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载钌介孔硅纳米芬顿反应器用于肿瘤微环境响应的精准癌症治疗。

Ruthenium-loaded mesoporous silica as tumor microenvironment-response nano-fenton reactors for precise cancer therapy.

机构信息

School of Life Sciences, Anhui Agricultural University, Hefei, 230036, China.

Department of Cardiovascular Medicine, Taian City Central Hospital, Taian, 271000, Shandong, China.

出版信息

J Nanobiotechnology. 2021 Apr 7;19(1):98. doi: 10.1186/s12951-021-00848-x.

DOI:10.1186/s12951-021-00848-x
PMID:33827604
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8028739/
Abstract

BACKGROUND

Nano-Fenton reactors as novel strategy to selectively convert hydrogen peroxide (HO) into active hydroxyl radicals in tumor microenvironment for cancer therapy had attracted much attention. However, side effects and low efficiency remain the main drawbacks for cancer precise therapy.

RESULTS

Here, ruthenium-loaded palmitoyl ascorbate (PA)-modified mesoporous silica (Ru@SiO-PA) was successfully fabricated and characterized. The results indicated that Ru@SiO-PA under pH6.0 environment displayed enhanced growth inhibition against human cancer cells than that of pH7.4, which indicated the super selectivity between cancer cells and normal cells. Ru@SiO-PA also induced enhanced cancer cells apoptosis, followed by caspase-3 activation and cytochrome-c release. Mechanism investigation revealed that Ru@SiO-PA caused enhanced generation of superoxide anion, which subsequently triggered DNA damage and dysfunction of MAPKs and PI3K/AKT pathways. Moreover, Ru@SiO-PA effectively inhibited tumor spheroids and tumor xenografts growth in vivo by induction of apoptosis. The real-time imaging by monitoring Ru fluorescence in vitro and in vivo revealed that Ru@SiO-PA mainly accumulated in cell nucleus and tumor xenografts. Importantly, Ru@SiO-PA showed no side effects in vivo, predicting the safety and potential application in clinic.

CONCLUSIONS

Our findings validated the rational design that Ru@SiO-PA can act as novel tumor microenvironment-response nano-Fenton reactors for cancer precise therapy.

摘要

背景

纳米芬顿反应器作为一种将过氧化氢（HO）选择性转化为肿瘤微环境中活性羟自由基的新型策略，在癌症治疗中引起了广泛关注。然而，副作用和低效率仍然是癌症精确治疗的主要障碍。

结果

本研究成功制备并表征了负载钌的抗坏血酸棕榈酸酯（PA）修饰的介孔硅（Ru@SiO-PA）。结果表明，在 pH6.0 环境下，Ru@SiO-PA 对人癌细胞的生长抑制作用明显高于 pH7.4，这表明了癌细胞和正常细胞之间的超高选择性。Ru@SiO-PA 还诱导了增强的癌细胞凋亡，随后激活了 caspase-3 和细胞色素 c 的释放。机制研究表明，Ru@SiO-PA 导致超氧阴离子的产生增强，进而引发 DNA 损伤和 MAPKs 和 PI3K/AKT 通路功能障碍。此外，Ru@SiO-PA 通过诱导细胞凋亡，有效地抑制了体内肿瘤球体和肿瘤异种移植的生长。通过监测体外和体内 Ru 荧光的实时成像发现，Ru@SiO-PA 主要积聚在细胞核和肿瘤异种移植中。重要的是，Ru@SiO-PA 在体内没有显示出副作用，预示着其在临床上的安全性和潜在应用。

结论

我们的研究结果验证了合理的设计，即 Ru@SiO-PA 可以作为新型肿瘤微环境响应的纳米芬顿反应器，用于癌症精确治疗。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fe5/8028739/3621c2a60aed/12951_2021_848_Fig11_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fe5/8028739/6847dd1a186f/12951_2021_848_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fe5/8028739/cf506f4ccb0f/12951_2021_848_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fe5/8028739/c3d926e8c239/12951_2021_848_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8fe5/8028739/f66c1afa2cf2/12951_2021_848_Fig9_HTML.jpg
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