Curcumin-Sodium Alginate and Curcumin-Chitosan Conjugates as Drug Delivery Systems: An Interesting Rheological Behaviour.

The conjugation of polyphenols is a valuable strategy with which to confer tailored properties to polymeric materials of biomedical interest. Within this investigation, we aim to explore the possibility to use this synthetic approach to increase the viscosity of conjugates, thus allowing the release of a loaded therapeutic to be better controlled over time than in neat polyphenols. Curcumin (CUR) was conjugated to sodium alginate (CA) and chitosan (CS) with functionalisation degrees of 9.2 (SA-CUR) and 15.4 (CS-CUR) mg g-1. Calorimetric analyses showed higher degrees of chain rigidity upon conjugation, with a shift of the degradation peaks to higher temperatures (from 239 to 245 °C and from 296 to 303 °C for SA-CUR and CS-CUR, respectively). Rheological analyses were used to prove the enhanced interconnection between the polymer chains in the conjugates, confirmed by the weak gel parameters, A and z. Moreover, the typical non-Newtonian behaviour of the high-molecular-weight polysaccharides was recorded, together with an enhancement of the activation energy, Ea, in CS-CUR vs. CS (opposite behaviour recorded for SA-CUR vs. SA). The evaluation of the delivery performance (of Doxorubicin as a model drug) showed sustained release profiles, opening opportunities for the development of controlled delivery systems.

Smart Lipid-Polysaccharide Nanoparticles for Targeted Delivery of Doxorubicin to Breast Cancer Cells.

In this study, actively-targeted (CD44-receptors) and dual stimuli (pH/redox)-responsive lipid-polymer nanoparticles were proposed as a delivery vehicle of doxorubicin hydrochloride in triple negative breast cancer cell lines. A phosphatidylcholine lipid film was hydrated with a solution of oxidized hyaluronic acid and doxorubicin, chosen as model drug, followed by a crosslinking reaction with cystamine hydrochloride. The obtained spherical nanoparticles (mean diameter of 30 nm) were found to be efficiently internalized in cancer cells by a receptor-mediated endocytosis process, and to modulate the drug release depending on the pH and redox potential of the surrounding medium. In vitro cytotoxicity assays demonstrated the safety and efficacy of the nanoparticles in enhancing the cytotoxic effect of the free anticancer drug, with the IC50 values being reduced by two and three times in MDA-MB-468 and MDA-MB-231, respectively. The combination of self-assembled phospholipid molecules with a polysaccharide counterpart acting as receptor ligand, and stimuli-responsive chemical moieties, was carried out on smart multifunctional nanoparticles able to actively target breast cancer cells and improve the in vitro anticancer activity of doxorubicin.

GO-SWCNT Buckypapers as an Enhanced Technology for Water Decontamination from Lead.

Water decontamination is an important challenge resulting from the incorrect disposal of heavy metal waste into the environment. Among the different available techniques (e.g., filtration, coagulation, precipitation, and ion-exchange), adsorption is considered the cheapest and most effective procedure for the removal of water pollutants. In the last years, several materials have been tested for the removal of heavy metals from water, including metal-organic frameworks (MOFs), single-walled carbon nanotubes (SWCNTs), and graphene oxide (GO). Nevertheless, their powder consistency, which makes the recovery and reuse after adsorption difficult, is the main drawback for these materials. More recently, SWCNT buckypapers (SWCNT BPs) have been proposed as self-standing porous membranes for filtration and adsorption processes. In this paper, the adsorption capacity and selectivity of Pb2+ (both from neat solutions and in the presence of other interferents) by SWCNT BPs were evaluated as a function of the increasing amount of GO used in their preparation (GO-SWCNT buckypapers). The highest adsorption capacity, 479 ± 25 mg g-1, achieved for GO-SWCNT buckypapers with 75 wt.% of graphene oxide confirmed the effective application of such materials for cheap and fast water decontamination from lead.

Removal of Non-Steroidal Anti-Inflammatory Drugs from Drinking Water Sources by GO-SWCNT Buckypapers.

Pharmaceutical products such as antibiotics, analgesics, steroids, and non-steroidal anti-inflammatory drugs (NSAIDs) are new emerging pollutants, often present in wastewater, potentially able to contaminate drinking water resources. Adsorption is considered the cheapest and most effective technique for the removal of pollutants from water, and, recently, membranes obtained by wet filtration method of SWCNT aqueous solutions (SWCNT buckypapers, SWCNT BPs) have been proposed as self-standing porous adsorbents. In this paper, the ability of graphene oxide/single-walled carbon nanotube composite membranes (GO-SWCNT BPs) to remove some important NSAIDs, namely Diclofenac, Ketoprofen, and Naproxen, was investigated at different pH conditions (pH 4, 6, and 8), graphene oxide amount (0, 20, 40, 60, and 75 wt.%), and initial NSAIDs concentration (1, 10, and 50 ppm). For the same experimental conditions, the adsorption capacities were found to strongly depend on the graphene oxide content. The best results were obtained for 75 wt.% graphene oxide with an adsorption capacity of 118 ± 2 mg g-1 for Diclofenac, 116 ± 2 mg g-1 for Ketoprofen, and 126 ± 3 mg g-1 for Naproxen at pH 4. Overall, the reported data suggest that GO-SWCNT BPs can represent a promising tool for a cheap and fast removal of NSAIDs from drinking water resources, with easy recovery and reusability features.

Alginate Bioconjugate and Graphene Oxide in Multifunctional Hydrogels for Versatile Biomedical Applications.

In this work, we combined electrically-conductive graphene oxide and a sodium alginate-caffeic acid conjugate, acting as a functional element, in an acrylate hydrogel network to obtain multifunctional materials designed to perform multiple tasks in biomedical research. The hybrid material was found to be well tolerated by human fibroblast lung cells (MRC-5) (viability higher than 94%) and able to modify its swelling properties upon application of an external electric field. Release experiments performed using lysozyme as the model drug, showed a pH and electro-responsive behavior, with higher release amounts and rated in physiological vs. acidic pH. Finally, the retainment of the antioxidant properties of caffeic acid upon conjugation and polymerization processes (Trolox equivalent antioxidant capacity values of 1.77 and 1.48, respectively) was used to quench the effect of hydrogen peroxide in a hydrogel-assisted lysozyme crystallization procedure.

Carbon Nanotubes Hybrid Hydrogels for Environmental Remediation: Evaluation of Adsorption Efficiency under Electric Field.

The performance of Carbon Nanotubes hybrid hydrogels for environmental remediation was investigated using Methylene Blue (MB), Rhodamine B (RD), and Bengal Rose (BR) as model contaminating dyes. An acrylate hydrogel network with incorporated CNT was synthesized by photo-polymerization without any preliminary derivatization of CNT surface. Thermodynamics, isothermal and kinetic studies showed favorable sorption processes with the application of an external 12 V electric field found to be able to influence the amount of adsorbed dyes: stronger interactions with cationic MB molecules (qexp and qexp12 of 19.72 and 33.45 mg g-1, respectively) and reduced affinity for anionic RD (qexp and qexp12 of 28.93 and 13.06 mg g-1, respectively) and neutral BR (qexp and qexp12 of 36.75 and 15.85 mg g-1, respectively) molecules were recorded. The influence of pH variation on dyes adsorption was finally highlighted by reusability studies, with the negligible variation of adsorption capacity after five repeated sorption cycles claiming for the suitability of the proposed systems as effective sorbent for wastewater treatment.

Functional Albumin Nanoformulations to Fight Adrenocortical Carcinoma: a Redox-Responsive Approach.

PURPOSE: Solid tumors exhibit an altered redox state in comparison with normal tissues due to tumor hypoxia, lower pH, and elevated levels of the tripeptide glutathione. This study describes the preparation of functional redox-responsive nanoparticles proposed as delivery vehicle of Doxorubicin in adrenocortical cancer in vitro. METHODS: Curcumin and Lipoic acid were conjugated to Human Serum Albumin and nanoparticle systems were prepared via a modified desolvation method. Scanning electron microscopy, Fourier transmission IR, dynamic light scattering and differential scanning calorimetry analyses were used to characterize the nanoparticles. Balb3T3 and H295R were used as in vitro models of health and cancer cells, respectively. RESULTS: Nanoparticles with a spherical shape and a mean diameter of 70 nm were observed, increasing up to ten-folds upon exposure to glutathione 10 mM. Redox responsive Doxorubicin release was recorded, with loaded nanoparticles significantly enhancing the drug cytotoxicity against H295R adrenocortical tumor cells. Cell uptake experiments revealed a rapid and efficient internalization of the nanoparticles. CONCLUSIONS: A valuable tools to actively improve the in vitro anticancer activity of Doxorubicin against adrenocortical cancer was proposed. The effectiveness of the delivery vehicle is related to the presence of both Lipoic acid and Curcumin moieties, enhancing the glutathione responsivity, and the drug cytotoxicity, respectively.

Functionalized Carbon Nanostructures Versus Drug Resistance: Promising Scenarios in Cancer Treatment.

Carbon nanostructures (CN) are emerging valuable materials for the assembly of highly engineered multifunctional nanovehicles for cancer therapy, in particular for counteracting the insurgence of multi-drug resistance (MDR). In this regard, carbon nanotubes (CNT), graphene oxide (GO), and fullerenes (F) have been proposed as promising materials due to their superior physical, chemical, and biological features. The possibility to easily modify their surface, conferring tailored properties, allows different CN derivatives to be synthesized. Although many studies have explored this topic, a comprehensive review evaluating the beneficial use of functionalized CNT vs G or F is still missing. Within this paper, the most relevant examples of CN-based nanosystems proposed for MDR reversal are reviewed, taking into consideration the functionalization routes, as well as the biological mechanisms involved and the possible toxicity concerns. The main aim is to understand which functional CN represents the most promising strategy to be further investigated for overcoming MDR in cancer.

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.

Carbon nanotubes buckypapers: A new frontier in wastewater treatment technology.

Occurrence of contaminants in water is one of the major global concerns humanity is still facing today: most of them are extremely toxic and dangerous for human health, obliging their removal for a proper and correct process of sanitation. Among wastewater treatment technologies, in the view of development of sustainable and environmentally friendly processes, membrane adsorption has proved to be a fast and simple method in the removal of pollutants, offering great contaminants recovery percentages, fast adsorbent regeneration and recycle, and easy scale-up. Due to their large surface area and tunable chemistry, carbon nanotubes (CNTs)-based materials revealed to be extraordinary adsorbents, exceeding by far performances of ordinary organic and inorganic membranes such as polyethersulfone, polyvinylidene fluoride, polytetrafluoroethylene, ceramics, currently employed in membrane technologies for wastewater treatment. In consideration of this, the review aims to summarize recent developments in the field of carbon nanotubes-based materials for pollutants recovery from water through adsorption processes. After a brief introduction concerning what adsorption phenomenon is and how it is performed and governed by using carbon nanotubes-based materials, the review discusses into detail the employment of three common typologies of CNTs-based materials (CNTs powders, CNTs-doped polymeric membranes and CNTs membranes) in adsorption process for the removal of water pollutants. Particularly focus will be devoted on the emergent category of self-standing CNTs membranes (buckypapers), made entirely of carbon nanotubes, exhibiting superior performances than CNTs and CNTs-doped polymeric membranes in terms of preparation strategy, recovery percentages of pollutants and regeneration possibilities. The extremely encouraging results presented in this review aim to support and pave the way to the introduction of alternative and more efficient pathways in wastewater treatment technologies to contrast the problem of water pollution.

Reactive Deep Eutectic Solvent for an Eco-Friendly Synthesis of Cellulose Carbamate.

The limited solubility of natural cellulose in water and common organic solvents hinders its diverse applications, despite being one of the most abundant and easily accessible biopolymers on Earth. Chemical derivatization, such as cellulose carbamate (CC), offers a pathway to enhance both solubility and industrial processability. In this study, CC was synthesized by exploiting a novel type IV deep eutectic solvent (DES) composed of erbium trichloride and urea. This DES was shown to be not only an environmentally friendly reaction medium/catalyst but also actively participated in the synthetic process as a reagent. The resultant cellulose carbamate samples were characterized through FT-IR and elemental analysis. A nitrogen content value of 1.59% was afforded determining a degree of substitution corresponding to a value of 0.19. One of the key scientific advancements lies in the preparation of cellulose carbamate using a straightforward and cost-effective method. This approach utilizes non-toxic compounds, aligning with the principles of green chemistry and contributing to sustainable development in cellulose derivative production.

Dual-responsive chondroitin sulfate self-assembling nanoparticles for combination therapy in metastatic cancer cells.

In this study, we developed self-assembling nanoparticles (LCPs) able to trigger the release of Chlorambucil (Chl) and Doxorubicin (DOX) to MDA-MB-231 cells by exploiting the enzyme and redox signals. The DOX loaded LCPs was prepared by the self-assembly of two chondroitin sulphate (CS) derivatives, obtained by the covalent conjugation of Lipoic Acid (LA) and Chlorambucil (Chl) to the CS backbone. After the physic-chemical characterization of the conjugates by FT-IR, 1H NMR, and determination of the critical aggregation concentration, spherical nanoparticles with mean hydrodynamic diameter of 45 nm (P.D.I. 0.24) and Z-potential of - 44 mV were obtained by water addition/solvent evaporation method. In vitro experiments for the release of Chl and DOX were performed in healthy and cancer cells, using a cell culture media to maintain the physiological intracellular conditions (pH 7.4) (and concentration of esterase and GSH. The results allowed the selective release of the payloads to be detected: Chl release of 0 and 41% were obtained after 2 h incubation in normal and in cancer cells respectively, while values of 35 (in healthy cells) and 60% (in cancer cells) were recorded for DOX release after 96 h. Finally, viability studies proved the ability of the newly proposed nanosystem to enhance the cytotoxic activity of the two drugs against cancer cells.

Nanomaterials for Drug Delivery and Cancer Therapy.

In recent decades, the interest in nanomaterials has grown rapidly for their applications in many research fields, including drug delivery and cancer therapy [...].

Facile one-pot hydrothermal synthesis of a zinc oxide/curcumin nanocomposite with enhanced toxic activity against breast cancer cells.

Zinc oxide/Curcumin (Zn(CUR)O) nanocomposites were prepared via hydrothermal treatment of Zn(NO3)2 in the presence of hexamethylenetetramine as a stabilizing agent and CUR as a bioactive element. Three ZnO : CUR ratios were investigated, namely 57 : 43 (Zn(CUR)O-A), 60 : 40 (Zn(CUR)O-B) and 81 : 19 (Zn(CUR)O-C), as assessed by thermogravimetric analyses, with an average hydrodynamic diameter of nanoaggregates in the range of 223 to 361 nm. The interaction of CUR with ZnO via hydroxyl and ketoenol groups (as proved by X-ray photoelectron spectroscopy analyses) was found to significantly modify the key properties of ZnO nanoparticles with the obtainment of a bilobed shape (as shown by scanning electron microscopy), and influenced the growth process of the composite nanoparticles as indicated by the varying particle sizes determined by powder X-ray diffraction. The efficacy of Zn(CUR)O as anticancer agents was evaluated on MCF-7 and MDA-MB-231 cancer cells, obtaining a synergistic activity with a cell viability depending on the CUR amount within the nanocomposite. Finally, the determination of reactive oxygen species production in the presence of Zn(CUR)O was used as a preliminary evaluation of the mechanism of action of the nanocomposites.

Evolving approaches in glioma treatment: harnessing the potential of copper metabolism modulation.

The key properties and high versatility of metal nanoparticles have shed new perspectives on cancer therapy, with copper nanoparticles gaining great interest because of the ability to couple the intrinsic properties of metal nanoparticles with the biological activities of copper ions in cancer cells. Copper, indeed, is a cofactor involved in different metabolic pathways of many physiological and pathological processes. Literature data report on the use of copper in preclinical protocols for cancer treatment based on chemo-, photothermal-, or copper chelating-therapies. Copper nanoparticles exhibit anticancer activity via multiple routes, mainly involving the targeting of mitochondria, the modulation of oxidative stress, the induction of apoptosis and autophagy, and the modulation of immune response. Moreover, compared to other metal nanoparticles (e.g. gold, silver, palladium, and platinum), copper nanoparticles are rapidly cleared from organs with low systemic toxicity and benefit from the copper's low cost and wide availability. Within this review, we aim to explore the impact of copper in cancer research, focusing on glioma, the most common primary brain tumour. Glioma accounts for about 80% of all malignant brain tumours and shows a poor prognosis with the five-year survival rate being less than 5%. After introducing the glioma pathogenesis and the limitation of current therapeutic strategies, we will discuss the potential impact of copper therapy and present the key results of the most relevant literature to establish a reliable foundation for future development of copper-based approaches.

Hyaluronic Acid within Self-Assembling Nanoparticles: Endless Possibilities for Targeted Cancer Therapy.

Self-assembling nanoparticles (SANPs) based on hyaluronic acid (HA) represent unique tools in cancer therapy because they combine the HA targeting activity towards cancer cells with the advantageous features of the self-assembling nanosystems, i.e., chemical versatility and ease of preparation and scalability. This review describes the key outcomes arising from the combination of HA and SANPs, focusing on nanomaterials where HA and/or HA-derivatives are inserted within the self-assembling nanostructure. We elucidate the different HA derivatization strategies proposed for this scope, as well as the preparation methods used for the fabrication of the delivery device. After showing the biological results in the employed in vivo and in vitro models, we discussed the pros and cons of each nanosystem, opening a discussion on which approach represents the most promising strategy for further investigation and effective therapeutic protocol development.

Encapsulation of Alpha-Lipoic Acid in Functional Hybrid Liposomes: Promising Tool for the Reduction of Cisplatin-Induced Ototoxicity.

In this study, in order to address the drawback of cisplatin (CDDP)-induced ototoxicity, we propose a straightforward strategy based on the delivery of a sulfur-based antioxidant, such as lipoic acid (LA), to HEI-OC1 cells. To this aim, hybrid liposomes (LA@PCGC) with a spherical shape and a mean diameter of 25 nm were obtained by direct sonication of LA, phosphatidylcholine and a gelatin-curcumin conjugate in a physiological buffer. LA@PCGC were found to be stable over time, were quickly (i.e., by 1 h) taken up by HEI-OC1 cells, and guaranteed strong retention of the bioactive molecule, since LA release was less than 20%, even after 100 h. Cell viability studies showed the efficiency of LA@PCGC for stabilizing the protective activity of LA. Curcumin residues within the functional liposomes were indeed able to maintain the biological activity of LA, significantly improving (up to 2.19-fold) the viability of HEI-OC1 cells treated with 5 µM CDDP. Finally, LA@PCGC was incorporated within an alginate-based injectable hydrogel carrier to create a formulation with physical chemical features suitable for potential ear applications.

CD44-targeted nanoparticles with GSH-responsive activity as powerful therapeutic agents against breast cancer.

DOX-loaded nanoparticles able to actively target CD44-receptors and respond to redox stimuli were proposed as non-conventional chemotherapeutic strategy in breast cancer. A covalent conjugate of human serum albumin and hyaluronic acid was prepared and assembled by a GSH-mediated desolvation in disulfide-crosslinked solid nanoparticles with mean diameter of 120 nm ± 3.4. The effective internalization of nanoparticles in cancer cells via CD44-receptors, together with the more efficient intracellular release, resulted in a significant increase of drug efficacy, with IC50 reduced from 0.9959 and 2.516 µg mL-1 to 0.4014 and 0.3094 µg mL-1 for MCF-7 and MDA-MB-231, respectively. Conversely, no enhancement in drug toxicity was recorded in healthy MCF-10A cells. The efficacy of the proposed formulation was further investigated in the different biological steps involved in metastasis process, paving the way for further in vivo experiments.

Dual-Targeted Hyaluronic Acid/Albumin Micelle-Like Nanoparticles for the Vectorization of Doxorubicin.

Drug targeting of tumor cells is one of the great challenges in cancer therapy; nanoparticles based on natural polymers represent valuable tools to achieve this aim. The ability to respond to environmental signals from the pathological site (e.g., altered redox potential), together with the specific interaction with membrane receptors overexpressed on cancer cells membrane (e.g., CD44 receptors), represent the main features of actively targeted nanoparticles. In this work, redox-responsive micelle-like nanoparticles were prepared by self-assembling of a hyaluronic acid-human serum albumin conjugate containing cystamine moieties acting as a functional spacer. The conjugation procedure consisted of a reductive amination step of hyaluronic acid followed by condensation with albumin. After self-assembling, nanoparticles with a mean size of 70 nm and able to be destabilized in reducing media were obtained. Doxorubicin-loaded nanoparticles modulated drug release rate in response to different redox conditions. Finally, the viability and uptake experiments on healthy (BALB-3T3) and metastatic cancer (MDA-MB-231) cells proved the potential applicability of the proposed system as a drug vector in cancer therapy.

Development of Spanish Broom and Flax Dressings with Glycyrrhetinic Acid-Loaded Films for Wound Healing: Characterization and Evaluation of Biological Properties.

The selection of an appropriate dressing for each type of wound is a very important procedure for a faster and more accurate healing process. So, the aim of this study was to develop innovative Spanish Broom and flax wound dressings, as alternatives to cotton used as control, with polymeric films containing glycyrrhetinic acid (GA) to promote wound-exudate absorption and the healing process. The different wound dressings were prepared by a solvent casting method, and characterized in terms of drug loading, water uptake, and in vitro release. Moreover, biological studies were performed to evaluate their biocompatibility and wound-healing efficacy. Comparing the developed wound dressings, Spanish Broom dressings with GA-loaded sodium hyaluronate film had the best functional properties, in terms of hydration ability and GA release. Moreover, they showed a good biocompatibility, determining a moderate induction of cell proliferation and no cytotoxicity. In addition, the wound-healing test revealed that the Spanish Broom dressings promoted cell migration, further facilitating the closure of the wound.