探討新型微脂粒LPPC包覆n-Butylidenephthalide (BP)對抗惡性腦瘤(GBM)之研究

多型性神經膠原母細胞瘤（Glioblastoma multiforme, GBM）為腦瘤中惡性度最高的惡性腦瘤，其死亡率高及預後差，並且在臨床GBM的化療藥物普遍效果都不佳，因此積極開發一個較佳的治療藥物成為目前迫切性的需求。正丁烯基苯酞（n-Butylidenephthalide, BP）為一種天然純化物，在過去的文獻中證實BP能夠有效對抗GBM，並能夠通過血腦障壁（Blood-brain barrier）達到原位治療效果，但BP的結構及活性不穩定且在身體內的半衰期（Half-life）時間短，因而降低BP的治療效果。新型微脂粒（LPPC）具有奈米化之大小（180 nm），並且可用以包覆水溶性及脂溶性藥物。本實驗目的為：利用新型微脂粒（LPPC）包覆BP，藉由LPPC達到穩定BP結構及活性，並延長BP於體內的Half life以提高對抗GBM之治療效果。在實驗結果中：第一階段為建立BP的測量系統，首先找到最佳的激發光為350 nm，接著建立BP standard後並推算包在LPPC上BP的濃度。第二階段為BP/LPPC complex於體外及體內試驗，首先找到BP/LPPC complex最佳包覆條件，並發現BP/LPPC complex在4oC最為穩定，接著觀察到BP/LPPC complex比BP及BP/lipo complex更具有毒殺腫瘤細胞的能力，其主要透過LPPC穩定BP結構進而維持BP的活性，並提高BP快速進入腫瘤細胞。在動物實驗中發現LPPC能夠有效提高BP於體內血清中的Half-life，對於正常生理及器官組織有極低或幾乎沒有毒性。因此BP/LPPC complex具有很高的潛力，在未來朝向開發成用於治療惡性腦瘤(GBM)的新一代抗癌藥物。

關鍵字

多型性神經膠原母細胞瘤；正丁烯基苯酞新型微脂粒（LPPC）

並列摘要

Glioblastoma multiforme (GBM) was one of the most malignant in brain tumor. Moreover, the patients had low survival rate and poor prognosis. In clinical, there was low effective drug for GBM. Therefore, it is important to research the drug for GBM therapy. Previous study showed that n-Butylidenephthalide (BP), a natural pure compound, could inhibit GBM tumor. In addition, BP could pass blood-brain barrier for in situ therapy. However, BP had unstable structure that reduced BP activity and half-life in vivo. For this reason, this study used the Polycationic Liposome Containing PEI and Polyethylene Glycol Complex (LPPC) to solve this problem. The LPPC had nanometer size (180 nm) and could encapsulate hydrophilic and hydrophobic compounds. The purpose of this study is to investigate the anti-tumor effect of LPPC encapsulating BP in GBM tumor. The experiments of this study were separated two parts. The first part is to set up BP detection system. The results showed that the BP optimal excitation wave was 350 nm. Next step was to calculate the BP concentration on LPPC after setting up BP standard curve. The second part was to investigate the anti-tumor effect of BP/LPPC complex in vitro and ex vivo. The result showed the optimal encapsulating condition was 1M/20µl BP mixed with 1mg/100µl LPPC. The BP/LPPC complex had well stability at 4oC storage and slowly released BP at 37oC protein rich environment. The BP/LPPC complex had higher cytotoxicity than BP and BP/lipo complex, because BP structure and activity were protected by LPPC. Beside, BP/LPPC complex had fast cell uptake into tumor cells. In ex vivo study, the LPPC could prolong the BP half-life in serum and reduce the value of BP penetration into normal tissues. BP/LPPC complex had low or no toxicity in normal organs and physical toxicity effects. Therefore, this study showed the BP/LPPC complex had high potential to develop an anti-tumor agent for GBM therapy in the further.

並列關鍵字

Glioblastoma multiforme (GBM) ； n-Butylidenephthalide (BP) ； Polycationic Liposome Containing PEI and Polyethylene Glycol Complex (LPPC)

參考文獻

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探討新型微脂粒LPPC包覆n-Butylidenephthalide (BP)對抗惡性腦瘤(GBM)之研究

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