Enzymatic Synthesis of Peptide Nanofibers for Self-Delivery of Indomethacin and Tyroservatide in Cancer Therapy
Non-steroidal anti-inflammatory drugs (NSAIDs) have drawn considerable attention in the field of cancer treatment, yet these drugs display limited potency and selectivity against cancer cells. To address these problems, we designed a peptide-based self-delivery system [Indomethacin-Phe-Phe-Tyr (H2PO3)-Ser-Val, IDM-FFpYSV] that combines an NSAID molecule (indomethacin, or IDM) and a segment of anticancer tripeptide (tyroservatide, or YSV). IDM-FFpYSV is capable of self-assembling in an aqueous solution to afford nanofibrillar hydrogels under the catalysis of alkaline phosphatases (ALPs), which are overexpressed on the plasma membrane of cancer cells. The IDM-FFpYSV + ALP hydrogel displays a continuous release profile of peptide drugs, whereas a solution mixture of pure drugs (IDM-OH + pYSV + ALP) shows burst release of drug moieties. The treatment of IDM-FFpYSV selectively inhibits the proliferation of HeLa cells in vitro, with precise regulations of intracellular targeting proteins (COX-2 and AC-H3). The enhanced potency and selectivity of IDM-FFpYSV are found to be attributed to enhanced cellular uptake of peptide drugs, which involves a caveolae-mediated endocytosis pathway. Furthermore, intravenous administration of the IDM-FFpYSV formulation significantly inhibits the tumor growth in a HeLa-xenografted mouse model, whereas treatment of solution mixtures of pure drugs (IDM-OH + pYSV) fails to do so. Taken together, the study provides a viable strategy to augment anticancer efficacies of self-delivery system through molecular integration of multiple anticancer elements with an enzyme-instructed self-assembly process.
危险品化学品经营许可证（带存储）