Molecular docking, synthesis, anticancer activity, and metabolomics study of boronic acid ester-containing fingolimod derivatives.

In recent years, drugs that contain boronic acid groups, such as ixazomib (Ninlaro™) and bortezomib (Velcade™), have been used in the treatment of bone marrow cancer. The activity of compounds has been found to increase with the addition of boron atoms to the structure. In addition to these compounds, studies have found that fingolimod (FTY720) is more effective against breast cancer than cisplatin. Therefore, in this study, the first examples of boron-containing derivatives of fingolimod were designed and synthesized; in addition, their structures were confirmed by spectroscopic techniques. The synthesized boron-containing drug candidates were found to significantly inhibit cell proliferation and induce apoptosis-mediated cell death in HT-29 (colorectal cells), SaOs-2 (osteosarcoma cells), and U87-MG (glioblastoma cells). Moreover, we revealed that the anticancer effects of boron-containing fingolimod compounds were found to be significantly enhanced over boron-free control groups and, strikingly, over the widely used anticancer drug 5-fluorouracil. The metabolomic analysis confirmed that administration of the boron-containing drug candidates induces significant changes in the metabolite profiles in HT-29, SaOs-2, and U87-MG cells. Altogether, our results showed that boron-containing fingolimod compounds can be further examined to reveal their potential as anticancer drug candidates.

Omics technologies for high-throughput-screening of cell-biomaterial interactions.

Recent research effort in biomaterial development has largely focused on engineering bio-instructive materials to stimulate specific cell signaling. Assessing the biological performance of these materials using time-consuming and trial-and-error traditional low-throughput screening techniques remains a critical challenge in the field. In contrast, the use of increasingly sophisticated omics technologies to facilitate high-throughput screening of unbiased global understanding of cell-biomaterial interactions at gene, epigenetic, mRNA, protein, metabolite, and lipid levels holds great potential to predict the therapeutic outcome of biomaterials with specific properties. In this review, we highlight the potential use of omics technologies - namely transcriptomics, proteomics, metabolomics and lipidomics - in biomaterial design and deciphering of the fundamental cell behaviors (e.g., adhesion, migration, differentiation) in response to cell-biomaterial interactions. Moreover, the potential challenges and prospects of high-throughput analysis platforms are discussed rationally, providing an insight into the developing field and its use in biomaterials science.

Mechanically robust hybrid hydrogels of photo-crosslinkable gelatin and laminin-mimetic peptide amphiphiles for neural induction.

Self-assembling bio-instructive materials that can provide a biomimetic tissue microenvironment with the capability to regulate cellular behaviors represent an attractive platform in regenerative medicine. Herein, we develop a hybrid neuro-instructive hydrogel that combines the properties of a photo-crosslinkable gelatin methacrylate (GelMA) and self-assembling peptide amphiphiles (PAs) bearing a laminin-derived neuro-inductive epitope (PA-GSR). Electrostatic interaction and ultraviolet light crosslinking mechanisms were combined to create dual-crosslinked hybrid hydrogels with tunable stiffness. Spectroscopic, microscopic and theoretical techniques show that the cationic PA-GSR(+) electrostatically co-assembles with the negatively charged GelMA to create weak hydrogels with hierarchically ordered microstructures, which were further photo-crosslinked to create mechanically robust hydrogels. Dynamic oscillatory rheology and micromechanical testing show that photo-crosslinking of the co-assembled GelMA and PA-GSR(+) hydrogel results in robust hydrogels displaying improved stiffness. Gene expression analysis was used to show that GelMA/PA-GSR(+) hydrogels can induce human mesenchymal stem cells (hMSCs) into neural-lineage cells and supports neural-lineage specification of neuroblast-like cells (SH-SY5Y) in a growth-factor-free manner. Also, metabolomics analysis suggests that the hydrogel alters the metabolite profiles in the cells by affecting multiple molecular pathways. This work highlights a new approach for the design of PA-based hybrid hydrogels with robust mechanical properties and biological functionalities for nerve tissue regeneration.