口腔鱗狀細胞癌在許多開發中國家都是十大癌症之一，而在台灣更是男性癌症死亡率排行第四名的癌症。如何降低癌症治療副作用與死亡率對目前癌症治療是一個巨大的挑戰。
在我們之前的研究中發現，鐵核金殼複合型奈米粒子(Fe@Au)對口腔癌細胞具有選擇性毒殺的功能(DOK, OECM1, SCC25, HCDB1, SCC9)，但相同劑量下對正常細胞並不會造成傷害(hNOK, HUVEC, Vero, gingiva fibroblast)。我們進一步又發現Fe@Au會造成癌細胞(OECM1)粒線體的膜電位喪失並引起細胞自噬作用導致癌細胞死亡。但對選擇性毒殺的詳細機制仍並不清楚。
在此研究中，我們發現許多含鐵奈米粒子(FeAu alloy, Fe@Ag, Armor-Fe, Fe@Mesoporous-Si)也具有和Fe@Au相同的選擇性毒殺功能。而在文獻中也有人發現鐵鉑合金奈米(FePt)對卵巢癌細胞(A2780)具有毒殺效果，這也暗示著「鐵」或許是一個重要的因子。因此，我們透過TEM的EDS分析這些含鐵奈米粒子中鐵和氧的比例與細胞毒性做比對，發現隨著氧化程度越高，這些含鐵奈米粒子對癌細胞的毒性就越低，因此我們認為其中未氧化的鐵是造成此選擇性毒殺的關鍵。我們更進一步發現這些具有大量未氧化鐵的含鐵奈米粒子會造成癌細胞的ROS與氧化壓力升高，造成粒線體膜電位的喪失，引起細胞自噬作用而導致細胞死亡。而動物實驗中也發現含有未氧化鐵的含鐵奈米粒子可以抑制腫瘤的生長。
總結來說，我們在這個研究中發現含鐵奈米粒子中的未氧化鐵扮演引發癌細胞ROS促使癌細胞經由自噬作用而死亡的角色。藉由這些發現我們期待未來能夠發展出更安全有效殺死癌細胞的新藥。

Oral squamous cell carcinoma is one of the top ten malignancies in many developing countries. According to Department of Health in Taiwan, oral cancer is ranked fourth leading cause of cancer death in male’s group. How to cure cancer while decrease the side effect and mortality is a big challenge to cancer therapy.
In previous published study, we discovered that iron-core-gold-shell nanoparticles (Fe@Au NPs) have selective cytotoxicity in oral cancer cells (DOK, OECM1, SCC25, HCDB1, SCC9), but not in normal cells (hNOK, HUVEC, Vero, and gingiva fibroblast). In addition, Fe@Au NPs can cause mitochondria membrane potential lost and induce autophagy in OEC-M1. However, the mechanism of the selective cytotoxicity remains unsolved.
In this study, we discovered that many iron-containing nanoparticles (FeAu alloy, Fe@Ag, Armor-Fe) also have the same selective cytotoxicity in OECM1. Furthermore, there is literature report that iron-platinum alloy (FePt) nanoparticles exhibit high cytotoxicity to ovarian cancer cell (A2780). These results suggest that iron element is a key factor in cytotoxicity effect. Base on this thinking, we identified through the Fe/O ratio analyzed by EDS that these iron-containing nanoparticles share one common characteristic, the non-oxidized iron, a possible key factor of the cytotoxicity. Otherwise, we also found that these iron-containing nanoparticles with high Fe/O ratio would induce severe ROS in cancer cells and caused irreversible mitochondria membrane potential lost. Furthermore, these iron-containing nanoparticles could also induce autophagy that caused autophagic cell death in cancer cells through the increased dose and time. In animal study, the iron-containing nanoparticles could inhibit tumor growth.
In summary, we discover from this study that the non-oxidized iron of the iron-containing nanoparticles can function as a ROS inducer that can cause cancer cell death through autophagy. According to these findings, we hope to develop a new theranostic anti-cancer drug that can kill cancer cells more effectively and safely in the future.

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