The past two decades have evidenced a tremendous growth in the field of responsive polymers, which can exhibit reversible or irreversible changes in physical properties and/or chemical structures to ...an external stimulus such as pH, temperature, ionic strength, light irradiation, mechanical forces, electric and magnetic fields, specific analytes, external additives (ions, bioactive molecules, etc.), or a combination of them. Responsive polymers can exist in the form of solutions, gels, self-assembled nanoparticles, (multilayer) films, and bulk solids. The field of responsive polymers has nowadays evolved well beyond the demonstration of novel and interesting properties. Currently, the exploitation of useful and advanced functions, e.g., drug or gene carriers with triggered release properties, catalysis, detection and imaging, environmentally adaptive coatings, and self-healing materials, has emerged to be a more relevant subject. In this Perspective, we focus on recent developments of responsive polymer-based chemo- and biosensors, highlighting this concept with selected literature reports. Such functional polymeric materials show prominent advantages such as tunable detection sensitivity, structural stability, aqueous dispersibility, biocompatibility, processability, and facile integration into detection devices, as compared to their small molecule analogues.
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.
Solution self-assembly of block copolymers (BCPs) typically generates spheres, rods, and vesicles. The reproducible bottom-up fabrication of stable planar nanostructures remains elusive due to their ...tendency to bend into closed bilayers. This morphological vacancy renders the study of shape effects on BCP nanocarrier-cell interactions incomplete. Furthermore, the fabrication of single BCP assemblies with built-in drug delivery functions and geometry-optimized performance remains a major challenge. We demonstrate that PEG-b-PCPTM polyprodrug amphiphiles, where PEG is poly(ethylene glycol) and PCPTM is polymerized block of reduction-cleavable camptothecin (CPT) prodrug monomer, with >50 wt % CPT loading content can self-assemble into four types of uniform nanostructures including spheres, large compound vesicles, smooth disks, and unprecedented staggered lamellae with spiked periphery. Staggered lamellae outperform the other three nanostructure types, exhibiting extended blood circulation duration, the fastest cellular uptake, and unique internalization pathways. We also explore shape-modulated CPT release kinetics, nanostructure degradation, and in vitro cytotoxicities. The controlled hierarchical organization of polyprodrug amphiphiles and shape-tunable biological performance opens up new horizons for exploring next-generation BCP-based drug delivery systems with improved efficacy.
In the past decade, responsive polymers exhibiting reversible or irreversible changes in physical properties and/or chemical structures in response to external stimuli have been extensively ...investigated. Among them, tertiary amine methacrylate-based block copolymers represent a unique category considering their responsiveness to multiple external stimuli (e.g., pH, temperature and salts), which are essentially relevant to the biological milieu. These intriguing properties allow for their applications in a variety of fields ranging from drug or gene delivery, imaging, diagnostics, antibacterial coatings, catalysis, and bio-separations. This review article highlights tertiary amine methacrylate-based block copolymers, focusing on recent advances in the synthesis of tertiary amine methacrylate-based block copolymers with varying chemical structures and chain topologies, their supramolecular self-assembly in aqueous media as well as in the bulk state, and the emerging functional applications.
Reactive oxygen species (ROS) and oxidative stress are implicated in various physiological and pathological processes, and this feature provides a vital biochemical basis for designing novel ...therapeutic and diagnostic nanomedicines. Among them, oxidation-responsive micelles and vesicles (polymersomes) of amphiphilic block copolymers have been extensively explored; however, in previous works, oxidation by ROS including H2O2 exclusively leads to microstructural destruction of polymeric assemblies. For oxidation-responsive polymersomes, fast release of encapsulated hydrophilic drugs and bioactive macromolecules will occur upon microstructural disintegration. Under certain application circumstances, this does not meet design requirements for sustained-release drug nanocarriers and long-acting in vivo nanoreactors. Also note that conventional polymersomes possess thick hydrophobic bilayers and compromised membrane permeability, rendering them as ineffective nanocarriers and nanoreactors. We herein report the fabrication of oxidation-responsive multifunctional polymersomes exhibiting intracellular milieu-triggered vesicle bilayer cross-linking, permeability switching, and enhanced imaging/drug release features. Mitochondria-targeted H2O2 reactive polymersomes were obtained through the self-assembly of amphiphilic block copolymers containing arylboronate ester-capped self-immolative side linkages in the hydrophobic block, followed by surface functionalization with targeting peptides. Upon cellular uptake, intracellular H2O2 triggers cascade decaging reactions and generates primary amine moieties; prominent amidation reaction then occurs within hydrophobic bilayer membranes, resulting in concurrent cross-linking and hydrophobic-to-hydrophilic transition of polymersome bilayers inside live cells. This process was further utilized to achieve integrated functions such as sustained drug release, (combination) chemotherapy monitored by fluorescence and magnetic resonance (MR) imaging turn-on, and to construct intracellular fluorogenic nanoreactors for cytosolic thiol-containing bioactive molecules.
Stimuli-triggered disassembly of block copolymer vesicles or polymersomes has been conventionally achieved via solubility switching of the bilayer-forming block, requiring cooperative changes of most ...of the repeating units. Herein we report an alternative approach by incorporating hydrophobic blocks exhibiting stimuli-triggered head-to-tail cascade depolymerization features. Amphiphilic block copolymers bearing this motif self-assemble into self-immolative polymersomes (SIPsomes). By modular design of terminal capping moieties, visible light, UV light, and reductive milieu can be utilized to actuate SIPsomes disintegration into water-soluble small molecules and hydrophilic blocks. The design of SIPsomes allows for triggered drug co-release and controllable access toward protons, oxygen, and enzymatic substrates. We also demonstrate programmed (OR-, AND-, and XOR-type logic) enzymatic reactions by integrating SIPsome encapsulation and trigger/capping moiety-selective cascade depolymerization events.
We report on the fabrication of photochromic polymersomes exhibiting photoswitchable and reversible bilayer permeability from newly designed poly(ethylene oxide)-b-PSPA (PEO-b-PSPA) diblock ...copolymers, where SPA is spiropyran (SP)-based monomer containing a unique carbamate linkage. Upon self-assembling into polymersomes, SP moieties within vesicle bilayers undergo reversible phototriggered isomerization between hydrophobic spiropyran (SP, λ2 > 450 nm irradiation) and zwitterionic merocyanine (MC, λ1 < 420 nm irradiation) states. For both SP and MC polymersomes, their microstructures are stabilized by multiple cooperative noncovalent interactions including hydrophobic, hydrogen bonding, π–π stacking, and paired electrostatic (zwitterionic) interactions, with the latter two types being exclusive for MC polymersomes. Control experiments using analogous block copolymers of hydrophobic SP monomer with a carbonate linkage (SPO) and conventional spiropyran methacrylate monomer (SPMA) containing a single ester functionality were then conducted, revealing that carbamate-incurred hydrogen bonding interactions in PEO-b-PSPA are crucial for polymersome stabilization in the zwitterionic MC state. Moreover, reversible phototriggered SP-to-MC polymersome transition is accompanied by membrane polarity and permeability switching from being nonimpermeable to selectively permeable toward noncharged, charged, and zwitterionic small molecule species below critical molar masses. Intriguingly, UV-actuated MC polymersomes possess two types of release modules: (1) sustained release upon short UV irradiation duration by taking advantage of the unexpectedly slow spontaneous MC-to-SP transition kinetics (t 1/2 > 20 h) under dark conditions; (2) on-demand and switchable release under alternated UV–vis light irradiation. We further demonstrate photoswitchable spatiotemporal release of 4′,6-diamidino-2-phenylindole (DAPI, cell nuclei-staining dye) within living HeLa cells.
Nitric oxide (NO) serves as a key regulator of many physiological processes and as a potent therapeutic agent. The local delivery of NO is important to achieve target therapeutic outcomes due to the ...toxicity of NO at high concentrations. Although light stimulus represents a non‐invasive tool with spatiotemporal precision to mediate NO release, many photoresponsive NO‐releasing molecules can only respond to ultraviolet (UV) or near‐UV visible light with low penetration and high phototoxicity. We report that coumarin‐based NO donors with maximal absorbances at 328 nm can be activated under (deep) red‐light (630 or 700 nm) irradiation in the presence of palladium(II) tetraphenyltetrabenzoporphyrin, enabling stoichiometric and self‐reporting NO release with a photolysis quantum yield of 8 % via photoredox catalysis. This NO‐releasing platform with ciprofloxacin loading can eradicate Pseudomonas aeruginosa biofilm in vitro and treat cutaneous abscesses in vivo.
Red‐light‐mediated photoredox catalysis for self‐reporting nitric oxide release is reported in the presence of palladium(II) tetraphenyltetrabenzoporphyrin. The NO‐releasing platform eradicates Pseudomonas aeruginosa biofilm in vitro and treats bacterial infection in vivo.
The fabrication of block copolymer (BCP) vesicles (polymersomes) exhibiting synchronized covalent crosslinking and bilayer permeabilization remains a considerable challenge as crosslinking typically ...leads to compromised membrane permeability. Herein it is demonstrated how to solve this dilemma by employing a stimuli‐triggered crosslinking strategy with amphiphilic BCPs containing photolabile carbamate‐caged primary amines. Upon self‐assembling into polymersomes, light‐triggered self‐immolative decaging reactions release primary amine moieties and extensive amidation reactions then occur due to suppressed amine pKa within hydrophobic milieu. This leads to serendipitous vesicle crosslinking and the process is associated with bilayer hydrophobicity‐to‐hydrophilicity transition and membrane permeabilization.
Two processes in one: A stimuli‐triggered crosslinking strategy was developed to concurrently crosslink and permeabilize block copolymer assemblies. Upon self‐assembling into polymersomes (see picture), light‐triggered self‐immolative decaging reactions release primary amine moieties and lead to extensive amidation reactions.
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