Reversible Light-Induced Dimerization of Secondary Face Azobenzene-Functionalized ß-Cyclodextrin Derivatives.

ß-cyclodextrin (ßCyD) derivatives equipped with aromatic appendages at the secondary face exhibit tailorable self-assembling capabilities. The aromatic modules can participate in inclusion phenomena and/or aromatic-aromatic interactions. Supramolecular species can thus form that, at their turn, can engage in further co-assembling with third components in a highly regulated manner; the design of nonviral gene delivery systems is an illustrative example. Endowing such systems with stimuli responsiveness while keeping diastereomeric purity and a low synthetic effort is a highly wanted advancement. Here, we show that an azobenzene moiety can be "clicked" to a single secondary O-2 position of ßCyD affording 1,2,3-triazole-linked ßCyD-azobenzene derivatives that undergo reversible light-controlled self-organization into dimers where the monomer components face their secondary rims. Their photoswitching and supramolecular properties have been thoroughly characterized by UV-vis absorption, induced circular dichroism, nuclear magnetic resonance, and computational techniques. As model processes, the formation of inclusion complexes between a water-soluble triazolylazobenzene derivative and ßCyD as well as the assembly of native ßCyD/ßCyD-azobenzene derivative heterodimers have been investigated in parallel. The stability of the host-guest supramolecules has been challenged against the competitor guest adamantylamine and the decrease of the medium polarity using methanol-water mixtures. The collective data support that the E-configured ßCyD-azobenzene derivatives, in aqueous solution, form dimers stabilized by the interplay of aromatic-aromatic and aromatic-ßCyD cavity interactions after partial reciprocal inclusion. Photoswitching to the Z-isomer disrupts the dimers into monomeric species, offering opportunity for the spatiotemporal control of the organizational status by light.

Tuning the Topological Landscape of DNA-Cyclodextrin Nanocomplexes by Molecular Design.

Original molecular vectors that ensure broad flexibility to tune the shape and surface properties of plasmid DNA (pDNA) condensates are reported herein. The prototypic design involves a cyclodextrin (CD) platform bearing a polycationic cluster at the primary face and a doubly linked aromatic module bridging two consecutive monosaccharide units at the secondary face that behaves as a topology-encoding element. Subtle differences at the molecular level then translate into disparate morphologies at the nanoscale, including rods, worms, toroids, globules, ellipsoids, and spheroids. In vitro evaluation of the transfection capabilities revealed marked selectivity differences as a function of nanocomplex morphology. Remarkably high transfection efficiencies were associated with ellipsoidal or spherical shapes with a lamellar internal arrangement of pDNA chains and CD bilayers. Computational studies support that the stability of such supramolecular edifices is directly related to the tendency of the molecular vector to form noncovalent dimers upon DNA templating. Because the stability of the dimers depends on the protonation state of the polycationic clusters, the coaggregates display pH responsiveness, which facilitates endosomal escape and timely DNA release, a key step in successful transfection. The results provide a versatile strategy for the construction of fully synthetic and perfectly monodisperse nonviral gene delivery systems uniquely suited for optimization schemes.

Xylylene Clips for the Topology-Guided Control of the Inclusion and Self-Assembling Properties of Cyclodextrins.

The topology of ß-cyclodextrin can be molded, from toroidal to ovoid basket-shaped, by the installation of an o- or m-xylylene moiety connecting two consecutive d-glucopyranosyl units through the secondary O-2(I) and O-3(II) positions. This strategy can be exploited advantageously to precast the cavity for preferential inclusion of globular or planar guests as well as to privilege dimeric or monomeric species in water solution.

Dynamic Control of the Self-Assembling Properties of Cyclodextrins by the Interplay of Aromatic and Host-Guest Interactions.

The presence of a doubly-linked naphthylene clip at the O-2I and O-3II positions in the secondary ring of ß-cyclodextrin (ßCD) derivatives promoted their self-assembly into head-to-head supramolecular dimers in which the aromatic modules act either as cavity extension walls (if the naphthalene moiety is 1,8-disubstituted) or as folding screens that separate the individual ßCD units (if 2,3-disubstituted). Dimer architecture is governed by the conformational properties of the monomer constituents, as determined by NMR, fluorescence, circular dichroism, and computational techniques. In a second supramolecular organization level, the topology of the assembly directs host-guest interactions and, reciprocally, guest inclusion impacts the stability of the supramolecular edifice. Thus, inclusion of adamantane carboxylate, a well-known ßCD cavity-fitting guest, was found to either preserve the dimeric arrangement, leading to multicomponent species, or elicit dimer disruption. The ensemble of results highlights the potential of the approach to program self-organization and external stimuli responsiveness of CD devices in a controlled manner while keeping full diastereomeric purity.