Gallic Acid-Based Hydrogels for Phloretin Intestinal Release: A Promising Strategy to Reduce Oxidative Stress in Chronic Diabetes.

Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia caused by abnormalities in insulin secretion and/or action. In patients with diabetes, complications such as blindness, delayed wound healing, erectile dysfunction, renal failure, heart disease, etc., are generally related to an increase in ROS levels which, when activated, trigger hyperglycemia-induced lesions, inflammation and insulin resistance. In fact, extensive cell damage and death occurs mainly due to the effect that ROS exerts at the level of cellular constituents, causing the deterioration of DNA and peroxidation of proteins and lipids. Furthermore, elevated levels of reactive oxygen species (ROS) and an imbalance of redox levels in diabetic patients produce insulin resistance. These destructive effects can be controlled by the defense network of antioxidants of natural origin such as phloretin and gallic acid. For this reason, the objective of this work was to create a nanocarrier (hydrogel) based on gallic acid containing phloretin to increase the antioxidant effect of the two substances which function as fundamental for reducing the mechanisms linked to oxidative stress in patients suffering from chronic diabetes. Furthermore, since the bioavailability problems of phloretin at the intestinal level are known, this carrier could facilitate its release and absorption. The obtained hydrogel was characterized using Fourier transform infrared spectroscopy (FT-IR). Its degree of swelling (a%) and phloretin release were tested under pH conditions simulating the gastric and intestinal environment (1.2, 6.8 and 7.4). The antioxidant activity, inhibiting lipid peroxidation in rat liver microsomal membranes induced in vitro by a free radical source, was evaluated for four hours. All results showed that gallate hydrogel could be applied for releasing intestinal phloretin and reducing the ROS levels.

Green Chemistry Principles for Nano- and Micro-Sized Hydrogel Synthesis.

The growing demand for drug carriers and green-technology-based tissue engineering materials has enabled the fabrication of different types of micro- and nano-assemblies. Hydrogels are a type of material that have been extensively investigated in recent decades. Their physical and chemical properties, such as hydrophilicity, resemblance to living systems, swelling ability and modifiability, make them suitable to be exploited for many pharmaceutical and bioengineering applications. This review deals with a brief account of green-manufactured hydrogels, their characteristics, preparations, importance in the field of green biomedical technology and their future perspectives. Only hydrogels based on biopolymers, and primarily on polysaccharides, are considered. Particular attention is given to the processes of extracting such biopolymers from natural sources and the various emerging problems for their processing, such as solubility. Hydrogels are catalogued according to the main biopolymer on which they are based and, for each type, the chemical reactions and the processes that enable their assembly are identified. The economic and environmental sustainability of these processes are commented on. The possibility of large-scale processing in the production of the investigated hydrogels are framed in the context of an economy aimed at waste reduction and resource recycling.

Nutraceutical-Based Nanoformulations for Breast and Ovarian Cancer Treatment.

Different strategies have been investigated for a more satisfactory treatment of advanced breast cancer, including the adjuvant use of omega-3 polyunsaturated fatty acids (PUFAs). These nutritional compounds have been shown to possess potent anti-inflammatory and antiangiogenic activities, the capacity to affect transduction pathways/receptors involved in cell growth and to reprogram tumor microenvironment. Omega-3 PUFA-containing nanoformulations designed for drug delivery in breast cancer were shown to potentiate the effects of enclosed drugs, enhance drug delivery to target sites, and minimize drug-induced side effects. We have critically analyzed here the results of the most recent studies investigating the effects of omega-3 PUFA-containing nanoformulations in breast cancer. The anti-neoplastic efficacy of omega-3 PUFAs has also been convincingly demonstrated by using preclinical in vivo models of ovarian cancer. The results obtained are critically analyzed here and seem to provide a sufficient rationale to move to still lacking interventional clinical trials, as well as to evaluate possible advantages of enclosing omega-3 PUFAs to drug-delivery nanosystems for ovarian cancer. Future perspectives in this area are also provided.

Production of α-Tocopherol-Chitosan Nanoparticles by Membrane Emulsification.

α-tocopherol (α-T) has the highest biological activity with respect to the other components of vitamin E; however, conventional formulations of tocopherol often fail to provide satisfactory bioavailability due to its hydrophobic characteristics. In this work, α-tocopherol-loaded nanoparticles based on chitosan were produced by membrane emulsification (ME). A new derivative was obtained by the cross-linking reaction between α-T and chitosan (CH) to preserve its biological activity. ME was selected as a method for nanoparticle production because it is recognized as an innovative and sustainable technology for its uniform-particle production with tuned sizes and high encapsulation efficiency (EE%), and its ability to preserve the functional properties of bioactive ingredients operating in mild conditions. The reaction intermediates and the final product were characterized by 1HNMR, Fourier-transform infrared spectroscopy (FTIR) and differential scanning calorimetry (DSC), while the morphological and dimensional properties of the nanoparticles were analyzed using electronic scanning microscopy (SEM) and dynamic light scattering (DLS). The results demonstrated that ME has high potential for the development of α-tocopherol-loaded nanoparticles with a high degree of uniformity (PDI lower than 0.2), an EE of almost 100% and good mechanical strength, resulting in good candidates for the production of functional nanostructured materials for drug delivery. In addition, the chemical bonding between chitosan and α-tocopherol allowed the preservation of the antioxidant properties of the bioactive molecule, as demonstrated by an enhanced antioxidant property and evaluated through in vitro tests, with respect to the starting materials.

Recent Advances in Nanotechnology for the Treatment of Melanoma.

Melanoma is one of the most aggressive forms of skin cancer, with few possibilities for therapeutic approaches, due to its multi-drug resistance and, consequently, low survival rate for patients. Conventional therapies for treatment melanoma include radiotherapy, chemotherapy, targeted therapy, and immunotherapy, which have various side effects. For this reason, in recent years, pharmaceutical and biomedical research has focused on new sito-specific alternative therapeutic strategies. In this regard, nanotechnology offers numerous benefits which could improve the life expectancy of melanoma patients with very low adverse effects. This review aims to examine the latest advances in nanotechnology as an innovative strategy for treating melanoma. In particular, the use of different types of nanoparticles, such as vesicles, polymers, metal-based, carbon nanotubes, dendrimers, solid lipid, microneedles, and their combination with immunotherapies and vaccines will be discussed.

Chitosan Membranes Filled with Cyclosporine A as Possible Devices for Local Administration of Drugs in the Treatment of Breast Cancer.

The aim of this work is the design, preparation and characterization of membranes based on cyclosporine A (CsA) and chitosan carboxylate (CC) to be used as an implantable subcutaneous medical device for a prolonged therapeutic effect in the treatment of breast cancer. The choice to use CsA is due to literature data that have demonstrated its possible antitumor activity on different types of neoplastic cells. To this end, CsA was bound to CC through an amidation reaction to obtain a prodrug to be dispersed in a chitosan-based polymeric membrane. The reaction intermediates and the final product were characterized by Fourier transform infrared spectroscopy (FT-IR) and proton nuclear magnetic resonance (1H-NMR). Membranes were analyzed by differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). The data obtained showed the effective formation of the amide bond between CsA and CC and the complete dispersion of CsA inside the polymeric membrane. Furthermore, preliminary tests, conducted on MDA-MB-231, a type of breast cancer cell line, have shown a high reduction in the proliferation of cancer cells. These results indicate the possibility of using the obtained membranes as an interesting strategy for the release of cyclosporin-A in breast cancer patients.

Valorization of Tomato Waste as a Source of Carotenoids.

Fast-accumulating scientific evidence from many studies has revealed that fruits and vegetables are the main source of bioactive compounds; in most cases, wastes and byproducts generated by the food processing industry present similar or a higher content of antioxidant compounds. In recent years, the ever-growing amount of agricultural and food wastes has raised serious concerns from an environmental point of view. Therefore, there is an increasing interest in finding new ways for their processing toward safely upgrading these wastes for recovering high-value-added products with a sustainable approach. Among food waste, the abundance of bioactive compounds in byproducts derived from tomato suggests possibility of utilizing them as a low-cost source of antioxidants as functional ingredients. This contribution gives an overview of latest studies on the extraction methods of carotenoids from tomato waste, along with an evaluation of their antioxidant activity, as well as their industrial applications.

Viscosified Solid Lipidic Nanoparticles Based on Naringenin and Linolenic Acid for the Release of Cyclosporine A on the Skin.

Psoriasis is one of the most common human skin disorders. Although its pathogenesis is complex and not completely know, the hyperactivation of the immune system seem to have a key role. In this regard, among the most effective systemic therapeutics used in psoriasis, we find cyclosporine, an immunosuppressive medication. However, one of the major problems associated with the use of cyclosporine is the occurrence of systemic side effects such as nephrotoxicity, hypertension, etc. The present work fits in this context and its aim is the design of suitable platforms for cyclosporine topical release in psoriasis treatment. The main objective is to achieve local administration of cyclosporine in order to reduce its systemic absorption and, consequently, its side effects. In order to improve dermal penetration, solid lipid nanoparticles (SLNs) are used as carriers, due to their lipophilicity and occlusive properties, and naringenin and linolenic acid are chosen, due to their properties, as starting materials for SLNs design. In order to have dermatological formulations and further modulate drug release, SLNs are incorporated in several topical vehicles obtaining gels with different degree of lipophilicity. Potential applications for psoriasis treatment were evaluated by considering the encapsulation efficiency, release profiles, in vitro skin permeation, and anti-inflammatory effects.

Green Synthesis of Privileged Benzimidazole Scaffolds Using Active Deep Eutectic Solvent.

The exploitation and use of alternative synthetic methods, in the face of classical procedures that do not conform to the ethics of green chemistry, represent an ever-present problem in the pharmaceutical industry. The procedures for the synthesis of benzimidazoles have become a focus in synthetic organic chemistry, as they are building blocks of strong interest for the development of compounds with pharmacological activity. Various benzimidazole derivatives exhibit important activities such as antimicrobial, antiviral, anti-inflammatory, and analgesic activities, and some of the already synthesized compounds have found very strong applications in medicine praxis. Here we report a selective and sustainable method for the synthesis of 1,2-disubstituted or 2-substituted benzimidazoles, starting from o-phenylenediamine in the presence of different aldehydes. The use of deep eutectic solvent (DES), both as reaction medium and reagent without any external solvent, provides advantages in terms of yields as well as in the work up procedure of the reaction.

Omega-3 PUFA Loaded in Resveratrol-Based Solid Lipid Nanoparticles: Physicochemical Properties and Antineoplastic Activities in Human Colorectal Cancer Cells In Vitro.

New strategies are being investigated to ameliorate the efficacy and reduce the toxicity of the drugs currently used in colorectal cancer (CRC), one of the most common malignancies in the Western world. Data have been accumulated demonstrating that the antineoplastic therapies with either conventional or single-targeted drugs could take advantage from a combined treatment with omega-3 polyunsaturated fatty acids (omega-3 PUFA). These nutrients, shown to be safe at the dosage generally used in human trials, are able to modulate molecules involved in colon cancer cell growth and survival. They have also the potential to act against inflammation, which plays a critical role in CRC development, and to increase the anti-cancer immune response. In the present study, omega-3 PUFA were encapsulated in solid lipid nanoparticles (SLN) having a lipid matrix containing resveratrol esterified to stearic acid. Our aim was to increase the efficiency of the incorporation of these fatty acids into the cells and prevent their peroxidation and degradation. The Resveratrol-based SLN were characterized and investigated for their antioxidant activity. It was observed that the encapsulation of omega-3 PUFA into the SLN enhanced significantly their incorporation in human HT-29 CRC cells in vitro, and their growth inhibitory effects in these cancer cells, mainly by reducing cell proliferation.

Hemostatic gauze based on chitosan and hydroquinone: preparation, characterization and blood coagulation evaluation.

This work concerns on the preparation and performance evaluation of a new chitosan hydroquinone based gauze for hemostatic use. Chitosan and hydroquinone were firstly connected by etherification and then linked to the pre-carboxylate gauze. The functionalized material and the chitosan-hydroquinone ether were characterized by Fourier Transform Infrared (FT-IR) Spectroscopy and Differential Scanning Calorimetry (DSC). FT-IR results showed that an esterification occurred on carboxylic group of the gauze. The gauze functionalization degree was also evaluated by volumetric analysis. The ether hydroquinone content was obtained by the Folin test. Moreover, the linkage between hydroquinone and chitosan was confirmed by nuclear magnetic resonance (NMR). The hemostatic activity of functionalized gauze was evaluated by dynamic blood clotting assays. The obtained results showed that the prepared material can shorten the blood clotting time and induce the adhesion and activation of platelets. Finally, swelling characteristic of the new gauze was evaluated to confirm its high capacity to absorb the blood.

Synthetic Haemostatic Sealants: Effectiveness, Safety, and In Vivo Applications.

Rapid haemostasis during surgery is essential when one wants to reduce the duration of operations, reduce the need for transfusions, and above all when one wants to achieve better patient management. The use of haemostatic agents, sealants, and adhesives improves the haemostatic process by offering several advantages, especially in vascular surgery. These agents vary widely in their mechanism of action, composition, ease of application, adhesion to wet or dry tissue, immunogenicity, and cost. The most used are cyanoacrylate-based glues (Glubran 2) or polysaccharide hydrogel-microsphere powder (AristaTMAH). This work is based on a retrospective study carried out on a sample of patients with different vascular diseases (FAV, pseudoaneurysm, and PICC application) in which two different haemostatic sealants were used. The aim was to assess the safety, the advantages, and the ability of both sealants to activate the haemostatic process at the affected site, also in relation to their chemical-physical characteristics. The obtained results showed that the application of Glubran 2 and AristaTMAH as surgical wound closure systems is effective and safe, as the success achieved was ≥94% on anastomoses of FAV, 100% on stabilization of PICC catheters, and ≤95% on pseudoaneurysms.

Polymeric Based Hydrogel Membranes for Biomedical Applications.

The development of biomedical applications is a transdisciplinary field that in recent years has involved researchers from chemistry, pharmacy, medicine, biology, biophysics, and biomechanical engineering. The fabrication of biomedical devices requires the use of biocompatible materials that do not damage living tissues and have some biomechanical characteristics. The use of polymeric membranes, as materials meeting the above-mentioned requirements, has become increasingly popular in recent years, with outstanding results in tissue engineering, for regeneration and replenishment of tissues constituting internal organs, in wound healing dressings, and in the realization of systems for diagnosis and therapy, through the controlled release of active substances. The biomedical application of hydrogel membranes has had little uptake in the past due to the toxicity of cross-linking agents and to the existing limitations regarding gelation under physiological conditions, but now it is proving to be a very promising field This review presents the important technological innovations that the use of membrane hydrogels has promoted, enabling the resolution of recurrent clinical problems, such as post-transplant rejection crises, haemorrhagic crises due to the adhesion of proteins, bacteria, and platelets on biomedical devices in contact with blood, and poor compliance of patients undergoing long-term drug therapies.

Transdermal Delivery of Phloretin by Gallic Acid Microparticles.

Exposure to ultraviolet (UV) radiation causes harmful effects on the skin, such as inflammatory states and photoaging, which depend strictly on the form, amount, and intensity of UV radiation and the type of individual exposed. Fortunately, the skin is endowed with a number of endogenous antioxidants and enzymes crucial in its response to UV radiation damage. However, the aging process and environmental stress can deprive the epidermis of its endogenous antioxidants. Therefore, natural exogenous antioxidants may be able to reduce the severity of UV-induced skin damage and aging. Several plant foods constitute a natural source of various antioxidants. These include gallic acid and phloretin, used in this work. Specifically, polymeric microspheres, useful for the delivery of phloretin, were made from gallic acid, a molecule that has a singular chemical structure with two different functional groups, carboxylic and hydroxyl, capable of providing polymerizable derivatives after esterification. Phloretin is a dihydrochalcone that possesses many biological and pharmacological properties, such as potent antioxidant activity in free radical removal, inhibition of lipid peroxidation, and antiproliferative effects. The obtained particles were characterized by Fourier transform infrared spectroscopy. Antioxidant activity, swelling behavior, phloretin loading efficiency, and transdermal release were also evaluated. The results obtained indicate that the micrometer-sized particles effectively swell, and release the phloretin encapsulated in them within 24 h, and possess antioxidant efficacy comparable to that of free phloretin solution. Therefore, such microspheres could be a viable strategy for the transdermal release of phloretin and subsequent protection from UV-induced skin damage.

Solid Lipid Nanoparticles Hydroquinone-Based for the Treatment of Melanoma: Efficacy and Safety Studies.

Classical melanoma therapy has several side effects that are responsible for a decrease in the final therapeutic efficacy. It is possible that the drug is degraded before reaching the target site and is metabolized by the body itself, resulting in repeated doses being administered throughout the day and a decrease in patient compliance. Drug delivery systems avoid degradation of the active ingredient, improve release kinetics, prevent the drug from being metabolized before reaching the site of action, and improve the safety and efficacy profiles of adjuvant cancer therapy. The solid lipid nanoparticles (SLNs) based on hydroquinone esterified with stearic acid realized in this work represent a chemotherapeutic drug delivery system that is useful in the treatment of melanoma. The starting materials were characterized by FT-IR and 1H-NMR, while the SLNs were characterized by dynamic light scattering. In efficacy studies, their ability to influence anchorage-dependent cell proliferation was tested on COLO-38 human melanoma cells. Furthermore, the expression levels of proteins belonging to apoptotic mechanisms were determined by analyzing the role of SLNs in modulating the expression of p53 and p21WAF1/Cip1. Safety tests were conducted to determine not only the pro-sensitizing potential but also the cytotoxicity of SLNs, and studies were conducted to assess the antioxidant and anti-inflammatory activity of these drug delivery.

Hyaluronic Acid-Mediated Phenolic Compound Nanodelivery for Cancer Therapy.

Phenolic compounds are bioactive phytochemicals showing a wide range of pharmacological activities, including anti-inflammatory, antioxidant, immunomodulatory, and anticancer effects. Moreover, they are associated with fewer side effects compared to most currently used antitumor drugs. Combinations of phenolic compounds with commonly used drugs have been largely studied as an approach aimed at enhancing the efficacy of anticancer drugs and reducing their deleterious systemic effects. In addition, some of these compounds are reported to reduce tumor cell drug resistance by modulating different signaling pathways. However, often, their application is limited due to their chemical instability, low water solubility, or scarce bioavailability. Nanoformulations, including polyphenols in combination or not with anticancer drugs, represent a suitable strategy to enhance their stability and bioavailability and, thus, improve their therapeutic activity. In recent years, the development of hyaluronic acid-based systems for specific drug delivery to cancer cells has represented a pursued therapeutic strategy. This is related to the fact that this natural polysaccharide binds to the CD44 receptor that is overexpressed in most solid cancers, thus allowing its efficient internalization in tumor cells. Moreover, it is characterized by high biodegradability, biocompatibility, and low toxicity. Here, we will focus on and critically analyze the results obtained in recent studies regarding the use of hyaluronic acid for the targeted delivery of bioactive phenolic compounds to cancer cells of different origins, alone or in combination with drugs.

Expanded Polytetrafluoroethylene Membranes for Vascular Stent Coating: Manufacturing, Biomedical and Surgical Applications, Innovations and Case Reports.

Coated stents are defined as innovative stents surrounded by a thin polymer membrane based on polytetrafluoroethylene (PTFE)useful in the treatment of numerous vascular pathologies. Endovascular methodology involves the use of such devices to restore blood flow in small-, medium- and large-calibre arteries, both centrally and peripherally. These membranes cross the stent struts and act as a physical barrier to block the growth of intimal tissue in the lumen, preventing so-called intimal hyperplasia and late stent thrombosis. PTFE for vascular applications is known as expanded polytetrafluoroethylene (e-PTFE) and it can be rolled up to form a thin multilayer membrane expandable by 4 to 5 times its original diameter. This membrane plays an important role in initiating the restenotic process because wrapped graft stent could be used as the treatment option for trauma devices during emergency situations and to treat a number of pathological vascular disease. In this review, we will investigate the multidisciplinary techniques used for the production of e-PTFE membranes, the advantages and disadvantages of their use, the innovations and the results in biomedical and surgery field when used to cover graft stents.

Preparation, characterization and efficacy evaluation of synthetic biocompatible polymers linking natural antioxidants.

The purpose of this work was the synthesis, characterization and efficacy evaluation of new biocompatible antioxidant polymers linking trans-ferulic acid or a-lipoic acid. In particular, ferulic or lipoic acid were introduced in the preformed polymeric backbone. The new antioxidant biopolymers were characterized by Fourier transform infrared spectroscopy and gel permeation chromatography. The degree of functionalization (moles of antioxidant per gram of polymer) was determined by the Gaur-Gupta method for free amino group determination and by the Folin method for the phenolic groups. Their ability to inhibit lipid peroxidation were estimated in rat liver microsomal membranes induced in vitro by tert-BOOH (tert-butyl hydroperoxide), as a source of free radicals. The DPPH (1,1-diphenyl-2-picrylhydrazyl) radical-scavenging effect was also evaluated. The obtained systems, with different solubility, showed strong antioxidant and antiradical activities, suggesting potential use as packaging materials for foods, cosmetics, pharmaceuticals and personal care products. Moreover, the cytotoxicity of the synthesized polymers was also evaluated on Caco-2 cell cultures in order to verify their biocompatibility when exposed to an absorptive epithelial cell line.

Preparation and Study of Solid Lipid Nanoparticles Based on Curcumin, Resveratrol and Capsaicin Containing Linolenic Acid.

Linolenic acid (LNA) is the most highly consumed polyunsaturated fatty acid found in the human diet. It possesses anti-inflammatory effects and the ability to reverse skin-related disorders related to its deficiency. The purpose of this work was to encapsulate LNA in solid lipid nanoparticles (SLNs) based on curcumin, resveratrol and capsaicin for the treatment of atopic dermatitis. These compounds were first esterified with oleic acid to obtain two moonoleate and one oleate ester, then they were used for SLN matrix realization through the emulsification method. The intermediates of the esterification reaction were characterized by FT-IR and 1N-MR analysis. SLNs were characterized by dimensional analysis and encapsulation efficiency. Skin permeation studies, antioxidant and anti-inflammatory activities were evaluated. LNA was released over 24 h from nanoparticles, and resveratrol monooleate-filled SLNs exhibited a good antioxidant activity. The curcumin-based SLNs loaded or not with LNA did not induce significant cytotoxicity in NCTC 2544 and THP-1 cells. Moreover, these SLNs loaded with LNA inhibited the production of IL-6 in NCTC 2544 cells. Overall, our data demonstrate that the synthesized SLNs could represent an efficacious way to deliver LNA to skin cells and to preserve the anti-inflammatory properties of LNA for the topical adjuvant treatment of atopic dermatitis.

Multifunctional Microspheres Based on D-Mannose and Resveratrol for Ciprofloxacin Release.

This article describes the preparation, characterization, and performance evaluation of functional microspheres useful for the release of ciprofloxacin. The particles were obtained using D-mannose, a natural aldohexose sugar, and resveratrol, a powerful antioxidant. In particular, the above compounds were initially converted into D-mannose carboxylate and resveratrol methacrylate and, therefore, subjected to an esterification reaction. The resulting product was used for the preparation of the microspheres which were characterized by light scattering, FT-IR spectrophotometry and scanning electron microscopy (SEM). Subsequently, their degree of bloating was evaluated at pH 1.2 to simulate the pH of the stomach, at pH 6.8 and pH 7.4 to mimic the intestinal environment. The antibiotic ciprofloxacin was then loaded into the microspheres, with an encapsulation efficiency of 100%. The cumulative amount of drug released was 55% at pH 6.8 and 99% at pH 7.4. The tests conducted to evaluate the antibacterial activity demonstrated the ability of the microspheres obtained to inhibit the growth of Escherichia coli. The antioxidant efficacy, due to the presence of resveratrol in their structure, was confirmed using rat liver microsomal membranes. The results obtained have highlighted how the microspheres based on D-mannose and resveratrol can be considered promising multifunctional vectors useful in the treatment of intestinal and urinary infections.