Comparative Preclinical Study of Lidocaine and Mepivacaine in Resilient Hyaluronic Acid Fillers.

BACKGROUND: Hyaluronic acid-based filler injections are now well-established aesthetic procedures for the correction of skin tissue defects and volume loss. Filler injections are becoming increasingly popular, with a growing number of injections performed each year. Although classified as a minimally invasive procedure, the introduction of a needle or a canula may remain painful for the patient. A major improvement was achieved with the incorporation of local anesthetics into the formulation for pain relief. METHODS: In this study, two well-known anesthetics, lidocaine and mepivacaine, were systematically compared to assess their influence on filler mechanical and biological features. The impact of each anesthetic was monitored in terms of gel rheological properties, stability, durability, and degradation. The release profiles of each anesthetic were also recorded. Finally, the pharmacokinetics of each anesthetic in rats were assessed. RESULTS: For all the rheological and biological experiments performed, lidocaine and mepivacaine influences were comparable. The addition of either anesthetic into a soft-tissue filler showed no significant modifications of the stability, durability, and degradability of the gel, with similar release profiles and pharmacokinetics at an equivalent concentration. CONCLUSIONS: Substituting lidocaine with mepivacaine does not impact the properties of the gels, and thus both can be equally incorporated as anesthetics in soft-tissue fillers.

Crosslinking hyaluronic acid soft-tissue fillers: current status and perspectives from an industrial point of view.

INTRODUCTION: Hyaluronan (HA)-based soft-tissue fillers are injectable crosslinked hydrogels aimed to counteract facial skin aging signs via minimally invasive procedures. The crosslinking step is required to drastically improve HA residence time in vivo and provide the gel with specific viscoelastic properties matching the clinical indications. While HA as a raw material and HA fillers are widely studied, little is reported about crosslinkers themselves used in commercial fillers. AREAS COVERED: This article introduces the specifications of the ideal crosslinker in HA fillers. The properties of commercially used crosslinkers are reviewed. An up-to-date review of innovative hydrogel fabrication alternatives is conducted, and advantages and drawbacks are discussed. EXPERT OPINION: HA fillers are predominantly manufactured using 1,4-butanediol diglycidyl ether (BDDE) which is considered as the gold standard crosslinker worldwide due to its proven and unrivaled clinical track record of more than 20 years. Extensive studies have been published covering BDDE-crosslinked HA fillers' chemistry, gel properties, and clinical effectiveness and safety. However, new hydrogel fabrication strategies have emerged, paving the way for innovative alternatives potentially bringing novel features to HA fillers. Nevertheless, major efforts must still be implemented to assess their safety, efficacy, stability and suitability for industrialization.

Efficient Photoinduced Energy and Electron Transfer in ZnII -Porphyrin/Fullerene Dyads with Interchromophoric Distances up to 2.6†nm and No Wire-like Connectivity.

The dyads 1-3 made of an alkynylated ZnII -porphyrin and a bis-methanofullerene derivative connected through a copper-catalyzed azide-alkyne cycloaddition have been synthesized. The porphyrin and fullerene chromophores are separated through a bridge made of a bismethanofullerene tether linked to different spacers conjugated to the porphyrin moiety [i.e., m-phenylene (1), p-phenylene (2), di-p-phenylene-ethynylene (3)]. Compounds 1-3 exhibit relatively rigid structures with an interchromophoric separation of 1.7, 2.0, and 2.6 nm, respectively, and no face-to-face or direct through-bond conjugation. The photophysical properties of compounds 1-3 have been investigated in toluene and benzonitrile with steady-state and time-resolved techniques as well as model calculations on the Förster energy transfer. Excited-state interchromophoric electronic interactions are observed with a distinct solvent and distance dependence. The latter effect is evidenced in benzonitrile, where compounds 1 and 2 exhibit a photoinduced electron transfer in the Marcus-inverted region, with charge-separated (CS) states living for 0.44 and 0.59 µs, respectively, whereas compound 3 only undergoes energy transfer, as in apolar toluene. The quantum yield of the charge separation (φCS ) of compounds 1 and 2 in benzonitrile is ≥0.75. It is therefore demonstrated that photoinduced energy and electron transfers in porphyrin-fullerene systems with long interchromophoric distances may efficiently occur also when the bridge does not provide a wire-like conjugation and proceed through the triplet states of the chromophoric moieties.

Self-organisation of dodeca-dendronized fullerene into supramolecular discs and helical columns containing a nanowire-like core.

Twelve chiral and achiral self-assembling dendrons have been grafted onto a [60]fullerene hexa-adduct core by copper-catalyzed alkyne azide "click" cycloaddition. The structure adopted by these compounds was determined by the self-assembling peripheral dendrons. These twelve dendrons mediate the self-organisation of the dendronized [60]fullerene into a disc-shaped structure containing the [60]fullerene in the centre. The fullerene-containing discs self-organise into helical supramolecular columns with a fullerene nanowire-like core, forming a 2D columnar hexagonal periodic array. These unprecedented supramolecular structures and their assemblies are expected to provide new developments in chiral complex molecular systems and their application to organic electronics and solar cells.

Redox switchable daisy chain rotaxanes driven by radical-radical interactions.

We report the one-pot synthesis and electrochemical switching mechanism of a family of electrochemically bistable 'daisy chain' rotaxane switches based on a derivative of the so-called 'blue box' (BB(4+)) tetracationic cyclophane cyclobis(paraquat-p-phenylene). These mechanically interlocked molecules are prepared by stoppering kinetically the solution-state assemblies of a self-complementary monomer comprising a BB(4+) ring appended with viologen (V(2+)) and 1,5-dioxynaphthalene (DNP) recognition units using click chemistry. Six daisy chains are isolated from a single reaction: two monomers (which are not formally 'chains'), two dimers, and two trimers, each pair of which contains a cyclic and an acyclic isomer. The products have been characterized in detail by high-field (1)H NMR spectroscopy in CD3CN-made possible in large part by the high symmetry of the novel BB(4+) functionality-and the energies associated with certain aspects of their dynamics in solution are quantified. Cyclic voltammetry and spectroelectrochemistry have been used to elucidate the electrochemical switching mechanism of the major cyclic daisy chain products, which relies on spin-pairing interactions between V(•+) and BB(2(•+)) radical cations under reductive conditions. These daisy chains are of particular interest as electrochemically addressable molecular switches because, in contrast with more conventional bistable catenanes and rotaxanes, the mechanical movement of the ring between recognition units is accompanied by significant changes in molecular dimensions. Whereas the self-complexed cyclic monomer-known as a [c1]daisy chain or molecular 'ouroboros'-conveys sphincter-like constriction and dilation of its ultramacrocyclic cavity, the cyclic dimer ([c2]daisy chain) expresses muscle-like contraction and expansion along its molecular length.

An electrochemically and thermally switchable donor-acceptor [c2]daisy chain rotaxane.

Although motor proteins are essential cellular components that carry out biological processes by converting chemical energy into mechanical motion, their functions have been difficult to mimic in artificial synthetic systems. Daisy chains are a class of rotaxanes which have been targeted to serve as artificial molecular machines because their mechanically interlocked architectures enable them to contract and expand linearly, in a manner that is reminiscent of the sarcomeres of muscle tissue. The scope of external stimuli that can be used to control the musclelike motions of daisy chains remains limited, however, because of the narrow range of supramolecular motifs that have been utilized in their templated synthesis. Reported herein is a cyclic daisy chain dimer based on π-associated donor-acceptor interactions, which can be actuated with either thermal or electrochemical stimuli. Molecular dynamics simulations have shown the daisy chain's mechanism of extension/contraction in the ground state in atomistic detail.

A supramolecular photosynthetic model made of a multiporphyrinic array constructed around a C60 core and a C60-imidazole derivative.

The photophysical properties of a supramolecular fullerene-porphyrin ensemble resulting from the self-assembly of a pyrrolidinofullerene-imidazole derivative (F1) with a multimetalloporphyrin array constructed around a hexasubstituted fullerene core (F(ZnP)12) have been investigated. The fullerene hexa-adduct core of the host system does not play any active role in the cascade of photoinduced events of the supramolecular ensemble, indeed no intercomponent photoinduced processes could be observed in host F(ZnP)12. In contrast, upon axial coordination with the monosubstituted fullerene guest F1, a quantitative quenching of the fluorescence signal of the metalloporphyrins was observed for the supramolecular complex [F(ZnP)12(F1)n] both in polar and nonpolar solvents. In toluene, the supramolecular ensemble exhibits a charge transfer emission centered around nm, suggesting the occurrence of intramolecular face-to-face interactions of F1 with neighboring metalloporphyrin moieties within the self-assembled photoactive array. This mechanism is supported by the fact that a one order of magnitude increase in the binding constant was observed for the supramolecular complex [F(ZnP)12(F1)n] when compared with a reference system lacking the pyrrolidinofullerene unit. In benzonitrile, a long-lived charge-separated state (τ=0.3 µs) has been detected for the supramolecular adduct.

Pillar[5]arene as a co-factor in templating rotaxane formation.

After the manner in which coenzymes often participate in the binding of substrates in the active sites of enzymes, pillar[5]arene, a macrocycle containing five hydroquinone rings linked through their para positions by methylene bridges, modifies the binding properties of cucurbit[6]uril, such that the latter templates azide-alkyne cycloadditions that do not occur in the presence of only the cucurbit[6]uril, a macrocycle composed of six glycoluril residues doubly linked through their nitrogen atoms to each other by methylene groups. Here, we describe how a combination of pillar[5]arene and cucurbit[6]uril interacts cooperatively with bipyridinium dications substituted on their nitrogen atoms with 2-azidoethyl- to 5-azidopentyl moieties to afford, as a result of orthogonal templation, two [4]rotaxanes and one [5]rotaxane in >90% yields inside 2 h at 55 °C in acetonitrile. Since the hydroxyl groups on pillar[5]arene and the carbonyl groups on cucurbit[6]uril form hydrogen bonds readily, these two macrocycles work together in a cooperative fashion to the extent that the four conformational isomers of pillar[5]arene can be trapped on the dumbbell components of the [4]rotaxanes. In the case of the [5]rotaxane, it is possible to isolate a compound containing two pillar[5]arene rings with local C5 symmetries. In addition to fixing the stereochemistries of the pillar[5]arene rings, the regiochemistries associated with the 1,3-dipolar cycloadditions have been extended in their constitutional scope. Under mild conditions, orthogonal recognition motifs have been shown to lead to templation with positive cooperativity that is fast and all but quantitative, as well as being green and efficient.

Selective isolation of gold facilitated by second-sphere coordination with α-cyclodextrin.

Gold recovery using environmentally benign chemistry is imperative from an environmental perspective. Here we report the spontaneous assembly of a one-dimensional supramolecular complex with an extended {[K(OH2)6][AuBr4](α-cyclodextrin)2}n chain superstructure formed during the rapid co-precipitation of α-cyclodextrin and KAuBr4 in water. This phase change is selective for this gold salt, even in the presence of other square-planar palladium and platinum complexes. From single-crystal X-ray analyses of six inclusion complexes between α-, ß- and γ-cyclodextrins with KAuBr4 and KAuCl4, we hypothesize that a perfect match in molecular recognition between α-cyclodextrin and [AuBr4](-) leads to a near-axial orientation of the ion with respect to the α-cyclodextrin channel, which facilitates a highly specific second-sphere coordination involving [AuBr4](-) and [K(OH2)6](+) and drives the co-precipitation of the 1:2 adduct. This discovery heralds a green host-guest procedure for gold recovery from gold-bearing raw materials making use of α-cyclodextrin-an inexpensive and environmentally benign carbohydrate.

γ-Cyclodextrin cuprate sandwich-type complexes.

Three structures, based on γ-cyclodextrin (γ-CD) and metal ions (Cu(2+), Li(+), Na(+), and Rb(+)), have been prepared in aqueous and alkaline media and characterized structurally by single-crystal X-ray diffraction. Their dimeric assemblies adopt cylindrical channels along the c axes in the crystals. Coordinative and hydrogen bonding between the cylinders and the solvent molecules lead to the formation of two-dimensional sheets, with the identity of the alkali-metal ion strongly influencing the precise nature of the solid-state structures. In the case of the Rb(+) complex, coordinative bonding involving the Rb(+) ions leads to the formation of an extended two-dimensional structure. Nonbound solvent molecules can be removed, and gas isotherm analyses confirm the permanent porosity of these new complexes. Carbon dioxide (CO2) adsorption studies show that the extended structure, obtained upon crystallization of the Rb(+)-based sandwich-type dimers, has the highest CO2 sequestration ability of the three γ-CD complexes reported.

Redox-controlled selective docking in a [2]catenane host.

The docking by neutral and charged guests selectively in two geometrically different binding pockets in a dynamic [2]catenane host is demonstrated in the solid state by manipulating its redox chemistry. The change in redox properties, not only alters the affinity of the host toward neutral and charged guests, but it also induces a profound change in the geometry of the host to accommodate them. X-ray crystallography, performed on the two different 1:1 complexes, demonstrates unambiguously the fact that the [2]catenane host provides a uniquely different binding pocket wherein a methyl viologen dication is stabilized by interacting with a bipyridinium radical cation, despite the presence of Coulombic repulsions.

Incorporation of an A1/A2-difunctionalized pillar[5]arene into a metal-organic framework.

An efficient synthetic route to an A1/A2-difunctionalized pillar[5]arene containing resolvable planar chirality has been developed and the arene employed as a strut in the synthesis of P5A-MOF-1, which has been demonstrated by X-ray powder diffraction analysis--supported by modeling--to be isoreticular with MOF-5. This metal-organic framework has an active domain that expresses good and selective uptake of neutral and positively charged electron-poor aromatic guests, which effect color changes of the cubic crystals from faint yellow to deep orange, arising from charge transfer between the guests and active domain of P5A-MOF-1.

A neutral naphthalene diimide [2]rotaxane.

A neutral donor-acceptor [2]rotaxane, which has been synthesized using click chemistry, has had its solid-state structure and superstructure elucidated by X-ray crystallography. Both dynamic (1)H NMR spectroscopy and electrochemical investigations have been employed in an attempt to shed light on both geometrical reorganization and redox-switching processes that are occurring or can be induced within the [2]rotaxane.

The inhibition of liposaccharide heptosyltransferase WaaC with multivalent glycosylated fullerenes: a new mode of glycosyltransferase inhibition.

L,D-Heptosides (L-glycero-D-manno-heptopyranoses) are found in important bacterial glycolipids such as lipopolysaccharide (LPS), the biosynthesis of which is targeted for the development of novel antibacterial agents. This work describes the synthesis of a series of fullerene hexa-adducts bearing 12 copies of peripheral sugars displaying the mannopyranose core structure of bacterial L,D-heptoside. The multimers were assembled through an efficient copper-catalyzed alkyne-azide cycloaddition reaction as the final step. The final fullerene sugar balls were assayed as inhibitors of heptosyltransferase WaaC, the glycosyltransferase catalyzing the incorporation of the first L-heptose into LPS. Interestingly, the inhibition of the final molecules was found in the low micromolar range (IC(50) =7-45 µM), whereas the corresponding monomeric glycosides displayed high micromolar to low millimolar inhibition levels (IC(50) always above 400 µM). When evaluated on a "per-sugar" basis, these inhibition data showed that, in each case, the average affinity of a single glycoside of the fullerenes towards WaaC was significantly enhanced when displayed as a multimer, thus demonstrating an unexpected multivalent effect. To date, such a multivalent mode of inhibition had never been evidenced with glycosyltransferases.

Artificial light-harvesting arrays: electronic energy migration and trapping on a sphere and between spheres.

A sophisticated model of the natural light-harvesting antenna has been devised by decorating a C(60) hexa-adduct with ten yellow and two blue boron dipyrromethene (Bodipy) dyes in such a way that the dyes retain their individuality and assist solubility of the fullerene. Unusually, the fullerene core is a poor electron acceptor and does not enter into light-induced electron-transfer reactions with the appended dyes, but ineffective electronic energy transfer from the excited-state dye to the C(60) residue competes with fluorescence from the yellow dye. Intraparticle electronic energy transfer from yellow to blue dyes can be followed by steady-state and time-resolved fluorescence spectroscopy and by excitation spectra for isolated C(60) nanoparticles dissolved in dioxane at 293 K and at 77 K. The decorated particles can be loaded into polymer films by spin coating from solution. In the dried film, efficient energy transfer occurs such that photons absorbed by the yellow dye are emitted by the blue dye. Films can also be prepared to contain C(60) nanoparticles loaded with the yellow Bodipy dye but lacking the blue dye and, under these circumstances, electronic energy migration occurs between yellow dyes appended to the same nanoparticle and, at higher loading, to dye molecules on nearby particles. Doping these latter polymer films with the mixed-dye nanoparticle coalesces these multifarious processes in a single system. Thus, long-range energy migration occurs among yellow dyes attached to different particles before trapping at a blue dye. In this respect, the film resembles the natural photosynthetic light-harvesting complexes, albeit at much reduced efficacy. The decorated nanoparticles sensitize amorphous silicon photocells.

A soluble hybrid material combining carbon nanohorns and C60.

A soluble hybrid nanomaterial that combines fullerenes and carbon nanohorns (CNHs) has been prepared and fully characterized. Electrochemical investigations revealed that the CNHs modify the electron accepting ability of C(60) in the hybrid material.

Gene delivery with polycationic fullerene hexakis-adducts.

Polyplexes prepared from DNA and globular compact polycationic derivatives constructed around a fullerene hexakis-adduct core have shown remarkable gene delivery capabilities.

Synthesis of dodecavalent fullerene-based glycoclusters and evaluation of their binding properties towards a bacterial lectin.

Multivalency is playing a major role in biological processes and particularly in lectin-carbohydrate interactions. The design of high-affinity ligands of lectins should provide molecules capable of interfering with these biological processes and potentially inhibit bacterial or viral infections. Azide-alkyne "click" chemistry was applied to the synthesis of dodecavalent fullerene-based glycoclusters. The conjugation could be efficiently performed from alkyne or azide functions on either partners (i.e. hexakis-fullerene adduct or glycoside). PA-IL is a bacterial lectin from the opportunistic pathogen Pseudomonas aeruginosa and is involved in the recognition of glycoconjugates on human tissues. The glycoclusters obtained were evaluated as ligands of PA-IL and for their potential for competing with its binding to glycosylated surfaces. The affinities measured by hemagglutination inhibition assay (HIA), enzyme-linked lectin assay (ELLA), and surface plasmon resonance (SPR) displayed a significant "glycoside cluster effect" with up to a 12,000-fold increase in binding when comparing a monovalent carbohydrate reference probe with a dodecavalent fullerene-based glycocluster, albeit with some differences depending on the analytical technique.

The functional valency of dodecamannosylated fullerenes with Escherichia coli FimH--towards novel bacterial antiadhesives.

Fullerene hexakis-adducts bearing 12 peripheral mannose moieties have been prepared by grafting sugar derivatives onto the fullerene core and assayed as inhibitors of FimH, a bacterial adhesin, using isothermal titration calorimetry, surface plasmon resonance and hemagglutination assays.