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  • 學位論文

發展褐藻醣膠自組裝奈米載體應用於抗腫瘤缺氧與光動力療法之改善

Development of fucoidan-based, self-assembled nanoformulations for overcoming tumor hypoxia and enhancing photodynamic therapy

指導教授 : 林政緯

摘要


對抗癌症的過程中,奈米藥物醫療有著許多其他傳統治療如手術切除、化學與放射治療所沒有的優點,包含低侵入性、減少傷口面積、使用具生物相容性材料提升藥物運輸效率、並深入病灶,更經常合併光動力療法、siRNA、或標靶抗體以提高治療效果;然而在臨床結果上仍有許多尚未克服的阻礙,諸如對不同癌症的專一標靶性不足、腫瘤內部較低的含氧量造成缺氧、和腫瘤微環境造成的免疫脫逃作用。因此,我們發展出一種由褐藻醣膠Fucoidan結合樹狀高分子Dendrimer之自組裝奈米載體,此奈米載體裝載光敏劑維替泊芬Verteporfin (VP)與二氧化錳奈米粒子MnO2 NPs,形成具有多重功效的奈米運輸載體FM@VP。由實驗結果發現,自主裝奈米載體具有雙硫敏感性,代表能在glutathione (GSH)含量較多的腫瘤細胞內裂解釋放,而不會影響正常細胞;外層包覆的褐藻醣膠還能提高針對高表現P-selectin三陰性乳癌的專一性。從細胞存活實驗也能發現FM@VP的細胞毒殺能力比VP溶液來的高,當FM@VP結合光動力療法時,效果更是明顯提升,另外FM@VP也能自發性緩解腫瘤球體內的缺氧現象,同時抑制細胞增生,進一步改善光動力療法的治療功效。在分析經過FM@VP處理後的乳癌細胞mRNA相對表現量與蛋白表現時,都可以發現FM@VP有效抑制促癌症發展轉移的訊息傳遞,包含YAP、VEGF、EGFR、Cyclin D1甚至PD-L1,種種結果指出擁有多重治療效能的FM@VP在對於癌症標靶治療與改善光動力療法上提供了一個有潛力的治療選擇。

並列摘要


Compared with traditional therapeutics such as surgeries, chemo- and radiotherapies, nanomedicines show great advantages, including less invasiveness, small wound, increasing drug delivery efficiency, and inner penetration. Nanomedicines combined with photodynamic therapy (PDT), siRNA, and antibodies are created to make treatments more effective. However, there are still many obstacles, such as low specificity, low oxygen levels, and a tolerant tumor microenvironment. Therefore, we developed a biocompatible nanoformulations based on a self-assembled nanocomplex formed by a functional fucoidan and a bioreducible polyamidoamine dendrimer, a photosensitizer verteporfin, and MnO2 nanoparticles into a multifunctional nanoparticle cluster. In this study, we found that the fucoidan-dendrimer nanocomplex specifically targeted P-selectin-overexpressed TNBC, and was sensitive to glutathione (GSH) in tumor, which could reduce the side effect of PDT. When we combined FM@VP and PDT, it showed a great improvement of phototoxicity. Moreover, this nanoformulations simultaneously overcame tumor hypoxia, inhibited cell proliferation, and suppressed oncogenic signaling, including YAP, VEGF, EGFR, Cyclin D1, even PD-L1. As a result, therapeutic efficacy of PDT was improved. This discovery provides us a promising strategy for synergetic cancer targeting and photodynamic therapy.

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