製備包覆靛氰綠及阿黴素之聚乳酸甘醇酸-聚乙二醇交聯標靶奈米粒子用於乳癌光/化學治療之研究;Fabrication and Characterization of HER2-Target Indocyanine Green-Doxorubicin-Loaded PLGA-PEG Nanoparticles for Chemo-/Photo-Therapy of Breast Cancer Cells

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题名:	製備包覆靛氰綠及阿黴素之聚乳酸甘醇酸-聚乙二醇交聯標靶奈米粒子用於乳癌光/化學治療之研究;Fabrication and Characterization of HER2-Target Indocyanine Green-Doxorubicin-Loaded PLGA-PEG Nanoparticles for Chemo-/Photo-Therapy of Breast Cancer Cells
作者:	張達盛;Chang,Da-Sheng
贡献者:	生物醫學工程研究所
关键词:	奈米藥物載體;聚乳酸甘醇酸;聚乙二醇;光-化學治療;阿黴素;靛氰綠;乳癌;Nanoparticle;Poly(lactic-co-glycolic acid);Polyethylene glycol;Photo-Chemo therapy;Doxorubicin;Indocyanine green;Breast cancer
日期:	2016-08-22
上传时间:	2016-10-13 13:04:03 (UTC+8)
出版者:	國立中央大學
摘要:	本研究以微乳液法製作包覆抗癌藥物阿黴素(Doxorubicin)與光敏試劑靛氰綠(Indocyanine Green；ICG)之聚乳酸甘醇酸(Poly(Lactic-co- Glycolic Acid)；PLGA)-聚乙二醇(Polyethylene glycol；PEG)並於表面接枝人類上皮生長因子2(human epidermal growth factor receptor 2；HER2)單株抗體之新穎生物可降解性標靶奈米藥物載體(HER2-target ICG-DOX-Loaded PLGA-PEG Co-polymeric Nanoparticles;；HIDPNPs)，並測試該載體對於乳癌細胞進行複合式癌症治療之可行性。本研究首先以傅立葉轉換紅外線光譜儀與核磁共振儀確認PLGA及PEG共聚高分子合成效果，完成載體製備後再以螢光表現抗體及BCA蛋白質檢測證明HER2抗體於產品表面之存在與生物活性。經過動態光散射儀器分析HIDPNPs之平均粒徑與表面電位分別為266  4.3 nm和-12  4.48 mV；對於DOX及ICG的包覆率分別約為35%及79%；包藥率則分別約為0.15%及0.34%。再由UV-Vis分光光度計分析降解率得到48小時內HIDPNPs在4℃及37℃環境下所包覆的ICG降解率比單純溶解於水中之ICG分別低11%及54%；48小時內HIDPNPs在4℃及37℃環境的DOX釋放率分別為13%及26%。以激發波長808 nm搭配強度為 6 W/cm2的近紅外光雷射照射HIDPNPs奈米載體，結果發現ICG包覆濃度大於1μM下照射90秒內溶液溫度上升超過40℃並且可維持高溫長達5分鐘，另外藉由SOSG檢測單態氧濃度發現於5分鐘內的單態氧生成量和HIDPNPs的濃度成正比關係，在包含相等於4μM ICG的HIDPNPs其單態氧生成量比在相同濃度下單純ICG水溶液高出約3倍。藉由偵測被細胞攝取後的HIDPNPs其所發射的ICG螢光強度發現MDA-MB-453(HER2+)的螢光值明顯大於MCF-7 (HER2-)，如此證明了HIDPNPs對HER2表現的細胞具有主動靶向的功能。將HIDPNPs和MDA-MB-453乳癌細胞而共同培養12小時再以近紅外光雷射照射5分鐘後，經由計算得知包覆4μM ICG及3μM DOX的HIDPNPs之毒殺細胞效率比單純使用ICG或DOX分別高了1.5 (P < 0.05)及2.6 (P < 0.05)倍，此一結果證明HIDPNP可以有效的減少化療劑量並且搭配光療法以增加或維持乳癌治療效果，因此有望發展成為一種治療癌症的材料。;Breast cancer has long been recognized as one of the most lethal gynecological disease for women due to high drug resistance and serious side effects during treatment. To resolve these issues, a multi-functional human epidermal growth factor receptor 2 (HER2)-targeted Indocyanine green (ICG)-Doxorubicin (DOX)-encapsulated poly( lactide- co-glycolide) -poly(ethylene glycol) copolymeric nanoparticles (HIDPNPs) was developed in this study. The mean size and surface charge of the HIDPNPs are 266 ± 4.26 nm and -12  4.48 mV, respectively, through measurements using dynamic light scattering technique. The encapsualtion efficiencies of ICG and DOX in HIDPNP are 79% and 35%, respectively, while the drug loading rates for ICG and DOX are 0.34% and 0.15%, respectively. The degradation rate of encapsulated ICG remarkably decreases 11% and 54% at 4 and 37oC, respectively, within 48 h as compared with freely dissolved ICG in PBS. The DOX release rates are 13% and 26% at 4 and 37oC, respectively, within 48 h. Through the detection of ICG-induced fluorescence, we found that the uptake efficiency of HIDPNPs in MDA-MB-453 cells (HER2+) was significantly higher than that in MCF7 cells (HER2-), showing that the HIDPNP enables to specifically target HER2-expressing cells. In terms of the therapeutic functionality of the agent, our data show that upon NIR laser exposure, the temperature of medium containing HIDPNPs with ≥ 1-μM equivalent ICG concentration enabled to reach > 40oC within 90 sec and its amount of singlet oxygen yielded significantly enhanced ≥ 3 folds after 5-min laser treatment. The capacity of HIDPNP in cancer cell killing was further verified by using MDA-MB-453 as the model cell that the motality of the cells which were treated by HIDPNPs including 4 and 3 μM of ICG and DOX, respectively for 12 h and followed by 5-min NIR laser irradiation significantly enhanced 1.5- (P < 0.05) and 2.6 folds (P < 0.05) as compared to the group treated with ICG or DOX alone, respectively. Overall, the HIDPNP which enables to provide both chemo and photo therapeutic effects exhibits a high potential for use in breast tumor destruction.
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