Construction of Polyelectrolyte-Responsive Microgels, and Polyelectrolyte Concentration and Chain Length-Dependent Adsorption Kinetics

We report on the construction of a polyelectrolyte-responsive system evolved from sterically stabilized protonated poly­(2-vinylpyridine) (P2VPH⁺) microgels. Negatively charged sodium dodecylbenzenesulfonate (SDBS) surfactants could be readily internalized into the cationic microgels by means of electrostatic interactions, resulting in microgel collapse and concomitant formation of surfactant micellar domains (P2VPH⁺/SDBS)-contained electrostatic complexes. These internal hydrophobic domains conferred the opportunity of fluorescent dyes to be loaded. The obtained fluorescent microgel complexes could be further disintegrated in the presence of anionic polyelectrolyte, poly­(sodium 4-styrenesulfonate) (PNaStS). The stronger electrostatic attraction between multivalent P2VPH⁺ microgels and PNaStS polyelectrolyte than single-charged surfactant led to triggered release of the encapsulated pyrene dyes from the hydrophobic interiors into microgel dispersion. The process was confirmed by laser light scattering (LLS) and fluorescence measurements. Furthermore, the entire dynamic process of PNaStS adsorption into P2VPH⁺ microgel interior was further studied by stopped-flow equipment as a function of polyelectrolyte concentration and degree of polymerization. The whole adsorption process could be well fitted with a double-exponential function, suggesting a fast (τ₁) and a slow (τ₂) relaxation time, respectively. The fast process (τ₁) was correlated well with the approaching of PNaStS with P2VPH⁺ microgel to form a nonequilibrium complex within the microgel shell, while the slow process (τ₂) was consistent with the formation of equilibrium complexes in the microgel deeper inside. This simple yet feasible design augurs well for the promising applications in controlled release fields

Schizophrenic Core–Shell Microgels: Thermoregulated Core and Shell Swelling/Collapse by Combining UCST and LCST Phase Transitions

A variety of slightly cross-linked poly­(2-vinylpyridine)–poly­(<i>N</i>-isopropylacrylamide) (P2VP–PNIPAM) core–shell microgels with pH- and temperature-responsive characteristic were prepared via seeded emulsion polymerization. Negatively charged sodium 2,6-naphthalenedisulfonate (2,6-NDS) could be internalized into the inner core, followed by formation of (P2VPH⁺/SO₃^2–) supramolecular complex through the electrostatic attractive interaction in acid condition. The thermoresponsive characteristic feature of the (P2VPH⁺/SO₃^2–)–PNIPAM core–shell microgels was investigated by laser light scattering and UV–vis measurement, revealing an integration of upper critical solution temperature (UCST) and lower critical solution temperature (LCST) behaviors in the temperature range of 20–55 °C. The UCST performance arised from the compromised electrostatic attractive interaction between P2VPH⁺ and 2,6-NDS at elevated temperatures, while the subsequent LCST transition is correlated to the thermo-induced collapse of PNIPAM shells. The controlled release of 2,6-NDS was monitored by static fluorescence spectra as a function of temperature change. Moreover, stopped-flow equipped with a temperature-jump accessory was then employed to assess the dynamic process, suggesting a millisecond characteristic relaxation time of the 2,6-NDS diffusion process. Interestingly, the characteristic relaxation time is independent of the shell cross-link density, whereas it was significantly affected by shell thickness. We believe that these dual thermoresponsive core–shell microgels with thermotunable volume phase transition may augur promising applications in the fields of polymer science and materials, particularly for temperature-triggered release

Highly Selective Fluorogenic Multianalyte Biosensors Constructed via Enzyme-Catalyzed Coupling and Aggregation-Induced Emission

The development of a highly selective and fast responsive fluorogenic biosensor for diverse analytes ranging from bioactive small molecules to specific antigens is highly desirable but remains a considerable challenge. We herein propose a new approach by integrating substrate-selective enzymatic reactions with fluorogens exhibiting aggregation-induced emission feature. Tyrosine-functionalized tetraphenylethene, TPE-Tyr, molecularly dissolves in aqueous media with negligible fluorescence emission; upon addition of horseradish peroxidase (HRP) and H₂O₂, effective cross-linking occurs due to HRP-catalyzed oxidative coupling of tyrosine moieties in TPE-Tyr. This leads to fluorescence emission turn-on and fast detection of H₂O₂ with high sensitivity and selectivity. As a validation of the new strategy’s generality, we further configure it into the biosensor design for glucose through cascade enzymatic reactions and for pathologically relevant antigens (e.g., human carcinoembryonic antigen) by combining with the ELISA kit

Photo- and Reduction-Responsive Polymersomes for Programmed Release of Small and Macromolecular Payloads

We report on the preparation of photo- and reduction-responsive diblock copolymers through reversible addition–fragmentation chain transfer (RAFT) polymerization of a coumarin-based disulfide-containing monomer (i.e., CSSMA) using a poly­(ethylene oxide) (PEO)-based macroRAFT agent. The resulting amphiphilic PEO-<i>b</i>-PCSSMA copolymers self-assembled into polymersomes with hydrophilic PEO shielding coronas and hydrophobic bilayer membranes. Upon irradiating the polymersomes with visible light (e.g., 430 nm), the coumarin moieties within the bilayer membranes were cleaved with the generation of primary amine groups, which spontaneously underwent inter/intrachain amidation reactions with the ester moieties, thereby tracelessly cross-linking and permeating the bilayer membranes. Notably, this process only gave rise to the release of small molecule payloads (e.g., doxorubicin hydrochloride, DOX) while large molecule encapsulants (e.g., Texas red-labeled dextran, TR-dextran) were retained within the cross-linked polymersomes due to the preservation of the integrity of the vesicular nanostructures. However, cross-linked polymersomes undergo further structural disintegration upon incubation with glutathione (GSH) due to the scission of disulfide linkages, resulting in the release of macromolecular payloads. Thus, dual-stimuli responsive polymersomes with tracelessly cross-linkable characteristics enable sequential release of payloads with spatiotemporal precision, which could be of promising applications in synergistic loading and programmed release of therapeutics

Rationally Engineering Phototherapy Modules of Eosin-Conjugated Responsive Polymeric Nanocarriers via Intracellular Endocytic pH Gradients

Spatiotemporal switching of respective phototherapy modes at the cellular level with minimum side effects and high therapeutic efficacy is a major challenge for cancer phototherapy. Herein we demonstrate how to address this issue by employing photosensitizer-conjugated pH-responsive block copolymers in combination with intracellular endocytic pH gradients. At neutral pH corresponding to extracellular and cytosol milieu, the copolymers self-assemble into micelles with prominently quenched fluorescence emission and low ¹O₂ generation capability, favoring a highly efficient photothermal module. Under mildly acidic pH associated with endolysosomes, protonation-triggered micelle-to-unimer transition results in recovered emission and enhanced photodynamic ¹O₂ efficiency, which synergistically actuates release of encapsulated drugs, endosomal escape, and photochemical internalization processes

Near-Infrared Light-Activated Photochemical Internalization of Reduction-Responsive Polyprodrug Vesicles for Synergistic Photodynamic Therapy and Chemotherapy

The use of intracellular reductive microenvironment to control the release of therapeutic payloads has emerged as a popular approach to design and fabricate intelligent nanocarriers. However, these reduction-responsive nanocarriers are generally trapped within endolysosomes after internalization and are subjected to unwanted disintegration, remarkably compromising the therapeutic performance. Herein, amphiphilic polyprodrugs of poly­(<i>N</i>,<i>N</i>-dimethylacrylamide-<i>co</i>-EoS)-<i>b</i>-PCPTM were synthesized via sequential reversible addition–fragmentation chain transfer (RAFT) polymerization, where EoS and CPTM are Eosin Y- and camptothecin (CPT)-based monomers, respectively. An oil-in-water (O/W) emulsion method was applied to self-assemble the amphiphilic polyprodrugs into hybrid vesicles in the presence of hydrophobic oleic acid (OA)-stabilized upconversion nanoparticles (UCNPs, NaYF₄:Yb/Er), rendering it possible to activate the EoS photosensitizer under a near-infrared (NIR) laser irradiation with the generation of singlet oxygen (¹O₂) through the energy transfer between UCNPs and EoS moieties. Notably, the <i>in situ</i> generated singlet oxygen (¹O₂) can not only exert its photodynamic therapy (PDT) effect but also disrupt the membranes of endolysosomes and thus facilitate the endosomal escape of internalized nanocarriers (i.e., photochemical internalization (PCI)). Cell experiments revealed that the hybrid vesicles could be facilely taken up by endocytosis. Although the internalized hybrid vesicles were initially trapped within endolysosomes, a remarkable endosomal escape into the cytoplasm was observed under 980 nm laser irradiation as a result of the PCI effect of ¹O₂. The escaped hybrid vesicles subsequently underwent GSH-triggered CPT release in the cytosol, thereby activating the chemotherapy process. The integration of PDT module into the design of reduction-responsive nanocarriers provides a feasible approach to enhance the therapeutic performance

Efficient Synthesis of Single Gold Nanoparticle Hybrid Amphiphilic Triblock Copolymers and Their Controlled Self-Assembly

We report on a robust approach to the size-selective and template-free synthesis of asymmetrically functionalized ultrasmall (<4 nm) gold nanoparticles (AuNPs) stably anchored with a single amphiphilic triblock copolymer chain per NP. Directed NP self-assembly in aqueous solution can be facilely accomplished to afford organic/inorganic hybrid micelles, vesicles, rods, and large compound micelles by taking advantage of the rich microphase separation behavior of the as-synthesized AuNP hybrid amphiphilic triblock copolymers, PEO–AuNP–PS, which act as the polymer–metal–polymer analogue of conventional amphiphilic triblock copolymers. Factors affecting the size-selective fabrication and self-assembly characteristics and the time-dependent morphological evolution of NP assemblies were thoroughly explored

Application of Heterocyclic Polymers in the Ratiometric Spectrophotometric Determination of Fluoride

Herein we report the use of heterocyclic functional polymers in the ratiometric spectrophotometric determination of fluoride (F^–). Polymers incorporating benzo­[d]­[1,2,3]­triazole moieties linked to the polymer backbone via urea links are demonstrated to have utility for the ratiometric detection of the F^– ion, with a detection limit in the order of ∼2 μM. The hydrogen-bonding recognition between the benzo­[d]­[1,2,3]­triazole moiety and F^– ion was investigated using UV–vis spectrophotometry and NMR analysis. The importance of the urea linkage was elucidated by investigating a second benzo­[d]­[1,2,3]­triazole functional monomer wherein the heterocyclic group is attached to the polymerizable group via a carbamate linkage. The replacement of the urea link with a carbamate group led to significantly reduced F^– sensitivity. Moreover, by examining an analogous benzo­[d]­imidazole monomer it was demonstrated that having a nitrogen atom in the 2-position of the heterocycle was important for maximizing the sensitivity of the assay. Taken together, these results demonstrated that the urea-substituted benzo­[d]­[1,2,3]­triazole motif greatly enhances F^– ion detection. Importantly, the F^– ion sensing capability of the monomer is retained after incorporating into a diblock copolymer using reversible addition–fragmentation chain transfer (RAFT) polymerization

Nitric Oxide (NO) Endows Arylamine-Containing Block Copolymers with Unique Photoresponsive and Switchable LCST Properties

The fabrication of materials that are responsive to endogenous gasotransmitter molecules (i.e., nitric oxide, hydrogen sulfide, and carbon monoxide) has emerged as an area of increasing research interest. In the case of nitric oxide (NO), <i>o</i>-phenylene­diamine derivatives have traditionally been employed due to their ability to react with NO in the presence of oxygen (O₂) with the formation of benzotriazole residues. Herein, we report the synthesis of a novel NO-responsive polymer containing aromatic primary amine groups derived from <i>p</i>-phenylene­diamine groups (i.e., isomers of <i>o</i>-phenylene­diamine). A new NO-responsive monomer, <i>N</i>-(4-amino­phenyl)­methacrylamide (<i>p</i>-NAPMA), was first synthesized via the amidation of one of the primary amine groups in the <i>p</i>-phenylene­diamine with methacrylic anhydride. Notably, the <i>p</i>-NAPMA monomer can efficiently react with NO in aqueous solution in the presence of O₂ with the generation of phenyl­diazonium groups rather than benzotriazole moieties. While the resultant phenyl­diazonium residues were relatively stable in aqueous solution, they were highly sensitive to UV irradiation (i.e., λ_max = 365 nm) which gave the formation of phenol derivatives. After incorporation into a thermoresponsive block copolymer using reversible addition–fragmentation chain transfer (RAFT) polymerization, the resulting diblock copolymer, poly­(ethylene glycol)-<i>b</i>-(<i>N</i>-isopropyl­acrylamide-<i>co</i>-<i>p</i>-NAPMA) (PEG-<i>b</i>-P­(NIPAM-<i>co</i>-<i>p</i>-NAPMA)), was rendered with unique NO- and UV-responsive characteristics. Specifically, the NO-triggered transformation of <i>p</i>-NAPMA moieties into phenyl­diazonium residues dramatically elevated the lower critical solution temperature (LCST) of the block copolymer due to increased water solubility of phenyl­diazonium residues at neutral pH (i.e., pH 7.4). Further, subsequent UV irradiation significantly decreased the LCST due to the formation of relatively hydrophobic phenol derivatives from the hydrophilic phenyl­diazonium intermediate. These results demonstrate, for the first time, that NO-responsive polymers can be synthesized without the necessity of incorporating <i>o</i>-phenylene­diamine groups and that a further solubility switch can be stimulated by irradiation with ultraviolet light

Photoregulated Cross-Linking of Superparamagnetic Iron Oxide Nanoparticle (SPION) Loaded Hybrid Nanovectors with Synergistic Drug Release and Magnetic Resonance (MR) Imaging Enhancement

The development of stimuli-responsive magnetic resonance imaging (MRI) contrast agents that can selectively enhance imaging contrasts at pathological sites is of potential use in clinical diagnosis. Herein, a <i>T</i>₂-type MRI contrast agent with synergistically photoregulated enhanced MRI contrast and drug release was achieved by coassembly of superparamagnetic iron oxide nanoparticles (SPIONs) and doxorubicin (DOX) with amphiphilic block copolymer assemblies. Photosensitive amphiphilic diblock copolymers, poly­(ethylene oxide)-<i>b</i>-poly­(2-((((2-nitrobenzyl)­oxy)­carbonyl)­amino)­ethyl methacrylate) (PEO-<i>b</i>-PNBOC), were synthesized through reversible addition–fragmentation chain transfer (RAFT) polymerizations. The resulting block copolymers were coassembled with hydrophobic oleic acid (OA)-stabilized SPIONs and DOX via an oil-in-water (O/W) emulsion and a subsequent solvent evaporation procedure, resulting in the formation of DOX/SPION coloaded hybrid nanovectors. The as-assembled hybrid nanovectors exhibited retarded DOX release and weak <i>T</i>₂ relaxivity (<i>r</i>₂) prior to UV-irradiation. However, upon UV-irradiation, the hybrid nanovectors underwent cross-linking and a hydrophobic-to-hydrophilic transition within the cores, thereby selectively triggering DOX release and elevating <i>T</i>₂ relaxivities. <i>In vitro</i> DOX release results revealed approximately 85% of DOX was released within 10 h under 20 min UV-irradiation, and this was in sharp contrast with less than 5% of DOX release without UV-irradiation. The selective DOX release under UV-irradiation showed significantly increased cytotoxicity toward HepG2 cells. Meanwhile, the <i>r</i>₂ of UV-irradiated nanovectors exhibited 4.5- and 1.9-fold increases as compared to cetyltrimethyl­ammonium bromide (CTAB)-stabilized monodispersed SPIONs and nonirradiated hybrid nanovectors. Moreover, there was a linear correlation between the <i>r</i>₂ changes and cumulative DOX release extents, enabling instantaneously visualizing the DOX release by the MRI technique. Further, we demonstrated that the cellular internalization efficiency of the coloaded hybrid nanovectors increased by 2.7-fold in the presence of an external magnet. The magnetically guided cellular uptake, triggered release profile, and enhanced MRI contrast characteristics may presage potential applications as a new generation of theranostic platform