功能性氧化矽奈米材料的發展與應用

Developing and Utilizing Functional Silica Nanoparticles

陳梓安(Zih-An Chen)

指導教授 ： 牟中原

國立臺灣大學/理學院/化學研究所/博士(2019年)

https://doi.org/10.6342/NTU202000104

摘要

中孔洞奈米矽材（MSNs）有高表面積、孔洞體積及表面官能化之特性，適用於標靶式藥物遞送。但其在臨床階段的瓶頸還有待解決，例如快速被代謝和無法通過腦部屏障。在本研究中，發展出嶄新的奈米矽材於生物醫學。以下為本論文之兩個主題:

(1) 治療免疫功能不全疾病的瓶頸包含頻繁給藥、嚴重的副作用及抗癌藥物缺乏特異性。因此，第一部分研究提出結合奈米矽材和紅血球（RBC）作為長時間生物傳遞系統。我們合成了一系列帶有螢光之中孔洞奈米矽材並於表面修飾聚乙二醇，從粒徑10至200奈米，並通過低滲透法研究其包覆在人類紅血球（hRBC）中之尺寸效應。證明小於水合粒徑30奈米是包覆於血球的關鍵條件。此生物載體系統可作為體內循環貯藏處，並利用血球內部之材料遞送藥物分子。

(2) 許多研究提出MSNs透過高滲透長滯留（EPR）效應可將化療藥物遞送至腫瘤。然而，由於血腦屏障（BBB）的存在，化療藥物及生物療法可達到腦瘤（例如神經膠質瘤）治療的數量仍是挑戰。在第二主題中，我們欲發展可通過血腦屏障（BBB）之奈米矽材。我們合成具有不同尺寸及表面電荷修飾之奈米矽材。在血腦屏障模組，尺寸較小 （25 奈米）並帶有正電荷（TA-silane）的矽材具有較高通透性。而且，活體腦部影像觀察到矽材分佈於腦血管之外。在活體腦部腫瘤，進一步證明此矽材可以攜帶藥物（阿黴素）藉由EPR效應累積在腫瘤組織。因此，此矽材可藉由EPR效應將藥物遞送至腦部腫瘤，並具有穿過腫瘤周圍的BBB之潛力。

總結上述，中孔洞奈米矽材與紅血球（RBC）之組合具有臨床應用的潛力。希望這項研究可以應用於人體試驗，解決當前藥物發展和治療的困境。另外，經由一系列的腦部實驗，證明粒徑較小且帶正電荷修飾之奈米矽材可通過血腦屏障並具藥物傳遞的潛力。在未來的研究中，我們將會發展此矽材並應用於治療腦部相關疾病。

關鍵字

中孔洞奈米矽材 ； 聚乙二醇化 ； 紅血球 ； 低滲透法 ； 高滲透長滯留效應 ； 血腦屏障 ； 表面電荷修飾 ； 阿黴素

並列摘要

Mesoporous silica nanoparticles (MSNs), which have large surface areas and pore volumes and facile functionalization, are well-suited for targeted drug delivery. However, during the preclinical stage, there are several bottlenecks in using MSN, such as rapid elimination and brain barrier impermeability, which importantly need to be addressed. In this study, a variety of highly promising silica nanoparticles were developed and utilized in biomedical. There are two topics in this thesis:

(1) The bottleneck of chemotherapy for immune-incompetent diseases involves frequent dosing, severe side effects, and lack of specificity of such anticancer drugs. Thus, my first research topic reported on a combination of nanoparticle and red blood cells (RBC) as a long-term delivery system. We synthesized a series of fluorescent PEGylated MSNs with different diameters ranging from 10 nm to 200 nm. Then, the variety of sizes effects on their encapsulation in human RBCs (hRBCs) were investigated based on hypotonic dialysis-method. We demonstrated that a hydrodynamic diameter below 30 nm is critical for efficient MSN encapsulation. The biomedical carrier system could act as a circulation reservoir for delivering pharmacological substances through the osmosis-based method with MSN.

(2) Many studies described MSNs can deliver chemotherapeutic drugs to solid tumors via the enhanced permeability and retention (EPR) effect. However, chemotherapeutics and bio-therapeutics can reach brain tumors (e.g., Gliomas) cells in adequate quantities remains a challenge due to the presence of the blood-brain barrier (BBB). To date, we developed the MSNs which capable of transporting therapeutics pass through the BBB in the second study. We synthesized fluorescent PEGylated MSNs with different sizes and surface-charges. The result showed small size (25 nm) of PEGylated MSNs with positive-charged (TA-silane) exhibited higher penetration in the in vitro BBB model. Also, the MSN is observed outside of the cerebrovascular in vivo brain imaging. Then, we demonstrated that the MSN could deliver BBB-impermeable drug (e.g., doxorubicin) specifically accumulates in tumor tissues via the EPR effect in vivo brain-tumor model. The result indicated that the small size of MSN with positive-charged modification could deliver drugs to brain tumors via the EPR effect and potentially can cross the BBB surrounding the tumor.
Overall, combinations of nanoparticle and red blood cell (RBC) for delivery hold potential for clinical application. We hope that this study can be applied in the human to address the current developmental and therapeutic challenges. Other points, the small size, and positive-charged MSNs hold great potential for drug delivery in crossing the BBB. In future work, we could use MSN for carrying the therapeutic agent for brain-related diseases treatment.

並列關鍵字

Mesoporous silica nanoparticles ； PEGylation ； Red blood cell ； Hypotonic dialysis ； Enhanced permeability and retention effect ； Blood-brain barrier ； Surface-charged modification ； Doxorubicin

參考文獻

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