合成明膠包覆中孔洞氧化矽奈⽶粒子應⽤於酵素響應藥物控制釋放系統:探討載體對人類口腔鱗狀上皮細胞癌之細胞毒殺及活體動物試驗

Synthesis of Gelatin-Capped Mesoporous Silica Nanoparticles for Enzyme-Responsive Drug Delivery System: In vitro and In vivo Study of Human Oral Squamous Cell Carcinoma

許雲東(Yun-Tung Hsu)

指導教授 ： 張正琪

共同指導教授 ： 吳嘉文(Kevin Chia-Wen Wu)

國立臺灣大學/牙醫專業學院/口腔生物科學研究所/碩士(2015年)

https://doi.org/10.6342/NTU.2015.02900

摘要

本研究利用明膠附著在中孔洞氧化矽奈米顆粒的表面(MSN@Gel)，透過基質金屬蛋白脢2 (MMP2) 可以將明膠分解的特性讓此系統可應用在口腔癌的治療中，在內生性腫瘤微環境的刺激下做藥物的控制釋放。明膠在此藥物釋放系統中扮演著一層保護膜避免藥物提早釋放且腫瘤微環境中有大量表現MMP2能將MSN表層的明膠慢慢降解而達到控制性的藥物釋放。順鉑(Cisplatin)是本實驗的抗癌藥物，MSN搭載cisplatin包覆明膠(Cis/MSN@Gel)應用在MMP的催化下做控制性藥物釋放。因為細胞的內吞作用而使搭載在載體內的cisplatin能夠更輕易的被細胞攝入，載體特性可以增加細胞攝入抗癌藥物的量，來達到降低藥物在體內的用量。在口腔鱗狀上皮癌（SAS cells）細胞實驗中，相較於cisplatin，實驗結果也顯示出細胞攝入cisplatin的量在搭配載體後高出1.55倍。在細胞活性測驗中，相較於cisplatin，Cis/MSN@Gel在較低的濃度中即可表現出細胞毒性。此外，透過活體動物實驗分析Cis/MSN@Gel對腫瘤生長的影響，結果顯示相較cisplatin，Cis/MSN@Gel更能在SAS皮下異種移植之腫瘤小鼠模式中抑制腫瘤生長。本研究展現Cis/MSN@Gel具有抑制癌細胞腫瘤生長和小鼠體重驟降的潛力。因此，Cis/MSN@Gel具有潛力成為開發癌症用藥、治療癌症的新材料。

關鍵字

中孔洞氧化矽奈⽶顆粒 ； 藥物運送 ； 明膠包覆 ； 控制釋放

並列摘要

In this study, the system of gelatin-coated mesoporous silica nanoparticles (MSN@Gel) was degraded by matrix metalloproteinase 2 (MMP2) to be designed for the endogenous tumor microenvironment-triggered release systems of oral cancer treatment. The gelatin coating on MSN causes the MMP2-digested substrates to respond to the solid tumor microenvironment and acts as a protective layer to prevent the leakage of drugs. As an antitumor drug, the encapsulated cisplatin in the Cis/MSNs@Gel was greatly delivered into the cancerous cells due to the endocytosis activity of delivery system, which could increase the amount of cellular uptake and alleviate systemic toxicity during the therapeutic treatments. In vitro studies show that the intracellular drug delivery efficiency was greatly enhanced (i.e. 1.55 folds) for the Cis/MSN@Gel drug delivery system compared to free cisplatin in the squamous cell carcinoma (SAS cells). Moreover, Cis/MSN@Gel displays toxicity in lower concentration compared to free cisplatin in SAS cells. Furthermore, in vivo studies reveal that the tumor growth of subcutaneous SAS xenogeneic tumor mice (SCID) treated with Cis/MSN@Gel is significantly delayed without any distinct body weight loss, which show the lower systemic toxicity of Cis/MSN@Gel compared to that of free cisplatin. Thus, this drug delivery system will provide a great potential for developing delivery of oral cancer therapeutic agents.

並列關鍵字

Mesoporous silica nanoparticle ； drug delivery ； gelatin coating ； stimuli-responsive controlled-release

參考文獻

33. Si-Han Wu C-YM (2008) Mesoporous Silica Nanoparticles for Biological Applications. CHEMISTRY (The Chinese Chemical Society, Taipei) 66.

1. Calixto G, Bernegossi J, Fonseca-Santos B, Chorilli M (2014) Nanotechnology-based drug delivery systems for treatment of oral cancer: a review. Int J Nanomedicine 9: 3719-3735.

2. Terry A. Day M, FACS et al., (2003) Oral caner treatment.

3. Zakrzewka JM (1999) Oral cancer. BMJ 318.

4. Siegel R, Naishadham D, Jemal A (2012) Cancer statistics, 2012. CA Cancer J Clin 62: 10-29.