Department of Pulmonary and Critical Care Medicine, Precision Medicine Center, Huaxi MR Research Center (HMRRC), Frontiers Science Center for Disease-Related Molecular Network, National Clinical Research Center for Geriatrics, Department of Respiratory Medicine, and Department of Radiology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
Department of Pulmonary and Critical Care Medicine, Precision Medicine Center, Huaxi MR Research Center (HMRRC), Frontiers Science Center for Disease-Related Molecular Network, National Clinical Research Center for Geriatrics, Department of Respiratory Medicine, and Department of Radiology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China; Frontier Medical Center, Tianfu Jincheng Laboratory, Sichuan Provincial Key Laboratory of Precision Medicine, Functional and Molecular Imaging Key Laboratory of Sichuan Province, and Research Unit of Psychoradiology, Chinese Academy of Medical Sciences, Chengdu 610041, China.
J Control Release. 2023 Nov;363:349-360. doi: 10.1016/j.jconrel.2023.09.044. Epub 2023 Sep 28.
Cancer stem cells (CSCs) have been demonstrated to be involved in tumor initiation and relapse, and the presence of CSCs in the tumor tissue often leads to therapeutic failure. BBI608 has been identified to eliminate CSCs by inhibiting signal transducer and activator of transcription 3 (STAT3). In this study, we confirm that BBI608 can efficiently suppress the proliferation and migration of non-small cell lung cancer (NSCLC) cells, and specifically kill the stemness-high population in chemoresistant NSCLC cells. To improve its bioavailability and tumor accumulation, BBI608 is successfully encapsulated into redox-responsive PEGylated branched N-(2-hydroxypropyl) methacrylamide (HPMA)-deoxy cholic acid (DA) polymeric nanoparticles (BBI608-SS-NPs). The BBI608-SS-NPs can release the drug in response to high concentrations of intracellular glutathione, and exhibit cytotoxicity against lung cancer cells and CSCs comparable to the free drug BBI608. Furthermore, the BBI608-SS-NPs preferentially accumulate in tumor sites, resulting in a superior anti-tumor efficacy in both cisplatin-resistant cell line-derived xenograft (CDX) and patient-derived xenograft (PDX) models of NSCLC. Mechanistic studies demonstrate that BBI608-SS-NPs not only directly inhibit the downstream genes of the STAT3 pathway, but also indirectly inhibit the Wnt pathway. Overall, this stimuli-responsive polymeric nanoformulation of BBI608 shows great potential in the treatment of chemoresistant NSCLC by targeting CSCs.
癌症干细胞（CSCs）已被证明参与肿瘤的起始和复发，肿瘤组织中 CSCs 的存在往往导致治疗失败。BBI608 通过抑制信号转导和转录激活因子 3（STAT3）被鉴定为可以消除 CSCs。在这项研究中，我们证实 BBI608 可以有效地抑制非小细胞肺癌（NSCLC）细胞的增殖和迁移，并特异性杀死耐药性 NSCLC 细胞中的干性高群体。为了提高其生物利用度和肿瘤积累，BBI608 成功地被包裹在氧化还原响应性聚乙二醇化支化 N-（2-羟丙基）甲基丙烯酰胺（HPMA）-脱氧胆酸（DA）聚合物纳米颗粒（BBI608-SS-NPs）中。BBI608-SS-NPs 可以响应细胞内高浓度的谷胱甘肽释放药物，并表现出与游离药物 BBI608 相当的对肺癌细胞和 CSCs 的细胞毒性。此外，BBI608-SS-NPs 优先在肿瘤部位积累，导致在顺铂耐药细胞系衍生的异种移植（CDX）和非小细胞肺癌患者来源的异种移植（PDX）模型中均具有优越的抗肿瘤疗效。机制研究表明，BBI608-SS-NPs 不仅直接抑制 STAT3 通路的下游基因，而且间接抑制 Wnt 通路。总的来说，这种针对 CSCs 的 BBI608 刺激响应性聚合物纳米制剂在治疗耐药性 NSCLC 方面具有很大的潜力。
