Department of Ultrasound and Chongqing Key Laboratory of Ultrasound Molecular Imaging, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P. R. China.
Department of Intensive Care Unit, the Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P. R. China.
Theranostics. 2022 Mar 21;12(6):2987-3006. doi: 10.7150/thno.71693. eCollection 2022.
Multidrug resistance (MDR) and metastasis of breast cancer remain major hurdles in clinical anticancer therapy. The unsatisfactory outcome is largely due to insufficient cytotoxicity of chemotherapeutic agents and limited immunogenic cell death (ICD). On the other hand, efflux proteins, especially P-glycoprotein (P-gp), can recognize and promote the efflux of drugs from tumor cells. In this study, silver nanoparticles (Ag NPs) and peptide- functionalized doxorubicin (DOX) were used to prepare a theranostic nanocomposite (Ag-TF@DOX), which induced organelle-mediated immunochemotherapy and drug efflux protein inhibition in drug-resistant breast cancer cells (MCF-7/ADR) via a strategy based on endoplasmic reticulum (ER) stress and cell-nucleus penetration. The silver nanoparticle-triggered persistent activation of ER stress synergizes with chemotherapy to enhance cytotoxicity and stimulate the ICD effect. It has the potential to enhance chemosensitivity by downregulating of P-gp expression due to the increased production of ATP-consuming chaperones. In addition, the novel peptide (CB5005), which not only penetrates the cell membrane but also has a nuclear localization sequence, is conjugated to DOX to improve both cellular internalization and intranuclear accumulation. Moreover, surface TA-Fe engineering endows the nanocomposite with ATP-responsive disassembly and ATP depletion properties to improve biocompatibility and decrease ATP-dependent drug efflux. Ag-TF@DOX has potential as a dual-mode (PAI/MRI) contrast-enhanced agent for realizing theranostic guidance. This theranostic nanocomposite greatly restricts the growth of drug-resistant breast tumors and activates a strong immune response as well, providing an opportunity for the development of therapeutics that reverse tumor MDR and metastasis at the subcellular level.
多药耐药（MDR）和乳腺癌转移仍然是临床抗癌治疗的主要障碍。不理想的结果在很大程度上是由于化疗药物的细胞毒性不足和免疫原性细胞死亡（ICD）有限。另一方面，外排蛋白，特别是 P-糖蛋白（P-gp），可以识别并促进药物从肿瘤细胞中流出。在这项研究中，使用银纳米粒子（Ag NPs）和肽功能化阿霉素（DOX）制备了一种治疗性纳米复合材料（Ag-TF@DOX），该复合材料通过基于内质网（ER）应激和细胞-核渗透的策略，在耐药乳腺癌细胞（MCF-7/ADR）中诱导细胞器介导的免疫化学治疗和药物外排蛋白抑制。银纳米粒子触发的持续 ER 应激激活与化疗协同作用，增强细胞毒性并刺激 ICD 效应。由于 ATP 消耗伴侣的增加，下调 P-gp 表达有可能增强化学敏感性。此外，新型肽（CB5005）不仅穿透细胞膜，而且具有核定位序列，与 DOX 缀合可提高细胞内吞作用和核内积累。此外，表面 TA-Fe 工程赋予纳米复合材料 ATP 响应性的组装和 ATP 耗竭特性，以提高生物相容性并降低 ATP 依赖性药物外排。Ag-TF@DOX 具有作为双重模式（PAI/MRI）对比增强剂的潜力，可实现治疗指导。这种治疗性纳米复合材料极大地限制了耐药性乳腺癌肿瘤的生长，并激活了强烈的免疫反应，为在亚细胞水平逆转肿瘤 MDR 和转移提供了治疗机会。
