Nucleoside-Derived Low-Molecular-Weight Gelators as a Synthetic Microenvironment for 3D Cell Culture

Abstract

For the last few decades, many efforts have been made in developing cell culture methods in order to overcome the biological limitations of the conventional two-dimensional culture. This paradigm shift is driven by a large amount of new hydrogelbased systems for three-dimensional culture, among other systems, since they are known to mimic some living tissue properties. One class of hydrogel precursors has received interest in the field of biomaterials, low-molecular-weight gelators (LMWGs). In comparison to polymer gels, LMWG gels are formed by weak interactions upon an external trigger between the molecular subunits, giving them the ability to reverse the gelation, thus showing potential for many applications of practical interest. This study presents the use of the nucleoside derivative subclass of LMWGs, which are glyco-nucleo-bola-amphiphiles, as a proof of concept of a 3D cell culture scaffold. Physicochemical characterization was performed in order to reach the optimal features to fulfill the requirements of the cell culture microenvironment, in terms of the mechanical properties, architecture, molecular diffusion, porosity, and experimental practicality. The retained conditions were tested by culturing glioblastoma cells for over a month. The cell viability, proliferation, and spatial organization showed during the experiments demonstrate the proof of concept of nucleoside-derived LMWGs as a soft 3D cell culture scaffold. One of the hydrogels tested permits cell proliferation and spheroidal organization over the entire culture time. These systems offer many advantages as they consume very few matters within the optimal range of viscoelasticity for cell culture, and the thermoreversibility of these hydrogels permits their use with few instruments. The LMWG-based scaffold for the 3D cell culture presented in this study unlocked the ability to grow spheroids from patient cells to reach personalized therapies by dramatically reducing the variability of the lattice used.

Synthetic approaches of carbohydrate based self-assembling systems

“…El Hamoui et al have synthesized glyconucleo-bola-amphiphiles (GNBs) linked through amide, urea, and carbamate functions and studied their self-assembling hydrogelation properties. 82,83 Some of these glyconucleoside-based LMWGs 158-159 are shown in Fig. 12.…”

Low Molecular Weight Supramolecular Gels as a Crystallization Matrix

“…The LMOGs are expected to have applications of the same order as polymeric gels in addition to the added utility due to their dynamic nature and responsiveness to different stimuli that open them up to easy chemical modification (Figure ). − The potential of such materials in drug delivery is explored mostly when they can form hydrogels and are biocompatible with human physiology. However, for fat- and oil-soluble drugs, LMOGs are preferred for oral and parenteral formulations.…”

Light-modulation of gel stiffness: a glyconucleoside based bolaamphiphile as a photo-cleavable low molecular weight gelator

“…Owing to their rheological properties gels have been used to mimic a natural extracellular matrix (ECM), 30,31 which possesses stiffness ranging from soft ( G ′ < 1 kPa) to hard materials ( G ′ > 100 kPa) depending on cell types. In this context, the storage or elastic modulus appears to be a pivotal feature, which can be modulated to mimic the G ′ of the natural ECM or to impact the cell fate.…”

“…Several gel-gel approaches have been investigated involving different physical stimuli, [18][19][20][21][22][23][24][25] with few examples based on photodeprotection 26 reactions. [27][28][29] Owing to their rheological properties gels have been used to mimic a natural extracellular matrix (ECM), 30,31 which possesses stiffness ranging from soft (G 0 o 1 kPa) to hard materials (G 0 4 100 kPa) depending on cell types. In this context, the storage or elastic modulus appears to be a pivotal feature, which can be modulated to mimic the G 0 of the natural ECM or to impact the cell fate.…”