuilt after the earthquakes and volcanic eruptions that occurred over time. The first building dates back to the period 1078-1093 and was built on the ruins of the Roman Achillean Baths, on the initiative of Count Roger, acquiring all the characteristics of an equipped (i.e. fortified) ecclesia. Already in 1169, a catastrophic earthquake demolished it almost completely, leaving intact only the apse. In 1194 a fire created considerable damage and finally in 1693 the earthquake that hit the Val di Noto destroyed it almost completely. The area around the Cathedral is today highly urbanized, but it was the locus of social and political life over the centuries for people of different cultures who have inhabited the area since the 8th century BC. Therefore, this area contains stratigraphically complex layers of buildings and other remains, which can help understand the use of this area of the town over many centuries. A ground-penetrating radar and electrical resistivity tomography surveys were performed inside and outside the Cathedral of Catania. Data were visualized in three-dimensions using a standard amplitude slice technique as well as the construction of isosurface images of amplitudes. These images reveal the position of architectural features whose shape, size and burial depth suggest they are Roman and earlier in age. The features mapped overlap the development of the Achillean Baths and the presence of some tombs and unknown rooms

Potential effects of vaccinations on the prevention of COVID-19: rationale, clinical evidence, risks, and public health considerations

IntroductionCoronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus (SARS-CoV-2), has quickly spread around the world. Areas coveredThis review will discuss the available immunologic and clinical evidence to support the benefit of the influenza, pneumococcal, and tuberculosis vaccines in the context of COVID-19 as well as to provide an overview on the COVID-19-specific vaccines that are in the development pipeline. In addition, implications for vaccination strategies from a public health perspective will be discussed. Expert opinionSome vaccines are being considered for their potentially beneficial role in preventing or improving the prognosis of COVID-19: influenza, pneumococcal and tuberculosis vaccines. These vaccines may have either direct effect on COVID-19 via different types of immune responses or indirect effects by reducing the burden of viral and bacterial respiratory diseases on individual patients and national healthcare system and by facilitating differential diagnoses with other viral/bacterial respiratory disease. On the other hand, a large number of candidate vaccines against SARS-CoV-2 are currently in the pipeline and undergoing phase I, II, and III clinical studies. As SARS-CoV-2 vaccines are expected to be marketed through accelerated regulatory pathways, vaccinovigilance as well as planning of a successful vaccination campaign will play a major role in protecting public health

Cyclodextrin Cationic Polymer-Based Nanoassemblies to Manage Inflammation by Intra-Articular Delivery Strategies

Injectable nanobioplatforms capable of locally fighting the inflammation in osteoarticular diseases, by reducing the number of administrations and prolonging the therapeutic effect is highly challenging. β-Cyclodextrin cationic polymers are promising cartilage-penetrating candidates by intra-articular injection due to the high biocompatibility and ability to entrap multiple therapeutic and diagnostic agents, thus monitoring and mitigating inflammation. In this study, nanoassemblies based on poly-β-amino-cyclodextrin (PolyCD) loaded with the non-steroidal anti-inflammatory drug diclofenac (DCF) and linked by supramolecular interactions with a fluorescent probe (adamantanyl-Rhodamine conjugate, Ada-Rhod) were developed to manage inflammation in osteoarticular diseases. PolyCD@Ada-Rhod/DCF supramolecular nanoassemblies were characterized by complementary spectroscopic techniques including UV-Vis, steady-state and time-resolved fluorescence, DLS and ζ-potential measurement. Stability and DCF release kinetics were investigated in medium mimicking the physiological conditions to ensure control over time and efficacy. Biological experiments evidenced the efficient cellular internalization of PolyCD@Ada-Rhod/DCF (within two hours) without significant cytotoxicity in primary human bone marrow-derived mesenchymal stromal cells (hMSCs). Finally, polyCD@Ada-Rhod/DCF significantly suppressed IL-1β production in hMSCs, revealing the anti-inflammatory properties of these nanoassemblies. With these premises, this study might open novel routes to exploit original CD-based nanobiomaterials for the treatment of osteoarticular diseasesThis research was funded by MaTisse (CNR-ISMN Project 4, A. P. 11/2017, Sicily Region, FSE 2014/2020) and PON03PE_00216_1 Drug DeliveryS