ZnO-Graphene Oxide Nanocomposite for Paclitaxel Delivery and Enhanced Toxicity in Breast Cancer Cells.

A ZnO-Graphene oxide nanocomposite (Z-G) was prepared in order to exploit the biomedical features of each component in a single anticancer material. This was achieved by means of an environmentally friendly synthesis, taking place at a low temperature and without the involvement of toxic reagents. The product was physicochemically characterized. The ZnO-to-GO ratio was determined through thermogravimetric analysis, while scanning electron microscopy and transmission electron microscopy were used to provide insight into the morphology of the nanocomposite. Using energy-dispersive X-ray spectroscopy, it was possible to confirm that the graphene flakes were homogeneously coated with ZnO. The crystallite size of the ZnO nanoparticles in the new composite was determined using X-ray powder diffraction. The capacity of Z-G to enhance the toxicity of the anticancer drug Paclitaxel towards breast cancer cells was assessed via a cell viability study, showing the remarkable anticancer activity of the obtained system. Such results support the potential use of Z-G as an anticancer agent in combination with a common chemotherapeutic like Paclitaxel, leading to new chemotherapeutic formulations.

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.

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.

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.

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.

Polyphenol Conjugates and Human Health: A Perspective Review.

In recent years, antioxidants have gained great importance because of their potential use in food, pharmaceutical, and cosmetic industries. This interest is rooted in the cumulative evidence connecting active oxygen and free radicals with numerous human degenerative disorders, such as cardiovascular diseases, cancer, aging, and atherosclerosis. Polyphenols are the major class of antioxidant able to reduce the oxidative damages of lipids, proteins, enzymes, carbohydrates, and DNA in living cells and tissues. Among the realm of polyphenol compounds, polyphenol conjugates have been proposed as innovative materials which, by combining the advantageous properties of both the components, can increase the efficiency of antioxidants and their range of application in nutritional and biomedical fields. This work is an overview of the different class of polyphenol conjugates, which will be analyzed in terms of nutritional and biological properties, showing how these bio-conjugates will positively affect the human health.

Coated biodegradable casein nanospheres: a valuable tool for oral drug delivery.

Biodegradable casein nanospheres for the sustained release of bioactive molecules in the gastro-intestinal tract were prepared by precipitation polymerization using sodium methacrylate (NaMA) and N,N'-methylene bis-acrylamide (MEBA) as pH-responsive monomer and cross-linker. Three materials with different casein amount were obtained and characterized by scanning electron microscopy, dimensional analysis, water uptake, cytotoxicity and enzymatic degradation experiments. Nanospheres biodegradability was tuned by coating with polyacrylic acid. Coated and uncoated materials were investigated as delivery vehicles for diclofenac sodium salt. For un-coated samples, the release raise 100% in 30 h, while for coated specimens these values were lower than 70%, due to the diffusional constraints of polymer layer.

Flavonoid-based pH-responsive hydrogels as carrier of unstable drugs in oxidative conditions.

In this study, pH-responsive hydrogels, synthesized by the coupling reaction of polyacrylic acid and catechin, are proposed as carriers of oxidable drugs toward the GI tract. The presence of polyphenolic moieties in the network gives the polymers properties suitable for the release of unstable drugs in oxidative conditions. The characterization of the hydrogels is obtained by means of morphological and physico-chemical analyses, antioxidant assays and evaluation of the swelling behavior in media simulating the gastric (pH 1.0) and the intestinal (pH 7.4) tracts. The hydrogels are tested as pH-responsive carriers in in vitro release studies of folic acid and thiamine, two model drugs easily degraded by oxidative conditions simulated by UV irradiation and t-butyl hydroperoxide treatment, respectively. Results show that catechin-based carriers are able to control the release of drugs at different pH values, giving a remarkable improvement in the stability of the therapeutics.

Synthesis, characterization and antimicrobial activity of conjugates based on fluoroquinolon-type antibiotics and gelatin.

Different fluoroquinolon-type antibiotics were conjugated to gelatin with the aim to synthesize biomacromolecules with antimicrobial properties. The covalent linkage of the antibiotic was performed by a radical process involving the residues in the side chains of gelatin able to undergo oxidative modifications. The conjugation of antibiotic moieties onto the protein structure was confirmed by FT-IR, UV-Vis, fluorescence, and calorimetric analyses. Biocompatibility tests were performed on human bone marrow mesenchymal stromal cells and the antibacterial properties of bioactive polymers were investigated by appropriate tests against Klebsiella pneumoniae and Escherichia coli. With regard to the tests conducted in the presence of E. coli, a minimum inhibitory concentration (MIC) ranging from 0.05 to 0.40 µg mL(-1) was recorded, while in the presence of K. pneumoniae this concentration varies from 0.10 to 1.60 µg mL(-1). In all the conjugates, the drug moieties retain their biological activity and the MIC values are lower than the resistance parameters of fluoroquinolon-type antibiotics versus Enterobacteriacae. The collected data suggest a broad range of applications, from biomedical to pharmaceutical and food science for all conjugates.

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.

Temperature-sensitive hydrogels by graft polymerization of chitosan and N-isopropylacrylamide for drug release.

Thermo-responsive polysaccharidic hydrogels were designed and synthesized by a free radical induced grafting procedure. Chitosan was chosen as biopolymer to impart biocompatibility and biodegradability to the macromolecular systems, while N-isopropylacrylamide (NIPAAm) was selected as co-monomer responsive for the thermo-sensitive properties. Ammonium persulfate was the initiator system and different polymeric networks have been synthesized by modulating the amount of NIPAAm in the polymerization feed. The resulting hydrogels were proposed as drug delivery devices and their performance was evaluated by using Diclofenac sodium salt as a model drug. Hydrogels were carefully characterized by FT-IR spectrophotometry, calorimetric analyses and swelling behavior in a temperature range of 15-45°C. Finally, to verify the suitability of these hydrogels as thermo-responsive devices, the drug release profiles were studied performing in vitro experiments around the swelling-shrinking transition temperatures of the macromolecular systems.

Flavonoids preservation and release by methacrylic acid-grafted (N-vinyl-pyrrolidone).

CONTEXT: Flavonoids preservation and release. OBJECTIVE: Synthesis of a polymeric material able to prevent thermal and photo degradation of a flavonoid model compound, such as (+)-catechin, and suitable for a controlled/sustained delivery of this molecule in gastro-intestinal simulating fluids. MATERIALS AND METHODS: Methacrylic acid (MAA) was grafted onto poly(N-vinyl-pyrrolidone) (PVP) by a free radical grafting procedure involving a single-step reaction at room temperature. For this purpose, hydrogen peroxide/ascorbic acid redox pair was employed as water-soluble and biocompatible initiator system. RESULTS AND DISCUSSION: FT-IR spectra confirmed the insertion of MAA onto the polymeric chain. Stability studies, performed under various conditions, such as freeze-thaw cycles, exposure to strong light, thermal stability studies under constant humidity and with light protection at different temperatures, showed the preservative properties of the polymeric material towards flavonoids. Furthermore, the biocompatibility was highlighted by Hen's Egg Test-Chorioallantoic Membrane assay and in vitro release studies demonstrated the possibility to employ PVP-MAA copolymer as a device for gastro-intestinal release of flavonoids. CONCLUSION: The coupling of good preservative properties together with biocompatibility and the usefulness as carrier in controlled release make this kind of material very interesting from an industrial point of view for different applications in food, pharmaceutical, and cosmetic fields.

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 [...].

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.

Dextran-catechin conjugate: a potential treatment against the pancreatic ductal adenocarcinoma.

PURPOSE: A polysaccharide-flavonoid conjugate was developend and proposed for the treatment of pancreatic ductal adenocarcinoma (PDAC). METHODS: The conjugate was synthesized by free radical grafting reaction between catechin and dextran. The chemical characterization of the conjugate was obtained by UV-Vis, 1H-NMR, FT-IR and GPC analyses, while the functionalization degree was determined by the Folin-Ciocalteu assay. The biological activity of the catechin-dextran conjugate was tested on two different cell lines derived from human pancreatic cancer (MIA PaCa-2 and PL45 cells), and the toxicity towards human pancreatic nestin-expressing cells evaluated. RESULTS: Both the cancer cell lines are killed when exposed to the conjugate, and undergo apoptosis after the incubation with catechin-dextran which resulted more effective in killing pancreatic tumor cells compared to the catechin alone. Moreover, our experimental data indicate that the conjugate was less cytotoxic to human pancreatic nestin-expressing cells which are considered a good model of non-neoplastic pancreatic cells. CONCLUSION: The suitability of newly synthesized Dextran-Catechin conjugate in the treatment of PDAC was proved confirming the high potential application of the proposed macromolecula system in the cancer therapy.

Starch-quercetin conjugate by radical grafting: synthesis and biological characterization.

A novel flavonoid-polysaccharide conjugate was synthesized by free radical grafting of quercetin on starch. The covalent insertion of quercetin in the polymeric chain was confirmed by FT-IR, DSC and fluorescence analyses, while an estimation of the amount of quercetin bound per g of polymer was obtained by the Folin-Ciocalteu assay. The conjugate shows improved UV stability and retains the antioxidant properties of free quercetin, such as scavenging activity towards free radicals (DPPH and peroxynitrite); inhibition of the free radical formation (peroxidation of linoleic acid) and total antioxidant activity. The conjugate also prevented drug degradation and shows potential health functionality in the treatment of Alzheimer disease, diabetes and as skin-whitening agent.

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.