Versatile Low‐Molecular‐Weight Hydrogelators: Achieving Multiresponsiveness through a Modular Design

Abstract

Multiresponsive low-molecular-weight hydrogelators (LMWHs) are ideal candidates for the development of smart, soft, nanotechnology materials. The synthesis is however very challenging. On the one hand, de novo design is hampered by our limited ability to predict the assembly of small molecules in water. On the other hand, modification of pre-existing LMWHs is limited by the number of different stimuli-sensitive chemical moieties that can be introduced into a small molecule without seriously disrupting the ability to gelate water. Herein we report the synthesis and characterization of multistimuli LMWHs, based on a modular design, composed of a hydrophobic, disulfide, aromatic moiety, a maleimide linker, and a hydrophilic section based on an amino acid, here N-acetyl-L-cysteine (NAC). As most LMWHs, these gelators experience reversible gel-to-sol transition following temperature changes. Additionally, the NAC moiety allows reversible control of the assembly of the gel by pH changes. The reduction of the aromatic disulfide triggers a gel-to-sol transition that, depending on the design of the particular LMWH, can be reverted by reoxidation of the resulting thiol. Finally, the hydrolysis of the cyclic imide moieties provides an additional trigger for the gel-to-sol transition with a timescale that is appropriate for use in drug-delivery applications. The efficient response to the multiple external stimuli, coupled to the modular design makes these LMWHs an excellent starting point for the development of smart nanomaterials with applications that include controlled drug release. These hydrogelators, which were discovered by serendipity rather than design, suggest nonetheless a general strategy for the introduction of multiple stimuli-sensitive chemical moieties, to offset the introduction of hydrophilic moieties with additional hydrophobic ones, in order to minimize the upsetting of the critical hydrophobic-hydrophilic balance of the LMWH.

Modulation of the cooperativity in the assembly of multistranded supramolecular polymers

“…In our system, increasing the salt concentration has no effect on K o , but increases K l which, according to equation (9) decreases the cooperativity factor. Therefore increasing K l leads to two somewhat contrasting effects: one is the increase in overall stability of the polymer, and the second is the decrease in cooperativity (as predicted by eq.…”

“…Examples are cell division and motility which are regulated by dynamic assembly of microtubules and actin filaments, respectively. [6][7][8] Some small synthetic molecules also undergo supramolecular polymerization to yield hydrogels that assemble and disassemble in response to external stimuli, 9,10 and are being developed for applications in controlled drug delivery 11,12 and tissue engineering. [13][14][15] Synthetic supramolecular polymers are also being exploited in nanofabrication, for the development of nanowires [16][17][18][19] or as components of artificial molecular machines.…”

High temperature resistant silane/zirconium‐oxocluster hybrid copolymers containing “free” thiol/ene functionalities in the polymer matrix

“…It is important to consider that while under oxidizing conditions thiol groups react to give disulfide bridges, under reducing conditions the disulfide bridges can be cleaved to re‐generate the thiol groups. A reversible disulfide cross‐linking would be an important achievement since is at the base of the development of mendable and smart materials 28–30…”

Multi stimuli response of a single surfactant presenting a rich self-assembly behavior

“…This property is widely required in many applications since it offers the possibility to predict, drive and program the behaviour of the aggregates in different environments. 1 Therefore, the development of such systems has a tremendous potential for application in complex processes such as drug delivery, [2][3][4] sensing and biomolecule identication. 5 Conventional triggers for stimuli sensitive systems are pH, temperature and electrolyte concentration, while more sophisticated approaches are also achieved by exploiting electrical potential, 6 light, [7][8][9][10] magnetic eld, 11 chemomechanical feedbacks 12 and enzyme activity.…”