Reduction-Responsive Cationic Vesicles from Bolaamphiphiles with Ionizable Amino Acid or Dipeptide Polar Heads.

This paper presents a study of the aggregation of cationic bolaamphiphilic molecules into vesicles. These molecules are based on a cystamine core with protonated terminal dipeptide groups. The study found that vesicles can be formed at pH 4 for all of the dipeptide-terminated bolaamphiphiles containing different combinations of l-valine, l-phenylalanine, and l-tryptophan. The concentration for aggregation onset was determined by using pyrene as a fluorescent probe or light dispersion for compounds with tryptophan. Dynamic light scattering (DLS) studies and transmission electron microscopy (TEM) reveal that the vesicles have diameters ranging from 140 to 500 nm and show the capability of loading hydrophobic cargos, such as Nile red, and their liberation in reductive environments. Furthermore, the bolaamphiphiles are only fully protonated and prone to vesicle formation at acidic pH, making them a promising alternative for gastrointestinal delivery.

Reduction-triggered Disassembly of Organic Cationic Nanorods Produces a Cysteine Protease Mimic (Miravet et†al.).

The emergence of catalytic activity associated with a disassembly process is reported, reminiscent of complex biological systems. A cystine derivative with pendant imidazole groups self-assembles into cationic nanorods in the presence of the cationic surfactants cetylpyridinium chloride (CPC) or cetyltrimethylammonium bromide (CTAB). Disulfide reduction triggers nanorod disassembly and the generation of a simple cysteine protease mimic, which shows a dramatically improved catalytic efficiency in the hydrolysis of p-nitrophenyl acetate (PNPA).

Alkaline cations dramatically control molecular hydrogelation by an amino acid-derived anionic amphiphile.

Understanding the factors that control the formation of (supra)molecular hydrogels permits a rational tuning of their properties and represents a primary challenge for developing smart biocompatible soft materials. Hydrogel formation by molecular amphiphilic anions at millimolar concentrations is counterintuitive, considering the solubility of these species in water. Here we report hydrogel formation by a simple anionic molecular amphiphile and a rationale for the fibrillisation process observed. The studied molecule, DodValSuc, consists of a 12C alkyl chain, an l-valine unit and a terminal succinic acid moiety. Hydrogelation depends to a large degree on the nature and concentration of the alkaline cations present in the medium (Li+, Na+ or K+). As a result, gelation efficiency and properties like thermal stability or rheology are highly tunable using the alkaline cation present or its concentration as variables. A detailed study is reported, which includes the determination of minimum gelation concentration (MGC) by tabletop rheology, critical micelle concentration (CMC) using pyrene as a fluorescent probe, thermal stability (solubility) by 1H NMR, the morphology of the fibres by transmission electron microscopy (TEM), crystallinity by X-ray diffraction (XRD) and gel strength by oscillatory rheology. Additionally, dynamic light scattering (DLS) was used to evaluate the size of the micelles and permitted monitoring of the fibrillisation process. Altogether, the results are consistent with the formation of micelles that experience head crystallisation and subsequent aggregation into crystalline fibres. The alkaline cations play a crucial role in providing the cement that glues together the gelator molecules, making their concentration a critical parameter for gelation efficiency and properties. Furthermore, the gelation-promoting effects are inversely correlated with the size of the cations so that the highest thermal stability and rheological strength were found for the hydrogels formed in the presence of Li+.

Photoreversible formation of nanotubes in water from an amphiphilic azobenzene derivative.

An anionic azobenzene-appended derivative of L-ValylGlycine self-assembles into nanotubes in water. Irradiation with 365 nm light provokes trans-cis isomerization of the azobenzene unit and subsequent tube disassembly. Thermal or photoinduced (457 nm light) recovery of the trans isomer restores the nanotubes.

Non-Polymeric Nanogels as Versatile Nanocarriers: Intracellular Transport of the Photosensitizers Rose Bengal and Hypericin for Photodynamic Therapy.

The use of nanocarriers for intracellular transport of actives has been extensively studied in recent years and represents a central area of nanomedicine. The main novelty of this paper lies on the use of nanogels formed by a low-molecular-weight gelator (1). Here, non-polymeric, molecular nanogels are successfully used for intracellular transport of two photodynamic therapy (PDT) agents, Rose Bengal (RB) and hypericin (HYP). The two photosensitizers (PSs) exhibit different drawbacks for their use in clinical applications. HYP is poorly water-soluble, while the cellular uptake of RB is hindered due to its dianionic character at physiological pH values. Additionally, both PSs tend to aggregate precluding an effective PDT. Despite the different nature of these PSs, nanogels from gelator 1 provide, in both cases, an efficient intracellular transport into human colon adenocarcinoma cells (HT-29) and a notably improved PDT efficiency, as assessed by confocal laser scanning microscopy and flow cytometry. Furthermore, no significant dark toxicity of the nanogels is observed, supporting the biocompatibility of the delivery system. The developed nanogels are highly reproducible due to their non-polymeric nature, and their synthesis is easily scaled up. The results presented here thus confirm the potential of molecular nanogels as valuable nanocarriers, capable of entrapping both hydrophobic and hydrophilic actives, for PDT of cancer.

Photobehavior of the antipsychotic drug cyamemazine in a supramolecular gel protective environment.

In this work, a molecular hydrogel made of gelator (S)-4-((3-methyl-1-(nonylamino)-1-oxobutan-2-yl)amino)-4-oxobutanoic acid (SVN) has been employed as soft container to modify the photochemical and photophysical behavior of the antipsychotic drug cyamemazine (CMZ). The interaction of CMZ with the gel network has been evidenced by fluorescence spectroscopy through a hypsochromic shift of the emission band (from λmax = 521 nm in solution to λmax = 511 nm in the gel) and an increase of the fluorescence lifetime (5.6 ns in PBS vs. 7.2 ns in the gel). In the laser flash photolysis experiments on CMZ/SVN systems, the CMZ triplet excited state (3CMZ*), monitored at λ = 320 nm, has been more efficiently generated and became much longer-lived than in solution (2.7 µs vs. 0.7 µs); besides, photochemical ionization leading to the radical cation CMZ+• was disfavored. In the steady-state experiments, photooxidation of CMZ to afford the N,S-dioxide derivative CMZ-SONO has been retarded in the gel, which provides a more lipophilic and constrained microenvironment. Both the photophysical properties and the photoreactivity are in agreement with CMZ located in a less polar domain when entrapped in the supramolecular gel, as result of the interaction of the drug with the fibers of the supramolecular SVN gel.

Liposome-Enveloped Molecular Nanogels.

Novel hydrogel@liposome particles were prepared by pH-triggered molecular gel formation inside of liposomes loaded with a low-molecular weight gelator derived from l-valine (1). Liposome formation was carried out using l-α-phosphatidylcholine (PC) and cholesterol as components of the lipid bilayer. Molecular hydrogelator 1 and pyranine, a ratiometric fluorescent pH probe, were entrapped in the liposomes at pH 9 and posterior acidification with d-glucono-1,5-lactone to pH 5-6 provoked intraliposomal gel formation. Removal of the lipid bilayer with sodium dodecyl sulfate yielded naked nanogel particles. The systems were characterized by transmission electron microscopy and dynamic light scattering. The hydrogel@liposomes were loaded with doxorubicin, showing a similar release than that observed for liposomes. The hybrid particles described here are the first case of nonpolymeric hydrogel@liposome systems reported. This type of nanocarriers merges the benefits of liposomal vehicles with the inherent stimuli responsiveness and enhanced biocompatibility of hydrogels formed by low-molecular weight molecules, foretelling a potential use in environmentally sensitive drug release.

Photoactive Hexanuclear Molybdenum Nanoclusters Embedded in Molecular Organogels.

Hexanuclear molybdenum clusters are attractive species because of their outstanding photonic properties, and in the past they have been attached to a variety of supports such as organic polymers and inorganic nanoparticles, as described in the recent literature. Here, a cluster of the formula TBA2[Mo6I8Ac6] (TBA = tetrabutylammonium; Ac = acetate) has been supported on molecular organogels for the first time, resulting in a new soft material with remarkable photoactivity. Electron and confocal microscopic analyses showed the alignment of the nanoclusters to 1D self-assembled fibers formed by the organic gelator, and emission spectroscopy corroborated the interaction of the emissive clusters with such fibrillary structures. The new hybrid system is a deep-red emissive material (phosphorescence maximum at ca. 680 nm), with chromatic coordinates x = 0.725 and y = 0.274, capable of efficiently generating singlet oxygen (1O2) upon illumination with white light, as demonstrated by the photooxygenation of 9,10-dimethylanthracene and 1,5-dihydroxynaphthalene. The organogels can been made in dichloromethane and toluene and in both solvents display phosphorescence emission and photocatalytic properties.

In between molecules and self-assembled fibrillar networks: highly stable nanogel particles from a low molecular weight hydrogelator.

The preparation of molecular, non-polymeric nanogels from a low molecular weight hydrogelator is reported. The molecular nanogels are expected to overcome issues associated with the use of polymeric nanogels in biomedicine such as biodegradability, stimuli responsiveness, polydispersity, and batch-to-batch reproducibility. Nanogels formed by compound 1 were reproducibly prepared by sonication of a xerogel in PBS, with a total concentration of ca. 2 mM. The intensity averaged diameter of ca. 200 nm was determined by DLS. Electron microscopy (TEM and cryo-TEM) showed spherical particles. Light scattering (SALS) indicates that water is the main component of the nanoparticles, and the concentration of 1 in the nanogels is ca. 3 mg mL-1. These particles can be considered to constitute an intermediate state between free molecules and self-assembled fibrillar networks. The nanogels present excellent temporal and thermal stability and accessible hydrophobic domains, as demonstrated by the incorporation of the fluorescent dye Nile Red.

Self-Assembly Controls Reactivity with Nitric Oxide: Implications for Fluorescence Sensing.

Three molecules containing the fluorophore 4-amino-1,8-naphthalimide (ANI) and showing different tendencies to self-assembly in aqueous environment have been prepared and fully characterized. The fluorescence emissions of two of these compounds in aqueous solutions are efficiently quenched in the presence of nitric oxide (NO) in aerated medium. Nuclear magnetic resonance and mass spectrometry techniques indicate that NO/O2 induces deamination of the ANI fluorophore, resulting in nonemissive 1,8-naphtalimide derivatives. It is found that the reactivity toward NO/O2 is regulated by the different aggregation modes presented by the molecules in aqueous medium. In this way, the molecules displaying fluorescence response toward NO/O2 are those with weak self-association properties whereas the compound with a high hydrophobic character (self-assembling into large nanoparticles) is insensitive to this species. Ultimately, the results described here could not only set the basis for the design of fluorescent bioprobes for NO/O2 based on ANI derivatives or other monoamino compounds but also could raise awareness about the importance of supramolecular interactions for the design of chemosensors.

Deamidation of pseudopeptidic molecular hydrogelators and its application to controlled release.

HYPOTHESIS: The incorporation of a succinic acid-derived moiety in amino acid derivatives would favor an intramolecular catalysis of a deamidation reaction. Such reaction would permit controlled disassembly of molecular hydrogelators and the use of the hydrogels for controlled release of actives. EXPERIMENTAL: Low molecular weight hydrogelators containing a succinic acid-derived moiety were prepared by conventional organic synthesis procedures. Hydrogels were examined by electron microscopy and 1HNMR studies were carried out to evaluate the solubility in water of the hydrogelators and the deamidation reaction. Liberation of Rose Bengal entrapped in the hydrogels was monitored by UV-Vis spectroscopy. FINDINGS: Molecular hydrogels formed by pseudopeptidic derivatives of l-valine suffer a thermal deamidation reaction, leading to partial disassembly. The succinic acid-derived moiety present in the gelators is responsible of intramolecular catalysis of a deamidation reaction. Such neighboring group effect is reminiscent of biochemical processes such as protein deamidation and self-excision of inteins. It has been found that the thermodynamic equilibrium of the deamidation reaction is regulated by the efficiency of hydrogelation. As a proof of concept, the thermally promoted deamidation is applied to controlled release of Rose Bengal.

Synthesis of a Double-Network Supramolecular Hydrogel by Having One Network Catalyse the Formation of the Second.

Self-assembly of biomolecules catalytically controls the formation of natural supramolecular structures, giving highly ordered complex materials. Such desirable hybrid systems are very difficult to design and construct synthetically. A hybrid double-network hydrogel with a maximum storage modulus (G'max ) of up to 55 kPa can be synthesized by using a self-assembled hydrogel that catalyses the formation of another kinetically arrested hydrogel network. Tuning of the catalytic efficiency of the first network allowed spatiotemporal control over the evolution of the second network and the resulting mechanical properties. The distribution of active catalytic sites was optimal for catalytic fibres prepared at the minimum gelation concentration (MGC) to give the double-network hydrogel with highest storage modulus. This approach could be very useful in preparing complex hierarchical structures with tailor-made properties.

Sucrose-fueled, energy dissipative, transient formation of molecular hydrogels mediated by yeast activity.

A biologically mediated, energy dissipative, reversible formation of fibrillar networks is reported. The process of gelation is linked to sucrose-fueled production of CO2 by baker's yeast (Saccharomyces cerevisiae). Continuous fueling of the system is required to maintain the self-assembled fibrillar network.

Improved Efficiency of Molecular-Gel Formation by Adjusting Preorganization of Amino-Acid-Derived Flexible Molecules: A NMR and Thermodynamic study.

The efficiency of the formation of molecular gels of simple derivatives of l-valine and l-isoleucine is greatly improved in different organic solvents when a hexyl fragment is replaced by a bulkier cyclohexyl one. A study using NMR and IR spectroscopy provides information on the preferred conformations of the molecules, indicating that the cyclohexyl moiety precludes intramolecular H bonding and preorganises the system for intermolecular interactions, which are responsible for fiber formation. NMR data of the gels provides thermodynamic data on fibrillization, revealing that the origin of this effect is mainly entropic. Electron microscopy (SEM and TEM) images show fibrillar and tape-like objects, which are observed commonly in molecular gels. Rheological measurements reveal significant differences between cyclohexyl and hexyl appended gelators. These findings could contribute to the rational design of small, flexible, building blocks for self-assembly.

Tandem reactions in self-sorted catalytic molecular hydrogels.

By equipping mutually incompatible carboxylic acid and proline catalytic groups with different self-assembling motives we have achieved self-sorting of the resulting catalytic gelators, namely SucVal8 and ProValDoc, into different supramolecular fibers, thus preventing the acidic and basic catalytic groups from interfering with each other. The resulting spatial separation of the incompatible catalytic functions is found to be essential to achieve one-pot deacetalization-aldol tandem reactions with up to 85% efficiency and 90% enantioselectivity. On the contrary, when SucVal8 was co-assembled with a structurally similar catalytically active hydrogelator (ProVal8), self-sorting was precluded and no tandem catalysis was observed.

In situ synthesis-gelation at room temperature vs. heating-cooling procedure. Fine tuning of molecular gels derived from succinic acid and L-valine.

HYPOTHESIS: The reaction between succinic anhydride and a diamine derived from L-valine should afford efficiently a molecular gelator. Based on this reaction, it should be feasible to prepare molecular gels at room temperature, avoiding the conventional thermal treatment required for the solubilization of the gelator, by in situ, simultaneous, synthesis and gelation. The gels prepared by in situ and conventional heating-cooling protocols could present important differences relevant for potential practical applications of these materials. EXPERIMENTAL: The gelator was synthesized by reaction of succinic anhydride and a diamine derived from L-valine, affording two new amide bonds. The molecular gels were studied by IR, NMR, electron microscopy, X-ray diffraction and DSC. FINDINGS: The results indicate that different polymorphic fibrillar networks are formed depending on the gel preparation method, highlighting how the properties of molecular gels can be tuned in this way. Significant differences between thermal and in situ gels were found in properties such as thermal stability, thixotropic behavior or release of an entrapped dye. In situ synthesis-gelation has also been shown to provide gels in media such as oleic acid which cannot be jellified by conventional heating-cooling procedures.

Synthesis and biological properties of the cytotoxic 14-membered macrolides aspergillide A and B.

Total, stereoselective syntheses of the naturally occurring, cytotoxic macrolides aspergillide A and B are described. Olefin metatheses and asymmetric allylations were key steps in the synthetic sequences. Cytotoxicity assays against several tumor cell lines have been performed for the two aspergillides and some of the intermediates or side products of the synthetic sequence. One of these intermediates has been found markedly active against the human leukemia cancer cell line HL-60, with an IC(50) value comparable with that of the clinical drug fludarabine.

Stereoselective synthesis and structural correction of the naturally occurring lactone stagonolide G.

A convergent synthesis of the structure proposed for the naturally occurring lactone stagonolide G is described. All three stereocenters were created with the aid of asymmetric Brown allylations. The lactone ring was built by means of a ring-closing metathesis (RCM). The synthetic and the natural compound differed in their spectral properties. A new structure is now proposed for stagonolide G and demonstrated by means of a chemical transformation.

Stereoselective synthesis of the cytotoxic 14-membered macrolide aspergillide A.

A stereoselective synthesis of the cytotoxic 14-membered macrolide aspergillide A has been performed. The preparation of a cis-2,6-disubstituted tetrahydropyran ring via stereoselective reduction of an intermediate cyclic hemiacetal was one key feature of the synthesis. The macrocyclic lactone ring was created by means of a ring-closing metathesis (RCM), whereby the new C=C bond displayed exclusively the undesired Z configuration. Conversion to the required E configuration was achieved via photochemical isomerization.