Intelligent anticancer drug delivery performances of two poly(N-isopropylacrylamide)-based magnetite nanohydrogels.

This article evaluates the anticancer drug delivery performances of two nanohydrogels composed of poly(N-isopropylacrylamide-co-itaconic anhydride) [P(NIPAAm-co-IA)], poly(ethylene glycol) (PEG), and Fe3O4 nanoparticles. For this purpose, the magnetite nanohydrogels (MNHGs) were loaded with doxorubicin hydrochloride (DOX) as a universal anticancer drug. The morphologies and magnetic properties of the DOX-loaded MNHGs were investigated using transmission electron microscopy (TEM) and vibrating-sample magnetometer (VSM), respectively. The sizes and zeta potentials (ξ) of the MNHGs and their corresponding DOX-loaded nanosystems were also investigated. The DOX-loaded MNHGs showed the highest drug release values at condition of 41 °C and pH 5.3. The drug-loaded MNHGs at physiological condition (pH 7.4 and 37 °C) exhibited negligible drug release values. In vitro cytotoxic effects of the DOX-loaded MNHGs were extensively evaluated through the assessing survival rate of HeLa cells using the MTT assay, and there in vitro cellular uptake into the mentioned cell line were examined using fluorescent microscopy and fluorescence-activated cell sorting (FACS) flow cytometry analyses. As the results, the DOX-loaded MNHG1 exhibited higher anticancer drug delivery performance in the terms of cytotoxic effect and in vitro cellular uptake. Thus, the developed MNHG1 can be considered as a promising de novo drug delivery system, in part due to its pH and thermal responsive drug release behavior as well as proper magnetite character toward targeted drug delivery.

Extracellular matrix-mimetic electrically conductive nanofibrous scaffolds based on polyaniline-grafted tragacanth gum and poly(vinyl alcohol) for skin tissue engineering application.

As pivotal role of scaffold in tissue engineering (TE), the aim of present study was to design and development of extracellular matrix (ECM)-mimetic electrically conductive nanofibrous scaffolds composed of polyaniline-grafted tragacanth gum (TG-g-PANI) and poly(vinyl alcohol) (PVA) with different PANI content for skin tissue engineering (STE) application. The fabricated scaffolds were preliminary evaluated in terms of some physicochemical and biological properties. Cytocompatibility and cells proliferation properties of the scaffolds were examined with the well-known MTT assay, and it was found that the developed scaffolds have proper cytocompatibilities and can enhances the mouse fibroblast L929 cells adhesion as well as proliferation, which confirm their potential for STE applications. Hemocompatibility assay revealed that the hemolysis rate of the fabricated scaffolds were <2 % even at a relatively high concentration (200 µgmL-1) of samples, therefore, these scaffolds can be considered as safe. Human serum albumin (HSA) protein adsorption capacities of the fabricated scaffolds were quantified as 42 and 49 µgmg-1 that represent suitable values for a successful TE. Overall, the fabricated scaffold with 20 wt% of TG-g-PANI showed higher potential in both physicochemical and biological features than scaffold with 30 wt% of mentioned copolymer for STE application.

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.

Electrically conductive nanofibrous scaffold composed of poly(ethylene glycol)-modified polypyrrole and poly(ε-caprolactone) for tissue engineering applications.

The aim of this study was to developing two novel nanofibrous scaffolds composed of poly(ethylene glycol)-modified polypyrrole [PEG-b-(PPy)4] and poly(ε-caprolactone) (PCL) for tissue engineering (TE) applications. For this purpose, pyrrole-functionalized PEGs AB4 macromonomers (PyPEGsM) were synthesized through the Steglich esterification of PEGs ends-caped tetraol [PEGs(OH)4] using pyrrole-2-carboxylic acid. These macromonomers were subsequently copolymerized with pyrrole monomer using chemical oxidation polymerization approach to produce PEGs-b-(PPy)4 copolymers. A solution of PCL and the synthesized PEGs-b-(PPy)4 copolymers were electrospun to fabricate uniform, conductive, and biocompatible nanofibrous scaffolds. The performances of the fabricated nanofibers as TE scaffolds were examined in terms of biological (biocompatibility and biodegradability) as well as physicochemical (electroactivity, conductivity, mechanical properties, and morphology) features. As the results, the fabricated electrospun nanofibers were found as proper scaffolds for use in TE applications that require electroactivity.

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.

A starch-based stimuli-responsive magnetite nanohydrogel as de novo drug delivery system.

A novel starch-based stimuli-responsive magnetite nanohydrogel (MNHG), namely Fe3O4-g-[poly(N-isopropylacrylamide-co-maleic anhydride)]@strach; Fe3O4-g-(PNIPAAm-co-PMA)@starch, was successfully developed for targeted delivery of doxorubicin (DOX) as an anticancer drug. First, magnetite nanoparticles (MNPs) was modified using chloroacetyl chloride moiety followed by grafting of NIPAAm and MA monomers through ATRP technique. The resultant Fe3O4-g-(PNIPAAm-co-PMA) nanocomposite was crosslinked through the reaction between the anhydride group of MA and hydroxyl groups of starch to afford a Fe3O4-g-(PNIPAAm-co-PMA)@starch MNHG. The chemical structure of the synthesized materials were confirmed using Fourier transform infrared (FTIR) spectroscopy. Furthermore, morphology, size, thermal property, and magnetic properties of the synthesized MNHG were studied. This MNHG was loaded with DOX, and drug loading and encapsulation efficiencies as well as pH- and temperature-responsive drug release behavior of the fabricated MNHG were also evaluated. As results, we envision that the developed MNHG has potential as de novo drug delivery system (DDS) due to its smart physicochemical features.

pH-controlled sunitinib anticancer release from magnetic chitosan nanoparticles crosslinked with κ-carrageenan.

The main objective of this work was to develop κ-carrageenan-crosslinked magnetic chitosan with different molecular weights as pH-responsive carriers for controlled release of anticancer drug sunitinib. The characterization of magnetic carriers revealed that the size of magnetic nanoparticles is affected by the molecular weight of chitosan. Drug encapsulation efficiency and release performance influenced by the size of magnetic nanoparticles. Encapsulation efficiencies of sunitinib by low, medium and high molecular weights of magnetic chitosan carriers were found to be 62.38, 69.57 and 78.42%, respectively. The in vitro sunitinib release from magnetic chitosan/κ-carrageenan carriers was pH-dependent and followed a Fickian release mechanism. Sunitinib was efficiently released from magnetic carriers into environment under acidic pHs and the release rate was size- and molecular weight-dependent. The pH-dependent release of sunitinib with a minimal release content at pH = 7.4 makes the present magnetic carriers as promising candidate for anticancer drugs with reduced side effects.

A novel starch-based stimuli-responsive nanosystem for theranostic applications.

The aim of this study was to synthesis and characterization of a novel stimuli-responsive polymeric nanosystem for theranostic applications. For this purpose, starch was modified by itaconic anhydride to afford an itaconat-functionalized starch macromonomer (starch-IA). This macromonomer with carboxylic functional groups was subsequently adsorbed onto the surface of iron oxide nanoparticles (Fe3O4 NPs), and then copolymerized with N-isopropylacrylamide (NIPAAm) monomer via a 'free' radical initiated polymerization technique to produce a temperature-responsive magnetic nanohydrogel (MNHG). The chemical structures of all samples as representatives were characterized by means of Fourier transform infrared (FTIR) spectroscopy. The lower critical solution temperature (LCST), thermal responsibility, morphology, elemental composition, thermal stability, and magnetic properties of the synthesized MNHG were investigated. In addition, the methotrexate (MTX)-loading capacity (∼74%) and stimuli-responsive drug release ability of the synthesized MNHG were also evaluated. As results, we envision that the synthesized starch-g-PNIPAAm/Fe3O4 MNHG may be find theranostic applications, in part due to its smart physicochemical properties.

A new style for synthesis of thermo-responsive Fe3O4/poly (methylmethacrylate-b-N-isopropylacrylamide-b-acrylic acid) magnetic composite nanosphere and theranostic applications.

In this work, a novel thermo-responsive Fe3O4/poly(methylmethacrylate-b-N-isopropylacrylamide-b-acrylic acid) magnetic composite nanosphere was synthesized for anticancer drug delivery applications. For this propose, the poly(methylmethacrylate-b-N-isopropylacrylamide-b-acrylic acid) [poly (MMA-b-NIPAAm-b-AAc)] was synthesized via reversible addition-fragmentation transfer method. The physic-chemical characterization of the Fe3O4/poly(MMA-b-NIPAAm-b-AAc) magnetic composite nanosphere was investigated by FTIR, HNMR spectroscopies and GPC, FESEM, XRD, VSM and DLS. The thermo-sensitivity of the Fe3O4/P(MMA-b-NIPAAm-b-AAc) magnetic composite nanosphere was confirmed via DLS at 40 °C. DOX encapsulation efficiency was calculated to be 98.2%. The effect of temperature and pH on release behaviors of stimuli responsive DOX-loaded Fe3O4/P(MMA-b-NIPAAm-b-AAc)] magnetic composite nanosphere were investigated. The release rate at pH 7.4, 5.4 and 4 (T = 37 °C) was reached about 24.4, 42.4 and 57.5 wt%, after 4-5 day. The release rate improved at tumor simulated environment (t:40 °C and pH ≤ 5.4). The cytotoxic effects of the magnetic composite nanosphere were appraised by MTT assay and the results indicated that novel developed smart nanocomposite here was nontoxic to MCF-7 cells and can be applied as anti-cancer drug delivery system. Also, the results of the Cellular uptake of MCF7 cells treated with rhodamine labeled DOX-loaded nanocarrier for 2 h have indicated that DOX can be applied as cytotoxic agent and targeting ligand.

Novel dual stimuli-responsive ABC triblock copolymer: RAFT synthesis, "schizophrenic" micellization, and its performance as an anticancer drug delivery nanosystem.

A novel pH- and thermo-responsive ABC triblock copolymer {poly[(2-succinyloxyethyl methacrylate)-b-(N-isopropylacrylamide)-b-[(N-4-vinylbenzyl),N,N-diethylamine]]} [P(SEMA-b-NIPAAm-b-VEA)] was successfully synthesized via reversible addition of fragmentation chain transfer (RAFT) polymerization technique. The molecular weights of PHEMA, PNIPAAm, and PVEA segments in the synthesized triblock copolymer were calculated to be 10,670, 6140, and 9060gmol-1, respectively, from proton nuclear magnetic resonance (1H NMR) spectroscopy. The "schizophrenic" self-assembly behavior of the synthesized P(SEMA-b-NIPAAm-b-VEA) triblock copolymer under pH and thermal stimulus were investigated by means of 1H NMR and ultraviolet-visible (UV-vis) spectroscopies as well as dynamic light scattering (DLS) and zeta potential (ξ) measurements. The doxorubicin hydrochloride (DOX)-loading capacity, and stimuli-responsive drug release ability of the synthesized triblock copolymer were also investigated. The biocompatibility of the synthesized triblock copolymer was confirmed through the assessing survival rate of breast cancer cell line (MCF7) using MTT assay. In contrast, DOX-loaded triblock copolymer exhibited an efficient anticancer performance in comparison with free DOX verified by MTT and DAPI staining assays. As the results, we envision that the synthesized P(SEMA-b-NIPAAm-b-VEA) triblock copolymer can be applied as an enhanced anticancer drug delivery nanosystem, mainly due to its smart physicochemical and biocompatibility properties.

Composite electrospun nanofibers of reduced graphene oxide grafted with poly(3-dodecylthiophene) and poly(3-thiophene ethanol) and blended with polycaprolactone.

In this paper, an effective method was employed for preparation of nanofibers using conducting polymer-functionalized reduced graphene oxide (rGO). First, graphene oxide (GO) was obtained from graphite by Hommer method. GO was reduced to rGO by NaBH4 and covalently functionalized with a 3-thiophene acetic acid (TAA) by an esterification reaction to reach 3-thiophene acetic acid-functionalized reduced graphene oxide macromonomer (rGO-f-TAAM). Afterward, rGO-f-TAAM was copolymerized with 3-dodecylthiophene (3DDT) and 3-thiophene ethanol (3TEt) to yield rGO-f-TAA-co-PDDT (rGO-g-PDDT) and rGO-f-TAA-co-P3TEt (rGO-g-PTEt), which were confirmed by Fourier transform infrared spectra. The grafted materials depicted better electrochemical properties and superior solubilities in organic solvents compared to GO and rGO. The soluble rGO-g-PDDT and rGO-g-PTEt composites blended with polycaprolactone were fabricated by electrospinning, and then cytotoxicity, hydrophilicity, biodegradability and mechanical properties were investigated. The grafted rGO composites exhibited a good electroactivity behavior, mainly because of the enhanced electrochemical performance. The electrospun nanofibers underwent degradation about 7 wt% after 40 days, and the fabricated scaffolds were not able to induce cytotoxicity in mouse osteoblast MC3T3-E1 cells. The soluble conducting composites developed in this study are utilizable in the fabrication of nanofibers with tissue engineering application.

Development of novel electrically conductive scaffold based on hyperbranched polyester and polythiophene for tissue engineering applications.

A novel electrically conductive scaffold containing hyperbranched aliphatic polyester (HAP), polythiophene (PTh), and poly(ε-caprolactone) (PCL) for regenerative medicine application was succesfully fabricated via electrospinning technique. For this purpose, the HAP (G4; fourth generation) was synthesized via melt polycondensation reaction from tris(methylol)propane and 2,2-bis(methylol)propionic acid (bis-MPA). Afterward, the synthesized HAP was functionalized with 2-thiopheneacetic acid in the presence of N,N-dicyclohexyl carbodiimide, and N-hydroxysuccinimide as coupling agent and catalyst, respectively, to afford a thiophene-functionalized G4 macromonomer. This macromonomer was subsequently used in chemical oxidation copolymerization with thiophene monomer to produce a star-shaped PTh with G4 core (G4-PTh). The solution of the G4-PTh, and PCL was electrospun to produce uniform, conductive, and biocompatible nanofibers. The conductivity, hydrophilicity, and mechanical properties of these nanofibers were investigated. The biocompatibility of the electrospun nanofibers were evaluated by assessing the adhesion and proliferation of mouse osteoblast MC3T3-E1 cell line and in vitro degradability to demonstrate their potential uses as a tissue engineering scaffold. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2673-2684, 2016.