Targeted in situ self-assembly augments peptide drug conjugate cell-entry efficiency

Peptide drug conjugate (PDC) has emerged as one of the new generations of targeted therapeutics for cancer, which owns the advantages of improved drug targetability and reduced adverse effects compared with traditional chemotherapy. However, the poor permeability of PDC drugs regarding tumor cells is an urgent problem to be solved. Herein, we design a PDC drug molecule, which is composed of three modules: targeting motif (RGD target), assembly motif (GNNNQNY) and cytotoxic payload (CPT molecule). This PDC in situ forms nanoclusters upon binding cellular receptor, resulting in improved PDC cell-entry efficiency and treatment efficacy. In addition, the PDC shows increased therapeutic efficacy and raises the maximum tolerance dose of the drug in breast and bladder xenografted mice models. This strategy leverages the assembly principle to promote penetration of peptide molecules into cells and increase intracellular drug bioavailability, which is of great significance for the development of PDC drugs in the future.