The clinical efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs)-based targeted molecular therapies (TMT) is inevitably hampered by the development of acquired drug resistance in non-small cell lung cancer (NSCLC) treatment. Sonodymanic therapy (SDT) is a promising new cancer treatment approach, but its effects are restricted by tumor hypoxia. Herein, a nanoplatform fabricated by erlotinib-modified chitosan loading sonosensitizer hematoporphyrin (HP) and oxygen-storing agent perfluorooctyl bromide (PFOB), namely CEPH, was developed to deliver HP to erlotinib-sensitive cells. CEPH with ultrasound could alleviate hypoxia inside the three-dimensional multicellular tumor spheroids, suppress NSCLC cell growth under normoxic or hypoxic condition, and enhance TMT/SDT synergistic effects through elevated production of reactive oxygen species, decrease of mitochondrial membrane potential, and down-regulation of the expression of the proteins EGFR, p-EGFR, and HIF-1α. Hence, CEPH could be a potential nanoplatform to improve the efficacy of oxygen-dependent SDT and overcome hypoxia-induced TMT resistance for enhanced synergistic TMT/SDT.

基于表皮生长因子受体酪氨酸激酶抑制剂 (EGFR-TKI) 的靶向分子疗法 (TMT) 的临床疗效不可避免地受到非小细胞肺癌 (NSCLC) 治疗中获得性耐药性的发展的阻碍。Sonodymanic 疗法 (SDT) 是一种很有前途的新型癌症治疗方法，但其效果受到肿瘤缺氧的限制。在此，开发了一种由厄洛替尼修饰的壳聚糖负载声敏剂血卟啉（HP）和储氧剂全氟辛基溴（PFOB）制成的纳米平台，即CEPH，用于将HP输送到厄洛替尼敏感细胞。超声CEPH可以缓解三维多细胞肿瘤球体内部的缺氧，在常氧或缺氧条件下抑制NSCLC细胞生长，并通过增加活性氧的产生、降低线粒体膜电位和下调 EGFR、p-EGFR 和 HIF-1α 蛋白的表达来增强 TMT/SDT 协同效应。因此，CEPH 可能是一个潜在的纳米平台，可提高氧依赖性 SDT 的功效，并克服缺氧诱导的 TMT 抗性以增强 TMT/SDT 的协同作用。