Ionic Liquid-Based Polymer Matrices for Single and Dual Drug Delivery: Impact of Structural Topology on Characteristics and In Vitro Delivery Efficiency.

Previously reported amphiphilic linear and graft copolymers, derived from the ionic liquid [2-(methacryloyloxy)ethyl]trimethylammonium chloride (TMAMA_Cl‾), along with their conjugates obtained through modification either before or after polymerization with p-aminosalicylate anions (TMAMA_PAS‾), were employed as matrices in drug delivery systems (DDSs). Based on the counterion type in TMAMA units, they were categorized into single drug systems, manifesting as ionic polymers with chloride counterions and loaded isoniazid (ISO), and dual drug systems, featuring ISO loaded in self-assembled PAS conjugates. The amphiphilic nature of these copolymers was substantiated through the determination of the critical micelle concentration (CMC), revealing an increase in values post-ion exchange (from 0.011-0.063 mg/mL to 0.027-0.181 mg/mL). The self-assembling properties were favorable for ISO encapsulation, with drug loading content (DLC) ranging between 15 and 85% in both single and dual systems. In vitro studies indicated ISO release percentages between 16 and 61% and PAS release percentages between 20 and 98%. Basic cytotoxicity assessments using the 2,5-diphenyl-2H-tetrazolium bromide (MTT) test affirmed the non-toxicity of the studied systems toward human non-tumorigenic lung epithelial cell line (BEAS-2B) cell lines, particularly in the case of dual systems bearing both ISO and PAS simultaneously. These results confirmed the effectiveness of polymeric carriers in drug delivery, demonstrating their potential for co-delivery in combination therapy.

Synthesis and Characterization of Graft Copolymers with Poly(ε-caprolactone) Side Chain Using Hydroxylated Poly(ß-myrcene-co-α-methyl styrene).

Graft copolymers have unique application scenarios in the field of high-performance thermoplastic elastomers, resins and rubbers. ß-myrcene (My) is a biomass monomer derived from renewable plant resources, and its homopolymer has a low glass transition temperature and high elasticity. In this work, a series of tapered copolymers P(My-co-AMS)k (k = 1, 2, 3) were first synthesized in cyclohexane by one-pot anionic polymerization of My and α-methyl styrene (AMS) using sec-BuLi as the initiator. PAMS chain would fracture when heated at high temperature and could endow the copolymer with thermal degradation property. The effect of the incorporation of AMS unit on the thermal stability and glass transition temperature of polymyrcene main chain was studied. Subsequently, the double bonds in the linear copolymers were partially epoxidized and hydroxylated into hydroxyl groups to obtain hydroxylated copolymer, which was finally used to initiate the ring-opening polymerization (ROP) of ε-caprolactone (ε-CL) to synthesize the graft copolymer with PCL as the side chain. All these copolymers before and after modifications were characterized by proton nuclear magnetic resonance (1H NMR), gel permeation chromatography (GPC), thermogravimetry analysis (TGA), and differential scanning calorimeter (DSC).

Casein-based conjugates and graft copolymers. Synthesis, properties, and applications.

Biobased natural polymers, including polymers of natural origin such as casein, are growing rapidly in the light of the environmental pollution caused by many mass-produced commercial synthetic polymers. Although casein has interesting intrinsic properties, especially for the food industry, numerous chemical reactions have been carried out to broaden the range of its properties, most of them preserving casein's nontoxicity and biodegradability. New conjugates and graft copolymers have been developed especially by Maillard reaction of the amine functions of the casein backbone with the aldehyde functions of sugars, polysaccharides, or other molecules. Carried out with dialdehydes, these reactions lead to the cross-linking of casein giving three-dimensional polymers. Acylation and polymerization of various monomers initiated by amine functions are also described. Other reactions, far less numerous, involve alcohol and carboxylic acid functions in casein. This review provides an overview of casein-based conjugates and graft copolymers, their properties, and potential applications.

Hierarchical Self-Assembly of Triphilic Main-Chain-Type Semifluorinated Alternating Graft Copolymers in Aqueous Solution.

Fluorinated copolymers can self-assemble in solution and form micelles with rare properties due to the peculiar behavior of fluorinated groups. However, the process description of the self-assembly is still largely phenomenological and difficult to explain due to the tendency of the fluorinated segments to segregate from both the hydrophilic and lipophilic segments, which can result in various morphologies. Herein, the controlled formation of ellipsoidal micelles, disklike micelles, and sheets by hierarchical self-assembly of triphilic main-chain-type semifluorinated alternating graft copolymers (AB)n A-g-mOEG is presented (where A represents unit of α,ω-diiodoperfluoroalkane, B represents the unit of α,ω-unconjugated diene, and mOEG represents methoxy oligo(ethylene glycol)), which are synthesized by step transfer-addition and radical-termination (START) polymerization and azide-alkyne click chemistry. Furthermore, the possible self-assembly mechanism of these micron-level aggregates is proposed, which is ascribed to the hierarchical self-assembly, crowding effect of hydrophilic chains and the interfacial tension between the fluoroalkane and alkane segments. This study can provide a facile and highly efficient approach to the synthesis of main-chain-type fluorinated graft copolymers and expand the research field for the solution self-assembly of fluorinated copolymers.

Synthesis of a New Poly(ε-caprolactone)-g-Chitosan Amphiphilic Graft Copolymer with a "Reverse" Structure.

Hydrophilic chitosan (CHT) and hydrophobic polyε-caprolactone (PCL) are well-known biocompatible and biodegradable polymers that have many applications in the biomedical and pharmaceutical fields. But the mixtures of these two compounds are considered incompatible, which makes them not very interesting. To avoid this problem and to further extend the properties of these homopolymers, the synthesis of a new graft copolymer, the fully biodegradable amphiphilic poly(ε-caprolactone-g-chitosan) (PCL-g-CHT) is described, with an unusual "reverse" structure formed by a PCL backbone with CHT grafts, unlike the "classic" CHT-g-PCL structure with a CHT main chain and PCL grafts. This copolymer is prepared via a copper-catalyzed 1,3-dipolar Huisgen cycloaddition between propargylated PCL (PCL-yne) and a new azido-chitosan (CHT-N3 ). In order to obtain an amphiphilic copolymer regardless of the pH, chitosan oligomers, soluble at any pH, are prepared and used. The amphiphilic PCL-g-CHT copolymer spontaneously self-assembles in water into nanomicelles that may incorporate hydrophobic drugs to give novel drug delivery systems.

Relationship between the Co-Continuous Morphology of Immiscible Polymer Blends and the Structure of an In Situ Formed Graft Copolymer.

In order to get stable co-continuous morphology in immiscible polymer blends, besides reducing the interfacial tension, the compatibilizer should not only promote the formation of flat interface between different phases, but also not hinder the coalescence of the dispersed phase. Herein, the relationship between the morphology of the compatibilized polystyrene/nylon 6/styrene-maleic anhydride (PS/PA6/SMA) immiscible polymer blends and the structures of the in-situ formed SMA-g-PA6 graft copolymers as well as the processing conditions are studied. Two kinds of SMA are used: SMA28 (28 wt.% MAH) and SMA11 (11 wt.% MAH). After melt blending with PA6, the in-situ formed copolymer SMA28-g-PA6 has on average of four PA6 side chains, while that of SMA11-g-PA6 has only one. Dissipative particle dynamics simulation results indicate that both SMA28-g-PA6 copolymer and PS/PA6/SMA28 blends tend to form co-continuous structure, while those related to SMA11 intend to form sea-island morphologies. These results are correct only at relatively low rotor speed (60 rpm). When the rotor speed is higher (105 rpm), sea-island morphologies are obtained in SMA28 systems, while that for SMA11 ones are co-continuous. This indicates that higher shear stress can elongate the minor phase domains to form flat interfaces, while the SMA28-g-PA6 copolymers can be pulled out from the interface.

Multifunctional Modified Chitosan Biopolymers for Dual Applications in Biomedical and Industrial Field: Synthesis and Evaluation of Thermal, Chemical, Morphological, Structural, In Vitro Drug-Release Rate, Swelling and Metal Uptake Studies.

The hydrogel materials are getting attention from the research due to their multidimensional usage in various fields. Chitosan is one of the most important hydrogels used in this regard. In this paper multifunctional binary graft copolymeric matrices of chitosan with monomer AA and various comonomers AAm and AN were prepared by performing free radical graft copolymerization in the presence of an initiator KPS. The binary grafting can be done at five different molar concentrations of binary comonomers at already optimized concentration of AA, KPS and other reaction conditions such as time, temperature, solvent amount, etc. Various optimum reaction conditions were investigated and presented in this work; the backbone as well as binary grafts Ch-graft-poly (AA-cop-AAm) and Ch-graft-poly (AA-cop-AN) were characterized via various physio-chemical techniques of analysis such as SEM analysis, Xray diffraction (XRD), TGA/DTA and FTIR. In the batch experiments, the binary grafts were investigated for the percent swelling with respect to pH (pH of 2.2, 7.0, 7.4 and 9.4) and time (contact time 1 to 24 h). Uploading and controllable in vitro release of the drug DS (anti-inflammatory) was examined with reverence to gastrointestinal pH and time. The binary grafts showed significantly better-controlled drug diffusion than the unmodified backbone. The kinetic study revealed that the diffusion of the drug occurred by the non-Fickian way. In the case of separation technologies, experiments (batch tests) were executed for the toxic bivalent metal ions Fe (II) and Pb (II) sorption from the aqueous media with respect to the parameters such as interaction period, concentration of fed metal ions in solution, pH and temperature. The binary grafted matrices showed superior results compared to chitosan. The kinetics study revealed that the matrices show pseudo-second order adsorption. The graft copolymer Ch-graft-poly (AA-cop-AAm) provided superior results in sustainable drug release as well as metal ion uptake. The study explored the potential of chitosan-based materials in the industry as well in the biomedical field. The results proved these to be excellent materials with a lot of potential as adsorbents.

Pharmaceutical Functionalization of Monomeric Ionic Liquid for the Preparation of Ionic Graft Polymer Conjugates.

Polymerizable choline-based ionic liquid (IL), i.e., [2-(methacryloyloxy)ethyl]-trimethylammonium (TMAMA/Cl¯), was functionalized by an ion exchange reaction with pharmaceutical anions, i.e., cloxacillin (CLX¯) and fusidate (FUS¯), as the antibacterial agents. The modified biocompatible IL monomers (TMAMA/CLX¯, TMAMA/FUS¯) were copolymerized with methyl methacrylate (MMA) to prepare the graft copolymers (19-50 mol% of TMAMA units) serving as the drug (co)delivery systems. The in vitro drug release, which was driven by the exchange reaction of the pharmaceutical anions to phosphate ones in PBS medium, was observed for 44% of CLX¯ (2.7 µg/mL) and 53% of FUS¯ (3.6 µg/mL) in the single systems. Similar amounts of released drugs were detected for the dual system, i.e., 41% of CLX¯ (2.2 µg/mL) and 33% of FUS¯ (2.0 µg/mL). The investigated drug ionic polymer conjugates were examined for their cytotoxicity by MTT test, showing a low toxic effect against human bronchial epithelial cells (BEAS-2B) and normal human dermal fibroblasts (NHDF) as the normal cell lines. The satisfactory drug contents and the release profiles attained for the well-defined graft polymers with ionically bonded pharmaceuticals in the side chains make them promising drug carriers in both separate and combined drug delivery systems.

Mechanochemical Transformations of Polysaccharides: A Systematic Review.

Taking into consideration the items of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), this study reviews application of mechanochemical approaches to the modification of polysaccharides. The ability to avoid toxic solvents, initiators, or catalysts during processes is an important characteristic of the considered approach and is in line with current trends in the world. The mechanisms of chemical transformations in solid reactive systems during mechanical activation, the structure and physicochemical properties of the obtained products, their ability to dissolve and swell in different media, to form films and fibers, to self-organize in solution and stabilize nanodispersed inorganic particles and biologically active substances are considered using a number of polysaccharides and their derivatives as examples.

Poly(ε-caprolactone)-Based Graft Copolymers: Synthesis Methods and Applications in the Biomedical Field: A Review.

Synthetic biopolymers are attractive alternatives to biobased polymers, especially because they rarely induce an immune response in a living organism. Poly ε-caprolactone (PCL) is a well-known synthetic aliphatic polyester universally used for many applications, including biomedical and environmental ones. Unlike poly lactic acid (PLA), PCL has no chiral atoms, and it is impossible to play with the stereochemistry to modify its properties. To expand the range of applications for PCL, researchers have investigated the possibility of grafting polymer chains onto the PCL backbone. As the PCL backbone is not functionalized, it must be first functionalized in order to be able to graft reactive groups onto the PCL chain. These reactive groups will then allow the grafting of new reagents and especially new polymer chains. Grafting of polymer chains is mainly carried out by "grafting from" or "grafting onto" methods. In this review we describe the main structures of the graft copolymers produced, their different synthesis methods, and their main characteristics and applications, mainly in the biomedical field.

Poly(Lactic Acid)-Based Graft Copolymers: Syntheses Strategies and Improvement of Properties for Biomedical and Environmentally Friendly Applications: A Review.

As a potential replacement for petroleum-based plastics, biodegradable bio-based polymers such as poly(lactic acid) (PLA) have received much attention in recent years. PLA is a biodegradable polymer with major applications in packaging and medicine. Unfortunately, PLA is less flexible and has less impact resistance than petroleum-based plastics. To improve the mechanical properties of PLA, PLA-based blends are very often used, but the outcome does not meet expectations because of the non-compatibility of the polymer blends. From a chemical point of view, the use of graft copolymers as a compatibilizer with a PLA backbone bearing side chains is an interesting option for improving the compatibility of these blends, which remains challenging. This review article reports on the various graft copolymers based on a PLA backbone and their syntheses following two chemical strategies: the synthesis and polymerization of modified lactide or direct chemical post-polymerization modification of PLA. The main applications of these PLA graft copolymers in the environmental and biomedical fields are presented.

3D Printable Conducting and Biocompatible PEDOT-graft-PLA Copolymers by Direct Ink Writing.

Tailor-made polymers are needed to fully exploit the possibilities of additive manufacturing, constructing complex, and functional devices in areas such as bioelectronics. In this paper, the synthesis of a conducting and biocompatible graft copolymer which can be 3D printed using direct melting extrusion methods is shown. For this purpose, graft copolymers composed by conducting polymer poly(3,4-ethylenedioxythiophene) (PEDOT) and a biocompatible polymer polylactide (PLA) are designed. The PEDOT-g-PLA copolymers are synthesized by chemical oxidative polymerization between 3,4-ethylenedioxythiophene and PLA macromonomers. PEDOT-g-PLA copolymers with different compositions are obtained and fully characterized. The rheological characterization indicates that copolymers containing below 20 wt% of PEDOT show the right complex viscosity values suitable for direct ink writing (DIW). The 3D printing tests using the DIW methodology allows printing different parts with different shapes with high resolution (200 µm). The conductive and biocompatible printed patterns of PEDOT-g-PLA show excellent cell growth and maturation of neonatal cardiac myocytes cocultured with fibroblasts.

Synthesis and Self-Assembly of Thermoresponsive Biohybrid Graft Copolymers Based on a Combination of Passerini Multicomponent Reaction and Molecular Recognition.

Amphiphilic graft copolymers exhibit fascinating self-assembly behaviors. Their molecular architectures significantly affect the morphology and functionality of the self-assemblies. Considering the potential application of amphiphilic graft copolymers in the fabrication of nanocarriers, it is essential to synthesize well-defined graft copolymers with desired functional groups. Herein, the Passerini reaction and molecular recognition are introduced to the synthesis of functional thermoresponsive graft copolymers. A bifunctional monomer 2-((adamantan-1-yl)amino)-1-(4-((2-bromo-2-methylpropanoyl)oxy)phenyl)-2-oxoethyl methacrylate (ABMA) with a bromo group for atom transfer radical polymerization (ATRP) and an adamantyl group for molecular recognition is synthesized through the Passerini reaction. The graft copolymers are prepared by reversible addition-fragmentation transfer (RAFT) copolymerization of ABMA and oligo(ethylene glycol) methyl ether methacrylate (OEGMA) followed by RAFT end group removal and ATRP of di(ethylene glycol)methyl ether methacrylate (DEGMA) initiated by the ABMA units. The graft copolymer P(OEGMA-co-ABMA)-g-PDEGMA can be functionalized with ß-cyclodextrin modified peptides, affording a thermoresponsive biohybrid graft copolymer. At a temperature above its lower critical solution temperature, the biohybrid graft copolymer self-assembles into peptide-modified polymersomes.

Triple-Responsive Polyampholytic Graft Copolymers as Smart Sensors with Varying Output.

Three triggers result in two measurable outputs from polymeric sensors: multiresponsive polyampholytic graft copolymers respond to pH-value and temperature, as well as the type and concentration of metal cations and therefore, allow the transformation of external triggers into simply measurable outputs (cloud point temperature (TCP ) and surface plasmon resonance (SPR) of encapsulated silver nanoparticles). The synthesis relies on poly(dehydroalanine) (PDha) as the reactive backbone and gives straightforward access to materials with tunable composition and output. In particular, a rather high sensitivity toward the presence of Cu2+ , Co2+ , and Pb2+ metal cations is found.

Biological In Vitro Evaluation of PIL Graft Conjugates: Cytotoxicity Characteristics.

In vitro cytotoxicity of polymer-carriers, which in the side chains contain the cholinum ionic liquid units with chloride (Cl) or pharmaceutical anions dedicated for antituberculosis therapy, i.e., p-aminosalicylate (PAS) and clavulanate (CLV), was investigated. The carriers and drug conjugates were examined, in the concentration range of 3.125-100 µg/mL, against human bronchial epithelial cells (BEAS-2B) and adenocarcinomic human alveolar basal epithelial cells (A549) as an experimental model cancer cell line possibly coexisting in tuberculosis. The cytotoxicity was evaluated by MTT test and confluency index, as well as by the cytometric analyses, including Annexin-V FITC apoptosis assay. The polymer systems showed supporting activity towards the normal cells and no tumor progress, especially at the highest concentration (100 µg/mL). The analysis of cell death did not show meaningful changes in the case of the BEAS-2B, whereas in the A549 cell line, the cytostatic activity was observed, especially for the drug-free carriers, causing death in up to 80% of cells. This can be regulated by the polymer structure, including the content of cationic units, side-chain length and density, as well as the type and content of pharmaceutical anions. The results of MTT tests, confluency, as well as cytometric analyses, distinguished the polymer systems with Cl/PAS/CLV containing 26% of grafting degree and 43% of ionic units or 46% of grafting degree and 18% of ionic units as the optimal systems.

Alginate-g-PNIPAM-Based Thermo/Shear-Responsive Injectable Hydrogels: Tailoring the Rheological Properties by Adjusting the LCST of the Grafting Chains.

Graft copolymers of alginate backbone and N-isopropylacrylamide/N-tert-butylacrylamide random copolymer, P(NIPAMx-co-NtBAMy), side chains (stickers) with various NtBAM content were designed and explored in aqueous media. Self-assembling thermoresponsive hydrogels are formed upon heating, in all cases, through the hydrophobic association of the P(NIPAMx-co-NtBAMy) sticky pendant chains. The rheological properties of the formulations depend remarkably on the NtBAM hydrophobic content, which regulates the lower critical solution temperature (LCST) and, in turn, the stickers' thermo-responsiveness. The gelation point, Tgel, was shifted to lower temperatures from 38 to 20 °C by enriching the PNIPAM chains with 20 mol % NtBAM, shifting accordingly to the gelation temperature window. The consequences of the Tgel shift to the hydrogels' rheological properties are significant at room and body temperature. For instance, at 37 °C, the storage modulus increases about two orders of magnitude and the terminal relaxation time increase about 10 orders of magnitude by enriching the stickers with 20 mol % hydrophobic moieties. Two main thermo-induced behaviors were revealed, characterized by a sol-gel and a weak gel-stiff gel transition for the copolymer with stickers of low (0.6 mol %) and high (14, 20 mol %) NtBAM content, respectively. The first type of hydrogels is easily injectable, while for the second one, the injectability is provided by shear-thinning effects. The influence of the type of media (phosphate buffer (PB), phosphate-buffered saline (PBS), Dulbecco's modified Eagle's medium (DMEM)) on the hydrogel properties was also explored and discussed. The 4 wt % NaALG-g-P(NIPAM80-co-NtBAM20)/DMEM formulation showed excellent shear-induced injectability at room temperature and instantaneous thermo-induced gel stiffening at body temperature, rendering it a good candidate for cell transplantation potential applications.

Grafting PMMA onto P(VDF-TrFE) by CF Activation via a Cu(0) Mediated Controlled Radical Polymerization Process.

In the present work, poly(methyl methacrylate) (PMMA) is successfully grafted onto poly(vinylidene fluoride-trifluoroethylene) (P(VDF-TrFE)) side chains via directly activated CF bonds using Cu(0)/2,2'-bipyridine as catalyst. The reaction mechanism and the initiating sites can be confirmed by the structure of the graft copolymer. The graft copolymerization exhibits first-order kinetics, and reaction conditions can affect the chemical composition of the graft copolymer, including reaction time, reaction temperature, solvents, the amount of catalyst, and monomer. The introduction of rigid PMMA side chains onto P(VDF-TrFE) can effectively tune the displacement-electric field hysteresis behaviors of P(VDF-TrFE) from normal ferroelectric to anti-ferroelectric, even linear-like dielectric, under high electric field, resulting in dramatically reduced energy loss while maintaining the discharged energy density. This work may provide an effective strategy to introduce functional groups into P(VDF-TrFE) copolymer via activation of CF bonds.

Biodegradable Cell Microcarriers Based on Chitosan/Polyester Graft-Copolymers.

Self-stabilizing biodegradable microcarriers were produced via an oil/water solvent evaporation technique using amphiphilic chitosan-g-polyester copolymers as a core material in oil phase without the addition of any emulsifier in aqueous phase. The total yield of the copolymer-based microparticles reached up to 79 wt. %, which is comparable to a yield achievable using traditional emulsifiers. The kinetics of microparticle self-stabilization, monitored during their process, were correlated to the migration of hydrophilic copolymer's moieties to the oil/water interface. With a favorable surface/volume ratio and the presence of bioadhesive natural fragments anchored to their surface, the performance of these novel microcarriers has been highlighted by evaluating cell morphology and proliferation within a week of cell cultivation in vitro.

Orientation of an Amphiphilic Copolymer to a Lamellar Structure on a Hydrophobic Surface and Implications for CO2 Capture Membranes.

The structural orientation of an amphiphilic crystalline polymer to a highly ordered microphase-separated lamellar structure on a hydrophobic surface is presented. It is formed by the surface graft polymerization of poly(ethylene glycol)behenyl ether methacrylate onto poly(trimethylsilyl) propyne in the presence of allylamine. In particular, allylamine plays a pivotal role in controlling the crystalline phase, configuration, and permeation properties. The resulting materials are effectively used to improve the CO2 capture property of membranes. Upon the optimization of the reaction conditions, a high CO2 permeability of 501 Barrer and a CO2 /N2 ideal selectivity of 77.2 are obtained, which exceed the Robeson upper bound limit. It is inspiring to surpass the upper bound limit via a simple surface modification method.

pH-Responsive Porous Nanocapsules for Controlled Release.

In this work pH-responsive porous nanocapsules have been successfully prepared from a ternary graft copolymer, poly(glycidyl methacrylate)-g-[poly(2-cinnamoyloxyethyl methacrylate)-r-poly(ethylene glycol) methyl ether-r-poly(2-diethylaminoethyl methacrylate)] or PGMA-g-(PCEMA-r-MPEG-r-PDEAEMA). The graft copolymers were fabricated by grafting three types of polymer chains onto the backbone polymer by using click chemistry. These ternary copolymers underwent self-assembly to form vesicles in a DMF/water solvent mixture. While the MPEG chains served as the corona and stabilized the vesicles, the vesicle wall was composed of a dominant PCEMA continuous phase that was interspersed by PDEAEMA domains. After photo-cross-linking, the PDEAEMA domains were embedded in the structurally locked PCEMA wall. By decreasing the pH of the external solution, we were able to trigger the release of encapsulated pyrene due to the capsule wall becoming porous as a result of the PDEAEMA chains bearing positively charged amine groups stretching into the water. While these pH-responsive porous nanocapsules exhibited potential applications in drug delivery, detection and catalysis, the strategy reported in this contribution also represented a new paradigm for the design and preparation of other novel stimuli-responsive porous nanocapsules.