酸鹼敏感型中孔洞二氧化矽奈米材料於癌症治療之設計

Designing pH-Responsive Mesoporous Silica Nanoparticle for Cancer Therapy

朱培瑞(Pei-Rui Zhu)

指導教授 ： 牟中原

國立臺灣大學/理學院/化學研究所/碩士(2021年)

https://doi.org/10.6342/NTU202102217

摘要

過去數十年，由於奈米藥物傳遞系統具有提升腫瘤選擇性及特異性的潛力，被視為前景光明的研究領域。其中酸鹼敏感型在癌症治療上已被廣泛設計成對環境敏感的特質，因為相較於正常的血液和組織 (pH ≈ 7.4)，發炎組織和腫瘤微酸性環境具有較低pH值，而有些胞器的pH值環境甚至更低，像是胞內體 (pH 5.5 ~ 6.0)或是溶酶體 (pH 4.5 ~ pH 5.5)。
　　中孔洞二氧化矽奈米材料因其表面易修飾、高表面積、易調控孔洞大小、生物相容性好等特性，使其成為生物醫學應用的理想選擇。在本物實驗當中，我們製備合成出具有酸鹼值敏感的官能基，藉由Benzoic imine鍵連接材料表面，而利用正負電吸附的方式搭載抗癌藥物艾黴素 (Doxorubicin)。為了使其在生物醫學上有更好的應用，聚乙二醇 (PEG)之有機官能機修飾能夠增加材料懸浮性和生物體內循環時間。
　　另一方面，我們設計出在不同pH值環境下，觀察酸鹼敏感型材料的藥物釋放情形，並在細胞實驗中利用小鼠乳腺癌細胞 (4T1 cells)，評估裝載DOX的材料對腫瘤細胞生長抑制效果以及生物相容性；此外，我們還藉由小鼠模型證明酸鹼敏感型材料因有優良的高滲透長滯留效應 (EPR effect)，在腫瘤抑制達到很好的效果。綜合以上實驗結果，酸鹼敏感型中孔洞二氧化矽奈米材料在癌症治療上是一種具潛力性的奈米藥物載體。

關鍵字

中孔洞二氧化矽奈米材料 ； 酸鹼敏感型材料 ； 艾黴素 ； 高滲透長滯留效應 ； 乳腺癌

並列摘要

During the past decades, developing tumor-targeted drug delivery systems (DDS) is considered as a promising research area due to the potential of enhancing tumor selectivity and specificity. A pH-responsive system is most widely used to design environment-sensitive nanomedicine for cancer therapy because the inflammatory tissues and tumor microenvironment have lower pH values than those in blood vessels and normal tissues (pH ≈ 7.4), and some organelles, such as endosomes (pH 5.5 ~ 6.0), or lysosomes (pH 4.5 ~ pH 5.5) exhibit even lower pH value.
　　Mesoporous Silica Nanoparticles (MSNs) are excellent candidates for biomedical applications, due to their facile functionalization chemistries, high surface area, tunable pore morphologies, biocompatibility, and so on. Here, we developed hybrid MSNs as a novel pH-responsive nanocarrier by employing benzoic imine-based linkages to the structure of the MSNs. Loading of anti-cancer drugs was then performed via electrostatic interaction. To better comply with biomedicine application, we also used poly(ethylene) glycol (PEG) for post-synthesis grafting to promote the suspension stability and blood circulation of MSNs.
　　On the other hand, we investigated drug release profiles under different pH conditions in vitro and evaluated the therapeutic activity as well as biocompatibility of DOX-loaded MSNs in 4T1 breast cancer cells. Moreover, we demonstrated the great therapeutic efficacy of hybrid MSNs, attributing to their superior enhanced permeability and retention effect, on 4T1 bearing mice in vivo. Taken together, these hybrid MSNs show potentials as a promising platform for synergistic therapy.

並列關鍵字

Mesoporous silica nanoparticles ； pH-responsive nanocarrier ； Doxorubicin ； EPR effect ； Breast cancer

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