Artificial Tyroserleutide Transporters for Synergistic Cancer Therapy

Peptide transporters are integral membrane proteins responsible for the cellular uptake of dipeptides and tripeptides from the extracellular environment, which play pivotal roles in nutrient absorption, antigen presentation, and cellular signaling. Despite their essential biological functions, the development of artificial peptide transporters capable of efficiently transporting charge-neutral peptides, which are highly polar and prone to aggregation, remains a significant challenge. Herein, we introduce a novel class of peptide transporters involving the integration of anion and cation transport functionalities. Notably, <b>5F-C12</b>, which functions as a molecular tweezer, forms a stable 1:1 complex with the charge-neutral peptide tyroserleutidean anticancer agent currently in Phase III clinical trialsand actively facilitates its transmembrane transport by shielding it from the membrane's hydrophobic core, achieving an EC₅₀ value of 7.5 μM. For the first time, <b>5F-C12</b> could remarkably enhance the peptide's bioavailability and exhibit a pronounced enhanced anticancer effect against MCF-7 breast cancer cells both <i>in vitro</i> and <i>in vivo</i>.