The Role of Polymer-AuNP Interaction in the Stimuli-Response Properties of PPA-AuNP Nanocomposites.

The helical sense control of dynamic helical polymers such as poly(phenylacetylene)s (PPAs) is greatly affected when they are conjugated to AuNPs through a strong thiol-Au connection, which restricts conformational changes at the polymer. Thus, the classical thiol-MNP bonds must be replaced by weaker ones, such as supramolecular amide-Au interactions. A straightforward preparation of the PPA-Au nanocomposite by reduction of a preformed PPA-Au3+ complex cannot be used due to a redox reaction between the two components of the complex which degrades the polymer. To avoid the interaction between the PPA and the Au3+ ions before the reduction takes place, the metal ions are added to the polymer solution capped as a TOAB complex, which keeps the PPA stable due to the lack of PPA-Au3+ interactions. Ulterior reduction of the Au3+ ions by NaBH4 affords the desired nanocomposite, where the AuNPs are stabilized by supramolecular anilide-AuNPs interactions. By using this approach, 3.7 nm gold nanoparticles are generated and aligned along the polymer chain with a regular distance between particles of 6 nm that corresponds to two helical pitches. These nanocomposites show stimuli-responsive properties and are also able to form macroscopically chiral nanospheres with tunable size.

Design and Testing of Efficient Mucus-Penetrating Nanogels-Pitfalls of Preclinical Testing and Lessons Learned.

Mucosal surfaces pose a challenging environment for efficient drug delivery. Various delivery strategies such as nanoparticles have been employed so far; yet, still yielding limited success. To address the need of efficient transmucosal drug delivery, this report presents the synthesis of novel disulfide-containing dendritic polyglycerol (dPG)-based nanogels and their preclinical testing. A bifunctional disulfide-containing linker is coupled to dPG to act as a macromolecular crosslinker for poly-N-isopropylacrylamide (PNIPAM) and poly-N-isopropylmethacrylamide (PNIPMAM) in a precipitation polymerization process. A systematic analysis of the polymerization reveals the importance of a careful polymer choice to yield mucus-degradable nanogels with diameters between 100 and 200 nm, low polydispersity, and intact disulfide linkers. Absorption studies in porcine intestinal tissue and human bronchial epithelial models demonstrate that disulfide-containing nanogels are highly efficient in overcoming mucosal barriers. The nanogels efficiently degrade and deliver the anti-inflammatory biomacromolecule etanercept into epithelial tissues yielding local anti-inflammatory effects. Over the course of this work, several problems are encountered due to a limited availability of valid test systems for mucosal drug-delivery systems. Hence, this study also emphasizes how critical a combined and multifaceted approach is for the preclinical testing of mucosal drug-delivery systems, discusses potential pitfalls, and provides suggestions for solutions.

The influence of the shape of Au nanoparticles on the catalytic current of fructose dehydrogenase.

Graphite electrodes were modified with triangular (AuNTrs) or spherical (AuNPs) nanoparticles and further modified with fructose dehydrogenase (FDH). The present study reports the effect of the shape of these nanoparticles (NPs) on the catalytic current of immobilized FDH pointing out the different contributions on the mass transfer-limited and kinetically limited currents. The influence of the shape of the NPs on the mass transfer-limited and the kinetically limited current has been proved by using two different methods: a rotating disk electrode (RDE) and an electrode mounted in a wall jet flow-through electrochemical cell attached to a flow system. The advantages of using the wall jet flow system compared with the RDE system for kinetic investigations are as follows: no need to account for substrate consumption, especially in the case of desorption of enzyme, and studies of product-inhibited enzymes. The comparison reveals that virtually identical results can be obtained using either of the two techniques. The heterogeneous electron transfer (ET) rate constants (kS) were found to be 3.8 ± 0.3 s-1 and 0.9 ± 0.1 s-1, for triangular and spherical NPs, respectively. The improvement observed for the electrode modified with AuNTrs suggests a more effective enzyme-NP interaction, which can allocate a higher number of enzyme molecules on the electrode surface. Graphical abstract The shape of gold nanoparticles has a crucial effect on the catalytic current related to the oxidation of D-(-)-fructose to 5-keto-D-(-)-fructose occurring at the FDH-modified electrode surface. In particular, AuNTrs have a higher effect compared with the spherical one.

An Anisotropic Hydrogel Actuator Enabling Earthworm-Like Directed Peristaltic Crawling.

Peristaltic crawling, which is the moving mechanism of earthworm-like limbless creatures in narrow spaces, is a challenging target to mimic by using soft materials. Here we report an unprecedented hydrogel actuator that enables not only a peristaltic crawling motion but also reversing its direction. Our cylindrically processed hydrogel contains gold nanoparticles for photothermal conversion, a thermoresponsive polymer network for switching the electrical permittivity of the gel interior, and cofacially oriented 2D electrolytes (titanate nanosheets; TiNSs) to synchronously change their anisotropic electrostatic repulsion. When a hydrogel, which was designed to include cofacially oriented TiNSs along the cylindrical gel axis, is pointwisely photoirradiated with a visible-light laser, it spatiotemporally expands immediately (<0.5 s) and largely (80 % of its original length) in an isovolumetric manner. When the irradiation spot is moved along the cylindrical gel axis, the hydrogel undergoes peristaltic crawling due to quick and sequential elongation/contraction events and moves oppositely toward the laser scanning direction. Thus, when the scanning direction is switched, the crawling direction is reversed. When gold nanorods are used in place of gold nanoparticles, the hydrogel becomes responsive to a near-infrared light, which can deeply penetrate into bio tissues.

Unexpected Chiro-Thermoresponsive Behavior of Helical Poly(phenylacetylene)s Bearing Elastin-Based Side Chains.

The thermoresponsive behavior of an elastin-based polymer can be altered by the polymeric macromolecular conformation. Thus, when the elastin basic amino acid sequence VPGVG is used as a pendant group of a poly(phenylacetylene) (PPA) its thermoresponsive behavior in water can be remotely detected through conformational changes on the formed helix. Circular dichroism at different temperatures shows an inversion of the first Cotton effect (450 nm) at 25.8 °C that matches with the cloud point temperature. The elastin-based side-chain poly(phenylacetylene) shows an upper critical solution temperature with low pH and concentration dependency, not expected in elastin-based polymers. It was found that the polymer self-assembles in water into spherical nanoparticles with hydrodynamic diameters of 140 nm at the hydrophobic state.

Chiral Nanostructures from Helical Copolymer-Metal Complexes: Tunable Cation-π Interactions and Sergeants and Soldiers Effect.

Poly(phenylacetylene) (PPA) copolymers containing (R)- or (S)-MPA as minor chiral pendant can be forced to selectively adopt the right- o left-handed helix, in the presence of small amounts of Na(+) or Ag(+) ("Sergeants and Soldiers Effect") by addition of a donor cosolvent. The helical sense depends exclusively on the chiral monomer/donor cosolvent ratio, and this allows a perfect on/off tuning of the helicity of the copolymer. When the amount of the donor cosolvent is low, the metal ion complex is stabilized by a cation-π interaction, which is selectively cleaved when the amount of cosolvent is higher. Macroscopically chiral nanospheres and nanotubes composed by helical copolymers with P or M helical sense are also described. Our results demonstrate that it is possible to obtain the two enantiomeric helical structures (P and M helicities) and the corresponding nanospheres and nanotubes from a single helical copolymer, by controlled activation/deactivation of the Sergeant and Soldiers Effect with a donor cosolvent.

Transferrin Decorated Thermoresponsive Nanogels as Magnetic Trap Devices for Circulating Tumor Cells.

A rational design of magnetic capturing nanodevices, based on a specific interaction with circulating tumor cells (CTCs), can advance the capturing efficiency and initiate the development of modern smart nanoformulations for rapid isolation and detection of these CTCs from the bloodstream. Therefore, the development and evaluation of magnetic nanogels (MNGs) based on magnetic nanoparticles and linear thermoresponsive polyglycerol for the capturing of CTCs with overexpressed transferrin (Tf(+) ) receptors has been presented in this study. The MNGs are synthesized using a strain-promoted "click" approach which has allowed the in situ surface decoration with Tf-polyethylene glycol (PEG) ligands of three different PEG chain lengths as targeting ligands. An optimal value of around 30% of cells captures is achieved with a linker of eight ethylene glycol units. This study shows the potential of MNGs for the capture of CTCs and the necessity of precise control over the linkage of the targeting moiety to the capturing device.

Stimuli-responsive nanogel composites and their application in nanomedicine.

Nanogels are nanosized crosslinked polymer networks capable of absorbing large quantities of water. Specifically, smart nanogels are interesting because of their ability to respond to biomedically relevant changes like pH, temperature, etc. In the last few decades, hybrid nanogels or composites have been developed to overcome the ever increasing demand for new materials in this field. In this context, a hybrid refers to nanogels combined with different polymers and/or with nanoparticles such as plasmonic, magnetic, and carbonaceous nanoparticles, among others. Research activities are focused nowadays on using multifunctional hybrid nanogels in nanomedicine, not only as drug carriers but also as imaging and theranostic agents. In this review, we will describe nanogels, particularly in the form of composites or hybrids applied in nanomedicine.

Exo-chirality of the α-helix.

The structure of helical polymers is dictated by the molecular chirality of their monomer units. Particularly, macromolecular helices with monomer sequence control have the potential to generate chiral topologies. In α-helical folded peptides, the sequential repetition of amino acids generates a chiral layer defined by the amino acid side chains projected outside the amide backbone. Despite being closely related to peptides' structural and functional properties, to the best of our knowledge, a general exo-helical symmetry model has not been yet described for the α-helix. Here, we perform the theoretical, computational, and spectroscopic elucidation of the α-helix principal exo-helical topologies. Non-canonical labeled amino acids are employed to spectroscopically characterize the different exo-helical topologies in solution, which precisely match the theorical prediction. Backbone-to-chromophore distance also shows the expected impact in the exo-helices' geometry and spectroscopic fingerprint. Theoretical prediction and spectroscopic validation of this exo-helical topological model provides robust experimental evidence of the chiral potential on the surface of helical peptides and outlines an entirely new structural scenario for the α-helix.

Self-assembly of cyclic peptide monolayers by hydrophobic supramolecular hinges.

Supramolecular polymerisation of two-dimensional (2D) materials requires monomers with non-covalent binding motifs that can control the directionality of both dimensions of growth. A tug of war between these propagation forces can bias polymerisation in either direction, ultimately determining the structure and properties of the final 2D ensemble. Deconvolution of the assembly dynamics of 2D supramolecular systems has been widely overlooked, making monomer design largely empirical. It is thus key to define new design principles for suitable monomers that allow the control of the direction and the dynamics of two-dimensional self-assembled architectures. Here, we investigate the sequential assembly mechanism of new monolayer architectures of cyclic peptide nanotubes by computational simulations and synthesised peptide sequences with selected mutations. Rationally designed cyclic peptide scaffolds are shown to undergo hierarchical self-assembly and afford monolayers of supramolecular nanotubes. The particular geometry, the rigidity and the planar conformation of cyclic peptides of alternating chirality allow the orthogonal orientation of hydrophobic domains that define lateral supramolecular contacts, and ultimately direct the propagation of the monolayers of peptide nanotubes. A flexible 'tryptophan hinge' at the hydrophobic interface was found to allow lateral dynamic interactions between cyclic peptides and thus maintain the stability of the tubular monolayer structure. These results unfold the potential of cyclic peptide scaffolds for the rational design of supramolecular polymerisation processes and hierarchical self-assembly across the different dimensions of space.

Synthesis of 11-cis-retinoids by hydrosilylation-protodesilylation of an 11,12-didehydro precursor: easy access to 11- and 12-mono- and 11,12-dideuteroretinoids.

An expeditious, highly efficient approach to 11-cis-retinoids was achieved by semihydrogenation of a readily available 11-yne precursor through a hydrosilylation-protodesilylation protocol. The complete chemo-, regio-, and syn-stereoselectivity of the method also allowed direct access to 11- and 12-monodeutero-, and 11,12-dideutero-11-cis-retinoids. The analogous trans series was not accessible by this route, and was synthesized by means of Hiyama coupling.

Cross-coupling reactions of organosilicon compounds in the stereocontrolled synthesis of retinoids.

This paper presents a full account of the use of Hiyama cross-coupling reactions in a highly convergent approach to retinoids in which the key step is construction of the central C10-C11 bond. Representatives of two families of oxygen-activated dienyl silanes (ethoxysilanes and silanols) and of all reported families of "safety-catch" silanols (siletanes, silyl hydrides, allyl-, benzyl-, aryl-, 2-pyridyl- and 2-thienylsilanes) were regio- and stereoselectively prepared and stereospecifically coupled to an appropriate electrophile by treatment with a palladium catalyst and a nucleophilic activator. Both all-trans and 11-cis-retinoids, and their chain-demethylated analogues, were obtained in good yields regardless of the geometry (E/Z) and of the steric congestion in each fragment. This comprehensive study conclusively establishes the Hiyama cross-coupling reaction, with its mild reaction conditions and stable, easily prepared, ecologically advantageous silicon-based coupling partners, as the most effective route to retinoids reported to date.

A hybrid thermoresponsive plasmonic nanogel designed for NIR-mediated chemotherapy.

Temperature-trigger chemotherapy is one of the state-of-the-art anti-tumoral strategies in nanomedicine. However, this strategy is in close relationship with the effect of the temperature in the tumor tissue. With high temperatures, the ablation of the tumor tissue can hinder a correct chemotherapy approximation. On the other hand, with moderate temperatures a negative vascularization that promotes the tumor growing is produced and competes with the chemotherapeutic effects. We have constructed one nanogel system composed of a thermoresponsive polymer cross-linked by plasmonic gold nanoparticles (AuNPs) for temperature-trigger chemotherapy. Doxorubicin loaded in the porous interior of the nanogel is released when the thermoresponsive network of the nanogel collapses due to the heat generated by the AuNPs upon near infra-red light irradiation. The hybrid nanogel system has been tested in vitro and in vivo, where it was observed that the temperatures reached in the in vivo NIR irradiation have an undesired effect on the inhibition of the tumor growth while the drug loaded systems considerably reduced the tumor sizes. This study shows the importance of design in temperature triggered antitumoral systems, where lower temperatures usually reached in practical situations due to light attenuation produced by the tissue can be positively utilized for enhancing the antitumoral effect of loaded drugs in the system.

Bottom-up supramolecular assembly in two dimensions.

The self-assembly of molecules in two dimensions (2D) is gathering attention from all disciplines across the chemical sciences. Attracted by the interesting properties of two-dimensional inorganic analogues, monomers of different chemical natures are being explored for the assembly of dynamic 2D systems. Although many important discoveries have been already achieved, great challenges are still to be addressed in this field. Hierarchical multicomponent assembly, directional non-covalent growth and internal structural control are a just a few of the examples that will be discussed in this perspective about the exciting present and the bright future of two-dimensional supramolecular assemblies.

Exploiting cyanine dye J-aggregates/monomer equilibrium in hydrophobic protein pockets for efficient multi-step phototherapy: an innovative concept for smart nanotheranostics.

After several decades of development in the field of near-infrared (NIR) dyes for photothermal therapy (PTT), indocyanine green (ICG) still remains the only FDA-approved NIR contrast agent. However, upon NIR light irradiation ICG can react with molecular oxygen to form reactive oxygen species and degrade the ICG core, losing the convenient dye properties. In this work, we introduce a new approach for expanding the application of ICG in nanotheranostics, which relies on the confinement of self-organized J-type aggregates in hydrophobic protein domains acting as monomer depots. Upon the fast photobleaching, while the dye is irradiated, this strategy permits the equilibrium-driven monomer replacement after each irradiation cycle that radically increases the systems' effectivity and applicability. Gadolinium-doped casein micelles were designed to prove this novel concept at the same time as endowing the nanosystems with further magnetic resonance imaging (MRI) ability for dual-modal imaging-guided PTT. By teaching a new trick to a very old dog, the clinical prospect of ICG will undoubtedly be boosted laying the foundation for novel therapeutics. It is anticipated that future research could be expanded to other relevant J-aggregates-forming cyanine dyes or nanocrystal formulations of poorly water-soluble photosensitizers.

Revealing the NIR-triggered chemotherapy therapeutic window of magnetic and thermoresponsive nanogels.

The combination of magnetic nanoparticles and thermoresponsive nanogels represents an appealing strategy for the development of theranostic probes. These hybrid nanocarriers present several advantages such as outstanding properties for guided therapy, magnetic resonance imaging, and triggered release of encapsulated cargoes. Most magnetic thermoresponsive nanogels are built with strategies that comprise a physical interaction of particles with the polymeric network or the covalent attachment of a single particle to the linear polymer. Herein, we report a facile synthetic approach for the synthesis of magnetic and thermoresponsive nanogels that allows the controlled incorporation of multiple superparamagnetic inorganic cores as covalent cross-linkers. An ultrasonication-assisted precipitation-polymerization afforded nanogels with sizes in the nanometric range and similar magnetization and light transduction properties compared to the discrete magnetic nanoparticles. The theranostic capability of these nanocarriers was further investigated both in vitro and in vivo. In vivo experiments demonstrated the capacity of these materials as nanocarriers for near-infrared (NIR) triggered chemotherapy and highlighted the relevance of the correct concentration/dose in this antitumoral modality to achieve a superior therapeutic efficacy.

Chiral gold-PPA nanocomposites with tunable helical sense and morphology.

A novel type of stimuli-responsive dynamic helical polymer-metal nanoparticle nanocomposite formed by a helical poly(phenylacetylene) (PPA) combined with gold nanoparticles (AuNPs) is described. Thus, several PPA copolymers containing the ethynyl-4-benzamide of (S)-phenylglycine methyl ester (M1) to dictate the helical structure/sense of the copolymer, and the ethynyl-4-benzamide of the 11-((2-(2-(2-aminoethoxy)ethoxy)ethyl)amino)undecane-1-thiol (M2) to link the copolymer to the AuNPs are prepared. Different morphologies of these nanocomposites were obtained by considering the thiol ratio and the self-assembly properties of the PPA, which generates from dispersed AuNPs to fibre-like structures. All these nanocomposites show a dynamic chiral behaviour, it being possible to manipulate their helical sense by the action of external stimuli. Moreover, it is possible to control the aggregation of these nanocomposites into macroscopically chiral nanospheres with low polydispersity by using Ba2+ as a crosslinking agent.

Galvanic Replacement as a Synthetic Tool for the Construction of Anisotropic Magnetoplasmonic Nanocomposites with Synergistic Phototransducing and Magnetic Properties.

Magnetoplasmonic nanomaterials, which combine light and magnetic field responsiveness in an advantageous manner, are attractive candidates for bio-nanoapplications. However, the synthetic access to such hybrid particles has been limited by the incompatibility of the iron- and gold-based lattices. In this work, we provide the first insights into a new synthetic strategy for developing magnetoplasmonic anisotropic nanocomposites with prominent phototransducing properties. In our approach, magnetic nanocubes based on an alloy of iron oxide, zinc, and silver were constructed. In a key second stage, the galvanic replacement of silver with gold atoms yielded satellite-like magnetoplasmonic anisotropic structures. Superior magnetic and photoconverting properties were observed for the novel magnetoplasmonic nanocomposites when compared with the pure parent structures. Moreover, the synergy between the magnetic and optical stimuli was examined, showing shape-dependent contributions in the magnetization experiments. More importantly, an excellent cell ablation capability upon laser irradiation was observed for the magnetoplasmonic nanocomposites compared to the pure magnetic or plasmonic controls. Further demonstration of these novel theragnostic agents as MRI contrast agents is also reported even during the light-irradiation event. Thus, the described particles showed promising properties for bioapplications emerging from the novel synthetic methodology.

The influence of shape and charge on protein corona composition in common gold nanostructures.

With increasing importance of gold nanoparticles (AuNPs) in the medical field, the understanding of their interactions in biological environments is essential. It is known that the exposure to biological fluids of particles in the nanometric range leads to accumulation of proteins on the particle surface proximity, generating the so-called protein corona. This fact can completely change the properties of AuNPs, thus drastically influencing the characteristics and intended purpose of the particles. Therefore, deep insight on the formation and composition of this protein corona is of extreme importance. Between the different factors that can alter the corona formation, our study focuses on the influence of the shape and particle surface charge. In detail, four different shapes of nanometrical scale (spheres, rods, stars and cages) of comparable size were used, all of them stabilized with three different heterofunctionalized poly(ethylene glycol) thiol (R-PEG-SH) linkers (R = OCH3, COOH or NH2) to check the effect of charge as well. After incubation with human serum, abundant proteins were identified via liquid chromatography-electrospray ionization-tandem mass spectroscopy (LC ESI MS/MS) and compared in terms of their relative abundance. On the basis of statistical evaluations, the shape of our AuNPs showed a greater influence than the surface charge. Especially, cage-shaped AuNPs showed a lower amount of total corona proteins. This shape showed differences in the abundances of individual proteins like albumin, vitronectin and members of the complement system. These results indicate that nanocages could present an improved biocompatibility compared with the other shapes due to the high curvature areas and dense ligation on the flat surfaces that could hinder opsonisation and fast removal by the immune system.