Smart delivery of therapeutic peptides that target cellular signaling pathways holds high specificity and great promise for cancer therapy. Here, DNA tetrahedrons (TDs) are designed to carry two therapeutic peptides-FAS peptide and FK-16 peptide. DNA TDs are designed with varied numbers and spatial placement of FAS peptides and FK-16 peptides, and tested for their anti-cancer efficacy. Trimerization of FAS receptors using TDs that are assembled with three FAS peptides enhances FAS-induced cell apoptosis. FK-16 peptides are conjugated to TDs via a peptide sequence sensitive to MMP-2/9 in tumor microenvironment. Therefore, FK-16 peptides are expected to detach from TDs once arrived the tumor microenvironment. A cell penetrating peptide (TAT) is also conjugated to the FK-16 peptide to facilitate its intracellular delivery, which increases the FK-16 peptide-induced cell apoptosis and autophagy. TD-3(TFM)3(FAS) (TFM: TAT + FK-16 + MMP-2/9) exhibits the highest HT-29 inhibition in vitro and in vivo among all therapies. In addition to the high anti-cancer efficacy, TD-3(TFM)3(FAS) shows a high specificity to HT-29 cells in vitro and in vivo. Low cell inhibition rates and cellular uptake are observed in normal cells. In sum, the multifunctional TD-3(TFM)3(FAS) provides a new platform for the smart delivery of anti-cancer peptides to achieve enhanced efficacy and high specificity.
Keywords: Anti-cancer peptides; Cell apoptosis; Cell autophagy; Colorectal cancer; DNA tetrahedron.
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