Biological Stimuli-responsive Polymer Systems:Design,Construction and Controlled Self-assembly

Biological stimuli-responsive polymers have increasingly attracted attention in recent years because it can satisfy many requirements of applications related with human body while traditional systems do not meet.Due to the importance of this burgeoning field,great efforts have been devoted and,up to now,polymer chemists have made a remarkable success in this prospective research topic.In this review,we systematically generalize the present state of biological stimuli-responsive polymer systems.We highlight several representative examples to specify the current problems and look ahead a clear sense of direction in this area.

Responsive polymer-based multicolor fluorescent probes for temperature and Zn^(2+) ions in aqueous media

We report on the fabrication of fluorescent and multicolor probes for Zn^2＋ ions and temperature from a mixture of three types of fluorophore-labeled responsive block copolymers in aqueous media. Quinoline-based Zn^2＋-recognizing fluorescent mono- mer ZQMA, red-emitting rhodamine B-based monomer RhBEA, and blue-emitting coumarin derivative Coum-OH, were syn- thesized first. A ZQMA-labeled well-defined double hydrophilic block copolymer （DHBC）, PEG-b-P（MEO2MA-co-ZQMA）, was synthesized via reversible addition-fragmentation chain-transfer （RAFT） polymerization of 2-（2-methoxyethoxy）ethyl methacrylate （MEOzMA） and ZQMA by utilizing a PEG-based macroRAFT agent. Following similar procedures, PEG-b-P（St-co-RhBEA） amphiphilic diblock copolymer and PEG-b-P（MEOzMA-co-Coum） DHBC were also synthesized, where P（St-co-RhBEA） was a RhBEA-labeled polystyrene （PS） block. At room temperature in aqueous solution, almost non- fluorescent PEG-b-P（MEOzMA-co-ZQMA） can effectively bind Zn2＋ ions, leading to prominent green fluorescence enhance- ment due to the coordination of ZQMA with Zn^2＋ ions. However, by mixing red-emitting PEG-b-P（St-co-RhBEA） and blue-emitting PEG-b-P（MEO2MA-co-Coum） with PEG-b-P（MEO2MA-co-ZQMA） at an appropriate ratio, three color transitions could be observed. In the absence of Zn^2＋ ions, a mixed pink fluorescent originating from Coum and RhBEA was ob- served; upon the addition of a certain amount of Zn^2＋ ions, the green fluorescence enhanced dramatically, leading to a white fluorescence readout. By further increasing the amount of Zn2＋ ions, the green fluorescence further enhanced and overwhelmed the blue and red emissions, leading to a green-dominant mixed-fluorescence emission. In addition, upon increasing the temperature, the fluorescence of Coum decreased considerably due to the fluorescence-resonance energy transfer （FRET） between Coum and ZQMA moieties. In this way, a ratiometric fluorescent thermometer can be constructed.

Responsive Polymers with Contraction-arisen Helicity and Biomimetic Membrane-spanning Transport Functions

Responsive polymers have attracted increasing attention for prospective design of smart materials.The development of multifunctional responsive materials is very dependent on polymeric structures that can be manipulated with the change of microenvironment at the molecular level.Herein,we report a type of responsive coordination polymers(RCPs)consisting of dual phenanthroline-oxadiazole(DPO)units and metal Zn^(2+)ions,which can contract from linear structure into topologically helical structure driven by hydrophobic effect while changing the microenvironment from nonpolar solvent to aqueous media.The symmetry breaking of RCPs was confirmed by circular dichroism(CD)spectra and atomic force microscope(AFM)images,clearly demonstrating the intramolecularly contraction-arisen helicity.Moreover,RCPs can intelligently adapt different microenvironments by changing their conformations,as evidenced by a demonstration of biomimetic lipid bilayer-based vesicle experiments.Furthermore,RCPs show significant concentration-dependent transmembrane transport functions,implying that RCPs are able to span cellular membranes to form channels inside the hydrophobic lipid bilayers.At the same time,the electrophysiological conductance experiments further underpin the biomimetic transport functions and channel-based conduction mechanism of RCPs.This study demonstrates an important paradigm of responsive polymers performing microenvironment-induced conformational change and thereof unique functions,and thus provides valuable insights on the development of functional responsive materials.

Controlling the Chain Folding for the Synthesis of Single-Chain Polymer Nanoparticles Using Thermoresponsive Polymers

Synthetic polymer single-chain nanoparticles(SCNPs)are an emerging new class of nanomaterials that possess similar folded structures as natural proteins.However,most SCNPs reported so far are packed loosely in their interior,resembling those of intrinsically disordered proteins(IDPs).Here,we report a facile strategy to synthesize SCNPs with controllable folding in aqueous solution.

Two-Photon Fluorescence Properties and Ultrafast Responses of a Hyperbranched Diketo-Pyrrolo-Pyrrole Polymer with Triphenylamine as the Core

The two-photon fluorescence properties and ultrafast responses of a hyperbranched polyyne （hb-DPP-J2） with triphenylamine as the central core, Diketo-Pyrrolo-Pyrrole as the connecting unit and electron acceptor are studied. The polymer has a D-π-A-π-D conjugated structure along the extended polyyne w-bridge systems, and the effective condugated unit repeats itself in the whole hyperbranehed polymer chain. The polymer exhibits a large two-photon absorption cross section and high fluorescence quantum yields. The ultrafast dynamic results give a deep understanding of the excited energy transfer processes under excitation, and reveal a long relaxation lifetime of the intramolecular charge transfer （ICT） state.

Manipulating the Phase Transition Behavior of Dual Temperature-Responsive Block Copolymers by Adjusting Composition and Sequence

Temperature-responsive polymers have garnered significant attention due to their ability to respond to external stimuli.In this work,dual temperature-responsive block copolymers are synthesized via reversible addition-fragmentation chain transfer polymerization(RAFT)polymerization utilizing zwitterionic monomer methacryloyl ethyl sulfobetaine(SBMA) and N-isopropyl acrylamide(NIPAAm) as monomers.The thermal responsive behaviors can be easily modulated by incorporating additional hydrophobic monomer benzyl acrylate(BN) or hydrophilic monomer acrylic acid(AA),adjusting concentration or pH,or varying the degree of polymerization of the block chain segments.The cloud points of the copolymers are determined by UV-Vis spectrophotometry,and these copolymers exhibit both controlled upper and lower critical solu bility temperatures(LCST and UCST) in aqueous solution.This study analyzes and summarizes the influencing factors of dual temperature responsive block copolymers by exploring the effects of various conditions on the phase transition temperature of temperature-sensitive polymers to explore the relationship between their properties and environment and structure to make them more selective in terms of temperature application range and regulation laws.It is very interesting that the introduction of poly-acrylic acid(PAA) segments in the middle of di-block copolymer PSBMA_(55)-b-PNIPAAm_(80) to form PSBMA_(55)-b-PAA_(x)-b-PNIPAAm_(80) results in a reversal of temperature-responsive behaviors from 'U'(LCST UCST) type,while the copolymer PSBMA_(55)-b-P(NIPAAm_(80)-co-AA_(x)) not.This work provides a clue for tuning the phase transition behavior of polymers for manufacture of extreme smart materials.

Smart polymers for the controlled delivery of drugs–a concise overview

Smart polymers have enormous potential in various applications.In particular,smart polymeric drug delivery systems have been explored as“intelligent”delivery systems able to release,at the appropriate time and site of action,entrapped drugs in response to specific physiological triggers.These polymers exhibit a non-linear response to a small stimulus leading to a macroscopic alteration in their structure/properties.The responses vary widely from swelling/contraction to disintegration.Synthesis of new polymers and crosslinkers with greater biocompatibility and better biodegradability would increase and enhance current applications.The most fascinating features of the smart polymers arise from their versatility and tunable sensitivity.The most significant weakness of all these external stimuli-sensitive polymers is slow response time.The versatility of polymer sources and their combinatorial synthesis make it possible to tune polymer sensitivity to a given stimulus within a narrow range.Development of smart polymer systems may lead to more accurate and programmable drug delivery.In this review,we discuss various mechanisms by which polymer systems are assembled in situ to form implanted devices for sustained release of therapeutic macromolecules,and we highlight various applications in the field of advanced drug delivery.

Ultraviolet-activated long-lived room-temperature phosphorescence from small organic molecule-doped polymer systems

Long-lived organic room-temperature phosphorescent(RTP)materials have attracted widespread attention because of their fantastic properties and application prospects.The current methods for developing RTP materials are mainly based on the synthesis of new chromophore molecules and crystallization engineering.However,there are great challenges in the preparation of new chromophore molecules and the use of crystalline materials.Herein,dynamic stimulus-responsive long-lived RTP systems with various emission colors are realized by doping organic chromophore molecules into polymer matrix prepared from vinyl acetate and acrylic acid.Through UV light irradiation,the growth process of long-lived RTP phenomena can be observed for up to 10 s.In particular,the phosphorescence intensity,lifetime,afterglow brightness,and quantum yield of one representative film(P2-M2)increase by 155,262,414,and 8 times after the irradiation,respectively.The unique photophysical phenomena are ascribed to the oxygen consumption characteristics of the polymer matrix under UV irradiation.Meanwhile,the information storage devices are prepared with these RTP systems.This work provides a strategy for achieving small organic molecule-doped polymer RTP systems that are easy to prepare,low-cost,and widely adaptable.

A novel supramolecular graft copolymer via cucurbit[8]uril-based complexation and its self-assembly

A novel supramolecular graft copolymer （SGP） composed of viologen-containing copolymer （P（DMA-co- diEV）） as the main chain and Np ended PNIPAM （Np-PNIPAm） as the grafts is prepared （DMA： N,N- dimethylacryamide, diEV： ethylviologen dimer, Np： naphthalene, PNIPAM： poly（N-isopropylacrylamide））. The grafting is based on the triple complexation among a host of cucurbit[8]uril （CB[8]） and two guests of diEV and Np, which is characterized by UV-vis spectra and ITC. Temperature sensitive property of PNIPAm moiety allows SGP to self-assemble into non-covalently connected micelle （NCCM） at high temperature. The micelles are sensitive to reducing agents, for example Na2S203, which breaks the current inclusion complex pair and induces aggregation.

Dental plaque-inspired versatile nanosystem for caries prevention and tooth restoration

Dental caries is one of the most prevalent human diseases resulting from tooth demineralization caused by acid production of bacteria plaque.It remains challenges for current practice to specifically identify,intervene and interrupt the development of caries while restoring defects.In this study,inspired by natural dental plaque,a stimuli-responsive multidrug delivery system(PMs@NaF-SAP)has been developed to prevent tooth decay and promote enamel restoration.Classic spherical core-shell structures of micelles dual-loaded with antibacterial and restorative agents are self-assembled into bacteria-responsive multidrug delivery system based on the pH-cleavable boronate ester bond,followed by conjugation with salivary-acquired peptide(SAP)to endow the nanoparticle with strong adhesion to tooth enamel.The constructed PMs@NaF-SAP specifically adheres to tooth,identifies cariogenic conditions and intelligently releases drugs at acidic pH,thereby providing antibacterial adhesion and cariogenic biofilm resistance,and restoring the microarchitecture and mechanical properties of demineralized teeth.Topical treatment with PMs@NaF-SAP effectively diminishes the onset and severity of caries without impacting oral microbiota diversity or surrounding mucosal tissues.These findings demonstrate this novel nanotherapy has potential as a promising biomedical application for caries prevention and tooth defect restoration while resisting biofilm-associated diseases in a controlled manner activated by pathological bacteria.

Tough Polyion Complex Hydrogel Films of Natural Polysaccharides

The developments of tough hydrogels in recent years have greatly expanded the applications of hydrogels as structural materials. However, most of the tough hydrogels are made of synthetic polymers. To develop biopolymer-based tough hydrogels has both fundamental and practical significances. Here we report a series of polysaccharides-based tough hydrogel films prepared by polyion complexation and solvent evaporation of chondroitin sulfate（CS） and protonated chitosan（CHT） solutions with different weight ratios. The obtained CS/CHT gel films with thickness of 40-80 μm and water content of 66 wt%-81 wt% possess excellent mechanical properties, with tensile breaking stress and breaking strain being 0.4-3 MPa and 160%-320%, respectively. We found that in the mixture solutions there are large amounts of excess CHT in terms of charges; after swelling the films in water, the acetic acid, which is used to protonate the amino groups of CHT, diffuses out of the gel matrix, enhancing the intermolecular interactions between CHT molecules and thus improving the mechanical properties of gel films, besides the ionic bonds between CS and CHT. Antimicrobial tests also showed that the gel films with low weight ratio of CS to CHT, corresponding to the case with excess CHT, have evident antimicrobial effect. These CS/CHT gel films with good mechanical properties and antimicrobial effect should extend the applications of hydrogels in biomedical fields.

Multi-bond Network Hydrogels with Robust Mechanical and Self-healable Properties

Multi-bond network（MBN） which contains a single network with hierarchical cross-links is a suggested way to fabricate robust hydrogels. In order to reveal the roles of different cross-links with hierarchical bond energy in the MBN, here we fabricate poly（acrylic acid） physical hydrogels with dual bond network composed of ionic cross-links between carboxylFe3＋ interactions and hydrogen bonds, and compare these dually cross-linked hydrogels with singly and ternarily cross-linked hydrogels. Simple models are employed to predict the tensile property, and the results confirm that the multi-bond network with hierarchical distribution in the bond energy of cross-links endows hydrogel with effective energy-dissipating mechanism. Moreover, the dually cross-linked MBN gels exhibit excellent mechanical properties（tensile strength up to 500 k Pa, elongation at break ~ 2400%） and complete self-healing after being kept at 50 °C for 48 h. The factors on promoting self-healing are deeply explored and the dynamic multi-bonds are regarded to trigger the self-healing along with the mutual diffusion of long polymer chains and ferric ions.

POSS-modified PEG Adhesives for Wound Closure

PEG-related adhesives are limited in clinical use because they are easy to swell and cannot support the cell growth. In this study, we produced a series of POSS-modified PEG adhesives with high adhesive strength. Introduction of inorganic hydrophobic POSS units decreased the swelling of the adhesives and enhanced cell adhesion and growth. The in vitro cytotoxicity and in vivo inflammatory response experiments clearly demonstrated that the adhesives were nontoxic and possessed excellent biocompatibility. Compared with the sutured wounds, the adhesive-treated wounds showed an accelerated healing process in wounded skin model of the Bama miniature pig, demonstrating that the POSS-modified PEG adhesive is a promising candidate for wound closure.