Amphiphilic ABA-type Triblock Copolymer Research Articles

Hydrogen Bond-Mediated Supramolecular Polymeric Nanomedicine with pH/Light-Responsive Methotrexate Release and Synergistic Chemo-/Photothermal Therapy.

Complete cancer cure and healing are still difficult, owing to its complexity and heterogeneity. Integration of supramolecular forces, for example, hydrogen bonds (H-bonds), to anti-cancer nanomedicine affords new scaffolds for biomedical material decoration, featuring the advantages of dynamic property and easier processability. Here, we target the construction of H-bond-mediated supramolecular polymer micelles, loaded with a chemotherapeutic drug along with a photothermal agent for synergistic chemo-/photothermal therapies (CT/PTT). To do so, we design and synthesize an amphiphilic ABA-type triblock copolymer, bearing H-bonding moiety (barbiturate, Ba) within the middle hydrophobic B block. The presence of pendant Ba moieties within the hydrophobic core promotes the loading capability of methotrexate (MTX) and transportation stability, benefitting from the formation of specific Ba/MTX H-bonding interactions. IR780, a photothermal agent, concomitantly encapsulated via hydrophobic interactions, facilitates the development of a synergistic CT/PTT modalities, where MTX can be released on demand owing to the dissociation of Ba/MTX H-bonding interactions induced by elevated temperature. Such H-bonding nanomedicine possesses enhanced drug loading capacity and transport performance and can also trigger stimuli-responsive drug release in the tumor zone. We believe that H-bonded nanomedicines provide a fine toolbox that is conducive to attaining biomedical requirements with remarkable values in theranostics that are highly promising in clinical applications.

A unique amphiphilic triblock copolymer, nontoxic to human blood and potential supramolecular drug delivery system for dexamethasone

The drug delivery system (DDS) often causes toxicity, triggering undesired cellular injuries. Thus, developing supramolecules used as DDS with tunable self-assembly and nontoxic behavior is highly desired. To address this, we aimed to develop a tunable amphiphilic ABA-type triblock copolymer that is nontoxic to human blood cells but also capable of self-assembling, binding and releasing the clinically used drug dexamethasone. We synthesized an ABA-type amphiphilic triblock copolymer (P2L) by incorporating tetra(aniline) TANI as a hydrophobic and redox active segment along with monomethoxy end-capped polyethylene glycol (mPEG2k; Mw = 2000 g mol−1) as biocompatible, flexible and hydrophilic part. Cell cytotoxicity was measured in whole human blood in vitro and lung cancer cells. Polymer-drug interactions were investigated by UV–Vis spectroscopy and computational analysis. Our synthesized copolymer P2L exhibited tuned self-assembly behavior with and without external stimuli and showed no toxicity in human blood samples. Computational analysis showed that P2L can encapsulate the clinically used drug dexamethasone and that drug uptake or release can also be triggered under oxidation or low pH conditions. In conclusion, copolymer P2L is nontoxic to human blood cells with the potential to carry and release anticancer/anti-inflammatory drug dexamethasone. These findings may open up further investigations into implantable drug delivery systems/devices with precise drug administration and controlled release at specific locations.

Self-Assembly of Block Copolymers in an Ionic Liquid and Properties of Resulting Ion Gels

Ionic liquids (ILs), which are salts with low melting points, show unique properties including non-volatility and high ionic conductivity. By combining an ionic liquid (IL) with an amphiphilic ABA-type triblock copolymer, polystyrene (PSt)-b-poly(methyl methacrylate) (PMMA)-b-PSt (SMS), insoluble A blocks aggregate and form cross-linking points, whereas soluble B blocks form a gel network swollen with the IL.[1,2] As a result, a self-standing and highly ion-conductive ion gels can be obtained, and they have been applied to electrochemical devices such as polymer actuators. In these devices, the mechanical toughness and ionic conductivity are important parameters. Thus, we have investigated the correlation between microstructures formed by the block copolymer and the properties of ion gels such as ionic conductivity and mechanical property. In particular, we focused on a gyroid structure in which both insoluble and soluble segments form continuous phases, because this unique microstructure is expected to exhibit high mechanical strength and favorable ionic conductivity, simultaneously. In this study, we directly observed microstructures using AFM to investigate how microstructures affect properties of the ion gel. Herein, we used poly(ethylene oxide) (PEO), which has a lower glass transition temperature (T g) than PMMA, as a middle block (PSt-PEO-PSt, SOS). Consequently, SOS showed various microstructures including the gyroid depending on block ratio and content of IL. It was found that ionic conductivity and mechanical property strongly depended on the connectivity of microstructures. Namely, the gyroid structure showed the enhanced mechanical property and good ionic conductivity.In addition, we observed in-situ change in the microstructure for a stimuli responsive ion gel containing temperature-responsive poly(N-isopropylacrylamide) (PNIPAm) blocks: PNIPAm is known to show lower critical solution temperature (LCST)-type phase behavior in water while showing upper critical solution temperature (UCST)-type phase behavior in ILs.[3] PNIPAm-b-PEO-b-PNIPAm (NON) exhibits gel-to-sol transition in IL with increasing temperature due to the UCST-type phase transition of PNIPAm blocks. We have also reported photo-responsive gel-to-sol transition of ion gels by introducing a photo-responsive azobenzene moiety to either IL or polymer.[2] These transition phenomena have been studied in terms of a macroscopic property such as rheological property. However, little is known about their microstructure during the photo-responsive change. Thus, we observed the photo-responsive change in the microstructure using AFM and investigated how the microstructure change is synchronized with the rheological response. We found that UV irradiation induced the change in the microstructures from a microphase-separated gel to a sol with a vague structure, and it was correlated with the photo-responsive change in the mechanical property and ionic conductivity. Acknowledgements This work was financially supported by the Grant-in-Aid for Scientific Research for Basic Research S (15H05758) from Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan.

Fighting against Drug-Resistant Tumors using a Dual-Responsive Pt(IV)/Ru(II) Bimetallic Polymer.

Drug resistance is a major problem in cancer treatment. Herein, the design of a dual-responsive Pt(IV)/Ru(II) bimetallic polymer (PolyPt/Ru) to treat cisplatin-resistant tumors in a patient-derived xenograft (PDX) model is reported. PolyPt/Ru is an amphiphilic ABA-type triblock copolymer. The hydrophilic A blocks consist of biocompatible poly(ethylene glycol) (PEG). The hydrophobic B block contains reduction-responsive Pt(IV) and red-light-responsive Ru(II) moieties. PolyPt/Ru self-assembles into nanoparticles that are efficiently taken up by cisplatin-resistant cancer cells. Irradiation of cancer cells containing PolyPt/Ru nanoparticles with red light generates 1 O2 , induces polymer degradation, and triggers the release of the Ru(II) anticancer agent. Meanwhile, the anticancer drug, cisplatin, is released in the intracellular environment via reduction of the Pt(IV) moieties. The released Ru(II) anticancer agent, cisplatin, and the generated 1 O2 have different anticancer mechanisms; their synergistic effects inhibit the growth of drug-resistant cancer cells. Furthermore, PolyPt/Ru nanoparticles inhibit tumor growth in a PDX mouse model because they circulate in the bloodstream, accumulate at tumor sites, exhibit good biocompatibility, and do not cause side effects. The results demonstrate that the development of stimuli-responsive multi-metallic polymers provides a new strategy to overcome drug resistance.

Microphase-separated structures of ion gels consisting of ABA-type block copolymers and an ionic liquid: A key to escape from the trade-off between mechanical and transport properties

Upon combination of an ionic liquid (IL) with an amphiphilic ABA-type triblock copolymer, the insoluble A blocks aggregate to form mechanical frameworks and the soluble B blocks form ion-transport paths by incorporating the IL. Consequently, a self-standing ion gel, exhibiting the characteristic high ionic conductivity of ILs, can be obtained. In this study, we investigated the effect of microstructures formed by the block copolymer (spherical, cylindrical, gyroid, and lamellar structures) on the ionic conductivity and mechanical properties of the ion gel by focusing on the microstructures. As a result, an ion gel that formed an isotropic bicontinuous structure was successfully obtained via a heat-induced order-order transition. The structure was maintained even at room temperature, and the ion gel having a bicontinuous structure exhibited favorable mechanical properties (storage modulus, G' ~ 1.0 MPa) and good ionic conductivity (σ ~ 0.1 mS cm−1). In contrast, the ion gels having anisotropic structures (cylindrical structure) exhibited weaker mechanical properties and lower ionic conductivity. The characteristics of bicontinuous structures may be the key to resolving the trade-off between mechanical and transport properties of electrolyte materials for electrochemical devices.

Transport and Mechanical Properties of ABA-type Triblock Copolymer Ion Gels Correlated with Their Microstructures

The microstructures of ion gels formed by the self-assembly of an amphiphilic ABA-type triblock copolymer in an ionic liquid (IL) were explored by using atomic force microscopy (AFM) along with sma...

Light and pH dual-degradable triblock copolymer micelles for controlled intracellular drug release.

A novel amphiphilic ABA-type triblock copolymer poly(ethylene glycol)-b-poly(ethanedithiol-alt-nitrobenzyl)-b-poly(ethylene glycol) (PEG-b-PEDNB-b-PEG) is successfully prepared by sequential thiol-acrylate Michael addition polymerization in one pot. PEG-b-PEDNB-b-PEG is designed to have light-cleavable o-nitrobenzyl linkages and acid-labile β-thiopropionate linkages positioned repeatedly in the main chain of the hydrophobic block. The light and pH dual degradation of PEG-b-PEDNB-b-PEG is traced by gel permeation chromatography (GPC). Such triblock copolymer can self-assemble into micelles, which can be used to encapsulate anticancer drug doxorubicin (DOX). Because of the different degradation chemistry of o-nitrobenzyl linkages and β-thiopropionate linkages, DOX can be released from the micelles by two different manners, i.e., light-induced rapid burst release and pH-induced slow sustained release. Confocal laser scanning microscopy (CLSM) results indicated that DOX-loaded micelles exhibited faster drug release in A549 cells after UV irradiation. Furthermore, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) results show that the DOX-loaded micelles under UV light degradation exhibit better anticancer activity against A549 cells than that of the nonirradiated ones.

Synthesis, characterization, and solution behavior of well-defined double hydrophilic linear amphiphilic poly (N-isopropylacrylamide)-b-poly (ε-caprolactone)-b-poly (N-isopropylacrylamide) triblock copolymers

Well-defined linear dihydrophilic amphiphilic ABA-type triblock copolymers of e-caprolactone (CL) and N-isopropylacrylamide (NIPAAm) have successfully been synthesized with a high yield by combining the ring opening polymerization (ROP) and xanthate-mediated reversible addition-fragmentation chain transfer (RAFT) polymerization methods. The resulted block copolymer shows the formation of micelles in water as supported by light scattering. The critical micelle concentration (cmc) value of the micelle increases with the increase in the chain length of the poly (N-isopropylacrylamide) (PNIPAAm) block. Cloud point of the block copolymers decreases with the decrease in the PNIPAAm chain length. The TGA analysis shows a one-step degradation and a lower thermal stability of the triblock copolymer than the PNIPAAm. The DSC analysis of the triblock copolymer shows the lowering of glass transition temperature (T g), and melting temperature (T m) peaks possibly due to the partial miscibility of the poly (e-caprolactone) (PCL) block with the amorphous PNIPAAm block through the interaction of ester groups of PCL with the amide groups of PNIPAAm. The XRD pattern of the triblock copolymer shows a broad peak due to the suppression of the crystallization of PCL block owing to the mixing of PNIPAAm block with the PCL block.

Block Copolymer Micelles with a Dual-Stimuli-Responsive Core for Fast or Slow Degradation

We report the design and demonstration of a dual-stimuli-responsive block copolymer (BCP) micelle with increased complexity and control. We have synthesized and studied a new amphiphilic ABA-type triblock copolymer whose hydrophobic middle block contains two types of stimuli-sensitive functionalities regularly and repeatedly positioned in the main chain. Using a two-step click chemistry approach, disulfide and o-nitrobenzyle methyl ester groups are inserted into the main chain, which react to reducing agents and light, respectively. With the end blocks being poly(ethylene oxide), micelles formed by this BCP possess a core that can be disintegrated either rapidly via photocleavage of o-nitrobenzyl methyl esters or slowly through cleavage of disulfide groups by a reducing agent in the micellar solution. This feature makes possible either burst release of an encapsulated hydrophobic species from disintegrated micelles by UV light, or slow release by the action of a reducing agent, or release with combined fast-slow rate profiles using the two stimuli.

Synthesis and self-assembly of amphiphilic ABA type triblock copolymer with well-defined glycopolymer segments

A novel amphiphilic ABA type triblock copolymer with well-defined glycopolymer segments was successfully synthesized via the atom transfer radical polymerization (ATRP) technique, using a bromo-terminated difunctional polysulfone as macroinitiator. The difunctional polysulfone macroinitiator was prepared by esterifying the phenolic end groups of polysulfone to α-haloesters. This macroinitiator was then used to initiate the polymerization of a glucose-carrying monomer, 3-O-methacryloyl-1,2:5,6-di-O-isopropylidene-D-glucofuranose (MAIpG), resulting an ABA type triblock copolymer. After acidolysis treatment, the isopropylidenyl groups of the protected sugar residues were removed, thus the amphiphilic ABA type triblock copolymer with well-defined glycopolymer segments was obtained. The polymers obtained were identified by FT-IR, 1H-NMR, GPC, and TGA. The self-assembly behavior of the amphiphilic glycopolymer in selective solvent (e.g. DMF/H2O) system was also preliminarily explored. The resultant amphiphilic glycopolymer shows potential applications in the fields of controlled release and delivery of drugs, micro-reactors, nano-materials, medical devices, and so on.

The Synthesis and Biodegradability of Poly(lactide-random-depsipeptide)-PEGPoly(lactide-random-depsipeptide) ABA-type Triblock Copolymers

Amphiphilic ABA-type triblock copolymers were synthesized to develop a biodegradable anti-adhesive membrane. In this particular synthesis, poly[L-lactide(LA)- co-depsipeptide] (poly[LA- co-(Glc-Leu)]: PLGL) was used as the A segment, and the poly(ethylene glycol)s (PEG)s, Mn 10,000 and Mn 20,500 were used as the B segment. The synthesis of the triblock copolymer (PLGL-PEG-PLGL) was carried out via a ring-opening copolymerization of L-lactide and cyclo(Glc-Leu) in the presence of hydroxytelechelic poly(ethylene glycol) using tin 2-ethylhexanoate as a catalyst. To evaluate the copolymer films as candidates for biodegradable anti-adhesive membranes, physicochemical properties such as degradation on behavior under physiological conditions and water absorption were investigated. The degradation rate of the PLGLPEG-PLGL films varied with changes in the molecular architecture; specifically, the molecular weight of the hydrophilic B segment and the depsipeptide unit content in the A segment were more prominent. The biocompatibility and resorption of the PLGL-PEG-PLGL films were also evaluated. The PLGLPEG-PLGL films were degraded and depleted gradually in vivo without inflammation.

Synthesis of Novel Amphiphilic Block Copolymers of Poly-N-vinylpyrrolidone and Poly (D, L-lactide) by Atom Transfer Radical Polymerization

In order to improve the hydrophilicity of poly (D,L-latide) (PDLLA), a novel amphiphilic ABA-type triblock copolymers of poly-N-vinylpyrrolidone (A) and poly (D, L-lactide) (B), were successfully synthesized by atom transfer radical polymerization (ATRP) using N-vinylpyrrolidone (VP) as monomer, bromide-terminated poly (D,L-latide) oligomer (Br-PDLLA-Br) as functional macromolecular initiator which was prepared when hydroxy-terminated poly(D,L-latide) oligomer (HO-PDLLA-OH) reacted with 2-bromopropanoyl bromide, CuBr/2,2’-bipyridine complex as the catalyst system. The resulting copolymers were characterized by various analytical techniques. The results showed that the introduction of poly (N-vinylpyrrolidone) (PVP) segments into polylactide enhanced the surface hydrophilicity of the copolymers remarkably and amphiphilic polymer can self-assemble into core-shell structure (polymer micelle) in water by the balance of the hydrophilic and hydrophobic interaction.