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.

Photochemical Electrocyclization of Poly(phenylacetylene)s: Unwinding Helices to Elucidate their 3D Structure in Solution.

Photochemical electrocyclization of poly(phenylacetylene)s (PPAs) is used for the structural elucidation of a polyene backbone. This method not only allows classification of PPAs in cis-cisoidal (ω1 <90°) or cis-transoidal structures (ω1 >90°), but also approximating ω1 . A PPA solution is illuminated with visible light and monitoring the photochemical electrocyclization of the PPA helix by measuring the ECD spectra at different times. PPAs with a cis-cisoidal structure show a reduction of the ECD signal of at least 50 % before 30 min of irradiation, while cis-transoidal helices need much longer time because the transoidal bond must be isomerized. The different cis-cisoidal and cis-transoidal helices require different times to decrease their ECD signal by 50 % (t1/2 ), depending on the degree of compression or stretching of the helix, establishing a relationship between the secondary structure adopted by PPA (ω1 ) and the time required to lose the ECD vinylic signal by light irradiation.

From Sergeants and Soldiers to Chiral Conflict Effects in Helical Polymers by Acting on the Conformational Composition of the Comonomers.

Different communication mechanisms can be switched within a copolymer by acting on the conformational composition of the components and their chirality. Thus, a sergeant and soldiers effect is produced in two diastereomeric copolymer series, poly[(S)-1r -co-(S)-2(1-r) ] and poly[(R)-1r -co-(S)-2(1-r) ], owing to the presence in chloroform of a preferred conformation in (S)-2, and a conformational equilibrium in 1, where a P helix is induced independently of the absolute configuration of the soldier. In THF, the presence of a conformational equilibrium at the pendants of the two components produces a reciprocal chiral enhancement effect by copolymerization of the two monomers, while in DMF, a third chiral to chiral communication switch is produced due to the presence of a single conformer at the pendant group of the two components. In such a case, a chiral conflict or chiral accord effect is produced depending if the two components induce the same or the opposite helical sense.

A Stimuli-Responsive Macromolecular Gear: Interlocking Dynamic Helical Polymers with Foldamers.

Herein, macromolecular gears composed of helical poly(phenylacetylenes) (PPAs) bearing short oligopeptides as pendant groups are described, in which the two structural motifs (framework and substituents) are combined. These gears are obtained by polymerization of the acetylene groups introduced at the C-terminus of short oligopeptides formed by achiral (Aib)n units (n=1-3) derivatized at the N-terminus by a single enantiomer (R or S) of α-methoxy-α-trifluoromethylphenylacetic acid (MTPA, Mosher's reagent). The chiral information of the MTPA is transmitted to the achiral Aib fragments and, through either chiral tele-induction and/or chiral harvesting mechanisms, is further transferred to the polyene backbones, which adopt preferentially P or M helical senses. Moreover, these materials also show dynamic behavior and respond to the action of external stimuli by either inverting the P/M sense and/or modifying the elongation in fully reversible processes.

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.

Chiral information harvesting in helical poly(acetylene) derivatives using oligo(p-phenyleneethynylene)s as spacers.

A chiral harvesting transmission mechanism is described in poly(acetylene)s bearing oligo(p-phenyleneethynylene)s (OPEs) used as rigid achiral spacers and derivatized with chiral pendant groups. The chiral moieties induce a positive or negative tilting degree in the stacking of OPE units along the polymer structure, which is further harvested by the polyene backbone adopting either a P or M helix.

Chiral Overpass Induction in Dynamic Helical Polymers Bearing Pendant Groups with Two Chiral Centers.

The dynamic behavior of helical polymers bearing pendant groups with two chiral centers was studied. Controlled conformational changes at the chiral units placed either closer to or further away from the main chain promote different helical structures. Although the first residue is usually responsible for determining a specific helicity (P or M), we now found that the second chiral center is also able to induce a preferred helical sense when it is located closer in space to the main chain, thereby cancelling the order from the first chiral moiety. This result was achieved through proper coordination with a metal cation. As proof of concept, poly(phenylacetylene)s (PPAs) that bear one and two chiral amino acid units of different sizes and configuration combinations (l/d-alanine and l/d-phenylalanine) as pendants were evaluated. In total, ten polymers were studied. This constitutes the first report of axial control from a remote stereocenter in polymers bearing complex chiral pendants.

Decoding the ECD Spectra of Poly(phenylacetylene)s: Structural Significance.

The role of the main dihedral angles in the electronic circular dichroism (ECD) spectra of poly(phenylacetylene)s (PPAs) was estimated by using time-dependent density functional theory (TD-DFT) for oligo(phenylacetylene)s (n = 12). These studies reveal that in cis-transoidal arrangements, the first Cotton effect is dominated by excitations involving molecular orbitals (MOs) mainly related to the polyene backbone. Hence, for this scaffold, the ± sign of the first Cotton effect reflects the P/M helical sense of the internal helix of the polymer. However, in cis-cisoidal arrangements, contribution of MOs in the polyene and the aryl rings of the PPA backbone produce the first Cotton effect band. As a result, two different ECD signatures with three or four alternating Cotton effects can be produced depending on the sign of the ω1 and ω3 dihedral angles which determine the helical sense of the polyene (ω1) and the relative orientation of the aryl ring toward the polyene (ω3), respectively. Thus, on the one hand, if ω1 and ω3 rotate in opposite directions, a CD with three alternating Cotton effects is observed, where the sign of first Cotton correlates with the P/M helical sense of the polyene. On the other hand, if ω1 and ω3 rotate in the same direction, a CD signature with four alternating Cotton effects is produced where the information relative to the P/M helical sense of the polyene is contained in the second Cotton effect.

Chiral Conflict as a Method to Create Stimuli-Responsive Materials Based on Dynamic Helical Polymers.

A new multi-sensor material based on helical copolymers showing the chiral conflict effect have been prepared. It can successfully detect and identify diverse metal cations in solution. The design of this material has taken into account not only the opposite helical senses induced by the two chiral monomers in the copolymer, but also their dynamic behavior. The induced helical sense can thus be enhanced, diminished, or inverted by interaction with different stimuli (that is, metal ions). Thus, depending on both the copolymer compositions (such as monomer ratios and absolute configurations) and the nature of the metal ion, the response of these dynamic helical copolymers to adopt a single-handed P or M helix is unique, making it possible not only to detect their presence, but also to identify them individually. New multi-sensors materials based and inspired on this effect should arise in the future choosing appropriate monomers and stimuli.

Stimuli-Directed Colorimetric Interconversion of Helical Polymers Accompanied by a Tunable Self-Assembly Process.

Interconversion between extended and bent structures at the pendant groups of a chiral polyene framework [poly(phenylacetylene) with (R)-(2-methoxy-2-phenylacetyl)glycine residues linked to 4-vinylanilines] allows the reversible colorimetric transformation from stretched to compressed helical cis-transoid polyenic structures through manipulation of the flexible spacer. This transformation generates either organogels (stretched helical form) or nanoparticles (compressed helical form) under the control of polar/low polar stimuli respectively and opens the way to the development of new sensors and stimuli-sensitive materials based on these concepts.

Filtering the NMR Spectra of Complex Mixtures through Polymer-Mediated Paramagnetic Spin Relaxation.

A polymer-mediated paramagnetic spin relaxation (PSR) filter is presented for the selective suppression of signals from polymer-interacting species in the 1D and 2D NMR spectra of mixtures. The combined use of Gd3+ and a polymer with a high transverse relaxation enhancement (R2p , which gives a measure of the Gd3+ -complexing ability) results in the suppression of signals from any polymer-interacting component in mixtures, irrespective of their R2p . By using poly(acrylic acid) (PAA) as a model system, we demonstrate selective filtering of the signals of typical low-R2p species (insensitive to Gd3+ ), such as molecular/polymeric cations and non-ionic polymers, which, through PAA recognition (electrostatic/hydrogen-bonding interactions), become exposed to the paramagnetic effect of Gd3+ , while leaving non-PAA-interacting species unaffected. Typical suppression conditions involve PAA (approximately equimolar amount with respect to the species to be filtered) accompanied by sub-mm concentrations of Gd3+ and T2 -filters ≤100 ms. Overall, by exploiting the PSR principles and the recognition properties of polymers, selective NMR filtrations that are not attainable by diffusion, relaxation, or direct PSR filters, can be achieved.

Chiral-to-Chiral Communication in Polymers: A Unique Approach To Control Both Helical Sense and Chirality at the Periphery.

A novel approach to the classical Sergeants and Soldiers effect, using chiral Sergeants and chiral Soldiers, allows control over both helical and external chirality in helical polymers. In the systems reported here, it is possible to induce the same helical sense ( M or P) from either of the two enantiomers of a chiral pendant group ["chiral Soldier", major component; i.e., ( R)- or ( S)-1] when it faces a single enantiomer of an appropriate "chiral Sergeant" [minor component; i.e., ( S)-2]. For instance, the copolymer series poly[( R)-1 r- co-( S)-2(1- r)], poly[( S)-1 r- co-( S)-2(1- r)], and poly[( rac)-1 r- co-( S)-2(1- r)] adopt the same P helix even though the major component shows the opposite absolute configuration. This chiral-to-chiral communication effect is transmitted by the stabilization of different conformations in each enantiomeric form of the Soldier. As a result, this groundbreaking approximation to the Sergeants and Soldiers effect allows the preparation of a single-handed helix-which depends only on the Sergeant's configuration-with different chiralities on the helix periphery. Thus, a P helix can be decorated with the R isomer, S isomer, or even a racemic mixture of the chiral Soldier. A change in the absolute configuration of the Sergeant affords the opposite M helix, which can also be decorated with the R isomer, S isomer, or racemic mixture of the chiral Soldier.

Sequential Induction of Chirality in Helical Polymers: From the Stereocenter to the Achiral Solvent.

Several steps of chiral induction have been detected in poly(phenylacetylene)s among their different hierarchical levels of chirality by vibrational circular dichroism, namely, (i) from the stereogenic centers to the innermost polyacetylene helical covalent backbone (helixint), (ii) from this to the external helix (helixext) formed by the side phenyl pendants that form a complementary helix or counter-helix, and (iii) from this pendant helix to the helical solvation sphere (helixsolv.), the last one being observed along this work. The pendant to polyene backbone chiral induction determines the helical structure adopted by the polymer and therefore the solvation helix. This helical structure is promoted by two mechanisms: steric effects and hydrogen bonding. An important finding concerns the demonstration by VCD of how an achiral solvent becomes chirally organized owing to the template effect of the covalent polymer helices, an effect that is silent to other structural techniques such as ECD or AFM and that hence significantly broadens the scope of these previous analyses.

Tuning the Size of Nanoassembles: A Hierarchical Transfer of Information from Dendrimers to Polyion Complexes.

The generation of dendrimers is a powerful tool in the control of the size and biodistribution of polyion complexes (PIC). Using a combinatorial screening of six dendrimers (18-243 terminal groups) and five oppositely charged PEGylated copolymers, a dendrimer-to-PIC hierarchical transfer of structural information was revealed with PIC diameters that increased from 80 to 500 nm on decreasing the dendrimer generation. This rise in size, which was also accompanied by a micelle-to-vesicle transition, is interpreted according to a cone- to rod-shaped progression in the architecture of the unit PIC (uPIC). This precise size tuning enabled dendritic PICs to act as nanorulers for controlled biodistribution. Overall, a domino-like control of the size and biological properties of PIC that is not attainable with linear polymers is feasible through dendrimer generation.

Predicting the Helical Sense of Poly(phenylacetylene)s from their Electron Circular Dichroism Spectra.

The calculated ECD spectrum (time-dependent density functional theory TD-DFT) for small oligomers of polyphenylacetylenes (PPAs) show a very good match with the experimental spectra of the PPA polymers, particularly with the first Cotton band associated to the helical sense of the internal polyenic backbone. This has been proven with a series of PPAs representative of cis-cisoidal, cis-transoidal, compressed and stretched polyene backbones, with identical or opposite internal/external rotational senses and allows the prediction of the helical sense of the internal helix of a PPA directly from its CD spectra.

Fast NMR Screening of Macromolecular Complexes by a Paramagnetic Spin Relaxation Filter.

The paramagnetic spin relaxation filter is described for the rapid NMR screening of intermolecular interactions between ligands and macromolecular anionic receptors with large transverse relaxation enhancements (R 2p). The addition of micromolar concentrations of Gd3+ to the mixture produces the immediate broadening/suppression of the NMR signals of interacting species while leaving unaffected those of noncompetitive binders (one-dimensional and two-dimensional experiments). The method is highly sensitive, unveiling interactions that are too weak to generate changes in chemical shifts or relaxation times. It is operationally very simple and hence, it is amenable to ready implementation by nonspecialists. Examples of application such as detecting the formation of interpolymer complexes, cyclodextrin host-guest interactions, and the screening of DNA ligands are included that demonstrate the reliability and broad applicability of the method.

Chiral Coalition in Helical Sense Enhancement of Copolymers: The Role of the Absolute Configuration of Comonomers.

Both the role of the absolute configuration and the tendency of a chiral monomer to promote a certain helical scaffold in a poly(phenylacetylene) (PPA) have been evaluated to study the communication between two chiral monomers within a copolymer chain. Nineteen different PPA copolymer series-47 helical copolymers altogether-were prepared to explore the existence of a chiral-to-chiral communication mechanism. From the data obtained, we found that communication between two different chiral monomers emerges when both exhibit two special features: (a) a different conformational composition-one must exist in a single low-energy conformation ("chiral Sergeant") and the other must present two conformers ("chiral Soldier")-and (b) the induction of a similar scaffold in the PPA, either cis-cisoidal or cis-transoidal. In the selected systems, the chiral Soldier includes the 4-ethynylanilide (para position) of either (R)- or (S)-2-methoxy-2-phenylacetic acid pendants characterized by their conformational flexibility (equilibrium between synperiplanar and antiperiplanar conformations). The chiral Sergeant contains the same chiral groups but linked to the backbone in meta position [3-ethynylanilide of (R)- or (S)-2-methoxy-2-phenylacetic acid] and is selected on the basis of its restricted antiperiplanar conformation. Incorporation of a very small amount (1%) of the Sergeant into a chain composed of just the Soldier transforms the originally axially racemic chain into a helix with strong sense preference (either M or P) that is determined by the absolute configuration of the Soldier.

The role of the secondary structure of helical poly(phenylacetylene)s in the formation of nanoparticles from polymer-metal complexes (HPMCs).

The great importance of the secondary structure (compressed/stretched) of helical poly(phenylacetylene)s (PPAs) in the formation of nanostructures (nanospheres and nanotoroids) by complexation with metal ions of diverse valences is demonstrated. PPAs bearing the same chelating units [anilide of (R)-methoxyphenylacetic acid] but displaying different helical scaffolds show great differences in their nanostructuration due to the different secondary structures of their helices despite the analogous ways in which their mono- and divalent metal ions form complexes. This key 3-D structural feature has not been taken into account previously when studying the nanostructuration of helical polymer-metal complexes (HPMCs).

Multipodal dynamic coordination involving cation-π interactions to control the structure of helical polymers.

A precise tuning of the four possible states of a helix (P/M helical sense and stretched/compressed helical backbone) is attained by controlling the complexation between Li+ and a poly(phenylacetylene) that bears amide, ester and phenyl ring functionalities at the pendant group. Depending on the MeOH ratio that is present as a cosolvent, different coordination sites are involved in interactions leading to complexes I-III, each one with a characteristic structure (tri-, bi-, and unipodal) and an associated helical state. This dynamic coordination allows the selective modification of the helical sense or the stretching/compression backbone of a helical polymer.

Biodegradable PEG-dendritic block copolymers: synthesis and biofunctionality assessment as vectors of siRNA.

One important drawback of most of the currently used dendrimers for biomedical applications is their high stability under physiological conditions that can result in cytotoxicity or complications induced by the accumulation of non-degradable synthetic materials in the organism. Particularly in the gene therapy field, vector stability can further hinder the intracellular release of the nucleic acid from the dendriplex, consequently leading to low transfection efficiencies. Therefore, biodegradable cationic dendritic structures have been eagerly awaited. However, the development of these dendritic nanocarriers is challenging because of the undesired and/or premature degradation observed during their synthesis and/or application. Here, we report new hybrid-biodegradable, biocompatible, non-toxic, and water-soluble azide-terminated PEG-GATGE dendritic block copolymers, based on a gallic acid (GA) core and triethylene glycol (TG) butanoate arms, incorporating ester bonds (E) at the dendritic arms/shell. Their successful functionalization by "click" chemistry with unprotected alkynated amines allowed complexation and delivery of siRNA. The hydrophobic character of the GATGE building unit confers to these hydrolyzable dendritic bionanomaterials a great ability to complex, protect and mediate the cellular internalization of siRNA. Moreover, the localization of the degradation points at the dendritic periphery, close to the complexed siRNA, was found to be important for nucleic acid release from the nanoparticles, rendering a significant improvement of the transfection efficiency compared to their hydrolytically stable PEG-GATG copolymer counterparts. The present study puts forward these biodegradable PEG-dendritic block copolymers not only as suitable vectors for nucleic acids, but also as new avenues for further developments exploring their use in theranostics.