Mitochondria-targeted accumulation of oxygen-irrelevant free radicals for enhanced synergistic low-temperature photothermal and thermodynamic therapy
Abstract Background 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...
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oai:doaj.org-article:63aca54dc73b40c9a1223457ed362ecf2021-11-28T12:26:40ZMitochondria-targeted accumulation of oxygen-irrelevant free radicals for enhanced synergistic low-temperature photothermal and thermodynamic therapy10.1186/s12951-021-01142-61477-3155https://doaj.org/article/63aca54dc73b40c9a1223457ed362ecf2021-11-01T00:00:00Zhttps://doi.org/10.1186/s12951-021-01142-6https://doaj.org/toc/1477-3155Abstract Background 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. Methods and results 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-mMnO2) as a core was designed and fabricated for the first time. This nanostructure endows a size-controllable hollow cavity mMnO2 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-mMnO2-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. Conclusions 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. Graphical AbstractHongzhi HuXiangtian DengQingcheng SongWenbo YangYiran ZhangWeijian LiuShangyu WangZihui LiangXin XingJian ZhuJunzhe ZhangZengwu ShaoBaichuan WangYingze ZhangBMCarticleLow temperature photothermal therapyThermodynamic therapyMitochondria-targetingMnO2 nanoparticleOxygen-irrelevant free radicalsAzo initiatorBiotechnologyTP248.13-248.65Medical technologyR855-855.5ENJournal of Nanobiotechnology, Vol 19, Iss 1, Pp 1-20 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
Low temperature photothermal therapy Thermodynamic therapy Mitochondria-targeting MnO2 nanoparticle Oxygen-irrelevant free radicals Azo initiator Biotechnology TP248.13-248.65 Medical technology R855-855.5 |
| spellingShingle |
Low temperature photothermal therapy Thermodynamic therapy Mitochondria-targeting MnO2 nanoparticle Oxygen-irrelevant free radicals Azo initiator Biotechnology TP248.13-248.65 Medical technology R855-855.5 Hongzhi Hu Xiangtian Deng Qingcheng Song Wenbo Yang Yiran Zhang Weijian Liu Shangyu Wang Zihui Liang Xin Xing Jian Zhu Junzhe Zhang Zengwu Shao Baichuan Wang Yingze Zhang Mitochondria-targeted accumulation of oxygen-irrelevant free radicals for enhanced synergistic low-temperature photothermal and thermodynamic therapy |
| description |
Abstract Background 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. Methods and results 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-mMnO2) as a core was designed and fabricated for the first time. This nanostructure endows a size-controllable hollow cavity mMnO2 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-mMnO2-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. Conclusions 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. Graphical Abstract |
| format |
article |
| author |
Hongzhi Hu Xiangtian Deng Qingcheng Song Wenbo Yang Yiran Zhang Weijian Liu Shangyu Wang Zihui Liang Xin Xing Jian Zhu Junzhe Zhang Zengwu Shao Baichuan Wang Yingze Zhang |
| author_facet |
Hongzhi Hu Xiangtian Deng Qingcheng Song Wenbo Yang Yiran Zhang Weijian Liu Shangyu Wang Zihui Liang Xin Xing Jian Zhu Junzhe Zhang Zengwu Shao Baichuan Wang Yingze Zhang |
| author_sort |
Hongzhi Hu |
| title |
Mitochondria-targeted accumulation of oxygen-irrelevant free radicals for enhanced synergistic low-temperature photothermal and thermodynamic therapy |
| title_short |
Mitochondria-targeted accumulation of oxygen-irrelevant free radicals for enhanced synergistic low-temperature photothermal and thermodynamic therapy |
| title_full |
Mitochondria-targeted accumulation of oxygen-irrelevant free radicals for enhanced synergistic low-temperature photothermal and thermodynamic therapy |
| title_fullStr |
Mitochondria-targeted accumulation of oxygen-irrelevant free radicals for enhanced synergistic low-temperature photothermal and thermodynamic therapy |
| title_full_unstemmed |
Mitochondria-targeted accumulation of oxygen-irrelevant free radicals for enhanced synergistic low-temperature photothermal and thermodynamic therapy |
| title_sort |
mitochondria-targeted accumulation of oxygen-irrelevant free radicals for enhanced synergistic low-temperature photothermal and thermodynamic therapy |
| publisher |
BMC |
| publishDate |
2021 |
| url |
https://doaj.org/article/63aca54dc73b40c9a1223457ed362ecf |
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