State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Science, Shanghai 201203, China.
Institute of Pediatrics of Children's Hospital and Biomedical Science, Fudan University, Shanghai 200032, China.
Theranostics. 2020 May 15;10(14):6122-6135. doi: 10.7150/thno.42234. eCollection 2020.
EGFR TKI therapy has become a first-line regimen for non-small cell lung cancer (NSCLC) patients with EGRF mutations. However, there are two big challenges against effective therapy--the secondary EGFR mutation-associated TKI resistance and brain metastasis (BMs) of lung cancer. The BMs is a major cause of death for advanced NSCLC patients, and the treatment of BMs with TKI resistance remains difficult. Tumor-associated macrophages (TAM) is a promising drug target for inhibiting tumor growth, overcoming drug resistance, and anti-metastasis. TAM also plays an essential role in regulating tumor microenvironment. We developed a dual-targeting liposomal system with modification of anti-PD-L1 nanobody and transferrin receptor (TfR)-binding peptide T12 for codelivery of simvastatin/gefitinib to treat BMs of NSCLC. The dual-targeting liposomes could efficiently penetrate the blood-brain barrier (BBB) and enter the BMs, acting on TAM repolarization and reversal of EGFR-associated drug resistance. The treatment mechanisms were related to the elevating ROS and the suppression of the EGFR/Akt/Erk signaling pathway. The dual-targeting liposomal codelivery system offers a promising strategy for treating the advanced EGFR NSCLC patients with BMs.
表皮生长因子受体酪氨酸激酶抑制剂（EGFR TKI）治疗已成为具有 EGFR 突变的非小细胞肺癌（NSCLC）患者的一线治疗方案。然而，针对有效的治疗存在两个主要挑战——继发性 EGFR 突变相关的 TKI 耐药和肺癌脑转移（BMs）。BMs 是晚期 NSCLC 患者死亡的主要原因，而针对 TKI 耐药的 BMs 的治疗仍然很困难。肿瘤相关巨噬细胞（TAM）是抑制肿瘤生长、克服耐药性和抗转移的有前途的药物靶点。TAM 还在调节肿瘤微环境中发挥着重要作用。我们开发了一种具有抗 PD-L1 纳米抗体和转铁蛋白受体（TfR）结合肽 T12 修饰的双靶向脂质体系统，用于同时递送辛伐他汀/吉非替尼治疗 NSCLC 的 BMs。双靶向脂质体能够高效穿透血脑屏障（BBB）并进入 BMs，作用于 TAM 重极化和逆转 EGFR 相关的耐药性。治疗机制与 ROS 的升高和 EGFR/Akt/Erk 信号通路的抑制有关。双靶向脂质体共递药系统为治疗具有 BMs 的晚期 EGFR NSCLC 患者提供了一种有前途的策略。
