In-situ forming Cu-based metal-organic framework in the presence of chitosan-Fe3O4 nanohybrids: A pH-sensitive carrier for controlled release of doxorubicin.

In recent years, stimuli-responsive drug delivery systems based on pH, particularly those developed using bio-derived nanocomposite systems, have gained significant attention. In this work, a novel magnetic carrier was designed based on biopolymeric chitosan and metal-organic framework (MOF) for pH-controlling the release of anticancer drugs. To end this, an in-situ green method was performed to form Cu-based MOF in the presence of a magnetic polysaccharide synthesized by precipitation method toward the construction of CS/Fe3O4/Cu-MOF nanocomposite. The nanocomposite was immersed in an aqueous solution of a model anticancer drug, doxorubicin (DOX), and a higher loading capacity (90.1 ±â€¯0.5 %) was achieved. The in-vitro drug release study showed low release rates in simulated physiological environments (pH 7.4, 37 °C, lower than about 20 %), but higher release rates in tumor tissue conditions (pH 4.5, 41 °C, higher than about 60 %) over 96 h, allowing for sustained and extended delivery of DOX. Additionally, the MTT assay demonstrated that the blank and DOX-loaded CS/Fe3O4/Cu-MOF had good cytocompatibility (over 80 % cell viability) and considerable cytotoxicity (lower than 40 % at 16 µg/mL) toward breast cancer (MCF-7) cell line, respectively. These results indicated that the synthesized nanocomposite with suitable pH-sensitivity has potential as a targeted anticancer agent.

Ultrasound-assisted synthesis of MIL-88(Fe) conjugated starch-Fe3O4 nanocomposite: A safe antibacterial carrier for controlled release of tetracycline.

A constructing antibiotic carrier with a sustained release profile is a promising method to stop long-term bacterial infection, which is of ideal interest in different biomedical fields. To end this, the present study aims to design a novel carrier based on the modification of biopolymeric starch for the rising possible interaction between carrier and antibiotic agent. We established an in-situ ultrasound-assisted method was applied to grow and create MIL-88(Fe) framework in the structure of magnetic polysaccharide (i.e., St/Fe3O4) synthesized by precipitation method resulting in St/Fe3O4/MIL-88(Fe) nanocomposite. It was loaded with a high amount of Tetracycline (TC) through its immersion into the TC aqueous solution. The release profile of TC-loaded St/Fe3O4/MIL-88(Fe) displays a lower initial burst release (about 26 % after 12 h) and followed by a controlled and sustained release (about 73 % up to 168 h) in the simulated physiological environment at pH 7.4. The in vitro cytotoxicity showed good cytocompatibility against Human skin fibroblast (HFF-1) cells. TC-loaded St/Fe3O4/MIL-88(Fe) showed higher antibacterial activity against both S. aureus and E. coli with the MIC value of 64 and 128 µg·mL-1, respectively.

A bio-inspired magnetic natural hydrogel containing gelatin and alginate as a drug delivery system for cancer chemotherapy.

This study aimed to design and development of a magnetic natural hydrogel based on alginate (Alg), gelatin (Gel), and Fe3O4 magnetic nanoparticles (MNPs) as an efficient and "smart" drug delivery system (DDS) for cancer therapy. First, Alg was partially oxidized (OAlg), and then the Alg-Gel chemical hydrogel was synthesized through "Shift-Base" condensation reaction. Afterward, Fe3O4 NPs were incorporated into the hydrogel through in situ chemical co-precipitation approach. The scanning electron microscopy (SEM) image exhibited that the fabricated Alg-Gel hydrogel has porous microstructure without microphase separation. Transmission electron microscopy (TEM) revealed the well-defined formation of Fe3O4 NPs throughout the Alg-Gel hydrogel with spherical shapes in the size range of 25 ± 10 nm. Saturation magnetization (δs) value of the Alg-Gel/Fe3O4 was obtained to be 31 emu g-1 that represent proper magnetic property for "smart" drug delivery purposes. The obtained Alg-Gel/Fe3O4 was loaded with doxorubicin hydrochloride (Dox), and its drug loading and encapsulation efficiencies as well as its anticancer activity was investigated against Hela cells. The formulated Alg-Gel/Fe3O4-Dox exhibited pH-dependent drug release behavior due to presence of carboxylic acid groups in the DDS. According to the results, the Alg-Gel/Fe3O4 magnetic hydrogel can be considered as an efficient and "smart" DDS for cancer therapy and diagnosis.

A novel bio-inspired conductive, biocompatible, and adhesive terpolymer based on polyaniline, polydopamine, and polylactide as scaffolding biomaterial for tissue engineering application.

A novel electrically conductive nanofibrous scaffold based on polyaniline-co-(polydopamine-grafted-poly(d,l-lactide)) [PANI-co-(PDA-g-PLA)] was fabricated using electrospinning technique and its physicochemical as well as biological characteristics toward bone tissue engineering (TE) were investigated extensively. In detail, PANI-co-PDA was synthesized via a one-step chemical oxidization approach. Then, d,l-lactaide monomer was grafted onto PDA segment using a ring opening polymerization (ROP) to afford PANI-co-(PDA-g-PLA) terpolymer. The successful synthesis of PANI-co-(PDA-g-PLA) terpolymer was confirmed using FTIR spectroscopy as well as TGA analysis. Finally, a solution of the synthesized terpolymer was electrospun to fabricate a conductive nanofibrous scaffold. Some physicochemical features such as mechanical, conductivity, electroactivity, hydrophobicity, and morphology as well as biological characteristics including biocompatibility, biodegradability, as well as enhancing the cells adhesion and proliferation were investigated. According to the above-mentioned experimental results, the fabricated electrospun nanofibers can be considered as a potential scaffold for TE application, mainly due to its proper physicochemical and biological properties.

Scaffolding polymeric biomaterials: Are naturally occurring biological macromolecules more appropriate for tissue engineering?

Nowadays, tissue and organ failures resulted from injury, aging accounts, diseases or other type of damages is one of the most important health problems with an increasing incidence worldwide. Current treatments have limitations including, low graft efficiency, shortage of donor organs, as well as immunological problems. In this context, tissue engineering (TE) was introduced as a novel and versatile approach for restoring tissue/organ function using living cells, scaffold and bioactive (macro-)molecules. Among these, scaffold as a three-dimensional (3D) support material, provide physical and chemical cues for seeding cells and has an essential role in cell missions. Among the wide verity of scaffolding materials, natural or synthetic biopolymers are the most commonly biomaterials mainly due to their unique physicochemical and biological features. In this context, naturally occurring biological macromolecules are particular of interest owing to their low immunogenicity, excellent biocompatibility and cytocompatibility, as well as antigenicity that qualified them as popular choices for scaffolding applications. In this review, we highlighted the potentials of natural and synthetic polymers as scaffolding materials. The properties, advantages, and disadvantages of both polymer types as well as the current status, challenges, and recent progresses regarding the application of them as scaffolding biomaterials are also discussed.

Chemotherapy of Breast Cancer Cells Using Novel pH-Responsive Cellulose-Based Nanocomposites.

Purpose: The objective of the current study was to compare the anticancer efficacy of doxorubicin-loaded cellulose based magnetic (Fe3O4), zinc oxide (ZnO) nanoparticles on and free doxorubicin (DOX) on MCF-7 breast cancer cells. Methods: Novel pH-sensitive cellulose-graft poly acrylic acid based Fe3O4 (Cellulose-g-PAAg- PAcMNPs) and ZnO (Cellulose-g-PAA-g-PAcZnO) nanocomposites were synthesized via polymerization of acrylic acid and modified 3-(trimethoxysilyl) propyl methacrylate onto the cellulosic backbone via reversible addition-fragmentation chain transfer (RAFT) method. Results : Cellulose-g-PAA-g-PAcMNPs and Cellulose-g-PAA-g-PAcZnO nanocarriers with mean diameter of 15 and 38 nm were prepared successfully. DOX was loaded effectively to the ZnO and Fe3O4 nanocarriers via complexing and electrostatic force with great encapsulation efficiency of 99.07% and 98.92%, respectively. DOX-loaded nanocarriers showed obvious pHdependent tumor specific drug release pattern. MTT assay results indicated that IC50 of the DOX loaded Cellulose-g-PAA-g-PAcZnO, DOX loaded Cellulose-g-PAA-g-PAcMNPs and free DOX after 48 hours treatment with MCF7 cell lines were about 24.03, 49.27 and 99.76 µg mL-1, respectively. Therefore both DOX nanoformulations significantly increase antitumor ability compared to free DOX (P < 0.05). The results of MTT assay and DAPI staining revealed that DOX-loaded Cellulose-g-PAA-g-PAcZnO NPs show higher chemotherapy efficiency in MCF7 breast cancer cell line compare to the DOX-loaded Cellulose-g-PAA-g-PAcMNPs due to high interaction of ZnO with DOX. Conclusion: The formation of the complexes between the DOX and ZnO nanoparticles at the chelating sites of the quinone and the phenolic oxygen molecules of DOX, lead to more sustained drug release and enhanced chemotherapy effectiveness by increasing the intracellular concentration of DOX.

A novel gold nanorods-based pH-sensitive thiol-ended triblock copolymer for chemo-photothermo therapy of cancer cells.

Currently an effective strategy in nanomedicine for cancer therapy is the combination of photothermal therapy with chemotherapy. Because combination cancer therapy improve the therapy efficiency by synergistic effects and overcoming drug resistance as compared to monotherapy possesses. According to these facts, gold nanorods-cored biodegradable micelles were prepared by coating gold nanorods (AuNRs) with synthesized pH-sensitive thiol-ended amphiphilic triblock copolymer (PAA-b-PDMAEMAQ-b-PCL-SH). The synthesized AuNRs@polymer was loaded with methotrexate (MTX) as an anticancer drug through electrostatic interactions to afford AuNRs@polymer-MTX. The success of the coating was investigated by means of atomic force microscopy (AFM), thermogravimetric analysis (TGA), transmission electron microscopy (TEM), Fourier transform infrared (FTIR) spectroscopy, ultraviolet-visible (UV-vis) spectroscopy, as well as dynamic light scattering (DLS), and zeta potential measurements. MTX-loading capacity, and pH triggered in vitro drug release behavior of the synthesized nanocomposites were also investigated. In vitro cytotoxic effects was comprehensively evaluated among free MTX, AuNRs@polymer, and AuNRs@polymer-MTX, with or without NIR light irradiation (1064 nm, 125 mJ/pulse, and 4 min) to improve curative effect of AuNRs@polymer-MTX led by the combination of photothermal therapy and chemotherapy.

A novel gold-based stimuli-responsive theranostic nanomedicine for chemo-photothermal therapy of solid tumors.

The chemo-photothermal therapy performance of a novel theranostic nanoparticles that fabricated through the conjugation of HS-poly(ε-caprolactone)-block-poly(N-isopropylacrylamide)-block-poly(acrylic acid) (HS-PCL-b-PNIPAAm-b-PAA) and gold nanoparticles (GNPs) was extensively investigated. The GNPs@polymer conjugate theranostic NPs was loaded with doxorubicin hydrochloride (DOX) as an anticancer drug through electrostatic interactions to afford GNPs@polymer-DOX theranostic nanomedicine. Temperature and pH-triggered in vitro drug release behavior of the developed theranostic nanomedicine were also examined. The biocompatibility of the synthesized GNPs@polymer theranostic NPs was confirmed through the assessing survival rate of breast cancer cell line (MCF7) using MTT assay. In vitro cytotoxic effects of the GNPs@polymer-DOX theranostic nanomedicine was also evaluated against MCF7 cells in both with or without laser irradiation (532 nm, 145 mJ per pulse, 5 min) conditions, and the results obtained were compared with free DOX as the reference. As the results, the developed GNPs@polymer-DOX can be considered as theranostic nanomedicine for chemo-photothermal therapy of solid tumors.

Chitosan-grafted-poly(methacrylic acid)/graphene oxide nanocomposite as a pH-responsive de novo cancer chemotherapy nanosystem.

The aim of this study was the design and development of a novel de novo drug delivery system for cancer chemotherapy. For this purpose, chitosan (CS) functionalized using phthalic anhydride followed by 4-cyano, 4-[(phenylcarbothioyl) sulfanyl] pentanoic acid as a chain transfer agent (CTA) to afford CS-CTA macroinitiator. The synthesized CS-CTA macroinitiator was then copolymerized with methacrylic acid (MAA) monomer using reversible addition-fragmentation chain transfer (RAFT) polymerization technique to produce chitosan-graft-poly(methacrylic acid) (CS-g-PMAA) graft copolymer. Afterward, graphene oxide (GO) nanosheets were incorporated into the synthesized copolymer through the physical interactions. The CS-g-PMAA/GO nanocomposite was loaded with doxorubicin hydrochloride (DOX) as a universal anticancer drug. The biocompatibility, DOX-loading capacity, and pH dependent drug release behavior of the developed nanocomposite were also investigated. As the experimental results, as well as superior biological and physicochemical features of CS and GO, we envision that the developed CS-g-PMAA/GO nanocomposite may be applied as de novo drug delivery nanosystem for cancer chemotherapy.

PEGylated graphene oxide/Fe3O4 nanocomposite: Synthesis, characterization, and evaluation of its performance as de novo drug delivery nanosystem.

This paper describes the development of mitoxantrone-loaded PEGylated graphene oxide/magnetite nanoparticles (PEG-GO/Fe3O4-MTX), and investigation of its preliminary drug delivery performance. For this, the GO was synthesized through oxidizing graphite powder, and subsequently carboxylated using a substitution nucleophilic reaction. The carboxylated GO (GO-COOH) was then conjugated with amine end-caped PEG chains by Steglich esterification. Afterward, GO-PEG/Fe3O4 nanocomposite was synthesized through the anchoring of Fe3O4 nanoparticles onto the surface of GO-PEG during the sonication. The biocompatibility and MTX-loading capacity of the synthesized GO-PEG/Fe3O4 nanocomposite were evaluated. The pH dependent drug release behavior and cytotoxicity effect of the MTX-loaded GO-PEG/Fe3O4 nanocomposite were also studied. According to biocompatibility, pH dependent drug release behavior as well as superior physicochemical and biological characteristics of graphene and magnetite nanoparticles, it is expected that the GO-PEG/Fe3O4 nanocomposite may be applied as de novo drug delivery system (DDS) for cancer therapy using both chemo- and photothermal therapy approaches.

Development and characterization dual responsive magnetic nanocomposites for targeted drug delivery systems.

A drug delivery system based on dual responsive units was developed. An appealing pH- and thermo-responsive triblock terpolymer as the drug carrier was synthesized by RAFT polymerization of N-isopropyl acrylamide and methacrylic acid monomers using PEG-RAFT agent. The Fe3O4 magnetic nanoparticles were synthesized by co-precipitation of Fe salts. Synthesized samples were characterized by FT-IR, XRD, GPC, SEM and TEM. The dual responsive behaviour and self-assembly of the triblock terpolymers in aqueous solution were investigated using UV-vis transmittance and DLS. Based on the results of DLS and TEM, the average size of micelles was 170, 125 and 30 nm. The triblock terpolymer was used as a chemotherapy drug carrier and doxorubicin as a model drug. The release rate of the drug at two different temperatures (37 °C and 42 °C) and pHs (5.8 and 7.4) was studied. The in vitro cytotoxicity assay of free doxorubicin and drug-loaded magnetic nanoparticles was studied. The MTT assay exhibited that these polymers are biocompatible and no toxicity. As well, IC50 of the DOX-loaded triblock terpolymer in MTT test demonstrated that these systems could be suitable for the treatment of cancer.

Synthesis of sharply thermo and PH responsive PMA-b-PNIPAM-b-PEG-b-PNIPAM-b-PMA by RAFT radical polymerization and its schizophrenic micellization in aqueous solutions.

Sharply thermo- and pH-responsive pentablock terpolymer with a core-shell-corona structure was prepared by RAFT polymerization of N-isopropylacrylamide and methacrylic acid monomers using PEG-based benzoate-type of RAFT agent. The PEG-based RAFT agent could be easily synthesized by dihydroxyl-capped PEG with 4-cyano-4-(thiobenzoyl) sulfanylpentanoic acids, using esterification reaction. This pentablock terpolymer was characterized by 1H NMR, FT-IR, and GPC. The PDI was obtained by GPC, indicating that the molecular weight distribution was narrow and the polymerization was well controlled. The thermo- and pH-responsive micellization of the pentablock terpolymer in aqueous solution was investigated using fluorescence spectroscopy technique, UV-vis transmittance, and TEM. The LCST of pentablock terpolymer increased (over 50 °C) compared to the NIPAM homopolymer (~32 °C), due to the incorporation of the hydrophilic PEG and PMA blocks in pentablock terpolymer (PNIPAM block as the core, PEG the block and the hydrophilic PMA block as the shell and the corona). Also, pH-dependent phase transition behavior shows at a pH value of about ~5.8, according to pKa of MAA. Thus, in acidic solution at room temperature, the pentablock terpolymer self-assembled to form core-shell-corona micelles, with the hydrophobic PMA block as the core, the PNIPAM block and the hydrophilic PEG block as the shell and the corona, respectively.

Grafting of aniline derivatives onto chitosan and their applications for removal of reactive dyes from industrial effluents.

A series of chitosan-grafted polyaniline derivatives {chitosan-g-polyaniline (CS-g-PANI), chitosan-g-poly(N-methylaniline) (CS-g-PNMANI), and chitosan-g-poly(N-ethylaniline) (CS-g-PNEANI)} were synthesized by in situ chemical oxidation polymerization method. The synthesized copolymers were analyzed by means of Fourier transform infrared (FTIR), and ultraviolet-visible (UV-vis) spectroscopies, thermogravimetric analysis (TGA), and field emission scanning electron microscopy (FE-SEM). These copolymers were applied as adsorbent for removal of acid red 4 (AR4) and direct red 23 (DR23) from aqueous solutions. The adsorption processes were optimized in terms of pH, adsorbent amount, and dyes concentrations. The maximum adsorption capacities (Qm) for the synthesized copolymers were calculated, and among them the CS-g-PNEANI sample showed highest Qm for both AR4 (98mgg-1) and DR23 (112mgg-1) dyes. The adsorption kinetics of AR4 and DR23 dyes follow the pseudo-second order kinetic model. The regeneration and reusability tests revealed that the synthesized adsorbents had the relatively good reusability after five repetitions of the adsorption-desorption cycles. As the results, it is expected that the CS-g-PANIs find application for removal of reactive dyes (especially anionic dyes) from industrial effluents mainly due to their low production costs and high adsorption effectiveness.

A Three-Component Reaction for the Synthesis of 1-Azabicyclo[3.1.0]hexane-3-enes.

A novel and simple synthesis of 1-azabicyclo[3.1.0]hexane-3-ene derivatives is described. The synthesis is carried out via a simple three-component reaction between aryl aldehydes, malononitrile, and hydroxylamine hydrochloride in water. Eco-friendliness, excellent product yields, short reaction time, inexpensive and readily available starting materials, and interesting reaction and products are the main advantages of this method.

Grafting of poly[(methyl methacrylate)-block-styrene] onto cellulose via nitroxide-mediated polymerization, and its polymer/clay nanocomposite.

For the first time, nitroxide-mediated polymerization (NMP) was used for synthesis of graft and block copolymers using cellulose (Cell) as a backbone, and polystyrene (PSt) and poly(methyl metacrylate) (PMMA) as the branches. For this purpose, Cell was acetylated by 2-bromoisobutyryl bromide (BrBiB), and then the bromine group was converted to 4-oxy-2,2,6,6-tetramethylpiperidin-1-oxyl group by a substitution nucleophilic reaction to afford a macroinitiator (Cell-TEMPOL). The macroinitiator obtained was subsequently used in controlled graft and block copolymerizations of St and MMA monomers to yield Cell-g-PSt and Cell-g-(PMMA-b-PSt). The chemical structures of all samples as representatives were characterized by FTIR and (1)H NMR spectroscopies. In addition, Cell-g-(PMMA-b-PSt)/organophilic montmorillonite nanocomposite was prepared through a solution intercalation method. TEM was used to evaluate the morphological behavior of the polymer-clay system. It was demonstrated that the addition of small percent of organophilic montmorillonite (O-MMT; 3wt.%) was enough to improve the thermal stability of the nanocomposite.

Physicochemical characteristics of Fe3O4 magnetic nanocomposites based on Poly(N-isopropylacrylamide) for anti-cancer drug delivery.

BACKGROUND: Hydrogels are a class of polymers that can absorb water or biological fluids and swell to several times their dry volume, dependent on changes in the external environment. In recent years, hydrogels and hydrogel nanocomposites have found a variety of biomedical applications, including drug delivery and cancer treatment. The incorporation of nanoparticulates into a hydrogel matrix can result in unique material characteristics such as enhanced mechanical properties, swelling response, and capability of remote controlled actuation. MATERIALS AND METHODS: In this work, synthesis of hydrogel nanocomposites containing magnetic nanoparticles are studied. At first, magnetic nanoparticles (Fe3O4) with an average size 10 nm were prepared. At second approach, thermo and pH-sensitive poly (N-isopropylacrylamide -co-methacrylic acid-co-vinyl pyrrolidone) (NIPAAm-MAA- VP) were prepared. Swelling behavior of co-polymer was studied in buffer solutions with different pH values (pH=5.8, pH=7.4) at 37 °C. Magnetic iron oxide nanoparticles (Fe3O4) and doxorubicin were incorporated into copolymer and drug loading was studied. The release of drug, carried out at different pH and temperatures. Finally, chemical composition, magnetic properties and morphology of doxorubicin-loaded magnetic hydrogel nanocomposites were analyzed by FT- IR, vibrating sample magnetometry (VSM), scanning electron microscopy (SEM). RESULTS: The results indicated that drug loading efficiency was increased by increasing the drug ratio to polymer. Doxorubicin was released more at 40 °C and in acidic pH compared to that 37 °C and basic pH. CONCLUSIONS: This study suggested that the poly (NIPAAm-MAA-VP) magnetic hydrogel nanocomposite could be an effective carrier for targeting drug delivery systems of anti-cancer drugs due to its temperature sensitive properties.