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| 题名: | 利用可注射化學交聯型水膠作為Trastuzumab皮下傳輸系統用於乳癌治療之研究
Subcutaneous Injection of In Situ Chemically Crosslinked Hydrogel for Delivery of Trastuzumab in the Treatment of Breast Cancer |
| 作者: | 羅友文
Lo, Yu-Wen |
| 贡献者: | 藥學系(碩博士班)
何秀娥
許明照 |
| 关键词: | 注射型水膠;長效釋放;皮下傳輸;順丁烯二醯亞胺修飾聚麩胺酸;四臂式末端硫醇基化聚乙二醇;trastuzumab
injectable hydrogels;sustained-release;subcutaneous delivery;maleimide modifiedγ-polyglutamic acid;thiol end-functionalized 4-arm poly(ethylene glycol);trastuzumab |
| 日期: | 2019-07-11 |
| 上传时间: | 2020-02-17 13:00:09 (UTC+8) |
| 摘要: | 近年來，新的治療型抗體傳輸系統引起廣泛興趣，特別是長效緩釋劑型。然而長效緩釋劑型需能攜帶高藥量抗體才能真正於臨床使用，目前仍為一大挑戰。本研究透過順丁烯二醯亞胺修飾聚麩胺酸(maleimide modifiedγ-polyglutamic acid, γ-PGA-MA)以及四臂式末端硫醇基化聚乙二醇(thiol end-functionalized 4-arm poly(ethylene glycol), 4 arm-PEG-SH)所形成之新穎注射型水膠進行trastuzumab皮下緩釋劑型開發。透過硫醇基-順丁烯二醯亞胺反應，γ-PGA-MA以及4-arm PEG-SH可形成水膠並具有剪切稀化(shear-thinning)以及膠體可回復之特性，TZB10GA10EG4-5k配方組成為1.5% γ-PGA-MA、1.5% 4-arm PEG5k-SH以及10 mg/mL trastuzumab，TZB133GA10EG4-5k配方組成為1.5% γ-PGA-MA、1.5% 4-arm PEG-SH以及133.6 mg/mL trastuzumab，TZB10GA10EG4-5kZn以及TZB133GA10EG4-5kZn組成分別為TZB10GA10EG4-5k以及TZB133GA10EG4-5k額外再添加ZnCl2溶液，使得配方最終Zn濃度為5mM，試驗結果顯示此水膠系統可裝載高藥量之trastuzumab (>100 mg/mL)並且透過電荷作用力吸引可持續釋放trastuzumab達數星期，此外，自水膠所釋放之trastuzumab仍能維持抗體結構完整性、Fab端抗原結合能力以及BT-474細胞生長抑制效果。藥動試驗證實TZB10GA10EG4-5k以及TZB10GA10EG4-5kZn相較於trastuzumab solution可有效降低Cmax，此外TZB10GA10EG4-5kZn由於水膠內trastuzumab可與γ-PGA-MA產生電荷作用力以及形成trastuzumab/Zn nanocomplexes，因此呈現較佳之抗體釋控作用。於小鼠腫瘤模式試驗，TZB10GA10EG4-5k呈現相似於trastuzumab solution之腫瘤抑制效果，相對的，TZB10GA10EG4-5kZn因Zn之作用呈現出顯著之腫瘤生長抑制效果。此實驗結果說明γ-PGA-MA以及4-arm PEG5k-SH所組成之注射型水膠具有相當潛力可作為蛋白質或抗體之緩釋載體，並可應用於局部或全身性給藥。 |
| 描述: | 博士
指導教授：何秀娥
共同指導教授：許明照
委員：黃耀斌
委員：林文貞
委員：莊國祥
委員：謝堅銘
Recently, novel delivery approaches for therapeutic antibody have attracted many interests, especially sustained-release formulations. However, the sustained-release formulations capable of carrying high antibody loading remain a challenge for practical use. In this study, a novel injectable hydrogel composed of maleimide modifiedγ-polyglutamic acid (γ-PGA-MA) and thiol end-functionalized 4-arm poly(ethylene glycol) (4 arm-PEG5k-SH) were developed for subcutaneous delivery of trastuzumab. The γ-PGA-MA and 4-arm PEG5k -SH could form a hydrogel via thiol–maleimide reactions which had shear-thinning properties and reversibility of rheological behavior. TZB10GA10EG4-5kwas composed of 1.5% γ-PGA-MA、1.5% 4-arm PEG-SH and 10 mg/mL trastuzumab. TZB133GA10EG4-5k was composed of 1.5% γ-PGA-MA、1.5% 4-arm PEG-SH and 133 mg/mL trastuzumab. For TZB10GA10EG4-5kZn and TZB133GA10EG4-5kZn, additional ZnCl2 solution was added into TZB10GA10EG4-5k and TZB133GA10EG4-5k respectively to achieve a final Zn concentration of 5 mM. The results showed that this novel hydrogel was capable of loading high content of trastuzumab (>100 mg/mL) and sustained release of trastuzumab over several weeks via the electrostatic attraction. In addition, released trastuzumab from hydrogel had good stability in terms of structure integrity, binding bioactivity and BT-474 cells anti-proliferation effect. Pharmacokinetic studies demonstrated that TZB10GA10EG4-5k and TZB10GA10EG4-5kZn could lower the Cmax in comparison to trastuzumab solution. Furthermore, TZB10GA10EG4-5kZn possessed better ability of controlled-release of trastuzumab ascribing to electrostatic attraction and formation of trastuzumab/Zn nanocomplexes. In the BT-474 xenograft tumor model, TZB10GA10EG4-5k had the similar tumor growth inhibition effect as compared to that of trastuzumab solution. In contrast, TZB10GA10EG4-5kZn exhibited superior capability of tumor growth inhibition due to the functionality of Zn. This study successfully demonstrated γ-PGA-MA and 4-arm PEG5k-SH based hydrogel has great potentials of serving as a delivery carrier for local or systemic delivery of therapeutic protein or antibody. |
| 数据类型: | thesis |
| 显示于类别: | [藥學系] 博碩士論文
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