Multifunctional stimuli responsive polymer-gated iron and gold-embedded silica nano golf balls:Nanoshuttles for targeted on-demand theranostics

Multi-functional nanoshuttles for remotely targeted and on-demand delivery of therapeutic molecules and imaging to defined tissues and organs hold great potentials in personalized medicine, including precise early diagnosis, efficient prevention and therapy without toxicity. Yet, in spite of 25 years of research, there are still no such shuttles available. To this end, we have designed magnetic and gold nanoparticles （NP）-embedded silica nanoshuttles （MGNSs） with nanopores on their surface. Fluorescently labeled Doxombicin （DOX）, a cancer drug, was loaded in the MGNSs as a payload. DOX loaded MGNSs were encapsulated in heat and pH sensitive polymer P（NIPAM-co- MAA） to enable controlled release of the payload. Magnetically-guided transport of MGNSs was examined in： （a） a glass capillary tube to simulate their delivery via blood vessels; and （b） porous hydrogels to simulate their transport in composite human tissues, including bone, cartilage, tendon, muscles and blood-brain barrier {BBB）. The viscoelastic properties of hydrogels were examined by atomic force microscopy （AFM）. Cellular uptake of DOX- loaded MGNSs and the subsequent pH and temperature-mediated release were demonstrated in differentiated human neurons derived from induced pluripotent stem cells （iPSCs） as well as epithelial HeLa cells. The presence of embedded iron and gold NPs in silica shells and polymer-coating are supported by SEM and TEM. Fluorescence spectroscopy and microscopy documented DOX loading in the MGNSs. Time-dependent transport of MGNSs guided by an external magnetic field was observed in both glass capillary tubes and in the porous hydrogel. AFM results affirmed that the stiffness of the hydrogels model the rigidity range from soft tissues to bone. pH and temperature-dependent drug release analysis showed stimuli responsive and gradual drug release. Cells＇ viability MTT assays showed that MGNSs are non-toxic. The cell death from on-demand DOX release was observed in both neurons and epithelial cells even though the drug release efficiency was higher in neurons. Therefore, development of smart nanoshuttles have significant translational potential for controlled delivery of theranostics＇ payloads and precisely guided transport in specified tissues and organs （for example, bone, cartilage, tendon, bone marrow, heart, lung, liver, kidney, and brain） for highly efficient personalized medicine applications.

Development of stimuli responsive polymeric nanomedicines modulating tumor microenvironment for improved cancer therapy

The complexity of the tumor microenvironment(TME)severely hinders the therapeutic effects of various cancer treatment modalities.The TME differs from normal tissues owing to the presence of hypoxia,lowpH,and immunesuppressive characteristics.Modulation of the TME to reverse tumor growth equilibrium is considered an effective way to treat tumors.Recently,polymeric nanomedicines have been widely used in cancer therapy,because their synthesis can be controlled and they are highly modifiable,and have demonstrated great potential to remodel the TME.In this review,we outline the application of various stimuli responsive polymeric nanomedicines to modulate the TME,aiming to provide insights for the design of the next generation of polymeric nanomedicines and promote the development of polymeric nanomedicines for cancer therapy.

Metal-Organic Gels Based on Carboxyl-Functionalized Benzimidazole and Their Stimuli Responsivenesses

Three multi-responsiveness supramolecular metal-organic gels(MOGs)have been prepared upon Ba(OAc)_(2),CdSO_(4)•8H_(2)O and Pb(NO_(3))_(2) with a simple ligand(G17)based on a carboxyl-functionalized benzimidazole derivative in alcoholic-water solutions.The MOGs display the formation of well-developed nanofibrillar networks composed of intertwined fibers which provide stability to gels structures through coordination,hydrogen bonding and π-π interactions characterized by using field emission scanning electron microscopy(FESEM),the fourier transform infrared(FT-IR)spectroscopy and powder X-ray diffraction(XRD)techniques.MOG-1 shows good stimuli responsiveness toward the changes in K_(2)CrO_(4),both MOG-2 and MOG-3 do good job toward the changes in Na_(2)S.Moreover,because these MOGs were formed easily by gelator with some heavy metal ion,such as Cd(Ⅱ)and Pb(Ⅱ),it might provide the basis for heavy metal ion capture and removal.

Multiple-Stimuli Responsive and Tunable Luminescent Suprarnolecular Assembly by Oligo（p-phenylvinylene） and Surfactant

Achieving multicolor photoluminescence under multiple stimuli response based on a single fluorescent compound remains a great challenge. Herein, we report a novel multicolor fluorescent supramolecular assembly, which was constructed from surfactant sodium dodecyl sulfate （SLS） and fluorescent compound 1 bearing a rigid symmetrical acceptor-donor-acceptor structure. The luminescence property of 1/SLS assembly showed the multiple stimuli response towards temperature, cyclodextrin complexation and UV light irradiation, exhibiting the tunable emission wavelengths from 490 nm to 590 nm and the multicolor photoluminescence including cyan, green, yellow and orange. Furthermore, this assembly could be used in light writing owing to the fast fluorescence change within 15 s. These results could provide a convenient and useful method for fabricating smart tunable photoluminescent materials.

Tumor microenvironment responsive drug delivery systems

Conventional tumor-targeted drug delivery systems(DDSs)face challenges,such as unsatisfied systemic circulation,low targeting efficiency,poor tumoral penetration,and uncontrolled drug release.Recently,tumor cellular molecules-triggered DDSs have aroused great interests in addressing such dilemmas.With the introduction of several additional functionalities,the properties of these smart DDSs including size,surface charge and ligand exposure can response to different tumor microenvironments for a more efficient tumor targeting,and eventually achieve desired drug release for an optimized therapeutic efficiency.This review highlights the recent research progresses on smart tumor environment responsive drug delivery systems for targeted drug delivery.Dynamic targeting strategies and functional moieties sensitive to a variety of tumor cellular stimuli,including pH,glutathione,adenosine-triphosphate,reactive oxygen species,enzyme and inflammatory factors are summarized.Special emphasis of this review is placed on their responsive mechanisms,drug loading models,drawbacks and merits.Several typical multi-stimuli responsive DDSs are listed.And the main challenges and potential future development are discussed.

Stimuli-responsive nanocarriers for bacterial biofilm treatment

Bacterial biofilm infections have been threatening the human’s life and health globally for a long time because they typically cause chronic and persistent infections.Traditional antibiotic therapies can hardly eradicate biofilms in many cases,as biofilms always form a robust fortress for pathogens inside,inhibiting the penetration of drugs.To address the issues,many novel drug carriers emerged as promising strategies for biofilm treatment.Among them,stimuli-responsive nanocarriers have attracted much attentions for their intriguing physicochemical properties,such as tunable size,shape and surface chemistry,especially smart drug release characteristic.Based on the microenvironmental difference between biofilm infection sites and normal tissue,many stimuli,such as bacterial products accumulating in biofilms(enzymes,glutathione,etc.),lower pH and higher H_(2)O_(2)levels,have been employed and proved in favor of“on-demand”drug release for biofilm elimination.Additionally,external stimuli including light,heat,microwave and magnetic fields are also able to control the drug releasing behavior artificially.In this review,we summarized recent advances in stimuli-responsive nanocarriers for combating biofilm infections,and mainly,focusing on the different stimuli that trigger the drug release.

Stimuli-responsive cyclometalated platinum complex bearing bent molecular geometry for highly efficient solution-processable OLEDs

Smart materials,such as stimuli-responsive luminescence,have attracted much attentions due to their potential application in semiconductor filed.In this context,platinum complexes of(dfppy-DC)Pt(acac) and(dfppy-O-DC)Pt(acac) were prepared and characterized,in which(2-(4',6'-difluorophenyl)pyridinato-N,C2')(2,4-pentanedionato-0,0)Pt(Ⅱ) was used as the planar emission core and 9-(4-(phenylsulfonyl)phenyl)-9 H-carbazole(DC) was regard as the bent pendent.Both platinum complexes showed bright emission in solution and solid state,concomitant with charming external-stimuli-responsive emission under mechanical grinding,organic solvent vapors and pressure.The change emission color spanned from yellow to near-infrared region.Using the platinum complexes as the dopant,solution processable organic light-emitting diodes(OLEDs) were fabricated and a maximum external quantum efficiency of ~18% was achieved,which is the highest value among the reported solution-processable OLEDs based on externalstimuli-responsive luminescence.This research demonstrated that platinum complex can show promising stimuli responsive emission via ingenious molecular design,indicating a novel way for developing the smart materials in semiconductor filed.

Ultra-stable and multistimuli-responsive nanoparticles coated with zwitterionic pillar[n]arene for enhanced cellular uptake

Nanoparticle surface property is crucial for circulation stability,cellullar uptake and other biological characteristics.Zwitte rionic pillar[n]arenes(ZPns)we re used to coat gold nanopa rticles(GNPs)via hostguest interaction.The resulting GNPs demonstrated higher stability in blood serum compared to polyethylene glycol(PEG)-coated GNPs.ZPn-coated GNPs were responsive to UV-irradiation,competitive displacement and acidic pH.UV-irradiation or competitive displacement could lead to the removal of ZPn coating to expose GNPs,which enhanced cell uptake efficiency by 5.9-and 7.4-fold,respectively.

Seeing Is Believing:Directly Imaging Contractions of Artificial Molecular Muscles with Platinum Atom Markers

Artificial molecular muscles undergo well-controlled contractile and extensile motions upon external stimulation,leading to remarkable length changes.Evaluating such length changes at the molecular level is essential to the design of integrated artificial molecular muscles that mimic biological muscles.Taking advantage of the strong contrast of platinum(Pt)atoms in high-angle annular dark-field scanning transmission electron microscopy images,we imaged Pt-containing molecular[c2]daisy chains directly by employing metal atom markers.The length changes and associated conformational transformations of these newly developed artificial molecular muscles have been measured experimentally in combination with theoretical calculations.The contraction ratios of these two molecular muscles with the TEMPO or pyrene anchoring group were calculated to be 21.0%or 15.7%respectively,suggesting a substantial anchoring effect.This study demonstrates the experimental measurement of the length changes of artificial molecular muscles and provides a new avenue for investigating the motion of artificial molecular machines.

Thermo-and pH-dual responsive inorganic-organic hybrid hydrogels with tunable luminescence

A thermo-and pH-dual responsive luminescent hydrogel was successfully constructed by coupling dysprosium-containing polyoxometalates Na_9 DyW_(10) O_(36)(DyW_(10)) with the ABA triblock copolymer, where the B block is PEO and the A block is the thermosensitive poly(methoxydi(ethylene glycol) methacrylate-co-N,N-dimethylaminoethyl methacrylate). The complex hybrid underwent a sol-gel phase transition above the lower critical solution temperature(LCST) of the A block. DyW_(10) was electrostatically encapsulated into the hydrophobic domain of the A block with enhanced photoluminescence. When temperature cooled down, the luminescence could be restored. By addition of acids to protonate the A block, and emission of DyW_(10) was simultaneously enhanced. Sensitivity of poly(N,N-dimethy laminoethyl methacrylate)(PDMAEMA) to pH also enabled the emission of DyW_(10)/copolymer hydrogel to be reversibly switched by alternating acid/base treatments.

An acid-base responsive linear-cyclic polymer rotaxane molecular shuttle with fluorescence signal output

The preparation of intelligent-responsive materials with controllable topology structure has long been a significant objective for chemists in the field of materials science. In this paper, we designed and prepared a linear-cyclic reversible topological structure polymer based on the bistable [1]rotaxane molecular shuttle. A ferrocene-functionalized [1]rotaxane and naphthalimide fluorophore group are introduced into the both ends of the polymer, which exhibit distance-induced photo-electron transfer effect. The structural transformation between linear and cyclic state of polymer is demonstrated by simple acid-base stimuli, accompanying visual fluorescence changes. The transformation process was characterized by 1H NMR spectra and fluorescence spectra. This work provides a novel strategy to construct functionalized polymers with topological structure.

Thermal and pH Dual Responsive Copolymer and Silver Nanoparticle Composite for Catalytic Application

N-Isopropylacrylamide and vinyl imidazole copolymer,P(NIPAM-co-VI),was synthesized by free radical emulsion polymerization.Then,the copolymer and silver nanoparticle composite,P(NIPAM-co-VI)-Ag,was pre-pared by in situ reduction of AgNO3 with NaBH4.Due to the coexistence of thermal-responsive PNIPAM and pH-responsive PVI,P(NIPAM-co-VI)and P(NIPAM-co-VI)-Ag exhibited both thermal and pH responsibility,their size would change while altering the temperature or pH of the circumvent.Their thermal and pH dual responsive properties were studied by dynamic light scattering(DLS).P(NIPAM-co-VI)-Ag could be stably dispersed in water at a pH range from 3.0 to 9.3,which is favorable to use P(NIPAM-co-VI)-Ag as a catalyst in the reduction reaction of p-nitrophenol.The reaction rate constant(kapp)increased with the decrease of pH or the increase of VI content in the copolymer.

Coordination-responsive drug release inside gold nanorod @ metal-organic framework core-shell nanostructures for near-infrared-induced synergistic chemo-photothermal therapy

Multifunctional core-shell nanostructures formed by integration of distinct components have received wide attention as promising biological platforms in recent years. In this work, crystalline zeolitic imidazolate framework-8 （ZIF-8）, a typical metal-organic framework （MOF）, is coated onto single gold nanorod （AuNR） core for successful realization of synergistic photothermal and chemotherapy triggered by near-infrared （NIR） light. Impressivel）~ high doxorubicin hydrochloride （DOX） loading capacity followed by pH and NIR light dual stimuli-responsive DOX release can be easily implemented through formation and breakage of coordination bonds in the system. Moreover, under NIR laser irradiation at 808 nm, these novel AuNR@MOF core-shell nanostructures exhibit effective synergistic chemo-photothermal therapy both in vitro and in vivo, confirmed by cell treatment and tumor ablation via intravenous injection.

SYNTHESIS OF pH-RESPONSIVE AMPHIPHILIC DIBLOCK COPOLYMERS CONTAINING POLYISOBUTYLENE via OXYANION-INITIATED POLYMERIZATION AND THEIR MULTIPLE SELF-ASSEMBLY MORPHOLOGIES

Two pH-responsive amphiphilic diblock copolymers, namely polyisobutylene-block-poly[2-（N,N- dimethylamino）ethyl methaerylate] （PIB-b-PDMAEMA） and polyisobutylene-block-poly（metharylic acid） （PIB-b-PMAA）, were synthesized via oxyanion-initiated polymerization, and their multiple self-assembly behaviors have been studied. An exo-01efin-terminated highly reactive polyisobutylene （HRPIB） was first changed to hydroxyl-terminated PIB （PIB-OH） via hydroboration-oxidation of C =C double bond in the chain end, and then reacted with KH to yield a potassium alcoholate of PIB （PIB-O-K＋）. PIB-O-K＋ was immediately used as a macroinitiator to polymerize DMAEMA monomer, resulting in a cationic diblock copolymer PIB-b-PDMAEMA. With the similar synthesis procedure, the anionic diblock copolymer PIB-b- PMAA could be prepared via a combination of oxyanion-initiated polymerization of tert-butyl methacrylate （tBMA） and subsequent hydrolysis of tert-butyl ester groups in PtBMA block. The functional PIB and block copolymers have been fully characterized by 1H-NMR, FT-IR spectroscopy, and gel permeation chromatography （GPC）. These samples allowed us to systematically investigate the effects of block composition on the pH responsivity and various self-assembled morphologies of the copolymers in THF/water mixed solvent. Transmission electron microscopy （TEM） images revealed that these diblock copolymers containing small amount of original PIB without exo-olefin-terminated group are able to self-assemble into micelles, vesicles with different particle sizes and cylindrical aggregates, depending on various factors including block copolymer composition, solvent polarity and pH value.

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.

Thermo-induced physically crosslinked polypeptide-based block copolymer hydrogels for biomedical applications

Stimuli-responsive synthetic polypeptide-containing block copolymers have received considerable attention in recent years.Especially,unique thermo-induced sol-gel phase transitions were observed for elaborately-designed amphiphilic diblock copolypeptides and a range of poly(ethylene glycol)(PEG)-polypeptide block copolymers.The thermo-induced gelation mechanisms involve the evolution of secondary conformation,enhanced intramolecular interactions,as well as reduced hydration and increased chain entanglement of PEG blocks.The physical parameters,including polymer concentrations,sol-gel transition temperatures and storage moduli,were investigated.The polypeptide hydrogels exhibited good biocompatibility in vitro and in vivo,and displayed biodegradation periods ranging from 1 to 5 weeks.The unique thermo-induced sol-gel phase transitions offer the feasibility of minimal-invasive injection of the precursor aqueous solutions into body,followed by in situ hydrogel formation driven by physiological temperature.These advantages make polypeptide hydrogels interesting candidates for diverse biomedical applications,especially as injectable scaffolds for 3D cell culture and tissue regeneration as well as depots for local drug delivery.This review focuses on recent advances in the design and preparation of injectable,thermo-induced physically crosslinked polypeptide hydrogels.The influence of composition,secondary structure and chirality of polypeptide segments on the physical properties and biodegradation of the hydrogels are emphasized.Moreover,the studies on biomedical applications of the hydrogels are intensively discussed.Finally,the major challenges in the further development of polypeptide hydrogels for practical applications are proposed.

Regulating the self-assembly of rigid 2D ribbon-like amphiphilic homopolymer via tailoring its holistic conformation

Amphiphilic rigid backbone polymers are traditionally seemed as one-dimensional(1D)rods and show distinct self-assembly behavior to flexible polymers,but they could hardly adapt morphology-tunable self-assembly by changing their holistic conformation upon external stimuli.In this study,we synthesized a series of amphiphilic homopolymers poly(acetylene azobenzene oligoethylene glycol)(P(AAzo-EGx))containing conjugated polyacetylene mainchain,azobenzene pendants and oligo ethylene glycol tails in each unit.This comb-like amphiphilic polymer could be treated as two-dimensional(2D)nanoribbons with tunable holistic conformation via meticulous tailoring intrastrand repulsion and interchainπ-πinteraction of azobenzene pendants by light,temperature,and solvent swelling.P(AAzo-EG_(2))could self-assemble into large vesicles in ambient,whereas transformed to supramolecular helix bundles(SHBs)at 65℃as well as depicted by dissipative particle dynamics(DPD)simulation,and then turned into grass leaf-like micelles upon sequential ultraviolet(UV)and blue light irradiation.The three assemblies featured different stacking mode of PAAzo skeletons although showed similar aggregate induce emission(AIE)effect.In this holistic macromolecular chain conformation-induced self-assembly and morphology transformation,temperature influenced the stacking of hydrophobic parts mainly by tuning the torsion of PAAzo skeleton.Certain amount of good solvent played a vital role by swelling of hydrophobic PAAzo skeleton,and helping the movement and rearrangement of azobenzene pendants and polyacetylene mainchains like a lubricant.The length and diameter of SHBs could be tuned by changing EGxtails.This work uncovered a facile strategy to tailor the self-assembly of rigid backbone polymers for fabrication of functional nanodevices.

GSH-sensitive polymeric prodrug: Synthesis and loading with photosensitizers as nanoscale chemo-photodynamic anti-cancer nanomedicine

Precisely delivering combinational therapeutic agents has become a crucial challenge for anti-tumor treatment. In this study, a novel redox-responsive polymeric prodrug(molecular weight,MW: 93.5 k Da) was produced by reversible addition-fragmentation chain transfer(RAFT) polymerization. The amphiphilic block polymer-doxorubicin(DOX) prodrug was employed to deliver a hydrophobic photosensitizer(PS), chlorin e6(Ce6), and the as-prepared nanoscale system [NPs(Ce6)] was investigated as a chemo-photodynamic anti-cancer agent. The glutathione(GSH)-cleavable disulfide bond was inserted into the backbone of the polymer for biodegradation inside tumor cells, and DOX conjugated onto the polymer with a disulfide bond was successfully released intracellularly. NPs(Ce6) released DOX and Ce6 with their original molecular structures and degraded into segments with low MWs of 41.2 k Da in the presence of GSH. NPs(Ce6) showed a chemo-photodynamic therapeutic effect to kill 4 T1 murine breast cancer cells, which was confirmed from a collapsed cell morphology, a lifted level in the intracellular reactive oxygen species, a reduced viability and induced apoptosis. Moreover, ex vivo fluorescence images indicated that NPs(Ce6) retained in the tumor, and exhibited a remarkable in vivo anticancer efficacy. The combinational therapy showed a significantly increased tumor growth inhibition(TGI,58.53%). Therefore, the redox-responsive, amphiphilic block polymeric prodrug could have a great potential as a chemo-photodynamic anti-cancer agent.

Fluorescent Organohydrogel with Thermal-Induced Color Change for Anti-counterfeiting

Smart fluorescent patterns enable dynamic color variation under external stimuli,showing a much higher security level in the field of anti-counterfeiting.However,there is still lacking of a simple and convenient way to achieve dynamic fluorescence changes.Herein,a fluorescent organohydrogel made up of a poly(N,/N-dimethylacrylamide-co-isopropylacrylamide)(p(DMA-NIPAM))hydrogel network and a polyflauryl methacrylate)(PLMA)organogel network was fabricated via a two-step interpenetrating technique.The former network bears naphthalimide moieties(DEAN,green fluorescent monomer)and the later contains 6-acrylamidopicolinic acid(6APA,fluorescent ligand),leading to emitting green fluorescence.When Eu^(3+) was introduced and coordinated with 6APA,the organohydrogel displays red fluorescence,which can further emit yellow after applying thermal stimulus.Furthermore,by adjusting the proportion of comonomers,various organohydrogels can be obtained,which can be programmed and act as an effective platform for the encryption and decryption of secret information.

Fluorescent Linear Supramolecular Polymer Based on Host-Guest Interactions

Construction of supramolecular polymers, in which functional monomer components are held together by non- covalent interactions, is considered as a promising design principle for functional materials. Linear fluorescent su- pramolecular polymer assembled on account of electrostatic attractions based host-guest interaction is synthesized and illustrated here. 1H NMR was involved to ensure the structure of guest and polymer, UV-vis and fluorescent spectra were recorded to be a readout signal to investigate the assemble process of polymer. TEM and AFM meas- urements were carried out to confirm the homogeneous nanometer-sized molecular assembly. It shows the way to be used as remote readout fluorescent functional material in the future.