- 學位論文
開發智慧型‟中途接駁”藥物傳遞系統 對深層腫瘤區域進行化療
Development of a Smart ‟Midway Pickup” Drug Delivery System for Chemotherapy to Tumor Hypoxic Regions
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摘要
本研究利用具高度生物相容性的團聯型高分子 poly(ethylene glycol)-b-poly(histamine methacrylamide) (PEG-b-PHMA) 與兼具生物可降解性的高分子 poly(lactic-co-glycolic acid)-modified hyaluronic acid (HA) 於水溶液中與疏水性化療藥物 SN-38 自組裝形成載藥奈米複合微胞 (hybrid micelles)，並利用此複合微胞對腫瘤微環境的特殊應答性，開創出新型“中途接駁”的藥物傳遞模式，改善化療藥物對深層腫瘤的治療效率。此智慧型載藥微胞系統粒徑大小約為 170奈米，藥物裝載效率及裝載量則分別可達製備微胞時進藥量的60%和高分子進料重的12 wt%。本研究的設計核心為，透過奈米粒子容易經由enhanced permeability and retention (EPR) effect快速且有效累積至腫瘤內後，再藉由腫瘤偏弱酸的微環境，促使微胞內 PEG-b-PHMA 高分子因大量 histidyl 基團質子化而脫離微胞，並暴露出微胞表面的對 CD44 受器具標的能力的 HA，提高載藥微胞對腫瘤組織內 CD44 受體過量表現的腫瘤巨噬細胞 (tumor-associated-macrophages, TAMs) 的結合能力。藉由於 PEG-b-PHMA 高分子上修飾螢光探針 Rhodamine B 和在 HA-g-PLGA 微胞的內部疏水核心中導入疏水螢光染劑 3,3´-dioctadecyloxacarbocyanine (DiO)，可利用 Fluorescence resonance energy transfer (FRET) 效應分析PEG-b-PHMA 於模擬腫瘤弱酸環境 (pH 6.5) 中從微胞表面脫附的脫附情形，再搭配上流式細胞儀分析PEG-b-PHMA脫附後，複合微胞對巨噬細胞的標的能力，可簡單於體外實驗中評估本研究設計的可行性。研究結果證實於弱酸環境中PEG-b-PHMA不僅會迅速從表面微胞脫附，微胞對巨噬細胞標的能力亦會大幅增加。另一方面，由於微胞的藥物釋放是受微胞內部核心 PLGA 的降解情形調控，PLGA的緩慢降解將能有效提高藥物透過腫瘤巨噬細胞傳遞至深層腫瘤內部的機會。相信這也就是為何利用螢光顯微鏡觀察經靜脈注射載藥複合微胞的動物腫瘤模型，其腫瘤切片影像中複合微胞不僅能有效累積於腫瘤巨噬細胞，並且也會伴隨著巨噬細胞一同遷移至深層腫瘤內部甚至是缺氧區域，造成該區域的癌細胞凋亡。綜合上述，本研究結果充分證實我們開創的‟中途接駁”藥物傳遞設計概念的可行性，也證實此設計能有效克服傳統藥物傳遞模式對深層腫瘤區域藥物傳遞不彰的課題。
並列摘要
In this study, the biocompatible and biodegradable polymers, poly(lactic acid-co-glycolic acid)-modified hyaluronic acid (HA-g-PLGA) and PEG-b-poly(histamine methacrylamide) (PEG-b-PHMA) were employed to develop a smart midway-pickup drug delivery system for improving therapeutic efficacy of tumor hypoxia. The SN38-loaded polymer micelles were first attained by the self-assembly of HA-g-PLGA and SN38 in aqueous solution. To further functionalize these artificial micelles with superior in vivo colloidal stability and pH-responsive detachment of PEG chain segments, PEG-b-PHMA was deposited in sequence onto the assembly outer surfaces. Taking advantage of nano-sized particles for drug delivery, this drug-loaded nanoparticles can largely accumulate within tumors via the enhanced permeability and retention (EPR) effect. Once they arrive at tumor sites, the HMA residues of the PEG-b-PHMA copolymer prefer to protonate under the acidic tumor microenvironment. These hydrophilic PEG-b-PHMA copolymers are prone to disassociate from the shell of polymeric micelles. As the same time, the CD44 targeting ligand, HA, becomes exposed on the surface of polymer micelle. These HA-covered polymer micelles show excellent effective internalization behavior by tumor-associated macrophages (TAMs) within the solid tumor via CD44 receptor-mediated endocytosis. The internalized polymer micelles could be further transported to tumor hypoxia due to the inherent TAM tropism toward hypoxia. The drug liberation was achieved via degradation of PLGA segments under acidic environment such as tumor microenvironment or intracellular endosome and lysosome. The SN38 released from the TAMs could be further internalized by cancer cells, with thus efficiently inhibiting the cell proliferation. Our results strongly indicate that this “midway pickup” drug delivery strategy could enhance the antitumor efficacy of chemotherapy in tumor hypoxia, which may create a new opportunity for the current anti-cancer research.
並列關鍵字
無資料參考文獻
1. Thanos D. Halazonetis, V.G.G., Jiri Bartek, An Oncogene-Induced DNA Damage Model for Cancer Development. science, 2008. 319: p. 1353-1355.
2. Sherr, C.J., Principles of Tumor Suppression. Cell, 2004. 116: p. 235–246.
3. M. S. Greenblatt, W.P.B., M. Hollstein, and C. C. Harris, Mutations in the p53 Tumor Suppressor Gene: Clues to Cancer Etiology and Molecular Pathogenesis. Cancer Research, 1994. 54: p. 4855-4878.
4. Michael Ho¨ckel, P.V., Tumor Hypoxia: Definitions and Current Clinical, Biologic, and Molecular Aspects. Journal of the National Cancer Institute, 2001. 93: p. 266-276.
5. L.Harris, A., HYPOXIA — A KEY REGULATORY FACTOR IN TUMOUR GROWTH. NATURE REVIEWS, 2002. 2: p. 38-47.