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Title

基於泊洛沙姆 188 環境響應性納米藥物遞送系統的研究

English Abstract

Poloxamer 188 (F68), a triblock copolymer comprising hydrophilic poly (ethylene oxide) (PEO) and lipophilic poly (propylene oxide) (PPO) structure, has been widely used in nanodrug delivery systems with good biocompatibility and low toxicity. However, due to the high ratio of PEO/PPO, F68 has high critical micelle concentration (CMC) and poor drug encapsulation capacity so that micelles formed by F68 will dissociate after intravenous injection. In order to enhance the kinetic stability of F68 micelles in blood circulation and improve the drug encapsulation efficiency, some strategies have been explored, including directly conjugating the hydrophobic drug at the end of F68 and introducing the additional lipophilic chains to reinforce the hydrophobic core of F68. Additionally, stimuli-responsive nanoparticulate drug delivery systems are designed to act dynamically in response to the internal triggers in tumor microenvironment, including the lowered interstitial/intracellular pH value and the high level of intracellular glutathione concentration. In this study, we developed a novel acid-responsive micelle (F68-Cis-Cur) for the delivery of curcumin (Cur), a highly pleiotropic anticancer agent, as well as a redox-sensitivity micelle (F68-s-s-LA) loaded with Brusatol (Bru), an inhibitor of transcription factor Nrf2. 1H NMR and FT-IR spectra were used to confirm the synthesis of F68-Cis-Cur and F68-s-s-LA. Both F68-CisCur and Bru loaded F68-s-s-LA could self-assemble into spherical micelles with average size about 100 nm in aqueous solution. Expectedly, the micelles were rupture and release the drugs rapidly stimulated by the certain triggers, while they kept stable in the harmonious environment. In vitro anticancer activity assays revealed the F68-Cis-Cur micelles induced higher cytotoxicity against both A2780 and SMMC 7721 cells than free Cur. Compared with the free Cur, F68-Cis-Cur remarkably increased cellular uptake, provided a larger decrease of mitochondrion membrane potential and induced cellular apoptosis. Similarly, based on the enhanced cellular internalization by both Bel-7402 and MCF-7 cells, Bru loaded F68-s-s-LA micelles (Bru/SS-M) showed higher cytotoxicity than free Bru. The improved anticancer effect was contributed to the remarkably decreased mitochondrial membrane potential, increased reactive oxygen species level and apoptotic rate. These results suggest that the stimuli-responsive nanoparticulate drug delivery systems based on F68 may be a promising strategy for improving intracellular drug delivery in cancer therapy.

Chinese Abstract

泊洛沙姆 188(F68)是一種由親水性的聚氧乙烯(PEO)和疏水性的聚氧丙 烯醚(PPO)組成的三嵌段共聚物,它具有很好的生物相容性和低毒性,已經被廣泛 應用于納米藥物遞送系統。然而, F68 的親水鏈段遠大於疏水鏈段,使得它具有很高 的臨界膠束濃度以及較差的藥物包封能力。為了增強 F68 在血液循環中的動力學穩定 性以及藥物包封效率,我們通過直接在 F68 的兩端接枝上疏水性的藥物和接枝其他的 疏水鏈段,來增強 F68 在水溶液中形成的疏水內核。此外,我們構建了對腫瘤微環境 內部一些啟動因子有動態響應的納米藥物遞送系統,包括腫瘤細胞內的低 pH 值和高 濃度穀胱甘肽含量。 本論文分別構建了酸敏感的薑黃素藥物遞送系統 F68-Cis-Cur 膠束,以及還原敏感的鴉 膽苦醇藥物遞送系統 Bru/F68-s-s-LA。通過核磁和紅外圖譜對 F68-Cis-Cur 和 F68-s-sLA 的結構進行了表征,證明材料合成成功。這兩種材料在水中都能自組裝形成粒徑為 100 nm 左右的球狀膠束,而且膠束粒子能夠在正常體液條件下保持穩定,但當他們處 於特定的酸性或者還原性條件下時,膠束會破裂并釋放出藥物。从體外抗腫瘤活性結 果可見,F68-Cis-Cur 膠束提高了薑黃素對卵巢癌細胞 A2780 以及肝癌細胞 SMMC 7721 的細胞毒性、細胞攝取,同時大幅度降低了線粒體膜電位從而誘導細胞凋亡。同 樣的,包載了鴉膽苦醇的 F68-s-s-LA 膠束(Bru/SS-M)提高了鴉膽苦醇對肝癌細胞 Bel-7402 和乳腺癌細胞 MCF-7 的細胞毒性、細胞攝取,同時,由於 Bru/SS-M 相對於 原藥降低了線粒體膜電位及提高了活性氧水平,從而增強了細胞凋亡。從結果可以看 出,本研究構建的基於 F68 的環境響應性納米藥物遞送系統是一種在腫瘤治療上提高 細胞內藥物遞送很有前景的策略。

Issue date

2016

Author

方曉斌

Faculty

Institute of Chinese Medical Sciences

Degree

M.Sc.

Subject

Medicinal plants -- China -- Analysis

藥用植物 -- 中國 -- 化學分析

Drug delivery systems

藥物傳輸系統

Chinese Medicinal Science -- Institute of Chinese Medical Sciences

中藥學 -- 中華醫藥研究院

Supervisor

陳美婉

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Library URL
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