In Situ-Induced Multivalent Anticancer Drug Clusters in Cancer Cells for Enhancing Drug Efficacy

Increasing intracellular drug concentration is an effective way for cancer chemotherapeutics to enhance efficacy and combat drug resistance. In this work, a series of anticancer drug conjugates were prepared by linking thiol-modified oligo(p-phenylene vinylene) with paclitaxel, vincristine, teniposide, tamoxifen, doxorubicin, or podophyllotoxin (OPV-S-Drugs) through a Michael addition reaction. These OPVS-Drugs could undergo intracellular assembly and aggregation upon oxidation to yield multivalent anticancer drug clusters, which inhibited their diffusion from cancer cells. The intracellular aggregation of OPV-S-Drugs originates from pi-pi stacking and hydrophobic interactions between OPV backbones, followed by cross-linking via disulfide bond formation in the presence of reactive oxygen species (ROS). The drug clusters occur only in the cytoplasm of cancer cells expressing high ROS levels, but not in healthy mammalian cells, thus reducing the cytotoxicity to normal cells. Specifically, the super-toxicity of podophyllotoxin to normal cells was obviously suppressed while the drug efficacy was maintained through our new strategy. The diverse action mechanisms of OPV-S-Drugs toward cancer cells is proposed.