Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Department of Orthopaedic Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, 050051, China.
J Nanobiotechnology. 2021 Nov 25;19(1):390. doi: 10.1186/s12951-021-01142-6.
Although lower temperature (< 45 °C) photothermal therapy (LPTT) have attracted enormous attention in cancer therapy, the therapeutic effect is still unsatisfying when applying LPTT alone. Therefore, combining with other therapies is urgently needed to improve the therapeutic effect of LPTT. Recently reported oxygen-irrelevant free radicals based thermodynamic therapy (TDT) exhibit promising potential for hypoxic tumor treatment. However, overexpression of glutathione (GSH) in cancer cells would potently scavenge the free radicals before their arrival to the specific site and dramatically diminish the therapeutic efficacy.
In this work, a core-shell nanoplatform with an appropriate size composed of arginine-glycine-aspartate (RGD) functioned polydopamine (PDA) as a shell and a triphenylphosphonium (TPP) modified hollow mesoporous manganese dioxide (H-mMnO) as a core was designed and fabricated for the first time. This nanostructure endows a size-controllable hollow cavity mMnO and thickness-tunable PDA layers, which effectively prevented the pre-matured release of encapsulated azo initiator 2,2'-azobis[2-(2-imidazolin-2-yl) propane] dihydrochloride (AIBI) and revealed pH/NIR dual-responsive release performance. With the mitochondria-targeting ability of TPP, the smart nanocomposites (AIBI@H-mMnO-TPP@PDA-RGD, AHTPR) could efficiently induce mitochondrial associated apoptosis in cancer cells at relatively low temperatures (< 45 °C) via selectively releasing oxygen-irrelevant free radicals in mitochondria and facilitating the depletion of intracellular GSH, exhibiting the advantages of mitochondria-targeted LPTT/TDT. More importantly, remarkable inhibition of tumor growth was observed in a subcutaneous xenograft model of osteosarcoma (OS) with negligible side effects.
The synergistic therapy efficacy was confirmed by effectively inducing cancer cell death in vitro and completely eradicating the tumors in vivo. Additionally, the excellent biosafety and biocompatibility of the nanoplatforms were confirmed both in vitro and in vivo. Taken together, the current study provides a novel paradigm toward oxygen-independent free-radical-based cancer therapy, especially for the treatment of hypoxic solid tumors.
尽管低温（<45°C）光热疗法（LPTT）在癌症治疗中引起了极大的关注，但单独应用 LPTT 时治疗效果仍不尽如人意。因此，迫切需要结合其他疗法来提高 LPTT 的治疗效果。最近报道的与氧无关的自由基基于热力学疗法（TDT）在缺氧肿瘤治疗方面显示出有前途的潜力。然而，癌细胞中谷胱甘肽（GSH）的过表达会在自由基到达特定部位之前强烈清除自由基，并显著降低治疗效果。
在这项工作中，首次设计和制备了一种由精氨酸-甘氨酸-天冬氨酸（RGD）功能化聚多巴胺（PDA）作为壳和三苯基膦（TPP）修饰的中空介孔氧化锰（H-mMnO）作为核的具有适当尺寸的核壳纳米平台。这种纳米结构赋予了可控制的中空腔 mMnO 和可调厚度的 PDA 层，有效地防止了包裹的偶氮引发剂 2,2'-偶氮双[2-（2-咪唑啉-2-基）丙烷]二盐酸盐（AIBI）的过早释放，并显示出 pH/NIR 双重响应释放性能。由于 TPP 的线粒体靶向能力，智能纳米复合材料（AIBI@H-mMnO-TPP@PDA-RGD，AHTPR）能够在相对较低的温度（<45°C）下通过选择性地在线粒体中释放与氧无关的自由基并促进细胞内 GSH 的耗竭，有效地诱导癌细胞发生与线粒体相关的凋亡，从而表现出线粒体靶向 LPTT/TDT 的优势。更重要的是，在骨肉瘤（OS）皮下异种移植模型中观察到显著的肿瘤抑制作用，且副作用可忽略不计。
通过体外有效诱导癌细胞死亡和体内完全消除肿瘤，证实了协同治疗效果。此外，还在体外和体内证实了纳米平台的优异的生物安全性和生物相容性。综上所述，本研究为基于与氧无关的自由基的癌症治疗提供了一种新的范例，特别是用于治疗缺氧的实体肿瘤。
