具酸鹼應答性複合型高分子微胞於光動力治療 合併化學療法上之應用

近年來癌症治療一直是生醫領域中熱門研究之一，目前治療癌症方式仍都以單一治療為主但其療效有限，最近結合治療被認為是相當具有前瞻性的治療策略，因其能夠提升療效並且降低副作用，例如結合光熱和化療藥物治療或光動力和化療藥物治療，然而為確保藥物能同時運送至腫瘤組織並且發揮協同作用提升療效，研究出一套安全且高效率之傳輸系統備顯重要。本論文利用原子轉移自由基聚合 (Atom transfer radical polymerization)製備一系列具有酸鹼應答特性之雙親性嵌段共聚物poly(ethylene glycol)-b-poly(2-(diisopropylamino)ethyl methacrylate) （mPEG-b-PDPA）以及利用點擊反應(Click reaction)將光敏劑tetrakis (4-hydroxyphenyl)porphyrin改質為具親水性poly(ethylene glycol)的星狀高分子，以混掺方式在水溶液中進行自組裝形成微胞，探討此複合式高分子微胞環境應答性質、奈米結構、作為藥物載體之可行性以及應用於結合治療上之評估。我們選用具酸鹼應答的DPA作為疏水鏈段以及星狀高分子疏水核心ZnTPP作為複合式高分子微胞疏水核，以此共同包覆疏水性抗癌藥物Dox於核內，使此載體不但具備有光動力治療能力並且能夠藉由調整DPA聚合度可有效控制pH應答變化範圍，進而影響藥物釋放速度。以33.33 wt% Star-PEG ZnTPP混掺mPEG-b-PDPA系列共聚物作為最佳混摻比，所形成之微胞利用動態光散射(Dynamic light scattering)量測微胞平均粒徑為122.3 ±5.1 nm，並且具有比單一共聚物更低的臨界微胞濃度0.322 mg/L，在長時間存放下微胞結構相當穩定，另外在酸鹼應答能力上其酸鹼應答pKa值約為5.3，在高於此pKa範圍微胞結構穩定，而低於此pKa可展現藥物快速釋放之結果，說明此載體具有環境應答之特性。在單重態氧之生成效率測試中，證實複合式高分子微胞載體均具備有光動力療法的潛力，在特定波長光源照射下，單重態氧之生成速率相當穩定，說明此載體具備有光動力治療之能力。以子宮頸癌細胞(HeLa calls)作細胞毒性測試，其結果顯示此複合式高分子所形成之微胞具有良好的生物相容性。而在化學治療(Chemotherapy)及光動力治療(Photodynamic therapy)雙重療法實驗顯示有包覆Dox. M2複合式微胞展現出協同作用，並提升HeLa細胞致死率。未來將調整光照時間與藥物濃度，期望此新型複合型高分子微胞能夠相輔相成提升對癌細胞之致死率且降低藥物副作用。

關鍵字

光動力治療；酸鹼應答性；高分子微胞；阿黴素

並列摘要

Cancer therapy has been always the important object in the field of biomedical research. Many attentions have been dedicated on improving therapeutic efficacy, which relys on only a single modality. Currently, combination therapy has emerged as a promising strategy in oncology, such as combination of photothermal and chemotherapy or photodynamic and chemotherapy. To ensure both therapeutic agents could be simultaneously accumulated within solid tumor and exert their synergistic effect, a safe and intelligent delivery system is highly demanded. In this study, we developed a series of pH-sensitive block copolymers, poly(ethylene glycol) methyl ether - block – poly(2-(diisopropylamino)ethyl methacrylate) (mPEG-b-PDPA) via atom transfer radical polymerization. In addition, click reaction was applied for modifying the insoluble photosensitizer zinc tetra(progaryloxyphenyl)porphyrin with poly(ethylene glycol) (Star-PEG-ZnTPP). 1H﹣NMR and GPC were used to characterize their chemical structures, purity and molecular weight. The mixed micelles were prepared by self-assembly from different weight ratios of mPEG-b-PDPA and Star-PEG-ZnTPP in an aqueous environment and further to encapsulate the anticancer drug doxorubicin (Dox) for combination therapy. The optimized mixed micelles (M2) show the average diameter of 122.3 ±5.1 nm by dynamic light scattering and good stability. Under light irradiation, ZnTPP can transfer its energy to surrounding oxygen to generate cytotoxic singlet oxygen, indicating our mixed micelles have the capability for photodynamic therapy. At neutural condition, the mixed micelles show a slower release rate than that of acid, indicating that the micelles are more stable in neutural condition, and at acidic condition the drugs release fast, so that they can be used in controlled drug release system . The cytotoxicity of blank M2 was tested against a cancer cell line, HeLa cells. No significant cytotoxicity was observed, indicating our mixed micelles have good biocompatibility. The cytotoxicity and phototoxicity of Dox-loaded M2 micelles showed significant improvement on the cytotoxicity of Dox in HeLa celles after irradiation. This result demonstrated our new mixed polymer micelles integrated with chemotherapy and photodynamic therapy can enhance the efficiency for the treatment of cancer.

並列關鍵字

Doxorubicin ； pH-responsive ； mixed micelles ； Photodynamic therapy

參考文獻

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具酸鹼應答性複合型高分子微胞於光動力治療合併化學療法上之應用

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