Stimuli-responsive Block Copolymers Research Articles

Dual Stimuli-Responsive Block Copolymers for Controlled Release Triggered by Upconversion Luminescence or Temperature Variation.

An amphiphilic block copolymer (BCP) which contains both photoresponsive and thermoresponsive blocks was synthesized by the atom transfer radical polymerization approach. Meanwhile, a new core/shell type of the upconversion nanoparticle (UCNP) LiYF4:Yb3+0.25,Tm3+0.01@LiYF4:Yb3+0.2 was successfully synthesized. By encapsulating UCNPs inside the micelles of the BCP and incorporating Nile red (NR) into the UCNP@BCP hybrid nanoparticles as a model drug, controlled release of the drug by the dual-stimuli BCP could be studied. After exposing the UCNP-loaded micellar solution to near-infrared (NIR) light, it was found that the UV light pumped from UCNPs could disrupt the polymer micelles and the fluorescence intensity of NR decreased with the increase of the irradiation time of the NIR light. The thermoresponsive study indicated that the fluorescence intensity of NR decreased with the increase of temperature of the micellar solution because of the release of NR into water arising from the contraction of the amphiphilic BCP.

Triple-Responsive Block Copolymer Micelles with Synergistic pH and Temperature Response

Multifunctional, stimuli-responsive block copolymers have been prepared via the sequential atom transfer radical polymerization (ATRP) of 2-(dimethylamino)ethyl methacrylate (DMAEMA) and the in-house synthesized 1′-(2-methacryloxyethyl)-3′,3′-dimethyl-6-nitrospiro-(2H-1-benzopyran-2,2′-indoline) (SPMA) monomer. Two PDMAEMA-b-PSPMA diblock copolymers, containing 3 and 14 mol % SPMA, were synthesized. The amphiphilic nature of the PDMAEMA-b-PSPMA diblock copolymers led to the formation of well-defined spherical micelles, comprising a hydrophobic PSPMA core and a hydrophilic PDMAEMA shell, in water. The combination of the pH- and temperature-responsive character of PDMAEMA with the pH-, temperature-, and light-sensitive properties of the PSPMA block has resulted in a complex responsive behavior of the copolymer micelles in aqueous solution, when applying three different external stimuli (i.e., light irradiation, pH, and temperature). More importantly, the synergistic response of the block copolymer micelles ...

Functional Modification of Silica through Enhanced Adsorption of Elastin-Like Polypeptide Block Copolymers.

A powerful tool for controlling interfacial properties and molecular architecture relies on the tailored adsorption of stimuli-responsive block copolymers onto surfaces. Here, we use computational and experimental approaches to investigate the adsorption behavior of thermally responsive polypeptide block copolymers (elastin-like polypeptides, ELPs) onto silica surfaces, and to explore the effects of surface affinity and micellization on the adsorption kinetics and the resultant polypeptide layers. We demonstrate that genetic incorporation of a silica-binding peptide (silaffin R5) results in enhanced adsorption of these block copolymers onto silica surfaces as measured by quartz crystal microbalance and ellipsometry. We find that the silaffin peptide can also direct micelle adsorption, leading to close-packed micellar arrangements that are distinct from the sparse, patchy arrangements observed for ELP micelles lacking a silaffin tag, as evidenced by atomic force microscopy measurements. These experimental findings are consistent with results of dissipative particle dynamics simulations. Wettability measurements suggest that surface immobilization hampers the temperature-dependent conformational change of ELP micelles, while adsorbed ELP unimers (i.e., unmicellized block copolymers) retain their thermally responsive property at interfaces. These observations provide guidance on the use of ELP block copolymers as building blocks for fabricating smart surfaces and interfaces with programmable architecture and functionality.

Dual Location, Dual Acidic pH/Reduction-Responsive Degradable Block Copolymer: Synthesis and Investigation of Ketal Linkage Instability under ATRP Conditions

Stimuli-responsive degradation (SRD) undergoing chemical transition through the cleavage of labile linkages has been proved to dramatically increase the versatility of stimuli-responsive block copolymers. In particular, dual or multiple stimuli-responsive degradable block copolymers that can be triggered by two endogenous stimuli of acidic pH and reduction are in high demand. Here, a new strategy utilizing atom transfer radical polymerization (ATRP) is reported to synthesize a dual acidic pH/reduction-responsive degradable block copolymer (DLDSRD) labeled with an acidic pH-labile ketal linkage at the block junction and pendant reductively cleavable disulfide groups in hydrophobic block at dual locations. A robust route with multiple steps utilizing carbamate chemistry to endow stability during protection/deprotection steps enables the synthesis of a novel poly(ethylene glycol)-based ATRP macroinitiator labeled with a ketal linkage (PEG-ketal-Br macroinitiator). Conducting ATRP allows for the synthesis of ...

A robust strategy for preparation of sequential stimuli-responsive block copolymer prodrugs via thiolactone chemistry to overcome multiple anticancer drug delivery barriers

Block copolymer prodrugs (BCPs) have attracted considerable attentions in clinical translation of nanomedicine owing to their self-assembly into well-defined core-shell nanoparticles for improved pharmacokinetics, stability in blood circulation without drug leakage, and optimized biodistribution. However, a cascade of physiological barriers against specific delivery of drugs into tumor cells limit the final therapeutic efficacy. Herein, we report a robust and facile strategy based on thiolactone chemistry to fabricate well-defined BCPs with sequential tumor pH-promoted cellular internalization and intracellular stimuli-responsive drug release. A series of BCPs were prepared through one-pot synthesis from clinically used small molecule anticancer drugs. The ring-opening reaction of drug-conjugated thiolactones releases mercapto groups via aminolysis by N-(3-aminopropyl)-imidazole, which further react with poly(ethylene glycol)-block-poly(pyridyldisulfide ethylmethacrylate) (PEG-PDSEMA) to produce imidazole and disulfide bonds-incorporated BCPs. Taking paclitaxel (PTX) for example, PTX BCPs exhibited high drug-loading content (>50%) and low critical micellization concentration (5 × 10−3 g/L), which can self-assemble into micellar nanoparticles in aqueous solution with a small size (∼40 nm). The nanoparticles showed high tumor accumulation and uniform distribution in hypopermeable tumors via systemic administration. Meanwhile, imidazole moieties endow nanoparticles tumor pH-sensitive charge transition from nearly neutral to positive, which promoted cellular internalization. Disulfide bonds can be cleaved by intracellular glutathione (GSH) of cancer cells, which accelerate the release of active PTX drug inside cells. Finally, highly aggressive murine breast cancer 4T1 tumor and hypopermeable human pancreatic adenocarcinoma BxPC3 tumor were completely ablated after treatment by PTX BCP nanoparticles. Consequently, the robust and facile preparation strategy based on thiolactone chemistry represents an efficient approach to construct multifunctional BCPs for better therapeutic efficacy via addressing multiple physiological barriers.

Novel Pentablock Copolymers as Thermosensitive Self-Assembling Micelles for Ocular Drug Delivery.

Many studies have focused on how drugs are formulated in the sol state at room temperature leading to the formation of in situ gel at eye temperature to provide a controlled drug release. Stimuli-responsive block copolymer hydrogels possess several advantages including uncomplicated drug formulation and ease of application, no organic solvent, protective environment for drugs, site-specificity, prolonged and localized drug delivery, lower systemic toxicity, and capability to deliver both hydrophobic and hydrophilic drugs. Self-assembling block copolymers (such as diblock, triblock, and pentablock copolymers) with large solubility variation between hydrophilic and hydrophobic segments are capable of making temperature-dependent micellar assembles, and with further increase in the temperature, of jellifying due to micellar aggregation. In general, molecular weight, hydrophobicity, and block arrangement have a significant effect on polymer crystallinity, micelle size, and in vitro drug release profile. The limitations of creature triblock copolymers as initial burst release can be largely avoided using micelles made of pentablock copolymers. Moreover, formulations based on pentablock copolymers can sustain drug release for a longer time. The present study aims to provide a concise overview of the initial and recent progresses in the design of hydrogel-based ocular drug delivery systems.

Stimuli-Responsive Block Copolymer-Based Assemblies for Cargo Delivery and Theranostic Applications.

Although a number of tactics towards the fabrication and biomedical exploration of stimuli-responsive polymeric assemblies being responsive and adaptive to various factors have appeared, the controlled preparation of assemblies with well-defined physicochemical properties and tailor-made functions are still challenges. These responsive polymeric assemblies, which are triggered by stimuli, always exhibited reversible or irreversible changes in chemical structures and physical properties. However, simple drug/polymer nanocomplexes cannot deliver or release drugs into the diseased sites and cells on-demand due to the inevitable biological barriers. Hence, utilizing therapeutic or imaging agents-loaded stimuli-responsive block copolymer assemblies that are responsive to tumor internal microenvironments (pH, redox, enzyme, and temperature, etc.) or external stimuli (light and electromagnetic field, etc.) have emerged to be an important solution to improve therapeutic efficacy and imaging sensitivity through rationally designing as well as self-assembling approaches. In this review, we summarize a portion of recent progress in tumor and intracellular microenvironment responsive block copolymer assemblies and their applications in anticancer drug delivery and triggered release and enhanced imaging sensitivity. The outlook on future developments is also discussed. We hope that this review can stimulate more revolutionary ideas and novel concepts and meet the significant interest to diverse readers.

Synthesis and self-assembly of high molecular weight polystyrene-block-poly[2-(N-morpholino)ethyl methacrylate]: A story about microphase separation, amphiphilicity, and stimuli-responsivity

The synthesis of polystyrene-block-poly[2-(N-morpholino)ethyl methacrylate] (PS-b-PMEMA) as a new highly amphiphilic and multiple stimuli-responsive block copolymer is presented. To achieve high molecular weights far beyond 100 kDa in a highly controlled manner (dispersities < 1.1), a synthetic route via sequential combination of anionic polymerization for the PS block and reversible addition–fragmentation chain transfer (RAFT) polymerization for the PMEMA block is used. The synthesized block copolymers are investigated regarding their microphase separation in bulk, which delivers well-ordered self-assembled bulk structures as evidenced by small-angle x-ray scattering (SAXS) and atomic force microscopy (AFM). In aqueous solution, the block copolymer self-assembles into narrowly size distributed micelles with a PMEMA corona. The stimuli-triggered micelle response towards temperature, pH, and kosmotropic as well as chaotropic salts is shown via various dynamic light scattering (DLS) experiments. Furthermore, a dependency of aggregate size on solvent composition in polymer/tetrahydrofuran/water mixtures is described. The reported findings deliver a feasible pathway to high molecular weight block copolymers with tailored chemical properties and show the potential of PS-b-PMEMA as material for mechanically demanding switchable devices.

Novel stimuli-responsive block copolymers as nonviral gene delivery vectors for efficiently overcoming physiologic barriers

Novel stimuli-responsive block copolymers as nonviral gene delivery vectors for efficiently overcoming physiologic barriers

Smart block copolymers of PVP and an alkylated PVP derivative: synthesis, characterization, thermoresponsive behaviour and self-assembly

Stimuli responsive block copolymers of biocompatible poly(3-ethyl-N-vinylpyrrolidone) and poly(N-vinylpyrrolidone), i.e. EPVP–PVP, were readily synthesized via RAFT-mediated polymerization.

Precise Control over the Rheological Behavior of Associating Stimuli-Responsive Block Copolymer Gels.

“Smart” materials have considerably evolved over the last few years for specific applications. They rely on intelligent macromolecules or (supra-)molecular motifs to adapt their structure and properties in response to external triggers. Here, a supramolecular stimuli-responsive polymer gel is constructed from heterotelechelic double hydrophilic block copolymers that incorporate thermo-responsive sequences. These macromolecular building units are synthesized via a three-step controlled radical copolymerization and then hierarchically assembled to yield coordination micellar hydrogels. The dynamic mechanical properties of this particular class of materials are studied in shear flow and finely tuned via temperature changes. Notably, rheological experiments show that structurally reinforcing the micellar network nodes leads to precise tuning of the viscoelastic response and yield behavior of the material. Hence, they constitute promising candidates for specific applications, such as mechano-sensors.

Preparation of dual stimuli-responsive block copolymers based on different activated esters with distinct reactivities

In the present study, we described a facile method for introducing functional moieties into block copolymer structures by sequential aminolysis of pentafluorophenyl acrylate (PFPA) ester and methyl salicylate acrylate (MSA) ester. For the first time, reversible addition-fragmentation transfer (RAFT) polymerization of MSA yielding block copolymers poly(MSA)-b-poly(PFPA) was reported. The yielded block copolymers were subsequently modified step-by-step using amino moieties, affording polymers with bespoke functionality. By exploring the reactivity difference of two activated esters (PFPA and MSA) toward amines, the installation of amine functionalities on polymer backbones while maintaining a block copolymer architecture was realized in a controlled manner. The selective reactivity of these two esters (PFPA and MSA) toward aliphatic amines, such as isopropylamine, cyclopropylamine and N,N-diethylethylenediamine, provided a novel synthetic approach in making temperature and pH dual responsive polymers. Finally, the self-assembly behavior of the obtained block copolymers was investigated.

Cytosol-Specific Fluorogenic Reactions for Visualizing Intracellular Disintegration of Responsive Polymeric Nanocarriers and Triggered Drug Release

Supramolecular aggregates of stimuli-responsive block copolymers are increasingly utilized as drug nanocarriers. Although in situ tracking their triggered disintegration and drug release processes at the cellular level is highly desirable, it remains a considerable challenge. We report the fabrication of double hydrophilic block copolymers covalently conjugated with α,β-unsaturated ketone-caged coumarin functionalities in the thermoresponsive block. Upon thermo-induced micellization and cellular uptake, Michael addition reaction of unsaturated ketone moieties with thiol compounds (GSH and Cys) in the reductive subcellular compartments leads to micelle-to-unimer transition. This is accompanied by concomitant fluorescence emission turn-on and triggered drug release, allowing for the process visualization.

Abstract 4889: Oncolytic adenovirus coated with stimuli responsive block copolymer mPEG-b-poly(His) induces tumor microenvironment-specific antitumor efficacy

Abstract Adenovirus (Ad) has shown great promise in cancer gene therapy. Ad coated with cationic polymers have already been shown to enhance transduction, but it showed nonspecific binding with cells, resulted in evoked side effect. To overcome these hurdles, in this study adenovirus coated with pH sensitive poly(His) polymer through ionic interaction for passive tumor targeting. We have characterized the effect of polymer concentration on particle size distribution, zeta potential, transduction efficiency, and structural properties. Remarkable enhanced transduction efficiency was observed in cells treated with Ad/poly(His) nanocomplex compared to naked Ad at low pH. In addition, cellular trafficking using time lapse total internal reflection fluorescence showed that the Ad/poly(His) nanocomplex was significantly enhanced cellular uptake at lower pH, in contrast to neutral pH. The biodistribution study confirmed that the Ad/poly(His) nanocomplex can effectively accumulate at the tumor site by the EPR effect and exhibited 3.3-fold higher luciferase expressions in tumor than the naked Ad. Additionally, MTT assay and cancer cell xenografts studies showed that polymer coated nanocomplex exhibited high cancer cell killing effect and also inhibited the tumor growth. Furthermore, poly(His)-coated Ad complex was not significantly inhibited by serum, in contrast to naked Ad. Moreover, Ad/poly(His) nanocomplex significantly reduced the innate immune response in contrast to naked Ad, as assessed by interleukin-6 cytokine release from macrophage cells in vivo. These results suggest that the stimuli-responsive Ad/poly(His) nanocomplex has potential to targeting tumors. Note: This abstract was not presented at the meeting. Citation Format: Chae-Ok Yun. Oncolytic adenovirus coated with stimuli responsive block copolymer mPEG-b-poly(His) induces tumor microenvironment-specific antitumor efficacy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4889. doi:10.1158/1538-7445.AM2014-4889

Synthesis and reduction-responsive disassembly of PLA-based mono-cleavable micelles

Stimuli-responsive block copolymers and their self-assembled nanostructures have been extensively studied as effective building blocks in construction of various nanomaterials in nanoscience and nanotechnology. A promising stimuli-responsive platform involves an incorportion of reduction-responsive disulfide linkages that can be cleaved to corresponding thiols when needed. Herein, we describe a novel approach utilizing a combination of ring-opening polymerization and a facile coupling reaction to synthesize a reduction-responsive triblock copolymer comprising biocompatible polylactide (PLA) and poly(ethylene glycol) (PEG) blocks, thus PEG-b(PLA-ss-PLA)-b-PEG (ssBCP). This copolymer self-assembles to form colloidally-stable mono-cleavable micelles having single disulfides in hydrophobic PLA cores surrounded with PEG coronas in aqueous solution. The reductive cleavage of the core disulfides results in changes in micelle morphologies to smaller nanostructures or larger aggregates, depending on the nature of reducing agents. In the presence of glutathione (a cellular reducing agent), the micelle size increases, which enhances the release of encapsulated anticancer drugs in vitro. For biological perspectives, the ssBCP micelles having hydrophilic PEG corona are non-cytotoxic and exhibit enhanced colloidal stability as well as non-specific interactions with proteins.

A supramolecular approach for fabrication of photo-responsive block-controllable supramolecular polymers

Self-assembly of stimuli-responsive block copolymers in aqueous solution has attracted considerable attention in the past few decades. Herein, we report a supramolecular modular synthetic approach for the fabrication of photo-responsive block-controllable supramolecular polymers (BSPs) based on the assembly of two homopolymers in water. The homopolymers, namely, the polystyrene modified with adamantane and azobenzene as the end groups (Ad–PS–Azo) and poly(ethylene glycol) modified with β-CD (PEG–β-CD), were successfully synthesized via atom transfer radical polymerization (ATRP) and click chemistry, respectively. The supramolecular triblock copolymer (STP) was constructed through host–guest interactions between β-CD and Ad/Azo moieties, and further self-assembled into micelles in aqueous solution, which were investigated by transmission electron microscopy (TEM) and dynamic light scattering (DLS). This well-defined supramolecular triblock copolymer can reversibly disassemble into a supramolecular diblock copolymer (SDP) by alternating irradiation of UV/visible light, which was revealed by TEM, UV-vis and 1H NMR.

Stimuli-responsive block copolymer micellar carriers with a spontaneous cylinder-to-sphere morphology evolution for nile red delivery and controlled release

Stimuli-responsive block copolymer micellar carriers with a spontaneous cylinder-to-sphere morphology evolution for nile red delivery and controlled release

Agarose Hydrogels Embedded with pH-Responsive Diblock Copolymer Micelles for Triggered Release of Substances

Hybrid agarose hydrogels embedded with pH-responsive diblock copolymers micelles were developed to achieve functional hydrogels capable of stimulus-triggered drug release. Specifically, a well-defined poly(ethylene oxide) (PEO)-based diblock copolymer, PEO-b-poly(2-(N,N-diisopropylamino)ethyl methacrylate) (PEO(113)-b-PDPAEMA(31), where the subscripts represent the degrees of polymerization of two blocks), was synthesized by atom transfer radical polymerization. PDPAEMA is a pH-responsive polymer with a pKa value of 6.3. The PEO(113)-b-PDPAEMA(31) micelles were formed by a solvent-switching method, and their pH-dependent dissociation behavior was investigated by dynamic light scattering and fluorescence spectroscopy. Both studies indicated that the micelles were completely disassembled at pH = 6.40. The biocompatibility of PEO(113)-b-PDPAEMA(31) micelles was demonstrated by in vitro primary cortical neural culture. Hybrid agarose hydrogels were made by cooling 1.0 wt % agarose solutions that contained various amounts of PEO(113)-b-PDPAEMA(31) micelles at either 2 or 4 °C. Rheological measurements showed that the mechanical properties of gels were not significantly adversely affected by the incorporation of diblock copolymer micelles with a concentration as high as 5.0 mg/g. Using Nile Red as a model hydrophobic drug, its incorporation into the core of diblock copolymer micelles was demonstrated. Characterized by fluorescent spectroscopy, the release of Nile Red from the hybrid hydrogel was shown to be controllable by pH due to the responsiveness of the block copolymer micelles. Based on the prominent use of agarose gels as scaffolds for cell transplantation for neural repair, the hybrid hydrogels embedded with stimuli-responsive block copolymer micelles could allow the controlled delivery of hydrophobic neuroprotective agents to improve survival of transplanted cells in tune with signals from the surrounding pathological environment.

556. Enhanced Anti-Tumor Efficacy by Oncolytic Adenovirus Using a Stimuli Responsive Block Copolymer mPEG-b-Poly(His)

556. Enhanced Anti-Tumor Efficacy by Oncolytic Adenovirus Using a Stimuli Responsive Block Copolymer mPEG-b-Poly(His)

Functional block copolymer assemblies responsive to tumor and intracellular microenvironments for site-specific drug delivery and enhanced imaging performance

Self-assembled nanostructures of amphiphilic and double hydrophilic block copolymers have been increasingly utilized as potent polymeric nanocarriers of therapeutic drugs, genes, bioactive molecules, and imaging/contrast agents due to improved water solubility, bioavailability, and extended blood circulation duration. Though passive and active targeted drug delivery strategies have long been proposed to promote desirable drug accumulation specifically at the disease sites, the introduction of stimuli-responsiveness into self-assembled block copolymer nanocarriers can additionally lead to controlled/triggered release of therapeutic/imaging agents into target pathological tissues and cells, with concomitant advantages of enhanced delivery efficiency and therapeutic efficacy. Appropriately designed stimuli-responsive block copolymer assemblies can exhibit chemical structure transformation, microstructural rearrangement and inversion, or even disassembly into unimers or smaller ones under external stimuli such as pH, temperature, ion strength, redox potential, light, electric, and magnetic fields, and specific bioactive molecules and metabolites. Compared to normal tissues, pathological sites such as tumor tissues typically exhibit vascular abnormalities, weak acidity (~pH 6.8), abnormal temperatures, over-expressed proteins and enzymes, hypoxia, high levels of metabolites and reactive small molecule species, etc. Moreover, upon cellular uptake, drug-loaded polymeric nanocarriers will be subjected to intracellular pH gradients (pH 5.9-6.2 in early endosomes and pH 5.0-5.5 in late endosomes and lysosomes) and redox and H2O2 gradients within different cell organelles and the cytosol. Thus, block copolymer nanocarriers responsive to the above described bio-relevant stimuli or biochemical signals characteristic of pathologic tissues and cells will provide an alternative type of "active targeting" strategy, which can be utilized to further boost therapeutic efficacy and imaging sensitivity via disease site-specific delivery and controlled release. A variety of extracellular or intracellular stimuli innate to disease sites, such as mildly acidic pH, temperature, enzymes (matrix metalloproteinase, β-glucuronidase, and phosphatase), oxidative/reductive microenvironments, and abnormal levels of bioactive molecules or metabolites, have been utilized for this purpose. In this review, we summarize recent advances in stimuli-responsive block copolymer assemblies which are responsive to tumor and intracellular microenvironments and their applications in anticancer drug delivery and enhanced imaging sensitivity.