Synergistic topological and supramolecular control of Diels-Alder reactivity based on a tunable self-complexing host-guest molecular switch.

Compartmentalization and binding-triggered conformational change regulate many metabolic processes in living matter. Here, we have synergistically combined these two biorelevant processes to tune the Diels-Alder (DA) reactivity of a synthetic self-complexing host-guest molecular switch CBPQT4+ -Fu, consisting of an electron-rich furan unit covalently attached to the electron-deficient cyclobis(paraquat-p-phenylene) tetrachloride (CBPQT4+ , 4Cl- ) host. This design allows CBPQT4+ -Fu to efficiently compartmentalize the furan ring inside its host cavity in water, thereby protecting it from the DA reaction with maleimide. Remarkably, the self-complexed CBPQT4+ -Fu can undergo a conformational change through intramolecular decomplexation upon the addition of a stronger binding molecular naphthalene derivative as a competitive guest, triggering the DA reaction upon addition of a chemical regulator. Remarkably, connecting the guest to a thermoresponsive lower critical solution temperature (LCST) copolymer regulator controls the DA reaction on command upon heating and cooling the reaction media beyond and below the cloud point temperature of the copolymer, representing a rare example of decreased reactivity upon increasing temperature. Altogether, this work opens up new avenues towards combined topological and supramolecular control over reactivity in synthetic constructs, enabling control over reactivity through molecular regulators or even mild temperature variations.

In Vitro and In Vivo Evaluation of a Bio-Inspired Adhesive for Bone Fixation.

Compared to metallic hardware, an effective bone adhesive can revolutionize the treatment of clinically challenging situations such as comminuted, articular, and pediatric fractures. The present study aims to develop such a bio-inspired bone adhesive, based upon a modified mineral-organic adhesive with tetracalcium phosphate (TTCP) and phosphoserine (OPS) by incorporating nanoparticles of polydopamine (nPDA). The optimal formulation, which was screened using in vitro instrumental tensile adhesion tests, was found to be 50%molTTCP/50%molOPS-2%wtnPDA with a liquid-to-powder ratio of 0.21 mL/g. This adhesive has a substantially stronger adhesive strength (1.0-1.6 MPa) to bovine cortical bone than the adhesive without nPDA (0.5-0.6 MPa). To simulate a clinical scenario of autograft fixation under low mechanical load, we presented the first in vivo model: a rat fibula glued to the tibia, on which the TTCP/OPS-nPDA adhesive (n = 7) was shown to be effective in stabilizing the graft without displacement (a clinical success rate of 86% and 71% at 5 and 12 weeks, respectively) compared to a sham control (0%). Significant coverage of newly formed bone was particularly observed on the surface of the adhesive, thanks to the osteoinductive property of nPDA. To conclude, the TTCP/OPS-nPDA adhesive fulfilled many clinical requirements for the bone fixation, and potentially could be functionalized via nPDA to offer more biological activities, e.g., anti-infection after antibiotic loading.

In vivo evaluation of a pro-healing polydopamine coated stent through an in-stent restenosis rat model.

Drug-eluting stents have demonstrated efficiency in in-stent restenosis (ISR) but induced a risk of late acute thrombosis by delaying strut re-endothelialization. Polydopamine (PDA), a biocompatible polymer inspired from adhesive proteins of mussels, has been reported to promote endothelial cell (EC) proliferation while limiting SMC proliferation in vitro, thus suggesting the pro-healing potential. This study aimed at evaluating in vivo the impact of the pro-healing PDA-coated stent on ISR and on the quality of the strut re-endothelialization in a rat model. PDA-coated stents demonstrated a significant reduction in ISR in vivo compared to bare metal stents (ratio neointima/media = 0.48 (±0.26) versus 0.83 (±0.42), p < 0.001). Western blot analyses identified a trend towards an increased activation of p38 MAPK phosphorylation and its anti-proliferative effects on vascular SMC that could explain the results observed in morphological analyses. This bioinspired and biocompatible polydopamine layer could intrinsically limit ISR. In addition, according to its latent reactivity, PDA offers the possibility to immobilize some relevant drugs on the PDA-functionalized stent to provide potential synergistic effects.

Immobilisation of an anti-platelet adhesion and anti-thrombotic drug (EP224283) on polydopamine coated vascular stent promoting anti-thrombogenic properties.

Current vascular drug-eluting stents based on immuno-proliferative drugs would reduce the rate of in-stent restenosis (ISR) but may be associated with a higher risk of acute stent thrombosis due to non-selective activity. In this paper, we aimed to develop a polydopamine (PDA) coated chromium­cobalt (CoCr) stent functionalised with EP224283 (Endotis Pharma SA), which combines both a GPIIbIIIa antagonist (tirofiban moiety) and a factor Xa inhibitor (idraparinux moiety) to reduce acute stent thrombosis. PDA-coated chromium­cobalt (CoCr) samples were first immersed in a polyethylenimine (PEI, pH 8.5) solution to increase amine function density (36.0 ± 0.1 nmol/cm2) on the CoCr surface. In a second step, avidin was grafted onto CoCr-PDA-PEI through the biotin linkage (strategy 1) or directly by coupling reactions (strategy 2). The HABA titration proved the fixation of biotin onto CoCr-PDA-PEI surface with a density of 0.74 nmol/cm2. The fixation of avidin was demonstrated by water contact angle (WCA) and surface plasmon resonance (SPR). SEM micrograph shows the flexibility of the thin layer coated onto the stent after balloon inflation. Independently of the strategy, a qualitative SEM analysis showed a reduction in platelet activation when the molecule EP224283 was immobilised on avidin. In parallel, the measurement of anticoagulant activity (anti-Xa) revealed a higher anti-factor Xa activity (2.24 IU/mL vs. 0.09 IU/mL in control) when EP224283 was immobilised on avidin. Interestingly, after seven days of degradation, the anticoagulant activity was persistent in both strategies and looked more important with the strategy 2 than in strategy 1. Throughout this work, we developed an innovative vascular stent through the immobilisation of EP224283 onto CoCr-PDA-PEI-(avidin) system, which provides a promising solution to reduce ISR and thrombosis after stent implantation.

Dual Responsive Regulation of Host-Guest Complexation in Aqueous Media to Control Partial Release of the Host.

The regulation of the concentration of a wide range of small molecules is ubiquitous in biological systems because it enables them to adapt to the continuous changes in the environmental conditions. Herein, we report an aqueous synthetic system that provides an orchestrated, temperature and pH controlled regulation of the complexation between the cyclobis(paraquat-p-phenylene) host (BBox) and a 1,5-dialkyloxynaphthalene (DNP) guest attached to a well-defined dual responsive copolymer composed of N-isopropylacrylamide as thermoresponsive monomer and acrylic acid as pH-responsive monomer. Controlled, partial release of the BBox, enabling control over its concentration, is based on the tunable partial collapse of the copolymer. This colored supramolecular assembly is one of the first synthetic systems providing control over the concentration of a small molecule, providing great potential as both T and pH chromic materials and as a basis to develop more complex systems with molecular communication.

Supramolecular Competitive Host-Guest Interaction Induced Reversible Macromolecular Metamorphosis.

In this work, a rational strategy of competitive host-guest complexation between dioxynaphthalene (Naph) and tetrathiafulvalene (TTF) subunits as guests and cyclophane cyclobis(paraquat-p-phenylene) (CBPQT4+ ) module as host is exploited to modify the macromolecular architecture, so-called supramolecular metamorphosis, in aqueous media. The architectures of the polymers can be reversibly transformed from a linear diblock copolymer AB to a linear AC block copolymer or from a linear block copolymer to a comb copolymer by redox switching. Interestingly, as TTF- and Naph-based complexes feature different characteristic colors, it offers a great opportunity to directly observe nanoscaled macromolecular metamorphosis of materials with the naked eye.

Dopamine-functionalized cyclodextrins: modification of reduced graphene oxide based electrodes and sensing of folic acid in human serum.

A mandatory step in any sensor fabrication is the introduction of analyte-specific recognition elements to the transducer surface. In this study, the possibility to anchor ß-cyclodextrin-modified dopamine to a reduced graphene oxide based electrochemical transducer for the sensitive and selective sensing of folic acid is demonstrated. The sensor displays good electrocatalytic activity toward the oxidation of folic acid. The strong affinity of the surface-confined ß-cyclodextrin for folic acid, together with favorable electron transfer characteristics, resulted in a sensor with a detection limit of 1 nM for folic acid and a linear response up to 10 µM. Testing of the sensor on serum samples from healthy individuals and patients diagnosed with folic acid deficiency validated the sensing capability. Graphical abstract.

Antifouling amphiphilic silicone coatings for dairy fouling mitigation on stainless steel.

Pasteurization of dairy products is plagued by fouling, which induces significant economic, environmental and microbiological safety concerns. Herein, an amphiphilic silicone coating was evaluated for its efficacy against fouling by a model dairy fluid in a pilot pasteurizer and against foodborne bacterial adhesion. The coating was formed by modifying an RTV silicone with a PEO-silane amphiphile comprised of a PEO segment and flexible siloxane tether ([(EtO)3Si-(CH2)2-oligodimethylsiloxanem-block-(OCH2CH2)n-OCH3]). Contact angle analysis of the coating revealed that the PEO segments were able to migrate to the aqueous interface. The PEO-modified silicone coating applied to pretreated stainless steel was exceptionally resistant to fouling. After five cycles of pasteurization, these coated substrata were subjected to a standard clean-in-place process and exhibited a minor reduction in fouling resistance in subsequent tests. However, the lack of fouling prior to cleaning indicates that harsh cleaning is not necessary. PEO-modified silicone coatings also showed exceptional resistance to adhesion by foodborne pathogenic bacteria.

Ultrafast Tailoring of Carbon Surfaces via Electrochemically Attached Triazolinediones.

The straightforward coupling between a triazolinedione (TAD) unit and citronellyl derivatives via an Alder-ene reaction has been exploited to tailor the physicochemical surface properties of glassy carbon (GC) surfaces in an ultrafast and additive-free manner. For this purpose, we first covalently grafted a TAD precursor onto GC via electrochemical reduction of an in situ generated diazonium salt, which was then electrochemically oxidized into the desired GC-bonded TAD unit. A kinetic study of the modification of this reactive layer with an electroactive ferrocene probe proved that a complete functionalization was obtained in merely 1 minute. Further modification experiments with a fluorinated probe demonstrated that the surface properties can be swiftly tailored on demand. The different modification steps, as well as the efficiency of this strategy, were investigated by electrochemistry, contact angle goniometry, and X-ray photoelectron spectroscopy analysis.

A supramolecular miktoarm star polymer based on porphyrin metal complexation in water.

A novel supramolecular miktoarm star polymer was successfully constructed in water from a pyridine end-decorated polymer (Py-PmDEGA) and a metalloporphyrin based star polymer (ZnTPP-(PEG)4) via metal-ligand coordination. The Py-PmDEGA moiety was prepared via a combination of reversible addition-fragmentation chain transfer polymerization (RAFT) and subsequent aminolysis and Michael addition reactions to introduce the pyridine end-group. The ZnTPP(PEG)4 star-polymer was synthesized by the reaction between tetrakis(p-hydroxyphenyl)porphyrin and toluenesulfonyl-PEG, followed by insertion of a zinc ion into the porphyrin core. The formation of a well-defined supramolecular AB4-type miktoarm star polymer was unambiguously demonstrated via UV-Vis spectroscopic titration, isothermal titration calorimetry (ITC) and diffusion ordered NMR spectroscopy (DOSY).

Reversible Tethering of Polymers onto Catechol-Based Titanium Platforms.

In this article, we report on the reversible tethering of end-functionalized polymers onto catechol-based titanium platforms by exploiting the reversible Diels-Alder (DA) cycloaddition reaction. For this purpose, furan and maleimide end-functionalized polymers, prepared via reversible addition-fragmentation chain transfer polymerization, were covalently grafted through a DA reaction onto reactive titanium platforms elaborated from catechol-based anchors incorporating either the furan or the maleimide moiety. As a proof of concept, a hydrophilic poly(oligo(ethylene glycol)acrylate) (POEGA) and a hydrophobic poly(2,2,2-trifluoroethyl acrylate) (PTFEA) were grafted onto titanium surfaces and subsequently detached by exploiting the thermoreversible nature of the DA reaction [i.e., retro Diels-Alder (rDA)]. These polymers were interchanged by performing a second DA reaction, thereby allowing the titanium surface wettability to be switched from hydrophobic to hydrophilic on demand. The grafting of furan/maleimide end-functionalized polymers onto functionalized (maleimide/furan, respectively) catechol-based titanium platforms and the subsequent rDA/DA sequence used for switching the titanium surface were evidenced by attenuated total reflectance-Fourier transform-infrared spectroscopy, X-ray photoelectron spectroscopy, and contact angle measurements.

Recognition-Mediated Hydrogel Swelling Controlled by Interaction with a Negative Thermoresponsive LCST Polymer.

Most polymeric thermoresponsive hydrogels contract upon heating beyond the lower critical solution temperature (LCST) of the polymers used. Herein, we report a supramolecular hydrogel system that shows the opposite temperature dependence. When the non-thermosesponsive hydrogel NaphtGel, containing dialkoxynaphthalene guest molecules, becomes complexed with the tetra cationic macrocyclic host CBPQT4+ , swelling occurred as a result of host-guest complex formation leading to charge repulsion between the host units, as well as an osmotic contribution of chloride counter-ions embedded in the network. The immersion of NaphtGel in a solution of poly(N-isopropylacrylamide) with tetrathiafulvalene (TTF) end groups complexed with CBPQT4+ induced positive thermoresponsive behaviour. The LCST-induced dethreading of the polymer-based pseudorotaxane upon heating led to transfer of the CBPQT4+ host and a concomitant swelling of NaphtGel. Subsequent cooling led to reformation of the TTF-based host-guest complexes in solution and contraction of the hydrogel.

Biomimetic Mussel Adhesive Inspired Anchor to Design ZnO@Poly(3-Hexylthiophene) Hybrid Core@Corona Nanoparticles.

The functionalization of zinc oxide (ZnO) nanoparticles by poly(3-hexylthiophene) (P3HT) brush is completed by the combination of a mussel inspired biomimetic anchoring group and Huisgen cyclo-addition "click chemistry." Herein, the direct coupling of an azide modified catechol derivative with an alkyne end-functionalized P3HT is described. This macromolecular binding agent is used to access core@corona ZnO@P3HT with a stable and homogeneous conjugated organic corona. Preliminary photoluminescence measurement proves an efficient electron transfer from the donor P3HT to the acceptor ZnO nanoparticles upon grafting, thus demonstrating the potential of such a combination in organic electronics.

Bioinspired Titanium Drug Eluting Platforms Based on a Poly-ß-cyclodextrin-Chitosan Layer-by-Layer Self-Assembly Targeting Infections.

In the field of implantable titanium-based biomaterials, infections and inflammations are the most common forms of postoperative complications. The controlled local delivery of therapeutics from implants through polyelectrolyte multilayers (PEMs) has recently emerged as a versatile technique that has shown great promise in the transformation of a classical medical implant into a drug delivery system. Herein, we report the design and the elaboration of new biodegradable multidrug-eluting titanium platforms based on a polyelectrolyte multilayer bioactive coating that target infections. These systems were built up in mild conditions according to the layer-by-layer (L-b-L) assembly and incorporate two biocompatible polysaccharides held together through electrostatic interactions. A synthetic, negatively charged ß-cyclodextrin-based polymer (PCD), well-known for forming stable and reversible complexes with hydrophobic therapeutic agents, was exploited as a multidrug reservoir, and chitosan (CHT), a naturally occurring, positively charged polyelectrolyte, was used as a barrier for controlling the drug delivery rate. These polyelectrolyte multilayer films were strongly attached to the titanium surface through a bioinspired polydopamine (PDA) film acting as an adhesive first layer and promoting the robust anchorage of PEMs onto the biomaterials. Prior to the multilayer film deposition, the interactions between both oppositely charged polyelectrolytes, as well the multilayer growth, were monitored by employing surface plasmon resonance (SPR). Several PEMs integrating 5, 10, and 15 bilayers were engineered using the dip coating strategy, and the polyelectrolyte surface densities were estimated by colorimetric titrations and gravimetric analyses. The morphologies of these multilayer systems, as well as their naturally occurring degradation in a physiological medium, were investigated by scanning electron microscopy (SEM), and their thicknesses were measured by means of profilometry and ellipsometry studies. Finally, the ability of the coated titanium multilayer devices to act as a drug-eluting system and to treat infections was validated with gentamicin, a relevant water-soluble antibiotic commonly used in medicine due to its broad bactericidal spectrum.

Programmable polymer-based supramolecular temperature sensor with a memory function.

A new class of polymeric thermometers with a memory function is reported that is based on the supramolecular host-guest interactions of poly(N-isopropylacrylamide) (PNIPAM) with side-chain naphthalene guest moieties and the tetracationic macrocycle cyclobis(paraquat-p-phenylene) (CBPQT(4+)) as the host. This supramolecular thermometer exhibits a memory function for the thermal history of the solution, which arises from the large hysteresis of the thermoresponsive LCST phase transition (LCST = lower critical solution temperature). This hysteresis is based on the formation of a metastable soluble state that consists of the PNIPAM-CBPQT(4+) host-guest complex. When heated above the transition temperature, the polymer collapses, and the host-guest interactions are disrupted, making the polymer more hydrophobic and less soluble in water. Aside from providing fundamental insights into the kinetic control of supramolecular assemblies, the developed thermometer with a memory function might find use in applications spanning the physical and biological sciences.

Mussel inspired coating of a biocompatible cyclodextrin based polymer onto CoCr vascular stents.

During the past decade, drug-eluting stents (DES) have been widely used for the treatment of occlusive coronary artery diseases. They are supposed to reduce the incidence of early in-stent restenosis by the elution of highly hydrophobic antiproliferative drugs. Nevertheless, the absence of long-term activity of these devices is responsible for late acute thrombosis probably due to the delayed re-endothelialization of the arterial wall over the bare metallic stent struts. Thus, a new generation of DES with a sustained release of therapeutic agents is required to improve long-term results of these devices. In this article, we report an original functionalization of CoCr vascular devices with a hydrophilic, biocompatible and biodegradable cyclodextrins based polymer which acts as a reservoir for lipophilic drugs allowing the sustained release of antiproliferative drugs. In this setting, polydopamine (PDA), a strong adhesive biopolymer, was applied as a first coating layer onto the surface of the metallic CoCr device in order to promote the strong anchorage of a cyclodextrin polymer. This polymer was generated "in situ" from the methylated cyclodextrins and citric acid as a cross-linking agent through a polycondensation reaction. After optimization of the grafting process, the amount of cyclodextrin polymer coated onto the CoCr device was quantified by colorimetric titrations and the resulting film was characterized by scanning electron microscopy (SEM) investigations. The cytocompatibility of the resulting coated film was assessed by cell proliferation and vitality tests. Finally, the ability of this coated device to act as a drug-eluting system was evaluated with paclitaxel, a strong hydrophobic antiproliferative drug, a reference drug used in current vascular drug-eluting stents.

Elaboration of thermoresponsive supramolecular diblock copolymers in water from complementary CBPQT4+ and TTF end-functionalized polymers.

A well-defined poly(N-isopropyl acrylamide) 1 incorporating at one termini a cyclobis(paraquat-p-phenylene) (CBPQT(4+)) recognition unit is prepared via a RAFT polymerization followed by a copper-catalyzed azide-alkyne cycloaddition (CuAAC). (1)H NMR (1D, DOSY), UV-vis and ITC experiments reveal that polymer 1 is able of forming effective host-guest complexes with tetrathiafulvalene (TTF) end-functionalized polymers in water, thereby leading to the formation of non-covalently-linked double-hydrophilic block copolymers. The effect of the temperature on both the LCST phase transition of 1 and its complexes and on CBPQT(4+)/TTF host-guest interactions is investigated.

Amplified plasmonic detection of DNA hybridization using doxorubicin-capped gold particles.

We show in this article that doxorubicin-modified gold nanoparticles (Au NP-DOX) can be used for the post-amplification of the wavelength shift of localized surface plasmon resonance (LSPR) signals after DNA hybridization events. We take advantage of the intercalation properties of DOX with guanine-rich oligonucleotides and the plasmon coupling between surface-linked gold nanostructures and Au NP-DOX in solution to detect in a sensitive manner DNA hybridisation events. Post-treatment of double-stranded DNA with Au NP-DOX resulted in a detection limit of ≈600 pM, several times lower than that without post-incubation (LOD ≈ 40 nM).

Thiol-yne click reactions on alkynyl-dopamine-modified reduced graphene oxide.

The large-scale preparation of graphene is of great importance due to its potential applications in various fields. We report herein a simple method for the simultaneous exfoliation and reduction of graphene oxide (GO) to reduced GO (rGO) by using alkynyl-terminated dopamine as the reducing agent. The reaction was performed under mild conditions to yield rGO functionalized with the dopamine derivative. The chemical reactivity of the alkynyl function was demonstrated by post-functionalization with two thiolated precursors, namely 6-(ferrocenyl)hexanethiol and 1H,1H,2H,2H-perfluorodecanethiol. X-ray photoelectron spectroscopy, UV/Vis spectrophotometry, Raman spectroscopy, conductivity measurements, and cyclic voltammetry were used to characterize the resulting surfaces.