Bioinspired Soft Matter Unit, Okinawa Institute of Science and Technology Graduate University, 1919-1 Tancha, Onna-son, Okinawa 904-0495, Japan.
Institute of Medical Engineering, Department of Biophysics, School of Basic Medical Sciences, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, China.
Nano Lett. 2021 Apr 14;21(7):3052-3059. doi: 10.1021/acs.nanolett.1c00233. Epub 2021 Mar 23.
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.
微管是癌症治疗的高度战略性靶标。小分子抗有丝分裂剂是迄今为止癌症治疗中最好的化疗药物。然而，高神经病变发生率和耐药性限制了它们的临床应用。受分子自组装（MSA）克服耐药性的多组分靶向特性的启发，我们合成了基于肽的转子分子，这些分子可以在响应周围环境时自组装，以靶向微管阵列。MSA 会根据 pH 值的变化和高尔基体-内体运输过程中的粘度变化进行形态上的自我调整，从而逃避运输货物，并最终以非特异性的方式物理结合到微管阵列上。这种非精制的纳米生物相互作用抑制了局部微管聚合，触发非典型的前中期-中期振荡，从而抑制各种癌细胞的增殖，而不会引起明显的神经毒性。MSA 在皮下宫颈癌异种移植肿瘤模型中也表现出很强的抗增殖作用，与顺铂相当，优于经典的抗有丝分裂药物紫杉醇。
