BACKGROUND: The construction of gels from low molecular weight gelators (LMWG) has been extensively studied in the fields of bio-nanotechnology and other fields. However, the understanding gaps still prevent the prediction of LMWG from the full design of those gel systems. Gels with multicomponent become even more complicated because of the multiple interference effects coexist in the composite gel systems.
OBJECTIVE: This review emphasizes systems view on the understanding of multicomponent low molecular weight gels (MLMWGs), and summarizes recent progress on the construction of desired networks of MLMWGs, including self-sorting and co-assembly, as well as the challenges and approaches to understanding MLMWGs, with the hope that the opportunities from natural products and peptides can speed up the understanding process and close the gaps between the design and prediction of structures.
UNASSIGNED: This review is focused on three key concepts. Firstly, understanding the complicated multicomponent gels systems requires a systems perspective on MLMWGs. Secondly, several protocols can be applied to control self-sorting and co-assembly behaviors in those multicomponent gels system, including the certain complementary structures, chirality inducing and dynamic control. Thirdly, the discussion is anchored in challenges and strategies of understanding MLMWGs, and some examples are provided for the understanding of multicomponent gels constructed from small natural products and subtle designed short peptides.

Fragrances are volatile organic compounds widely used in our daily life. Unfortunately, the high volatility required to reach human receptors reduces their persistency in the air. To contrast this effect, several strategies may be used. Among them, we present here the combination of two techniques: the microencapsulation in supramolecular gels and the use of profragrances. We report a study on the controlled lactonization of four esters derived from o-coumaric acid. The ester lactonization spontaneously occurs after exposure to solar light, releasing coumarin and the corresponding alcohol. To determine the rate of fragrance release, we compared the reaction in solution and in a supramolecular gel and we demonstrated that the lactonization reaction always occurs slower in the gel. We also studied the more suitable gel for this aim, by comparing the properties of two supramolecular gels obtained with the gelator Boc-L-DOPA(Bn)2-OH in a 1:1 ethanol/water mixture in different gelator concentration (0.2% and 1% w/v). The gel prepared with 1% w/v gelator concentration is stronger and less transparent than the other and was used for the profragrances encapsulation. In any case, we obtained a significative reduction of lactonization reaction in gel, compared with the same reaction in solution.

pH dependence on water soluble aggregates is well-known in the field of low molecular weight gelators (LMWGs), with different aggregates sometimes having very different properties depending on their final pH. This aggregation determines their applications and performance. Here, we investigate the pH dependence of perylene bisimide gels; initially solutions are formed at a high pH and gels form as the pH is decreased. We find it is not only the final pH but also the starting pH that can impact the resulting gel. We use small angle neutron scattering (SANS), rheology, 1 H NMR spectroscopy and absorption spectroscopy to examine the effect of starting pH on gelation kinetics and final gel properties. Adjusting the solution from pH 9 (where there are few or no aggregates) to pH 6 results in the formation of different worm-like micelles than the ones directly formed at pH 6, leading to again gels with different mechanical properties. This work highlights the importance of controlling the pH of solutions before gelation, but also opens up more possible morphologies and therefore more properties from the same molecule.

Mixing low molecular weight gelators (LMWGs) can be used to combine favorable properties of the individual components within a multifunctional gel. Such multicomponent systems are complex enough in themselves but the method of combining components is not commonly considered something to influence self-assembly. Herein, two multicomponent systems comprising of a naphthalene-based dipeptide hydrogelator and one of two modified naphthalene diimides (NDIs), one of which forms gels, and the other does not, are investigated. These systems are probed, examining the structures formed and their gel properties (when preparing a solution from either a mixed powder of both components or by mixing pre-formed solutions of each component) using rheology, small angle neutron scattering (SANS), and absorbance spectroscopy. It is found that by altering the method of preparation, it is can either induce self-sorting or co-assembly within the fibers formed that underpin the gel network.

The development of redox-triggerable peptide hydrogels poses fundamental challenges, since the highly specific peptide architectures required inevitably limit the versatility of such materials. A powerful, yet rarely applied approach to bypass those barriers is the application of a mediating redox reaction to gradually decrease the pH during hydrogel formation. We report a versatile strategy to trigger the formation of peptide hydrogels from readily accessible acid-triggerable gelators by generating protons by oxidation of thioethers with triiodide. Adding thiodiglycol as a readily available thioether auxiliary to the basic precursor solution of a peptide gelator efficiently yielded hydrogels after mixing with triiodide, as studied in detail for Nap-FF and demonstrated for other peptides. Furthermore, incorporation of the thioether moiety in the gelator backbone via the amino acid methionine, as shown for the tailormade Nap-FMDM peptide, reduces the number of required additives.

Multicomponent low molecular weight gelators (LMWGs) may self-assemble by co-assembly (CA), social self-sorting (SSS), or narcissistic self-sorting (NSS). Understanding the nuances of the self-assembly processes is important to predict the behavior of multicomponent organogels. Here, we investigate the effect of molecular structure on self-assembly in a series of amino-acid based bicomponent LMWGs that differ in headgroup and alkyl chain length. Packing preference of the organogels was determined using differential scanning calorimetry, nuclear magnetic resonance spectroscopy and small angle X-ray scattering. From 66 bicomponent samples we found 50 CA, 14 SSS and 2 NSS. Furthermore, we performed statistical analysis to investigate the role of hydrophobicity and chain length on the overall pathway of self-assembly for these systems. We found the hydrophobicity of the headgroup strongly affected the assembly preference of the organogel, but alkyl chain length only played a small role.

In the last years, physical hydrogels have been widely studied due to the characteristics of these structures, respectively the non-covalent interactions and the absence of other necessary components for the cross-linking processes. Low molecular weight gelators are a class of small molecules which form higher ordered structures through hydrogen bonding and π-π interactions. In this context it is known that the formation of hydrogels based on FMOC-amino acids is determined by the primary structures of amino acids and the secondary structure arrangement (alpha-helix or beta-sheet motifs). The present study aimed to obtain supramolecular gels through co-assembly phenomenon using FMOC-amino acids as low molecular weight gelators. The stability of the new structures was evaluated by the vial inversion test, while FTIR spectra put into evidence the interaction between the compounds. The gel-like structure is evidenced by viscoelastic parameters in oscillatory shear conditions. SEM microscopy was used to obtain the visual insight into the morphology of the physical hydrogel network while DLS measurements highlighted the sol-gel transition. The molecular arrangement of gels was determined by circular dichroism, fluorescence and UV-Vis spectroscopy.

Herein, an injectable formulation composed of a low molecular weight gelator (LMWG) based hydrogel and drug-loaded polymeric nanocapsules (NCs) is described. The NCs, made of hyaluronic acid and polyglutamic acid and loaded with C14-Gemcitabine (GEM C14), showed a size of 40 and 80 nm and a encapsulation efficiency >90%. These NCs exhibited a capacity to control the release of the encapsulated drug for >1 month. GEM C14-loaded NCs showed activity against various cancer cell lines in vitro; cell growth inhibition by 50% (GI50) values of 15 ± 6, 10 ± 9, 13 ± 3 and 410 ± 463 nM were obtained in HCT 116, MIA PaCa-2, Panc-1 and Panc-1 GEM resistant cell lines respectively. Nanocomposite hydrogels were prepared using the LMWG - N4-octanoyl-2\'-deoxycytidine and loaded for the first time with polymeric NCs. 2% and 4% w/v nanocapsule concentrations as compared to 8% w/v NC concentrations with 2% and 3% w/v gelator concentrations gave mechanically stronger gels as determined by oscillatory rheology. Most importantly, the nanocomposite formulation reformed instantly into a gel after injection through a needle. Based on these properties, the nanocomposite gel formulation has potential for the intratumoural delivery of anticancer drugs.

The work presented here shows that the growth of supramolecular hydrogel fibers can be spatially directed at the nanoscale by catalytic negatively charged nanoparticles (NCNPs). The NCNPs with surfaces grafted with negatively charged polymer chains create a local proton gradient that facilitates an acid-catalyzed formation of hydrogelators in the vicinity of NCNPs, ultimately leading to the selective formation of gel fibers around NCNPs. The presence of NCNPs has a dominant effect on the properties of the resulting gels, including gelation time, mechanical properties, and network morphology. Interestingly, local fiber formation can selectively entrap and precipitate out NCNPs from a mixture of different nanoparticles. These findings show a new possibility to use directed molecular self-assembly to selectively trap target nano-objects, which may find applications in therapy, such as virus infection prevention, or engineering applications, like water treatment and nanoparticle separation.

Low molecular weight gelators (LMWGs) of chemotherapeutic drugs represent a valid alternative to the existing polymer-based formulations used for targeted delivery of anticancer drugs. Herein we report the design and development of novel self-assembling gelators of the antitumor benzothiazole 5F 203 (1). Two different types of derivatives of 1 were synthesized, formed by an amide (2) and a carbamate (3a-3d) linker, respectively, which showed potent in vitro antitumor activity against MCF-7 mammary and IGROV-1 ovarian carcinoma cells. In contrast, MRC-5 fibroblasts were inherently resistant to the above derivatives (GI50 > 10 μM), thus revealing stark selectivity against the malignant cell lines over the nontransformed fibroblasts. Western blots assays demonstrated induction of CYP1A1 by 1 and its derivatives only in sensitive malignant cells (MCF-7), corroborating conservation of a CYP1A1-mediated mechanism of action. The ability to form stable gels under relatively high strains was supported by rheological tests; in addition, their inner morphology was characterized as possessing a crossed-linked nanostructure, with the formation of thick aggregates with variable widths between 1100 and 400 nm and lengths from 8 to 32 μm. Finally, in vitro dissolution studies proved the ability of hydrogel 2 to release 48% of 2 within 80 h, therefore demonstrating its ability to act as a platform for localized delivery.