Photosensitive Chitosan-Based Injectable Hydrogel Chemically Cross-Linked by Perylene Bisimide Dopamine with Robust Antioxidant and Cytotoxicity Enhancer Properties for In Vitro Photodynamic Therapy of Breast Cancer.

Here, we report the fabrication of an antioxidant photosensitizing hydrogel system based on chitosan (CS-Cy/PBI-DOPA) covalently cross-linked with perylene bisimide dopamine (PBI-DOPA) as a photosensitizer. The severe insolubility and low tumor selectivity limitations of perylene were overcome by conjugation with dopamine and then to the chitosan hydrogel. The mechanical and rheological study of CS-Cy/PBI-DOPA photodynamic antioxidant hydrogels illustrated interconnected microporous morphologies with high elasticity, swelling ability, and suitable shear-thinning behavior. Bio-friendly properties, such as biodegradability and biocompatibility, excellent singlet oxygen production abilities, and antioxidant properties were also delivered. The antioxidant effects of the hydrogels control the physiological levels of reactive oxygen species (ROS) generated by photochemical reactions in photodynamic therapy (PDT), which are responsible for oxidative damage to tumor cells while protecting normal cells and tissues from ROS damage, including blood and endothelial cells. In vitro, PDT tests of hydrogels were conducted on two human breast cancer cell lines, MDA-MB-231 and MCF-7. These hydrogels offered more than 90% cell viability in the dark and good photocytotoxicity performance with 53 and 43% cell death for MCF-7 and MDA-MB-231 cells, which confirmed their promising potential for cancer therapeutic applications.

Dual antioxidant-photosensitizing hydrogel system: Cross-linking of chitosan with tannic acid for enhanced photodynamic efficacy.

Herein, a new antioxidant-photosensitizing hydrogel based on chitosan has been developed to control photodynamic therapy (PDT) activity in cancer treatment. In PDT, photosensitizers generate reactive oxygen species (ROS) during photochemical reactions, leading oxidative damage to cancer cells. However, high ROS levels are lethal to non-target healthy cells and tissues such as endothelial cells and blood cells. To mediate these drawbacks, we improved PDT with a natural polyphenolic antioxidant, Tannic acid (TA), to control the ROS level and minimize side effects through singlet oxygen (1O2) scavenging. In this work, chitosan-based hydrogels were designed using tannic acid as an antioxidant cross-linker and loaded with water-soluble N, N'-di-(l-alanine)-3,4,9,10-perylene tetracarboxylic diimide (PDI-Ala) as a photosensitizer. Our results showed that the hydrogel formed a three-dimensional (3D) microstructure with good mechanical strength and significant singlet oxygen production and antioxidant activity. In addition, the behavior of human melanoma cell line A375 and dental pulp stem cells (as normal cells) was compared and studied during an in vitro photodynamic treatment. Normal cells had a higher viability than cancer cells, indicating that the PDT is more effective on cancer cells than on normal cells. The new hydrogels could be applied as an effective new drug to control PDT performance.

Design of nanostructure chitosan hydrogels for carrying zinc phthalocyanine as a photosensitizer and difloxacin as an antibacterial agent.

Here, we develop homogeneous hydrogel networks containing zinc tetraamino-phthalocyanine (ZnTAPc) as photosensitizer cross-linked with glutaraldehyde. The cross-linking process occurs via imine bond formation by reaction of NH2 groups of ZnTAPc and chitosan with aldehyde groups of the glutaraldehyde. Insertion of ZnTAPc interestingly increases its solubility in water medium. 2.0% and 4% w/w of the ZnTAPc were used with respect to chitosan polymer to generate hydrogel photosensitizer. FT-IR and UV-Vis spectroscopy, scanning electron microscopy, and rheological measurements were applied to evaluate the properties of the prepared hydrogels. Finally, difloxacin HCl was selected as a fluoroquinolone drug for the assessment of the drug release features of the made hydrogels. The difloxacin release was affected by the amount of ZnTAPc and pH medium. The activity of the hydrogels in photosensitizing process was considered by computing the rate of 1,3-diphenylisobenzofuran adsorption reduction as a singlet oxygen chemical quencher.

Design of photodynamic chitosan hydrogels bearing phthalocyanine-colistin conjugate as an antibacterial agent.

The fabrication of a new antibacterial system is an essential medical requirement to treat wounds caused by multidrug-resistant Gram-negative bacteria, mostly Pseudomonas aeruginosa. Antibacterial photodynamic therapy (APDT) is an encouraging therapy modality for bacterial infection. Anyhow, the applications of most photosensitizers are restricted by their poor water solubility and their inefficiency in disruption of the outer membrane of Gram-negative bacteria. In this context, zinc phthalocyanine-colistin (ZnPc-Col) conjugate as a new photosensitizer was synthesized in the hope of improving interaction of phthalocyanine with the surface of Gram-negative bacteria. Overcoming the low solubility of phthalocyanine, was achieved by the incorporation of ZnPc-Col into chitosan hydrogel. The weight percentages of ZnPc-Col and glutaraldehyde had remarkable effects in determining the hydrogel microstructure. Different spectroscopic methods, SEM, and rheological measurements were used to assess the properties of ZnPc-Col and prepared hydrogels. The photosensitizing activity of the hydrogels was investigated by application of 1,3-diphenylisobenzofuran as a singlet oxygen chemical quencher. Hydrogels bearing zinc phthalocyanine-colistin adduct revealed an improved APDT efficiency compared to hydrogels containing just zinc phthalocyanine component. This enhancement has been seen against P. aeruginosa.

Chitosan hydrogels cross-linked with tris(2-(2-formylphenoxy)ethyl)amine: Swelling and drug delivery.

Tris(2-(2-formylphenoxy)ethyl)amine was designed and synthesized by reaction of salicylaldehyde with tris(2-chloroethyl)amine hydrochloride and evaluated as a new multi-functional cross-linker for preparation of new pH- and thermo-responsive chitosan hydrogels through formation of covalent Schiff-base linkage. The structure and properties of the hydrogels were characterized by FT-IR, 1H NMR and scanning electron microscopy (SEM). The swelling behavior of prepared hydrogels at different pHs and temperatures was investigated. Also, in vitro controlled release behavior of the metronidazole model drug was studied with prepared hydrogels. The release profiles of metronidazole from the hydrogels were determined by UV-Vis absorption measurement. The results showed that the new hydrogels exhibit a pH and temperature-responsive swelling ratio. Also, the pH and temperature were found to strongly influence the drug release behavior of these swollen polymers. Due to the concurrent rapid and significant stimuli-response, these smart hydrogels prepared from chitosan as a natural polymer may expand the scope of hydrogel applications in various fields of research such as targeted (cellular or tissue) delivery of drugs. In addition, these new hydrogels can be used to improve bioavailability, sustain release of drugs or solubilize drugs for systemic delivery.

Synthesis and Characterization of Temperature-Sensitive and Chemically Cross-Linked Poly( N-isopropylacrylamide)/Photosensitizer Hydrogels for Applications in Photodynamic Therapy.

A novel poly( N-isopropylacrylamide) (PNIPAM) hydrogel containing different photosensitizers (protoporphyrin IX (PpIX), pheophorbide a (Pba), and protoporphyrin IX dimethyl ester (PpIX-DME)) has been synthesized with a significant improvement in water solubility and potential for PDT applications compared to the individual photosensitizers (PSs). Conjugation of PpIX, Pba, and PpIX-DME to the poly( N-isopropylacrylamide) chain was achieved using the dispersion polymerization method. This study describes how the use of nanohydrogel structures to deliver a photosensitizer with low water solubility and high aggregation tendencies in polar solvents overcomes these limitations. FT-IR spectroscopy, UV-vis spectroscopy, 1H NMR, fluorescence spectroscopy, SEM, and DLS analysis were used to characterize the PNIPAM-photosensitizer nanohydrogels. Spectroscopic studies indicate that the PpIX, Pba, and PpIX-DME photosensitizers are covalently conjugated to the polymer chains, which prevents aggregation and thus allows significant singlet oxygen production upon illumination. Likewise, the lower critical solution temperature was raised to ∼44 °C in the new PNIPAM-PS hydrogels. The PNIPAM hydrogels are biocompatible with >90% cell viability even at high concentrations of the photosensitizer in vitro. Furthermore, a very sharp onset of light-dependent toxicity for the PpIX-based nanohydrogel in the nanomolar range and a more modest, but significant, photocytotoxic response for Pba-PNIPAM and PpIX-DME-PNIPAM nanohydrogels suggest that the new hydrogels have potential for applications in photodynamic therapy.

Cell-specific and pH-sensitive nanostructure hydrogel based on chitosan as a photosensitizer carrier for selective photodynamic therapy.

The major problems of porphyrins as promising materials for photodynamic therapy (PDT) are their low solubility, subsequently aggregation in biological environments, and a lack of tumor selectivity. With this in mind, a chitosan-based hydrogel conjugated with tetrakis(4-aminophenyl)porphyrin (NH2-TPP) and 2,4,6-tris(p-formylphenoxy)-1,3,5-triazine (TRIPOD) via Schiff base linkage, functionalized with folate was designed and synthesized as a pH-sensitive, self-healable and injectable targeted PS delivery system. This new hydrogel was characterized by FT-IR, 1H NMR, SEM, UV-vis, fluorescence spectroscopy and zeta potential. Formation of imine bonds with the aldehyde group of TRIPOD and amine group of NH2-TPP and chitosan, as a dynamic connection, was approved by rheological analysis. Spectroscopic characterizations revealed that aggregation of porphyrin in aqueous media was eliminated due to diminished π stacking interaction of porphyrin in 3D cross-linked hydrogel structure. Hydrogel 3D microporous structure efficiently transfers the excitation energy to the porphyrin unit, yielding improvement singlet oxygen releases. Cytotoxicity and phototoxicity analysis of the CS/NH2-TPP/FA hydrogels indicating an excellent capability to kill cancer cells selectively and prevent damage to normal cells. This work presents a new and efficient model for the preparation of highly efficient and targeting photosensitizer delivery system.

1,3,5-Triazine-2,4,6-tribenzaldehyde derivative as a new crosslinking agent for synthesis of pH-thermo dual responsive chitosan hydrogels and their nanocomposites: Swelling properties and drug release behavior.

In this work, 1,3,5-triazine-2,4,6-tribenzaldehyde was synthesized and chosen as the cross-linking agent for preparation of novel thermo- and pH-responsive hydrogels based on chitosan. The cross-linking proceeds through formation of imine bond by reaction of amino groups of chitosan with aldehyde groups of the cross-linker. The various amounts (6, 10, 14% w/w) of the cross-linker were used with respect to chitosan to produce three 1,3,5-triazine-2,4,6-tribenzaldehyde cross-linked chitosans. Then, their hydrogel nanocomposites were prepared by crosslinking of chitosan with 1,3,5-triazine-2,4,6-tribenzaldehyde in the presence of 0.1% and 0.3% (w/w) multi-walled carbon nanotubes (MWCNTs). The structure and properties of the hydrogels and their nanocomposites were characterized by FT-IR, 1H NMR and scanning electron microscopy (SEM). The swelling behavior of prepared hydrogels and their nanocomposites at different pHs and temperatures was investigated. The results showed that they exhibit a pH and temperature-responsive swelling ratio. The swelling behavior of the prepared chitosan hydrogels was strongly dependent on the amounts of cross-linker and MWCNTs. In vitro controlled release behavior of metronidazole model drug was studied with prepared hydrogels and nanocomposite hydrogels. The pH, temperature and wt% of MWCNTs were found to strongly influence the drug release behavior of the hydrogels.

Mechanically Robust 3D Nanostructure Chitosan-Based Hydrogels with Autonomic Self-Healing Properties.

Fabrication of hydrogels based on chitosan (CS) with superb self-healing behavior and high mechanical and electrical properties has become a challenging and fascinating topic. Most of the conventional hydrogels lack these properties at the same time. Our objectives in this research were to synthesize, characterize, and evaluate the general properties of chitosan covalently cross-linked with zinc phthalocyanine tetra-aldehyde (ZnPcTa) framework. Our hope was to access an unprecedented self-healable three-dimensional (3D) nanostructure that would harvest the superior mechanical and electrical properties associated with chitosan. The properties of cross-linker such as the structure, steric effect, and rigidity of the molecule played important roles in determining the microstructure and properties of the resulting hydrogels. The tetra-functionalized phthalocyanines favor a dynamic Schiff-base linkage with chitosan to form a 3D porous nanostructure. Based on this strategy, the self-healing ability, as demonstrated by rheological recovery and macroscopic and microscopic observations, is introduced through dynamic covalent Schiff-base linkage between NH2 groups in CS and benzaldehyde groups at cross-linker ends. The hydrogel was characterized using FT-IR, NMR, UV/vis, and rheological measurements. In addition, cryogenic scanning electron microscopy (cryo-SEM) was employed as a technique to visualize the internal morphology of the hydrogels. Study of the surface morphology of the hydrogel showed a 3D porous nanostructure with uniform morphology. Furthermore, incorporating the conductive nanofillers, such as carbon nanotubes (CNTs), into the structure can modulate the mechanical and electrical properties of the obtained hydrogels. Interestingly, these hydrogel nanocomposites proved to have very good film-forming properties, high modulus and strength, acceptable electrical conductivity, and excellent self-healing properties at neutral pH. Such properties can be finely tuned through variation of the cross-linker and CNT concentration, and as a result these structures are promising candidates for potential applications in various fields of research.

The prevalence and clinical features of amphetamine-induced obsessive compulsive disorder.

BACKGROUND: Amphetamine abuse is increasing worldwide, and the occurrence of amphetamine-induced (AI) psychiatric issues further complicates treatment. In response, the DSM 5 has introduced the classification of amphetamine-induced obsessive-compulsive disorders (AI-OCD), though little has been published on either its prevalence rates or its clinical features. The aim of the present study was therefore to investigate the prevalence of AI-OCD, to describe patients' clinical features, and to compare the prevalence rate among such patients with those for OCD in the general population in Western countries and Iran. METHODS: A total of 547 patients with amphetamine abuse or dependency and with a positive urine test (mean age: 31.64 years; 75.5% males) took part in the study. A psychiatric interview was carried out, covering both socio-demographic and illness-related information. RESULTS: 18 (3.3%) patients suffered from OCD prior to amphetamine abuse, 491 (89.8%) had no OCD, and 38 (6.9%) suffered from AI-OCD. Neither socio-demographic nor illness-related dimensions predicted patients with diagnosed AI-OCD. The prevalence of AI-OCD was significantly higher than that for OCD in the general population (2.3% in Western countries, 1.8% in Iran). CONCLUSIONS: Data suggest that prevalence rate of AI-OCD is about 7%. Neither socio-demographic nor illness-related dimensions predicted the occurrence of AI-OCD. Thus, it remains unclear why some amphetamine abusers develop AI-OCD while others do not.

Wells-Dawson heteropolyacid supported on silica: a highly efficient catalyst for synthesis of 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted imidazoles.

Heteropolyacid H(6)P(2)W(18)O(62)·24H(2)O (WD) supported on silica (WD/SiO(2)) has been used as an effective catalytic system for the synthesis of various 1,2,4,5-tetrasubstituted imidazoles by four-component condensation of benzil, aldehydes, amines and ammonium acetate under solvent-free conditions. This approach can be useful for three-component synthesis of 2,4,5-trisubstituted imidazoles. The same reactions were repeated by using benzoin instead of benzil.

Pseudo five-component synthesis of bis-alpha-acyloxy-beta-diketo amides from diimide-dicarboxylic acids.

Diimide-dicaboxylic acids derived from condensation of alpha-amino acids with the 2,3,5,6-bicyclo[2.2.2] oct-2-enetetracarboxylic-2,3:5,6-dianhydride or 1,2,4,5- bezenetetracarboxylic-1,2:4,5-dianhydride react with ninhydrin and isocyanides to produce some novel interesting bis-alpha-acyloxy-beta-diketo amides.

A novel one-pot synthesis of some new interesting pyrrole derivatives.

[reaction: see text] 11-(1H-Pyrrol-1-yl)-11H-indeno[1,2-b]quinoxaline and 3-(1H-pyrrol-1-yl)indolin-2-one derivatives have been synthesized in good yields in a novel, one-pot, and efficient process by condensation of 11H-indeno[1,2-b]quinoxalin-11-one or isatin derivatives with 4-hydroxyproline on solid-support montmorillonite K10 under microwave irradiation.