In this study, we developed iRGD targeting and redox-sensitive mixed micelle based on LA-TPGS-PLGA and DSPE-PEG as a vehicle to deliver Docetaxel(DTX). DTX is a new cytotoxic agent ofncreatic, breast, urothelial carcinomas, and gastric etc. Nevertheless, the development and applications of DTX had been hampered by its poor aqueous solubility, low gastrointestinal absorption, and rapid metabolism in the body. Herein, iRGD modified reduction-responsive core-crosslinked mixed micelles iRGD-M(DTX/Crosslink) was developed for efficient incorporation and persistent release of DTX, which were proved stable with a desirable drug entrapment efficiency(84.17±1.15 %) and drug loading efficiency(6.21±0.07 %). Importantly, this redox-sesitive iRGD-M(DTX/Crosslink) were destroyed and dissociated fast under the mimic intracellular reductive environment(10 mM DTT)and thus it could immediately release encaupsulated DTX in vitro. By the evaluations of MTT, cellular uptake, cell apoptosis, cell cycle arrest, and immunofluorescence assay, M(iRGD-DTX/ Crosslink)could enhance the cellular uptake and significantly inhibit cell proliferation on HeLa cells, compared with M(DTX/Non-crosslink) micelles and M(DTX/Crosslink). Taken together, our results suggest that iRGD-M(DTX/Crosslink) may serve as stable and efficient tumor targeting system for the first-line chemotherapy for treating cancer by its high antitumor effects against ovarian, paliverying of DTX.

本論文運用硫辛酸接枝的聚乙二醇 1000 維生素 E-琥珀酸酯修飾的聚乳酸乙醇酸 (LA-PLGA-TPGS)和二硬脂醯磷脂乙醇胺接枝聚乙二醇(DSPE-PEG)製備還原型可逆核 交聯聚合物混合膠束。該膠束在催化量的二硫蘇糖醇(DTT)作用下，通過二硫鍵觸發形 成核交聯還原敏感核交聯膠束。該膠束具有良好的穩定性、載藥量(6.21±0.07 %)、以 及包封率(84.17±1.15 %)，並且能夠在腫瘤細胞高還原環境下被觸發，更快解離從而快 速釋放藥物。通過對該核交聯的膠束進行更進一步靶向修飾，iRGD 接枝於該膠束外表 面，以增強其對腫瘤的靶向作用。細胞攝取實驗證實，對比未接枝靶頭的膠束，iRGD 靶向核交聯膠束能夠更多地被腫瘤細胞攝入。細胞毒性試驗證實，包載多西紫杉醇的 iRGD 靶向核交聯膠束對比于多西紫杉醇原藥以及包載多西紫杉醇的未交聯的膠束，對 宮頸癌細胞 HeLa 具有更強的生長抑制作用。通過進一步探究其抑制生長機制，我們 發現包載多西紫杉醇的 iRGD 核交聯膠束細胞週期和凋亡實驗下證實其可以更加有效 的將宮頸癌細胞 HeLa 週期抑制於 G2/M 期，同時可以更明顯地導致宮頸癌細胞 HeLa 的凋亡。另外，通過免疫螢光實驗證實，多西紫杉醇在經過 iRGD 核交聯膠束包載後 具備更加明顯的抑制微管蛋白的解聚。 綜上所述，實驗成功製備了包載多西紫杉醇的 iRGD 靶向核交聯混合膠束。此具 有良好載藥量以及包封率的靶向還原敏感膠束具有較好的包封率和載藥量能夠在模擬 細胞內環境條件下成功觸發釋放。體外實驗證實，包載多西紫杉醇的 iRGD 核交聯膠 束能夠顯著抑制腫瘤細胞增殖、促進週期阻滯、誘導細胞凋亡。因此，該 iRGD 靶向 還原敏感核交聯膠束是一種具備良好穩定性，有效靶向性，以及還原敏感功能性的藥 物遞送系統。 關鍵字：iRGD，核交聯，抗腫瘤，氧化還原敏感