Structure–Property Relationships in Symmetrical Bolaamphiphilic Dehydrodipeptides: Self-Assembled Injectable Hydrogels for Anticancer Drug Delivery

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Peptide-based supramolecular hydrogels have emerged as promising biomaterials due to inherent biocompatibility, tunable self-assembly, and structural similarity to the extracellular matrix. This work describes the design, synthesis and characterization of a library of symmetrical bolaamphiphiles based on dehydropeptides, systematically varying both the dehydroamino acid residue and the linker. Aromatic and aliphatic dicarboxylic acids with distinct rigidities were employed to elucidate their influence on molecular self-assembly, hydrogelation, and functional performance. Hydrogel formation was triggered using a pH-responsive approach, and critical aggregation and gelation concentrations were determined. Morphological analysis by transmission electron microscopy revealed dense fibrillar networks with nanometer-scale fiber diameters, while rheological studies demonstrated viscoelastic behavior, tunable mechanical strength, and, in selected systems, efficient self-healing properties. The incorporation of phenylalanyldehydrophenylalanine significantly enhanced hydrogel formation, highlighting the importance of π-π interactions and hydrophobicity. Biological evaluation using HaCaT keratinocytes confirmed low cytotoxicity across the series. A representative injectable hydrogel exhibited sustained release of the anticancer drug methotrexate, governed predominantly by Fickian diffusion. These results establish clear structure-property-function relationships and demonstrate the potential of symmetrical bolaamphiphilic dehydropeptides as versatile platforms for controlled drug delivery.

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