Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL 36849, USA.
Department of Oncology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, PR China; Department of Hematology and Medical Oncology, Emory University School of Medicine and Winship Cancer Institute, Atlanta, GA 30322, USA.
Acta Biomater. 2021 Jul 15;129:258-268. doi: 10.1016/j.actbio.2021.05.018. Epub 2021 May 25.
Osimertinib (OSI) is the first FDA-approved third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). It can be used for treating non-small cell lung cancer (NSCLC) patients with activating EGFR mutation and for patients who are resistant to first-generation EGFR TKIs due to T790M resistance mutation. However, patients treated with OSI ultimately develop acquired resistance, which prevents its long-term benefit for patients. Therefore, the development of effective strategies to overcome OSI resistance will address a significant clinical challenge and benefit patients by prolonging their survival time. Our previous studies indicated that combination therapy was a promising strategy for overcoming OSI resistance. In this study, we developed nanoparticle (NP) formulations for co-delivery of osimertinib (OSI) and selumetinib (SEL) to treat OSI-resistant NSCLC effectively. We conjugated SEL with PEG through a reactive oxygen species (ROS)-responsive linker to generate polyethylene glycol (PEG)-SEL conjugate prodrug (PEG-S-SEL). Due to the amphiphilic nature of PEG-S-SEL, it can self-assemble in an aqueous solution to form micelle NP and serve as a delivery carrier for OSI. The ROS-responsive linker can facilitate the release of drugs in the tumor microenvironment with elevated ROS levels. OSI and SEL combination NP can overcome OSI resistance by simultaneously inhibiting both EGFR and mitogen-activated protein kinase (MEK), thus effectively inducing apoptosis in OSI-resistant NSCLC cells and inhibiting OSI-resistant tumors in vivo. In conclusion, the OSI+SEL NP combination therapy showed promising anticancer efficacy and demonstrated potential for treating NSCLC patients with OSI acquired resistance. STATEMENT OF SIGNIFICANCE: Osimertinib (OSI) is the first FDA-approved third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor. It has been successfully used for treating non-small cell lung cancer (NSCLC) patients with activating EGFR mutation. However, patients treated with OSI ultimately develop acquired resistance. This study developed OSI and selumetinib (SEL) co-delivering nanoparticles to overcome OSI-acquired resistance in NSCLC. PEG-SEL conjugate functions as reactive oxygen species (ROS)-responsive prodrug and forms micelle nanoparticles through self-assembly to deliver OSI. The combination NP can simultaneously inhibit EGFR and mitogen-activated protein kinase (MEK), thus effectively inducing apoptosis in OSI-resistant NSCLC cells. In summary, the OSI and SEL nanoparticle combination therapy showed promising anticancer efficacy and demonstrated potential for treating NSCLC patients with OSI acquired resistance.
奥希替尼（OSI）是首个获得美国食品药品监督管理局（FDA）批准的第三代表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKI）。它可用于治疗具有激活 EGFR 突变的非小细胞肺癌（NSCLC）患者，以及因 T790M 耐药突变而对第一代 EGFR TKI 耐药的患者。然而，接受 OSI 治疗的患者最终会产生获得性耐药，这限制了它对患者的长期获益。因此，开发有效的克服 OSI 耐药的策略将是一项重大的临床挑战，通过延长患者的生存时间，使患者受益。我们之前的研究表明，联合治疗是克服 OSI 耐药的一种有前途的策略。在这项研究中，我们开发了纳米颗粒（NP）制剂，用于同时递送奥希替尼（OSI）和塞来替尼（SEL），以有效治疗 OSI 耐药的 NSCLC。我们通过活性氧（ROS）响应性连接子将 SEL 与聚乙二醇（PEG）偶联，生成聚乙二醇（PEG）-SEL 共轭前药（PEG-S-SEL）。由于 PEG-S-SEL 的两亲性，它可以在水溶液中自组装形成胶束 NP，并作为 OSI 的递送载体。ROS 响应性连接子可以促进在 ROS 水平升高的肿瘤微环境中药物的释放。OSI 和 SEL 联合 NP 可以通过同时抑制 EGFR 和丝裂原活化蛋白激酶（MEK）来克服 OSI 耐药，从而有效诱导 OSI 耐药 NSCLC 细胞凋亡，并抑制体内 OSI 耐药肿瘤。总之，OSI+SEL NP 联合治疗显示出有希望的抗癌疗效，并为治疗 OSI 获得性耐药的 NSCLC 患者提供了潜力。
奥希替尼（OSI）是首个获得美国食品药品监督管理局（FDA）批准的第三代表皮生长因子受体（EGFR）酪氨酸激酶抑制剂。它已成功用于治疗具有激活表皮生长因子受体（EGFR）突变的非小细胞肺癌（NSCLC）患者。然而，接受 OSI 治疗的患者最终会产生获得性耐药。本研究开发了 OSI 和塞来替尼（SEL）共递纳米颗粒，以克服 NSCLC 中的 OSI 获得性耐药。PEG-SEL 缀合物作为活性氧（ROS）响应性前药，通过自组装形成胶束纳米颗粒，以递送 OSI。联合 NP 可同时抑制 EGFR 和丝裂原活化蛋白激酶（MEK），从而有效诱导 OSI 耐药 NSCLC 细胞凋亡。总之，OSI 和 SEL 纳米颗粒联合治疗显示出有希望的抗癌疗效，并为治疗 OSI 获得性耐药的 NSCLC 患者提供了潜力。
