Cationic Alternating Copolymerization of Vinyl Esters and 3-Alkoxyphthalides: Side Chain-Crosslinkable Polymers for Acid-Degradable Single-Chain Nanoparticles.

Cationic copolymerization of vinyl acetate and 3-alkoxyphthalides (ROPTs) was demonstrated to proceed using GaCl3 as a Lewis acid catalyst. Both monomers did not undergo homopolymerization, while copolymerization smoothly occurred via the crossover reactions, resulting in alternating copolymers with molecular weights of over 104. The obtained copolymers could be degraded by acid due to the cleavage of the diacyloxymethine moieties, which were derived from the crossover reactions from vinyl acetate to ROPT, in the main chain. An advantage of not radical but cationic copolymerization of vinyl esters was exerted by copolymerizations of radically reactive group-containing vinyl esters with ROPTs. For example, vinyl cinnamate was successfully copolymerized with an ROPT by the cationic mechanism, while keeping the cinnamoyl groups intact. The obtained alternating copolymer was subjected to a photodimerization reaction of the cinnamoyl groups in the side chains, resulting in an acid-degradable single-chain nanoparticle via the intramolecular crosslinking reactions.

In Situ and Ex Situ Studies of Ring-Like Assembly of Silica Nanoparticles in the Presence of Poly(propylene oxide)-Poly(ethylene oxide) Block Copolymers.

Block copolymer-mediated self-assembly of colloidal nanoparticles has attracted great attention for fabricating various nanoparticle arrays. We have previously shown that silica nanoparticles (SNPs) assemble into ring-like nanostructures in the presence of temperature-responsive block copolymers poly[(2-ethoxyethyl vinyl ether)-block-(2-methoxyethyl vinyl ether)] (PEOVE-PMOVE) in an aqueous phase. The ring-like nanostructures formed within an aggregate of PEOVE-PMOVE when the temperature was increased to 45 °C, at which the polymer is amphiphilic. Herein, we report that SNPs assemble into ring-like nanostructures even with a different temperature-responsive, amphiphilic block copolymer poly(propylene oxide)-block-poly(ethylene oxide) (PPO-PEO) at 45 °C. Field-emission scanning electron microscopy for SNP assemblies that were spin-coated on a substrate indicated that SNP first assembled into chain-like nanostructures and then bent into closed loops over several days. In contrast, in situ small-angle X-ray diffraction measurements revealed the formation of SNP nanorings within 75 s at 45 °C in the liquid phase. These results indicated that ring-like assembly of SNPs occurs quickly in the liquid phase, but the slow formation of Si-O-Si bonds between SNPs leads to their structure being destroyed by spin-coating. Intriguingly, SNPs with a diameter of 15 nm form a well-defined nanoring structure, with five SNPs located at the vertex points of a regular pentagon. Additionally, small-angle neutron scattering, where the contrast of the solvent (a mixture of H2O and D2O) matches that of SNPs, clarified that SNPs are contained within the spherical micelle formed from PPO-PEO. This work offers a facile and versatile approach to preparing ring-like arrays from inorganic colloidal nanoparticles, leading to applications including sensing, catalysis, and nanoelectronics.

Multifunctional Traceable Liposomes with Temperature-Triggered Drug Release and Neovasculature-Targeting Properties for Improved Cancer Chemotherapy.

Poor distribution of nanocarriers at the tumor site and insufficient drug penetration into the tissue are major challenges in the development of effective and safe cancer therapy. Here, we aim to enhance the therapeutic effect of liposomes by accumulating doxorubicin-loaded liposomes at high concentrations in and around the tumor, followed by heat-triggered drug release to facilitate low-molecular-weight drug penetration throughout the tumor. A cyclic RGD peptide (cRGD) was incorporated into liposomes decorated with a thermosensitive polymer that allowed precise tuning of drug release temperature (i.e., Polymer-lip) to develop a targeted thermosensitive liposome (cRGD-Polymer-lip). Compared with conventional thermosensitive liposomes, cRGD-Polymer-lip enhanced the binding of liposomes to endothelial cells, leading to their accumulation at the tumor site upon intravenous administration in tumor-bearing mice. Drug release triggered by local heating strongly inhibited tumor growth. Notably, tumor remission was achieved via multiple administrations of cRGD-Polymer-lip and heat treatments. Thus, combining the advantages of tumor neovascular targeting and heat-triggered drug release, these liposomes offer high potential for minimally invasive and effective cancer chemotherapy.

Relationship between Ionic Conductivity, Glass Transition Temperature, and Dielectric Constant in Poly(vinyl ether) Lithium Electrolytes.

We report a partial elucidation of the relationship between polymer polarity and ionic conductivity in polymer electrolyte mixtures comprising a homologous series of nine poly(vinyl ether)s (PVEs) and lithium bis(trifluoromethylsulfonyl)imide. Recent simulation studies have suggested that low dielectric polymer hosts with glass transition temperatures far below ambient conditions are expected to have ionic conductivity limited by salt solubility and dissociation. In contrast, high dielectric hosts are expected to have the potential for high ion solubility but slow segmental dynamics due to strong polymer-polymer and polymer-ion interactions. We report results for PVEs in the low polarity regime with dielectric constants of about 1.3 to 9.0. Ionic conductivity measured for the PVE and salt mixtures ranged from about 10-10 to 10-3 S/cm. In agreement with the predictions from computer simulations, the ionic conductivity increased with dielectric constant and plateaued as the dielectric approached 9.0, comparable to the dielectric constant of the widely used poly(ethylene oxide).

tert-Butyl Esters as Potential Reversible Chain Transfer Agents for Concurrent Cationic Vinyl-Addition and Ring-Opening Copolymerization of Vinyl Ethers and Oxiranes.

tert-Butyl esters are demonstrated to function as chain transfer agents (CTAs) in the cationic copolymerization of vinyl ether (VE) and oxirane via concurrent vinyl-addition and ring-opening mechanisms. In the copolymerization of isopropyl VE and isobutylene oxide (IBO), the IBO-derived propagating species reacts with tert-butyl acetate to generate a copolymer chain with an acetoxy group at the ω-end. This reaction liberates a tert-butyl cation; hence, a polymer chain with a tert-butyl group at the α-end is subsequently generated. Other tert-butyl esters also function as CTAs, and the substituent attached to the carbonyl group affects the chain transfer efficiency. In addition, ethyl acetate does not function as a CTA, which suggests the importance of the liberation of a tert-butyl cation for the chain transfer process. Chain transfer reactions by tert-butyl esters potentially occur reversibly through the reaction of the propagating cation with the ester group at the ω-end of another chain.

Precise synthesis of amphiphilic diblock copolymers consisting of various ionic liquid-type segments and their influence on physical gelation behavior in water.

Appropriately designed amphiphilic diblock vinyl ether (VE) copolymers consisting of an ionic liquid-type segment and a hydrophobic segment were demonstrated to undergo physical gelation in water at extremely low concentrations. The precursor diblock copolymers were synthesized by the living cationic polymerization of 2-chloroethyl VE with a hydrophobic VE through an appropriately designed initiating system such as optimized temperature and catalyst. A relatively high temperature such as 20 °C was important for controlled polymerization of octadecyl VE. Ionic liquid moieties with imidazolium salt structures were subsequently introduced into the side chains of the diblock copolymers via chemical modifications of the 2-chloroethyl groups. The physical gelation behavior of the obtained diblock copolymers was examined in water, with a particular focus on the influence of the hydrophobic VEs, the hydrophilicity of the counteranions and the substituents on the ionic liquid-type segments, and the length of each segment. Based on this systematic investigation, physical gelation at concentrations as low as 0.2 wt% was achieved with diblock copolymers with a suitable balance of these factors.

Tandem Unzipping and Scrambling Reactions for the Synthesis of Alternating Copolymers by the Cationic Ring-Opening Copolymerization of a Cyclic Acetal and a Cyclic Ester.

Cationic copolymerization of different types of monomers, 4-hydroxybutyl vinyl ether (HBVE) and ε-caprolactone (CL), was explored using EtSO3H as an acid catalyst, producing copolymers with a remarkably wide variety of compositions and sequences. In the initial stage of the reaction, HBVE was unexpectedly isomerized to 2-methyl-1,3-dioxepane (MDOP), followed by concurrent copolymerization of MDOP and CL via active chain end and activated monomer mechanisms, respectively. The compositions and sequences of the copolymers were tunable, depending on the initial monomer concentrations. Moreover, a unique method was developed for transforming a copolymer with no CL homosequences into an "alternating" copolymer by removing MDOP from the system using a vacuum pump. This was achieved by the tandem reactions of depolymerization (unzipping) and random transacetalization (scrambling) under thermodynamic control. Specifically, the unzipping of HBVE homosequences proceeded at the oxonium chain end until a nondissociable ester bond emerged next to the chain end, while the scrambling of the main chain via transacetalization transferred midchain HBVE homosequences into the polymer chain end.

Bioinspired Approach to Silica Nanoparticle Synthesis Using Amine-Containing Block Copoly(vinyl ethers): Realizing Controlled Anisotropy.

Core-shell polymer-silica hybrid nanoparticles smaller than 50 nm in diameter were formed in the presence of micelles of poly(2-aminoethyl vinyl ether-block-isobutyl vinyl ether) (poly(AEVEm-b-IBVEn)) through the hydrolysis and polycondensation of alkoxysilane in aqueous solution at a mild pH and temperature. The size of the nanoparticles as well as the number and size of the core parts were effectively controlled by varying the molecular weight of the copolymers. The polymers could be removed by calcination to give hollow silica nanoparticles with Brunauer-Emmett-Teller surface areas of more than 500 m2 g-1. Among these, silica nanoparticles formed with poly(AEVE115-b-IBVE40) displayed an anisotropy of single openings in the shell. The use of an alternative copolymer, poly(AEVE-b-2-naphthoxyethyl vinyl ether) (poly(AEVE113-b-ßNpOVE40)), yielded core-shell nanoparticles with less pronounced anisotropy. These results showed that the degree of anisotropy could be controlled by the rigidity of micelles; the micelle of poly(AEVE115-b-IBVE40) was more deformable during silica deposition than that of poly(AEVE113-b-ßNpOVE40) in which aromatic interactions were possible. This bioinspired, environmentally friendly approach will enable large-scale production of anisotropic silica nanomaterials, opening up applications in the field of nanomedicine, optical materials, and self-assembly.

Cationic Ring-Opening Co- and Terpolymerizations of Lactic Acid-Derived 1,3-Dioxolan-4-ones with Oxiranes and Vinyl Ethers: Nonhomopolymerizable Monomer for Degradable Co- and Terpolymers.

Lactic acid-derived 1,3-dioxolan-4-ones (DOLOs), which do not undergo cationic homopolymerization, were demonstrated to yield copolymers with oxiranes through a cationic copolymerization via frequent crossover reactions. Acetal and ester moieties were generated in the main chain of the copolymers via crossover reactions from DOLO to oxirane and from oxirane to DOLO, respectively, which is in contrast to the unsuccessful generation of hemiacetal ester moieties in the homopropagation of DOLO. In addition, the terpolymerization of DOLO, oxirane, and vinyl ether (VE) proceeded via crossover reactions, while copolymers could not be generated from VE and DOLO in the absence of oxirane. The obtained co- and terpolymers could be degraded under acidic conditions due to the acetal moieties in the main chain. The strategy devised in this study shows a promising avenue for employing plant-derived "nonhomopolymerizable" compounds as building blocks for the synthesis of degradable co- and terpolymers with general-purpose monomers.

Desilylation-Triggered Degradable Silylacetal Polymers Synthesized via Controlled Cationic Copolymerization of Trimethylsilyl Vinyl Ether and Cyclic Acetals.

Silylacetal was demonstrated to function as a promising cleavable moiety for preparing polymers degradable via desilylation under diverse, mild conditions. The silylacetal moieties were installed in the main chain of the polymers via the controlled cationic copolymerization of trimethylsilyl vinyl ether (TMSVE) and a cyclic acetal under appropriately designed conditions. Importantly, desilylation reactions of the silylacetal units occurred under weak acid, base, or fluoride ion conditions, which triggered the degradation of the polymer via the spontaneous cleavage of the unstable hemiacetal moieties generated by the desilylation. Moreover, silylacetal moieties were successfully incorporated at the desired positions in the main chain via the addition of a small portion of TMSVE during the controlled cationic copolymerization of a vinyl ether and cyclic acetal. The strategy devised in this study will allow the design of elaborate polymers that undergo degradation triggered by various stimuli.

Ring-Like Assembly of Silica Nanospheres in the Presence of Amphiphilic Block Copolymer: Effects of Particle Size.

Block copolymer-mediated self-assembly of colloidal nanoparticles has attracted great attention for the fabrication of a wide variety of nanoparticle arrays. We have previously shown that silica nanospheres (SNSs) 15 nm in diameter assemble into ring-like nanostructures in the presence of amphiphilic block copolymers poly[(2-ethoxyethyl vinyl ether)- block-(2-methoxyethyl vinyl ether)] (EOVE-MOVE) in an aqueous phase. Here, the effects of particle size of SNSs on this polymer-mediated self-assembly are studied systematically using scanning electron microscopy to observe SNSs of seven different sizes between 13 to 42 nm. SNSs of 13, 16, 19, and 21 nm in diameter assemble into nanorings in the presence of EOVE-MOVE. In contrast, larger SNSs of 26, 34, and 42 nm aggregate heavily, form chain-like networks, and remain dispersed, respectively, instead of forming ring-like nanostructures. The assembly trend for 26-42 nm-SNSs agrees with that expected from the increased colloidal stability for larger particles. Time-course observation for the assembled morphology of 16 nm-SNSs reveals that the nanorings, once formed, assemble further into network-like structures, as if the nanorings behave as building units for higher-order assembly. This indicates that the ring-like assembly is a fast process that can proceed onto random colloidal aggregation. Detailed analysis of nanoring structures revealed that the average number of SNSs comprising one ring decreased from 5.0 to 3.1 with increasing the SNS size from 13 to 21 nm. A change in the number of ring members was also observed when the length of EOVE-MOVE varied while the size of SNSs was fixed. Dynamic light scattering measurements and atomic force microscopy confirmed the SNSs/polymer composite structures. We hypothesize that a stable composite morphology may exist that is influenced by both the size of SNSs and the polymer molecular structures.

Aggregation of Cationic Amphiphilic Block and Random Copoly(vinyl ether)s with Antimicrobial Activity.

In this study, we investigated the aggregation behaviors of amphiphilic poly(vinyl ether)s with antimicrobial activity. We synthesized a di-block poly(vinyl ether), B3826, composed of cationic primary amine and hydrophobic isobutyl (iBu) side chains, which previously showed antimicrobial activity against Escherichia coli. B3826 showed similar uptake behaviors as those for a hydrophobic fluorescent dye, 1,6-diphenyl-1,3,5-hexatriene, to counterpart polymers including homopolymer H44 and random copolymer R4025, indicating that the iBu block does not form strong hydrophobic domains. The cryo-TEM observations also indicated that the polymer aggregate of B3826 appears to have low-density polymer chains without any defined microscopic structures. We speculate that B3826 formed large aggregates by liquid-liquid separation due to the weak association of polymer chains. The fluorescence microscopy images showed that B3826 bonds to E. coli cell surfaces, and these bacterial cells were stained by propidium iodide, indicating that the cell membranes were significantly damaged. The results suggest that block copolymers may provide a new platform to design and develop antimicrobial materials that can utilize assembled structures and properties.

Heterogeneous adhesion of cells on polymer surfaces with underlying amorphous/crystalline phases.

Fibroblastic adhesion behaviour on films of a poly[(2-methoxyethyl vinyl ether) (PMOVE)-block-(l-lactic acid) (PLLA)], in which the surface was covered with PMOVE, was studied. Fibroblasts were sufficiently sensitive to identify crystalline/non-crystalline regions existing beneath the surface PMOVE layer.

Tandem Reaction of Cationic Copolymerization and Concertedly Induced Hetero-Diels-Alder Reaction Preparing Sequence-Regulated Polymers.

A unique tandem reaction of sequence-controlled cationic copolymerization and site-specific hetero-Diels-Alder (DA) reaction is demonstrated. In the controlled cationic copolymerization of furfural and 2-acetoxyethyl vinyl ether (AcOVE), only the furan ring adjacent to the propagating carbocation underwent the hetero-DA reaction with the aldehyde moiety of another furfural molecule. A further and equally important feature of the copolymerization is that the obtained copolymers had unprecedented 2:(1 + 1)-type alternating structures of repeating sequences of two VE and one furfural units in the main chain and one furfural unit in the side chain. The specific DA reaction is attributed to the delocalization of the positive charge to the side furan ring.

Evaluation of a combination tumor treatment using thermo-triggered liposomal drug delivery and carbon ion irradiation.

The combination of radiotherapy with chemotherapy is one of the most promising strategies for cancer treatment. Here, a novel combination strategy utilizing carbon ion irradiation as a high-linear energy transfer (LET) radiotherapy and a thermo-triggered nanodevice is proposed, and drug accumulation in the tumor and treatment effects are evaluated using magnetic resonance imaging relaxometry and immunohistology (Ki-67, n = 15). The thermo-triggered liposomal anticancer nanodevice was administered into colon-26 tumor-grafted mice, and drug accumulation and efficacy was compared for 6 groups (n = 32) that received or did not receive the radiotherapy and thermo trigger. In vivo quantitative R1 maps visually demonstrated that the multimodal thermosensitive polymer-modified liposomes (MTPLs) can accumulate in the tumor tissue regardless of whether the region was irradiated by carbon ions or not. The tumor volume after combination treatment with carbon ion irradiation and MTPLs with thermo-triggering was significantly smaller than all the control groups at 8 days after treatment. The proposed strategy of combining high-LET irradiation and the nanodevice provides an effective approach for minimally invasive cancer treatment.

Concurrent Cationic Vinyl-Addition and Coordination Ring-Opening Copolymerization via Orthogonal Propagation and Transient Merging at the Propagating Chain End.

Controlled cationic vinyl-addition polymerization of an alkyl vinyl ether (VE) and ring-opening polymerization of ε-caprolactone (CL) simultaneously proceeded using HfCl4/Hf(OBu)4 as a dual-role catalyst for both mechanisms, yielding a graft copolymer consisting of a poly(VE) main chain and several poly(CL) side chains. The copolymer of conventionally incompatible monomers was generated via the unprecedented mechanisms consisting of orthogonal propagating reactions and transient merging. Specifically, the poly(CL) chains were incorporated into a poly(VE) chain through an exchange reaction between the VE-derived alkoxy group and the propagating poly(CL) chain at the acetal moiety of the propagating end of the poly(VE) chain. An appropriate ratio of HfCl4 and Hf(OBu)4 was indispensable for both the simultaneous vinyl-addition and ring-opening polymerizations and the alkoxy group exchange reaction.

Stereospecific Living Cationic Polymerization of N-Vinylcarbazole through the Design of ZnCl2-Derived Counteranions.

Highly stereospecific living polymerization of N-vinylcarbazole (NVC) successfully proceeded via a cationic mechanism as a result of the elaborate design of counteranions using an initiating system consisting of CF3SO3H, nBu4NX (X = Cl, Br, I), and a Lewis acid catalyst. The use of ZnCl2 and an appropriate amount of nBu4NCl quantitatively generated highly isotactic polymers (mm = 94%) with narrow molecular weight distributions (Mw/Mn ∼ 1.3) and molecular weights proportional to monomer conversion. In this system, a ZnCl42- species, which was formed as a counteranion of the propagating carbocation, most likely contributed to the stereoregulation of the polymers because the mm value drastically varied depending on the polymerization conditions, such as the Lewis acid catalyst and amount of added salt. Isotactic poly(N-vinylcarbazole) (PVK) showed different properties than atactic PVK based on fluorescence and differential scanning calorimetry (DSC) analysis.

Multifunctional liposomes having target specificity, temperature-triggered release, and near-infrared fluorescence imaging for tumor-specific chemotherapy.

We designed functional liposomes with target specificity, temperature-triggered drug release, and near-infrared fluorescence imaging. We prepared the liposomes by triple functionalization of stable pegylated liposomes with thermosensitive poly[2-(2-ethoxy)ethoxyethyl vinyl ether] chains (lower critical solution temperature around 38 °C) with conjugation of antibody trastuzumab (Herceptin, HER), which targets human epidermal growth factor 2, and with incorporation of indocyanine green for near-infrared fluorescence imaging. The liposomes retained DOX in the interior below physiological temperature but released DOX immediately at temperatures higher than 40 °C. The liposomes exhibited excellent ability for association and internalization to target cells overexpressing Her-2, such as SK-OV3 and SB-BR3 cells, and killed these cells when heated at 45 °C for 5 min. When administered intravenously to mice bearing SK-OV3 tumor, the liposomes having HER accumulated in the tumor more efficiently than the liposomes without HER. They stayed there more than 48 h, as judged with near-infrared fluorescence imaging. Furthermore, when the tumor sites of the mice being administered with the DOX-loaded liposomes were heated mildly at 44°C for 10 min at 7h after administration, tumor growth was suppressed strongly thereafter. Treatment with the HER-conjugated liposomes produced more efficient tumor-suppressive effects. Results demonstrate that the synergy of target-specific association, temperature-triggered drug release, and imaging is important for efficient tumor chemotherapy.

Thermoactivatable polymer-grafted liposomes for low-invasive image-guided chemotherapy.

The objective of this study was to develop a thermotriggered, polymer-based liposomal drug carrier with an activatable magnetic resonance imaging (MRI) contrast property for monitoring the release of substances and for localized tumor therapy. The multimodal thermoactivatable polymer-grafted liposomes (MTPLs) were tested to investigate whether the accumulation of MTPLs in colon-26 grafted tumors could be visualized in vivo using MRI and optical imaging, whether MTPLs induce signal enhancement, reflecting the release of their contents, after triggering by short-term heating (42.5°C for 10 minutes) 9 hours after MTPL administration (late-phase triggering), and whether MTPLs can provide a sufficient antitumor effect. The imaging and therapeutic properties of MTPLs were tested both in vitro and in vivo (BALB/c nude mice: heated group with MTPLs (n = 5), nonheated group with MTPLs (n = 5), heated group with doxorubicin-free MTPLs (n = 5), nonheated group with manganese-free MTPLs (n = 5), and kinetics observation group (n = 3); N = 23). Through in vivo MRI and fluorescent imaging, the MTPLs were shown to have significantly accumulated in the grafted colon-26 tumors 8 hours after administration. Delayed thermotriggering (9 hours after administration) caused MR signal enhancement, reflecting the release of their contents, after a short exposure to tolerable heat. In addition, significant antitumor effects were observed after treatment. The proposed polymer-based activatable MTPLs with a "delayed thermotrigger" provide a promising technology for cancer theranostics that allows minimal adverse effects and rapid interactive therapy.

Switchable dispersivity and molecular-trapping performance of mesostructured CaCO3-thermosensitive polymer composite microspheres.

Monodispersed thermosensitive microspheres were synthesized by the combination of poly(N-isopropylacrylamide) (PNIPAAm) and a mesostructured framework consisting of vaterite CaCO3 nanocrystals ∼20 nm in diameter. The switchable dispersivity in water and organic media was provided to the rigid porous framework by the soft shell of the thermosensitive organic component. The microspheres were shuttlecocked between water and hydrophobic organic media by a swing in temperature across the lower critical solution temperature (LCST). The composite microspheres performed as an active carrier of organic molecules due to their switchable property. Hydrophobic molecules were captured by the microspheres dispersed in an organic medium above LCST and were then delivered and released to another organic phase through a water phase by a swing in temperature.