School of Science, RMIT University, Melbourne, Victoria, 3000, Australia.
Department of Chemical Engineering, The University of Melbourne, Parkville, Victoria, 3010, Australia.
Adv Mater. 2022 Apr;34(13):e2107964. doi: 10.1002/adma.202107964. Epub 2022 Feb 18.
Reconfiguring the structure and selectivity of existing chemotherapeutics represents an opportunity for developing novel tumor-selective drugs. Here, as a proof-of-concept, the use of high-frequency sound waves is demonstrated to transform the nonselective anthracycline doxorubicin into a tumor selective drug molecule. The transformed drug self-aggregates in water to form ≈200 nm nanodrugs without requiring organic solvents, chemical agents, or surfactants. The nanodrugs preferentially interact with lipid rafts in the mitochondria of cancer cells. The mitochondrial localization of the nanodrugs plays a key role in inducing reactive oxygen species mediated selective death of breast cancer, colorectal carcinoma, ovarian carcinoma, and drug-resistant cell lines. Only marginal cytotoxicity (80-100% cell viability) toward fibroblasts and cardiomyocytes is observed, even after administration of high doses of the nanodrug (25-40 µg mL ). Penetration, cytotoxicity, and selectivity of the nanodrugs in tumor-mimicking tissues are validated by using a 3D coculture of cancer and healthy cells and 3D cell-collagen constructs in a perfusion bioreactor. The nanodrugs exhibit tropism for lung and limited accumulation in the liver and spleen, as suggested by in vivo biodistribution studies. The results highlight the potential of this approach to transform the structure and bioactivity of anticancer drugs and antibiotics bearing sono-active moieties.
重新构建现有化疗药物的结构和选择性为开发新型肿瘤选择性药物提供了机会。在这里，作为概念验证，证明了使用高频声波将非选择性蒽环类药物阿霉素转化为肿瘤选择性药物分子。转化后的药物在水中自组装形成 ≈200nm 的纳米药物，无需有机溶剂、化学试剂或表面活性剂。纳米药物优先与癌细胞线粒体中的脂筏相互作用。纳米药物在诱导活性氧介导的乳腺癌、结直肠癌、卵巢癌和耐药细胞系选择性死亡中起着关键作用。即使给予高剂量的纳米药物（25-40µgmL），也仅观察到对成纤维细胞和心肌细胞的轻微细胞毒性（80-100%细胞活力）。通过在灌注生物反应器中使用癌症和健康细胞的 3D 共培养物和 3D 细胞-胶原构建体，验证了纳米药物在肿瘤模拟组织中的穿透性、细胞毒性和选择性。体内生物分布研究表明，纳米药物对肺部具有趋向性，在肝脏和脾脏中的积累有限。这些结果强调了这种方法在改变具有声活性部分的抗癌药物和抗生素的结构和生物活性方面的潜力。
