Versatile Small Molecule Motifs for Self-assembly in Water and Formation of Biofunctional Supramolecular Hydrogels

1. Introduction

Self-assembly is ubiquitous in nature, ranging from the generation of sand dunes to the formation of double helices of deoxynucleotide acid (DNA).1 The exploration of self-assembly at molecular level has offered scientists a powerful strategy (i.e., “bottom-up” method) to develop a range of materials for many useful applications.2,3 One kind of these materials is supramolecular hydrogels as the consequence of self-assembly of certain small molecules (referred to as “supramolecular hydrogelators” or “molecular hydrogelators)4,5,6 in water to form matrices or networks of nanofibers that immobilize water. Although self-assembly and hydrogelation are two separate phenomena, the formation of a supramolecular hydrogel is resulted from the self-assembly of the hydrogelators in water. Unlike polymeric hydrogels7 resulted from the network of cross-linked random polymer chains, supramolecular hydrogels have three subtle but advantageous features. (i) Despite the random entanglement of the nanofibers, the molecular arrangement displays a significant order within the nanofibers (as a form of secondary structure). (ii) The relatively easy structural modification of the small molecules allows tailoring of the molecular order within the nanofibers. And more importantly, (iii) small molecules are more accessible to enzymes and more easily to be converted into hydrogelators according to biochemical cues.6 Molecular hydrogels bear some similar features to those of extracellular matrix (ECM) and respond to a wide range of stimuli, thus supramolecular hydrogels are attractive for generating new biomaterials for tissue engineering, drug delivery, and other applications.5,8

Although molecular hydrogelators share common features, such as amphiphilicity and supramolecular interactions (for example, π-π interactions, hydrogen bonding, and charge interactions among the molecules) that contribute to the formation of nanostructures and the three-dimensional networks as the matrices of hydrogels, it remains a challenge to predict whether a molecule can act as a hydrogelator. This challenge, unfortunately, limits the research capability for exploring new molecular hydrogelators for desirable applications. One short-term solution to this currently intractable problem is to start the molecular design with a motif known to self-assemble for generating ordered nanostructures in water and promoting hydrogelation. We refer such kind of motifs as “samogens” within the context. A samogen represents the fundamental unit of a molecule that promotes self-assembly. Among the samogens used for making hydrogels, a few oligomeric peptides (with and without lipid-like structures) have received the most extensive exploration and (probably) are the most successful ones up-to-date, especially in the development of biomaterials.9 Despite some successes achieved, the oligomeric peptide-based molecular hydrogelators are expensive and still have to be prepared via multiple step synthesis, which limits the exploration of these molecules as samogens for constructing a wide range of supramolecular materials.

In this article, we introduce a simple samogen, compound 1 (abbreviated as NapFF in this text), which can be easily prepared in the gram scale. Particularly, we demonstrate the ability of 1 to convert bioactive molecules into molecular hydrogelators (Scheme 1) and summarize the properties and applications of these NapFF-derived molecular hydrogelators. We arrange the content of this article in the following way. First, we analyze the structural uniqueness of 1 to elucidate the molecular anatomy, properties of hydrogelation, and possible self-assembled superstructure of this samogen. Second, we briefly illustrate the capability of 1 for enabling other biofunctional molecules to self-assemble in water as the molecular hydrogelators that exhibit useful properties for applications. Third, we offer several anecdotal examples of molecular hydrogelators (Scheme 3) derived from the samogens that share the features displayed by 1. In last section, we summarize the versatility of the samogens discussed and the general challenges associated with the exploration of molecular hydrogelators.