含pH應答性與兩性離子型磺基甜菜鹼之嵌段共聚高分子作為藥物載體之研究

癌症的治療一直是生醫領域中一個重要議題，由於傳統化療藥物不僅對腫瘤沒有專一性，也對人體造成很大的副作用，因此科學家們朝著開發新型的藥物載體而努力，但藥物載體是否能控制藥物於目標位置釋放以避免正常細胞與組織受到破壞，也是目前面臨的困難與挑戰。本論文之目的是希望藉由溫度和pH應答性高分子微胞能有效地控制藥物釋放，提高治療效率，並選用兩性離子高分子以兼具微胞載體抵抗蛋白質吸附能力；在高分子合成上是利用原子轉移自由基聚合法(Atom transfer radical polymerization, ATRP)製備一系列具pH應答性與兩性離子型之嵌段共聚高分子Polyethylene glycol-block-(poly(2-(methacryloyloxy) ethyl)dimethyl (3-sulfopropyl) ammonium hydroxide)-co-poly(2-(diiso- propylamino) ethyl methacrylate)), mPEG-b-(PSBMA-co-PDPA)。本實驗合成四組不同SBMA/DPA莫耳比之共聚高分子，由於其不同SBMA與DPA鏈段長度，將影響pH及溫度應答之特性；實驗結果顯示，僅PS50D50此組高分子於水溶液中形成單一波峰粒徑分布之微胞，動態光散射儀(DLS)量測粒徑大約195 nm，且微胞具有最佳穩定性，所以本研究以此PS50D50高分子作為包覆藥物之載體，DLS結果顯示此載體在牛血清白蛋白水溶液中，粒徑未有大幅度的變動，展示了其具抗蛋白吸附能力，而PS50D50微胞包覆薑黃素的最高藥物乘載量 (Loading content, LC %)為14.0 %，粒徑約231 nm。在藥物釋放實驗中，藉由pH值降低或溫度提高可使微胞有更佳藥物釋放率，說明了此高分子微胞具溫度與pH應答之能力。在細胞毒性測試中證明此微胞具良好生物相容性，而包覆藥物微胞細胞毒性的測試中顯示隨著薑黃素劑量增加，細胞存活率成反比遞減，說明對子宮頸癌細胞(Hela cell)是有毒殺性的，其半抑制濃度(Half maximal inhibitory concentration, IC50)為10.81μg/ml (29.3μM)。由於薑黃素具有光化學作用，未來可結合其光動力治療（Photodynamic therapy, PDT）療效，以減少薑黃素使用量。

關鍵字

溫度應答性； pH應答性；兩性離子型高分子；薑黃素；藥物載體

並列摘要

Cancer treatment has been viewed as a vital issue in biomedical field. Because traditional chemotherapeutic drugs not only show no specificity for tumors but also cause a lot of side effects on human body, scientists have dedicated to improvement on their problems. Currently, utilization of a drug carrier, which can control the drug release rate at the target site, is still challenging. Therefore, the aim of this study is to develop a controlled drug release carrier with thermo- and pH-responsive properties. In addition, we introduced zwitterionic polymer into the carriers to prevent nonspecific protein adsorption. In this study, a series of zwitterionic-containing block copolymers with pH-responsive property was prepared: Polyethylene glycol -block-(Poly(2-(methacryloyloxy)ethyl)dimethyl-(3-sulfopropyl)ammonium hydroxide)-co-Poly(2-(diisopropylamino)ethyl methacrylate)), mPEG-b- (PSBMA-co-PDPA) via atom transfer radical polymerization (ATRP). The PSBMA segment showed thermo-sensitivity, good biocompatibility and anti-non-specific protein adsorption, and PDPA segment showed pH-responsivity. Four different compositions of PEG/SBMA/DPA were synthesized. From the results, only PS50D50 showed mono-dispersed size distribution with micellar size about 195nm as well as good storage stability and anti-bioadhesive properties. PS50D50 was used to encapsulate therapeutic drugs curcumin (CUR) to investigate its surface morphology, controlled drug release rate and in vitro cytotoxicity tests. CUR-loaded PS50D50 micelles showed slightly larger micelle size around 231 nm than that of blank PS50D50 micelles. The highest CUR drug loading content (LC%) of PS50D50 micelles are up to approximately 14.0 %. In drug release experiment, reducing pH value or elevating temperature could increase the drug release rate. These results indicated that the polymer micelles have dual temperature and pH response. The cytotoxicity study proved these blank micelles have good biocompatibility against cervical cancer (Hela cells) cell using MTT assay. Moveover, the cytotoxicity of CUR-loaded micelles showed dose-dependant nature and the half-inhibition to cell growth (IC50) is 10.81μg/ml (29.3μM). Because CUR has photochemical effects, we will further study its photodynamic therapeutic effect in the future.

並列關鍵字

Thermo-responsive ； pH-responsive ； zwitterionic polymers ； curcumin ； drug carrier

參考文獻

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含pH應答性與兩性離子型磺基甜菜鹼之嵌段共聚高分子作為藥物載體之研究

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