功能性中孔洞氧化矽奈米材料於腫瘤治療之應用

Developing and Utilizing Functional Mesoporous Silica Nanoparticles for Cancer Therapy

許立(Li Xu)

指導教授 ： 牟中原

國立臺灣大學/理學院/化學研究所/博士(2022年)

https://doi.org/10.6342/NTU202200356

摘要

癌症是由快速生長的異常細胞所引起的一組導致身體失常的疾病的通稱，這些異常細胞可超越其通常邊界生長並侵襲擴散到其他器官。長久以來，癌症通常以結合手術、化療及放射療法的方式進行治療，但是這些傳統療法在臨床應用上始終有一定的侷限性。近年來，隨著科學研究的進步，基於人體自身免疫機制而開發的免疫治療及利用奈米科技開發的新型藥物和診斷試劑吸引了越來越多的目光，並已逐步進入臨床，諸如免疫檢查點抑制劑、脂質體藥物製劑等已在臨床上取得了矚目的成果。在本研究中，我們利用高生物相容性的中孔洞氧化矽奈米材料為主體，利用其具有的高比表面積、孔洞體積及表面官能修飾之特性，結合不同結構修飾及藥物負載，將其應用於腫瘤治療並取得了一定成效。本論文具體可分為以下三個主題：
（1）如何克服腫瘤所建立的免疫抑制微環境，是腫瘤免疫治療一大挑戰。在此部份研究中，我們以正電荷修飾之中孔洞氧化矽奈米材料為載體，利用其攜帶干擾素基因刺激蛋白（STING）通路激動劑環二鳥苷酸（c-di-GMP, cdG）作為免疫佐劑，並通過腫瘤原位疫苗技術應用於小鼠乳癌腫瘤模型。實驗證明利用中孔洞氧化矽奈米製劑可以提升環二鳥苷酸療效，增加腫瘤微環境中樹突狀細胞、巨噬細胞及T細胞的比例，並最終有效抑制腫瘤生長。
（2）利用反相微乳系統及基於結構差異之選擇性蝕刻策略合成了具有中空結構的空心球狀中孔洞氧化矽奈米材料。將此材料應用於小鼠乳癌腫瘤模型，發現材料本身即具有佐劑特質，可以提高腫瘤微環境中巨噬細胞及細胞毒性T細胞的比例，並一定程度上抑制腫瘤生長。將其與免疫檢查點抑制劑anti-PD-1聯合使用，可達到進一步抑制腫瘤之效果。
（3）利用反相微乳系統及基於結構差異之選擇性蝕刻策略合成了具有雙層球殼結構的空心球狀中孔洞氧化矽奈米材料。我們結合腫瘤微環境通常具有酸性特質及較高濃度的過氧化氫之特性，進一步在雙層空心球狀中孔洞氧化矽奈米材料結構中引入一定含量的氧化錳（MnOx），主要利用二氧化錳與過氧化氫之反應性，從而得到了具有腫瘤微環境特異性的奈米載體。利用此載體攜帶化療藥物阿黴素應用於雞胚胎腫瘤模型，相同藥物劑量治療後，載體-阿黴素製劑具有更好之腫瘤抑制效果。
綜上所述，不同表面或者結構修飾之中孔洞氧化矽奈米材料，作為載體與其他生物試劑諸如免疫佐劑或者化療藥物組合，可用於動物腫瘤模型並展現出良好的腫瘤抑制效果。此外，具有中空結構之中孔洞氧化矽奈米材料本身亦具有免疫佐劑之潛力。在之後的研究中，我們希望進一步探究此類中孔洞氧化矽奈米材料的作用機制及應用，並評估其進一步往臨床實驗之可能。

關鍵字

中孔洞氧化矽奈米材料 ； 腫瘤微環境 ； 腫瘤治療 ； 腫瘤原位疫苗 ； 佐劑 ； 雙層空心球氧化矽奈米材料

並列摘要

Cancer is basically the result of uncontrolled cell growth of abnormal cancer cells which can metastasize to other parts of the body. Conventional therapeutics for cancer including surgery, chemotherapy and radiation have been used over the past decade, however, these traditional treatments still have limitations in clinic. In recent years, cancer immunotherapy based on host’s immunity response and novel drug formulations based on nanotechnology have drawn intense attention. Some latest progresses, for instance, the immune checkpoint inhibitors and liposome have had shining successes in clinic. In this study, biocompatible mesoporous silica nanoparticles (MSNs) with large surface areas, pore volumes and facile functionalization are utilized for cancer therapy. In summary, there are three topics in this thesis:
(1) How to overcome the tumor-induced immunosuppressive microenvironment is one of the major challenges for antitumor immunotherapies. Herein, cationic PEGylated mesoporous silica nanoparticles were synthesized as the nanocarriers to deliver the immune modulator cyclic diguanylate monophosphate (c-di-GMP or cdG), which is an agonist of stimulator of interferon genes (STING). We applied this MSN-formulated cdG in 4T1 tumor bearing Balb/c mice via in situ vaccination. The results revealed that MSN-formulated cdG could recruit dendritic cells, macrophages and T cells to tumor site and further inhibited the tumor growth.
(2) Hollow mesoporous silica nanospheres were synthesized within a water-in-oil reverse microemulsion system via structural-difference based selective etching method. Intravenous injection of obtained hollow mesoporous silica nanospheres enhanced the macrophages and CD8a+ tumor-infiltrating lymphocytes in 4T1 tumor bearing Balb/c mice, resulting in inhibition of tumor growth. Besides, better outcome could be achieved by combinational therapy with anti-PD-1. Thus, we proposed that plain hollow mesoporous silica nanospheres could act as self-adjuvant and stimulate antitumor immunity in vivo for cancer therapy.
(3) Cancer, especially solid cancer commonly results in very unique tumor microenvironment (TME) with acidosis, hypoxia and higher levels of H2O2. To develop a tumor-microenvironment-responsive nanocarrier, we designed a manganese oxide (MnOx) decorated double-shell hollow mesoporous silica nanosphere in this part. Owing to the incorporation of manganese oxide, which has high reactivity toward H2O2, the as-synthesized nanoparticles could decompose in tumor microenvironment and produce oxygen simultaneously. Moreover, nanoparticle-formulated doxorubicin (DOX) outperformed the free drug in the chicken chorioallantoic membrane tumor model.
To sum up, we highlighted that functionalized mesoporous silica nanoparticles as nanocarriers for adjuvants or chemodrugs showed great potential in antitumor therapy. Furthermore, plain hollow mesoporous silica nanosphere could also act as self-adjuvant, leading to tumor regression. The immune modulate mechanisms and applications of hollow mesoporous silica nanospheres deserve more attention in future research.

並列關鍵字

Mesoporous silica nanoparticles ； Tumor microenvironment ； Cancer therapy ； In situ vaccination ； Adjuvant ； Doule-shell hollow mesoporous silica nanospheres

參考文獻

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