Microtubule-Targeted Self-Assembly Triggers Prometaphase-Metaphase Oscillations Suppressing Tumor Growth.

Abstract

Microtubules are highly strategic targets of cancer therapies. Small molecule antimitotic agents are so far the best chemotherapeutic medication in cancer treatment. However, the high rate of neuropathy and drug resistance limit their clinical usage. Inspired by the multicomponent-targeting feature of molecular self-assembly (MSA) overcoming drug resistance, we synthesized peptide-based rotor molecules that self-assemble in response to the surrounding environment to target the microtubule array. The MSAs self-adjust morphologically in response to the pH change and viscosity variations during Golgi-endosome trafficking, escape trafficking cargos, and eventually bind to the microtubule array physically in a nonspecific manner. Such unrefined nano-bio interactions suppress regional tubulin polymerization triggering atypical prometaphase--metaphase oscillations to inhibit various cancer cells proliferating without inducing obvious neurotoxicity. The MSA also exerts potent antiproliferative effects in the subcutaneous cervix cancer xenograft tumor model equivalent to Cisplatin, better than the classic antimitotic drug Taxol.