12-Hydroxy-Lauric Acid Tethered Self-Assembled Heterochiral Diphenylalanine-Based Mechanoresponsive and Proteolytically Stable Hydrogel: A Dual Player for Handling Cancer and Bacterial Challenges

Deciphering the most promising strategy for the evolution of cancer patient management remains a multifaceted, challenging affair to date. Additionally, such approaches often lead to microbial infections as side effects, probably due to the compromised immunity of the patients undergoing such treatment. Distinctly, this work delineates a rational combinatorial strategy harnessing stereogenic harmony in the diphenylalanine fragment, tethering it to an amphiphile 12-hydroxy-lauric acid at the N-terminus (compounds I-III) such that a potential therapeutic could be extracted out from the series. Aligned to the goal, the cytotoxic properties and cell viability of the compounds were investigated using two distinct cell lines: MCF-7 (human breast cancer cell) and HEK 293 (human embryonic kidney). Our rigorous investigations revealed that compounds I-III exhibited substantial cytotoxic impact on the MCF7 cell line. But from a pool of three constructs, compound III (12-hydroxy-lauric acid -d-Phe-l-Phe-OH) showed better selectivity toward cancerous MCF7 over normal HEK 293 in comparison to others, backed by computational calculations. Henceforth, it was fished out from the series and used for its elaborate anticancer activities using cell reactive oxygen species generation, DNA fragmentation, and caspase-dependent gene expression employing extrinsic and intrinsic apoptotic factors as well as inflammatory biomarkers, namely, TNF-α and IL1-β. We anticipated that compound III, possessing mechanoresponsiveness and a nanofibrillar network, could be administered in patients with injections because of its shear-thinning properties. Moreover, the optimum partition coefficient of compound III might have allowed the scaffold to penetrate the cellular membranes and form a dilactate complex (compound VI) when exposed to the accumulated lactates/lactic acids, a common phenomenon observed within the hypoxic cancerous tumor cores, in accordance with the Warburg mechanism, thereby evading the cytotoxicity within normal cells. Besides, the supramolecular β-sheets of compound III manifest substantial antimicrobial efficacy against the common pathogens, two Gram-positive bacteria, S. aureus and B. subtilis, two Gram-negative bacteria, E. coli and P. aeruginosa, and a fungus, C. albicans, along with proteolytic stability and high mechanical strength at physiological pH. Overall, we speculate that the discovery of these multifunctional bioinspired materials holds future promise as preferential therapeutics for the remediation of immune-susceptible cancer patients, afflicted by microbial infections arising alone or as side effects of chemotherapeutic medications.