Tumor Microenvironment pH-Sensitive Peptidomimeticsfor Targeted Anticancer Drug Delivery

Cell-penetrating peptides (CPPs) are known for their effective intracellular transport of bioactives such as therapeutic proteins, peptides, nucleic acid, and small molecule drugs. However, the excessive cationic charges that promote their membrane permeability result in nonselective delivery and cellular toxicity. In this study, we report a decamer cell-penetrating peptidomimetic, <b>Hkd</b>, designed to selectively deliver anticancer drugs into tumor cells in response to the acidic microenvironment. The pH-sensitive histidine (H) imidazole side chain undergoes protonation in acidic environments, facilitating membrane permeability. The rigid cyclic dipeptide (CDP) core (kd) of <b>Hkd</b> has multiple hydrogen bond donor and acceptor sites, enabling selective interaction-driven cellular uptake. Pharmacokinetic studies revealed the excellent serum stability of <b>Hkd</b>. Cellular uptake studies of <b>Hkd</b> showed improved uptake at a lower pH than physiological pH. Conjugation of <b>Hkd</b> to the anticancer drug camptothecin (Cpt) reduced nonselective drug transport to normal cells while effectively delivering the drug into cancerous cells at the tumor microenvironment pH and retaining the therapeutic potential of the drug. The systematic design of pH-sensitive peptidomimetics offers a viable method to overcome the challenges of stability and selectivity faced by traditional highly cationic CPPs, potentially expanding the application range of this delivery system.