Key Laboratory of Radiopharmacokinetics for Innovative Drugs, Chinese Academy of Medical Sciences, and Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, People's Republic of China.
Laboratory of Functional and Biomedical Nanomaterials, College of Materials Science and Engineering, Qingdao University of Science and Technology, Qingdao 266042, People's Republic of China.
ACS Nano. 2022 Sep 27;16(9):14644-14657. doi: 10.1021/acsnano.2c05263. Epub 2022 Sep 1.
As it is closely associated with tumor proliferation, metastasis, and the immunosuppressive microenvironment, the dysfunctional Hippo pathway has become an extremely attractive target for treating multiple cancers. However, to date, the corresponding chemotherapeutic nanomedicines have not been developed. Herein, a supramolecular self-delivery nanomedicine with transforming capacity was tailor-constructed for Hippo-pathway restoration, and its inhibitory effect against tumor growth and metastasis was investigated in a highly aggressive triple-negative breast cancer (TNBC) model. Stimulated by overexpressed glutathione (GSH) and esterase in cancer cells, the self-assembled nanomedicine transformed from inactive nanospheres to active nanofibers conjugating tyrosvaline and spatiotemporally synchronously released the covalently linked flufenamic acid , together activating the maladjusted Hippo pathway by simultaneously acting on different targets upstream and downstream. The transcriptional expression of Yes-associated protein (YAP) and related growth-promoted genes were significantly reduced, finally significantly repressing the proliferation and metastasis of cancer cells. Additionally, the Hippo-pathway restoration showed an excellent radiosensitization effect, making the targeted therapy combined with radiotherapy display a prominent synergistic anticancer effect against TNBC. This work reports a specifically designed smart nanomedicine to restore the function of the Hippo pathway and sensitize radiotherapy, providing an attractive paradigm for targeted drug delivery and cancer combination therapy.
由于其与肿瘤增殖、转移和免疫抑制微环境密切相关，功能失调的 Hippo 通路已成为治疗多种癌症的极具吸引力的靶点。然而，迄今为止，尚未开发出相应的化疗纳米药物。在此，我们设计了一种具有转化能力的超分子自递药纳米医学，用于 Hippo 通路的恢复，并在高度侵袭性三阴性乳腺癌（TNBC）模型中研究了其对肿瘤生长和转移的抑制作用。受癌细胞中过表达的谷胱甘肽（GSH）和酯酶的刺激，自组装的纳米医学从无活性的纳米球转变为具有活性的纳米纤维，连接酪氨酸，并时空同步释放共价连接的氟芬那酸，同时通过作用于不同的上游和下游靶点，激活失调的 Hippo 通路。Yes 相关蛋白（YAP）和相关促生长基因的转录表达显著降低，最终显著抑制癌细胞的增殖和转移。此外，Hippo 通路的恢复显示出优异的放射增敏作用，使靶向治疗与放射治疗相结合对 TNBC 显示出突出的协同抗癌作用。这项工作报道了一种专门设计的智能纳米医学，用于恢复 Hippo 通路的功能并敏化放射治疗，为靶向药物输送和癌症联合治疗提供了有吸引力的范例。
