利用二氧化矽奈米顆粒裝載抗癌藥物發展的新型態癌症結合療法

Abstract

過去治療癌症通常是以化療藥物直接去毒殺癌症細胞,然而這樣的方式對於癌症 治療有諸多的限制及副作用產生,這可能是由於化療藥物的非專一性、腫瘤本身產 生的抗藥性及腫瘤環境血管分佈複雜等情形而產生。因此在近年來,科學家們轉而 將治療癌症的目光放在了腫瘤周邊的各微環境因子,希望藉由調控不同微環境因 子去達到更佳的抗癌治療策略。 在本題目中,我所針對的腫瘤微環境因子有二,其一為腫瘤環境中的巨噬細胞群, 在腫瘤環境中,巨噬細胞會分化為兩種截然不同的型態,一種為 M1 型態,在早先 的研究中,它被認為是一種會促進發炎反應的巨噬細胞型態,也因此被認為是一種 能促進免疫反應的巨噬細胞; 而另一種型態為 M2 型態,是在腫瘤環境中較常見的 巨噬細胞型態,其被認為是一種能促進組織修復及抗免疫反應的巨噬細胞型態,因 此在我自己的題目中,想藉由給予免疫調節藥物使腫瘤環境的巨噬細胞,分化為類 似於 M1 的巨噬細胞,以達到免疫治療癌細胞的效果。 另一個我想針對的腫瘤微環境因子為低氧環境,在整個腫瘤中存在著一些血管 難以到達的地方,這些地方的癌細胞由於長期處於缺氧環境下,產生了較強的轉移 能力及抗藥性,因此若使用傳統化療策略可能將無法根治這些區域的癌細胞,導致 療程失敗,在此我想利用一個處於低氧環境才會被活化的前驅藥物來專一性的清 除位於低氧環境的癌細胞,希望能藉此避免產生對處於正常氧環境的正常細胞的 副作用,同時也能根除這些難以清除的癌細胞。 在此,我使用了矽奈米載體同時裝載低氧環境前驅藥物跟免疫調節藥物,一方 面轉變腫瘤環境巨噬細胞型態,另一方面則可以毒殺處於低氧環境的癌細胞,來達 到免疫治療及化療的效果,並期望結合兩者促成更強大的協同效應來治療癌症。 在實驗方面,我們先以動態光散射確認載體在載藥後的大小,且也確認了藥物 裝載效率為何;在細胞實驗中我們測試了奈米劑型化藥物的效果,我們先以MTT assay測試並發現裝載於載體中的低氧環境前驅藥物能夠達到更強的癌細胞毒殺能 力,且用q-PCR及flow cytometry證實免疫調節藥物裝載於載體中能持續地使巨噬細 胞轉變為M1-like 巨噬細胞。 在細胞實驗中我們已經確定了裝載於載體的兩種藥物均能達到原本的效用,最 後在活體實驗上,我們可以看到兩種藥物奈米劑型化為單一載體後對於腫瘤的生 長能力確實有抑制的作用,而且效果目前看來是比 free drug 形式來的更好的。

Chemotherapy is a category of traditional cancer treatment that uses one or more anti- cancer drugs as part of a standardized chemotherapy regimen to eliminate tumor cells, but its major problems including identification of the dose for best anti-tumor effect, and minimization of unpleasant adverse effect. In recent years, tumor microenviroment (TME) has caught a lot of attention in improving therapeutic efficiency for cancer. Tumor- associated macrophages (TAMs) are one of the major factors affecting tumor microenvironment, and two types of macrophages, M1 and M2- type, are found in the TME. M1-type macrophages are anti-tumor macrophages; however, macrophages reside in the TME are often M2-type, which function in promoting the tumor growth through the release of anti-inflammatory cytokines. Therefore, the regulation of the M1:M2 ratio may be a novel, effective and smart strategy for the anti-cancer strategy. Furthermore the hypoxia stands as another key microenvironmental factor regulating multiple phenomenon associated with tumor progression. In this study, silica mesoporous nanoparticles (MSNs) were used to deliver multiple drugs (a hypoxia-activated prodrug and an immunomodulator) via the enhanced permeability and retention (EPR). This combinational strategy was anticipated to inhibit tumor growth and concurrently activate the immune system, leading to the production of tumor-specific CD8+ T cells. The brilliance of our newly designed combination therapy is to prevent the formation of secondary tumor by induction of the immune memory. Our preliminary results showed that hypoxia-activated prodrug was able to inhibit Lewis lung carcinoma (LLC2) growth in hypoxia condition, and immunomodulator was sufficient to induce polarization of M1- type macrophages. Also, we verified that our nanodrug exhibited better efficiency in growth inhibition of LLC2 and M1 polarization. In summary, this silica based combination therapeutic strategy holds the promising potential for clinical use.