Tumor-Responsive Delivery of 5-Fluorouracil from a Redox-Triggered Supramolecular Gelator

5-Fluorouracil (5-FU) is a chemotherapeutic drug that is widely used to treat gastrointestinal cancers (e.g., hepatocellular carcinoma). Unfortunately, its systemic toxicity limits its clinical utility; therefore, new means for its targeted delivery at the pathological site are highly sought after to enhance therapeutic efficacy. In this work, we describe a 5-FU covalent conjugate with the self-assembling, heterochiral tripeptide DLeu-Phe-Phe (lFF) via a redox-sensitive linker (5-FU-SS-lFF). The conjugate yields supramolecular hydrogels with rheological properties similar to those of lFF hydrogels and enables 5-FU release under reducing conditions, such as those present in the tumor microenvironment. We demonstrate the selectivity of the drug release under such conditions over a period of 24 h, with consequent significant cytotoxicity on cancer cells, as demonstrated on hepatocellular carcinoma spheroids. Overall, this study opens new opportunities for peptide-based supramolecular hydrogels as versatile and smart vehicles for the selective release of anticancer drugs under tumor-like reducing conditions.