Luca Scrivano

Quercetin derivatives as novel antihypertensive agents: Synthesis and physiological characterization

The antihypertensive flavonol quercetin (Q1) is endowed with a cardioprotective effect against myocardial ischemic damage. Q1 inhibits angiotensin converting enzyme activity, improves vascular relaxation, and decreases oxidative stress and gene expression. However, the clinical application of this flavonol is limited by its poor bioavailability and low stability in aqueous medium. In the aim to overcome these drawbacks and preserve the cardioprotective effects of quercetin, the present study reports on the preparation of five different Q1 analogs, in which all OH groups were replaced by hydrophobic functional moieties. Q1 derivatives have been synthesized by optimizing previously reported procedures and analyzed by spectroscopic analysis. The cardiovascular properties of the obtained compounds were also investigated in order to evaluate whether chemical modification affects their biological efficacy. The interaction with β-adrenergic receptors was evaluated by molecular docking and the cardiovascular efficacy was investigated on the ex vivo Langendorff perfused rat heart. Furthermore, the bioavailability and the antihypertensive properties of the most active derivative were evaluated by in vitro studies and in vivo administration (1month) on spontaneously hypertensive rats (SHRs), respectively. Among all studied Q1 derivatives, only the ethyl derivative reduced left ventricular pressure (at 10(-8)M÷10(-6)M doses) and improved relaxation and coronary dilation. NOSs inhibition by L-NAME abolished inotropism, lusitropism and coronary effects. Chronic administration of high doses of this compound on SHR reduced systolic and diastolic pressure. Differently, the acetyl derivative induced negative inotropism and lusitropism (at 10(-10)M and 10(-8)÷10(-6)M doses), without affecting coronary pressure. Accordingly, docking studies suggested that these compounds bind both β1/β2-adrenergic receptors. Taking into consideration all the obtained results, the replacement of OH with ethyl groups seems to improve Q1 bioavailability and stability; therefore, the ethyl derivative could represent a good candidate for clinical use in hypertension.

Mesoporous nanocrystalline TiO2 loaded with ferulic acid for sunscreen and photo-protection: safety and efficacy assessment

In the present study, the use of surfactant-free mesoporous TiO2 combined with an antioxidant and photo-protecting agent, such as ferulic acid (FA), as a sunscreen was investigated for the first time. Ferulic acid is a natural antioxidant characterized by UV absorption capacity and radical scavenging activities and, due to these properties, it has been approved as an active ingredient in several skin lotions and sunscreens. However, despite the double function exerted by FA, the use of this molecule in the cosmetic field is limited by its poor stability. Aiming to overcome this drawback, mesoporous TiO2, prepared by using a sol–gel route assisted by a polyoxyethylene–polyoxypropylene block copolymer template followed by solvothermal treatment, was used as a matrix for the encapsulation of ferulic acid. The stability studies performed confirmed the ability of the prepared material to preserve the active molecule from degradation induced by light and, therefore, its properties. Antioxidant and anti-inflammatory activities of FA-loaded titania (TiO2@FA) and titania matrix (TiO2) were evaluated and high scavenging activity towards DPPH, ABTS and NO radicals were recorded. The in vitro assessment of the spectrophotometric Sun Protection Factor (SPF) was also performed and a value of 14.7 was observed for TiO2@FA while mesoporous TiO2 showed a lower SPF value equal to 2.6. These results suggested the potential application of the titania-doped FA as a “booster of SPF” that is able to enhance the SPF of a sunscreen. Furthermore, in vitro safety studies confirmed the biocompatibility of the prepared material and the absence of skin irritation.

New insights for the use of quercetin analogs in cancer treatment

AIM Quercetin (Q1) is a flavonoid widely present in plants and endowed with several pharmacological properties mostly due to its antioxidant potential. Q1 shows anticancer activity and could be useful in cancer prevention. On the other hand, Q1 is poorly soluble in water and unstable in physiological systems, and its bioavailability is very low. METHODS A small set of Q1 derivatives (Q2-Q9) has been synthesized following opportunely modified chemical procedures previously reported. Anticancer activity has been evaluated by MTT assay. Human Topoisomerases inhibition has been performed by direct enzymatic assays. Apoptosis has been evaluated by TUNEL assay. ROS production and scavenging activity have been determined by immunofluorescence. RESULTS The anticancer profile of a small library of Q1 analogues, in which the OH groups were all or partially replaced with hydrophobic functional groups, has been evaluated. Two of the studied compounds demonstrated an interesting cytotoxic profile in two breast cancer models showing the capability to inhibit human Topoisomerases. CONCLUSION The studied compounds represent suitable leads for the development of innovative anticancer drugs. [Formula: see text].

Biopolymeric self-assembled nanoparticles for enhanced antibacterial activity of Ag-based compounds

Microbial infections still remain one of the main issues for human health. The rapid development of resistance towards the most common antimicrobial drugs in bacteria represents today a challenge in the infections management. In the present work we have investigated the antibacterial activity of a group of compounds, namely silver N-heterocyclic carbene complexes, against a broad spectrum of bacteria. For the most promising compound, a biopolymeric nanocarrier has been developed, in order to potentiate the metal complex activity against both Gram +ve and Gram -ve. The polymeric nanovehicle is based on dextran, modified with oleic acid residues, that confer amphiphilic properties to the polysaccharide. We have characterized the obtained biomaterial and studied its ability to self-assemble into nanoparticles in aqueous environment. Next, the transdermal diffusion analyses have been carried out to evaluate the ability of the polymeric particles to penetrate tissues. Thanks to the strategy adopted, we have fabricated an antibacterial system to which K. pneumoniae and E. coli are the most sensitive.

Calabrian Goji vs. Chinese Goji: A Comparative Study on Biological Properties

Lycium barbarum (Goji) fruits are mainly cultivated in northwestern China and are well known for their beneficial and healthy effects. In this work, the biological and functional properties of Calabrian Goji extract, obtained from Goji berries cultivated in the Sibari Plain (in the Italian region of Calabria), were demonstrated. In order to evaluate the use of this extract as a food supplement for cognitive and mental disorders, the quantification of Carotenoids as Zeaxanthin equivalents was made. The antioxidant activity was investigated by evaluating the scavenging properties against 2,2′-diphenyl-1-picrylhydrazyl (DPPH) and 2,2′-Azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radicals and by performing the ORAC (Oxygen Radical Absorbance Capacity) assay. The inhibition of lipid peroxidation was quantified by bleaching test and the ability to inhibit acetylcholinesterase enzyme and to scavenge nitric oxide radical was also evaluated. All the results were compared to those obtained from a Chinese Goji extract used as a reference. Based on the reported data, Calabrian Goji might be used as a food supplement with a possible application in cognitive disorders, mental impairments and other neurodegenerative diseases, due to its biological properties and the high levels of Carotenoids.

Polymeric nanoparticle constructs as devices for antibacterial therapy

HIGHLIGHTSMicrobial infections are one of the major causes of death among world population.The antibacterial resistance results in the failure of the antibiotic therapy.Exploration of new strategies to increase the efficacy of available antibiotics.Polymers with antibacterial activity or modified to confer bactericidal power.Polymer‐based nanoparticles as antibiotic drugs delivery systems. &NA; Diseases related to bacterial infections represent a relevant challenge for public health. Despite the success obtained with the conventional antibiotic therapies, indeed, new drawbacks have been identified. In addition to poor drugs solubility and stability, adverse side effects, and many other factors which together lead to a low patient compliance, the antibiotic resistance and the lack in the development of new antimicrobial agents are the main problems. On the basis of these considerations, the research interest is focused on the exploration of new strategies able to circumvent these drawbacks improving the efficacy of current antibiotics. In this context, nanosized systems, which allow to enhance both the pharmacokinetic profiles and the mechanism of action of drugs, play a key role.

Engineered Polymer-Based Nanomaterials for Diagnostic, Therapeutic and Theranostic Applications

Nanomedicine can be defined as the medical application of molecular nanotechnology and it plays a key role and pharmaceutical research and development, especially related to cancer prevention, monitoring, diagnosis and treatment. In this context, nanomaterials are attracting significant research interest due to their abilities to stay in the blood for long time, accumulate in pathological sites including tumors or inflammatory areas via the enhanced permeability and retention (EPR) effect, and facilitate targeted delivery of specific therapeutic agents. In the last decades, considerable attention was attracted by the development of nano-sized carriers, based on natural or synthetic polymers, able to provide the controlled release of anticancer drugs in the aim to overcome the drawbacks associated to the conventional chemotherapy. Furthermore, when loaded with imaging agents, this kind of systems offers the opportunity to exploit optical or magnetic resonance imaging (MRI) in cancer diagnosis. Polymeric materials are characterized by several functionalities where both therapeutic and imaging components, and also targeting moieties, can be attached for simultaneous targeted therapy and imaging providing innovative platforms defined as theranostic agents with a great potential in monitoring and treatment of cancer.

Smart Bandage Based on Molecularly Imprinted Polymers (MIPs) for Diclofenac Controlled Release

The aim of the present study was the development of a “smart bandage” for the topical administration of diclofenac, in the treatment of localized painful and inflammatory conditions, incorporating Molecularly Imprinted Polymers (MIPs) for the controlled release of this anti-inflammatory drug. For this purpose, MIP spherical particles were synthesized by precipitation polymerization, loaded with the therapeutic agent and incorporated into the bandage surface. Batch adsorption binding studies were performed to investigate the adsorption isotherms and kinetics and the selective recognition abilities of the synthesized MIP. In vitro diffusion studies were also carried out using Franz cells and the obtained results were reported as percentage of the diffused dose, cumulative amount of diffused drug, steady-state drug flux and permeability coefficient. Moreover, the biocompatibility of the developed device was evaluated using the EPISKIN™ model. The Scatchard analysis indicated that the prepared MIP is characterized by the presence of specific binding sites for diclofenac, which are not present in the corresponding non-imprinted polymer, and the obtained results confirmed both the ability of the prepared bandage to prolong the drug release and the absence of skin irritation reactions. Therefore, these results support the potential application of the developed “smart bandage” as topical device for diclofenac sustained release.

Interconnected PolymerS TeChnology (IPSTiC): An Effective Approach for the Modulation of 5α-Reductase Activity in Hair Loss Conditions

Hair loss represents a condition that adversely affects the social life of patients. The most common cause is androgenetic alopecia (AGA), which is a genetically determined progressive hair-loss condition involving 5α-reductase. In this study, a novel anti-baldness agent based on Interconnected PolymerS TeChnology (IPSTiC), which is an effective strategy for the delivery of bioactive molecules, was developed. This product (IPSTiC patch hair) is based on a polymeric blend consisting of high molecular weight hyaluronic acid and soybean proteins and is able to improve efficacy and stability of bioactive ingredients such as Origanum vulgare leaf extract, Camellia Sinensis leaf extract, and Capsicum Annuum fruit extract. The efficacy of the developed anti-baldness agent was investigated by performing several tests including NO radical and 5α-reductase inhibition assays, stability studies under different conditions, and in vitro diffusion studies using Franz cells. The biocompatibility of IPSTiC patch hair was also evaluated by in vitro analysis of the pro-sensitising potential and EPISKIN model. The obtained results confirmed both the efficacy and safety of IPSTiC patch hair supporting the potential use of this product in the topical treatment of AGA.

Molecularly Imprinted Microrods via Mesophase Polymerization

The aim of the present research work was the synthesis of molecularly imprinted polymers (MIPs) with a rod-like geometry via “mesophase polymerization”. The ternary lyotropic system consisting of sodium dodecyl sulfate (SDS), water, and decanol was chosen to prepare a hexagonal mesophase to direct the morphology of the synthesized imprinted polymers using theophylline, methacrylic acid, and ethylene glycol dimethacrylate as a drug model template, a functional monomer, and a crosslinker, respectively. The obtained molecularly imprinted microrods (MIMs) were assessed by performing binding experiments and in vitro release studies, and the obtained results highlighted good selective recognition abilities and sustained release properties. In conclusion, the adopted synthetic strategy involving a lyotropic mesophase system allows for the preparation of effective MIPs characterized by a rod-like morphology.