Design And Research Of Novel Antitumor Peptide-drug Conjugate

Chemotherapeutic drugs often accumulate in normal tissues due to lack of targeting ability which may cause adverse effects; while therapeutic monoclonal antibodies have significant immunogenicity because of their large molecular weights. Peptide-drug conjugate(PDC) is a new technology for drug modification which connects a targeting peptide to the the small molecule drug through a flexible/pH sensitive/enzyme sensitive linker to enhance the stability and targeting ability or the efficacy. Resveratrol and Combretastatin A-4(CA4) were reported as potential anticancer prodrugs in preclinical studies. CA4 P can be dephosphorylated by phosphatases to turn to the active substance in vivo, and subsequently combines to the microtubules of the vascular endothelial cells to suppress angiogenesis; while resveratrol exerts anticancer effects through cell cycle arrest, apoptosis promotion, and block of the cell growth signal pathway. However, these two compounds failed in clinical trials due to their low stability and lack of cancer-targeting ability. In previous study, we modified the structures of these two antitumor compounds, CA4 and resveratrol. We connected them with two peptides, IF7 and Apelin13, through different linkers to get a series of PDC compounds that have improved stability and cancer-targeting ability. In this research we screened PDC compounds with strong pharmacological activity through cell animal experiments. And we also explored further into the molecular mechanism. Together we developed a series of PDC compounds that have potential to be anticancer therapeutic drugs, and provided theory foundation for the future drug research and development.