Department of Oncology, Shanghai Key Laboratory of Chemical Assessment and Sustainability, School of Chemical Science and Engineering, East Hospital Affiliated to Tongji University, Tongji University School of Medicine, Tongji University, Shanghai 200092, PR China.
State Key Laboratory of Molecular Reaction Dynamics, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, PR China.
Acta Biomater. 2022 Aug;148:218-229. doi: 10.1016/j.actbio.2022.06.011. Epub 2022 Jun 12.
Triple negative breast cancer (TNBC) is highly malignant and prone to recurrence and metastasis. Patients with TNBC usually have poor prognosis. Hence, it is urgent to develop new comprehensive treatments for TNBC. The combination of heat shock protein (HSP) inhibitor and the photothermal agent can reduce the temperature required to kill tumor cells, thus achieving mild-temperature photothermal therapy (PTT). Compared with traditional PTT, mild-temperature PTT not only decreases tumor thermoresistance introduced by the overexpression of HSP, but also reduces the damage to normal tissues. Meanwhile, Azo initiator 2,2-azobis[2-(2-imidazolin-2-yl) propane]-dihydroch-loride (AIPH) can be thermally decomposed to generate oxygen-independent free radicals. Herein, a new therapeutic multifunctional nanoplatform (M-17AAG-AIPH) by loading heat shock protein 90 (HSP90) inhibitor (17AAG) and AIPH incorporated into mesoporous polydopamine (MPDA) was successfully constructed for mild-temperature PTT combined with oxygen-independent cytotoxic free radicals against TNBC. Under 808 nm laser irradiation, the mild-temperature PTT arising from the combined effects of 17AAG and MPDA induced a rapid release and decomposition of AIPH, promoting the apoptosis of cancer cells in hypoxic microenvironments. Both in vitro and in vivo results showed that the designed nanoplatform can significantly inhibit tumor growth and provided an efficient new therapeutic strategy for TNBC. STATEMENT OF SIGNIFICANCE: There is still an urgent need for new strategies for the treatment of triple negative breast cancer (TNBC). In this work, we successfully constructed a new therapeutic multifunctional nanoplatform (M-17AAG-AIPH) by co-carrying heat shock protein 90 (HSP90) inhibitor (17AAG) and AIPH on mesoporous polydopamine (MPDA). MPDA owned good biocompatibility and outstanding photothermal-conversion ability. The loading of 17AAG can reduce the heat resistance of tumor cells via specifically inhibiting the activity of HSP90, so as to achieve mild-temperature PTT. Meanwhile, 17AAG and MPDA mediated mild-temperature PTT promoted the decomposition of AIPH into oxygen-independent cytotoxic free radicals. Both in vitro and in vivo results showed that M-17AAG-AIPH can significantly inhibit tumor growth and provided an efficient new therapeutic strategy for TNBC.
三阴性乳腺癌（TNBC）恶性程度高，易复发转移，患者预后较差。因此，迫切需要开发针对 TNBC 的新的综合治疗方法。热休克蛋白（HSP）抑制剂与光热剂的联合使用可以降低杀死肿瘤细胞所需的温度，从而实现温和温度的光热治疗（PTT）。与传统的 PTT 相比，温和温度的 PTT 不仅降低了 HSP 过表达引起的肿瘤热抗性，还降低了对正常组织的损伤。同时，偶氮引发剂 2,2-偶氮双[2-(2-咪唑啉-2-基)丙烷]-二盐酸盐（AIPH）可以在热作用下分解生成氧非依赖性自由基。在此，通过负载热休克蛋白 90（HSP90）抑制剂 17AAG 和掺入介孔聚多巴胺（MPDA），成功构建了一种新的治疗多功能纳米平台（M-17AAG-AIPH），用于温和温度 PTT 联合氧非依赖性细胞毒性自由基治疗 TNBC。在 808nm 激光照射下，17AAG 和 MPDA 的联合作用引起 AIPH 的快速释放和分解，从而促进缺氧微环境中癌细胞的凋亡。体外和体内结果均表明，所设计的纳米平台能够显著抑制肿瘤生长，为 TNBC 提供了一种高效的新治疗策略。
