- 學位論文
具標靶與溫敏性功能之複合型高分子微胞 於光動力治療之研究
Folate-targeted and Thermo-reponsive Polymeric Micelles for Application in Photodynamic Therapy
摘要
光動力治療(photodynamic therapy)是運用特定波長的光照射光敏劑(photosensitizers)，激發氧分子形成單重態氧(1O2)與其他活性氧分子(ROS)，達到破壞腫瘤組織的效果。但由於光敏劑本身水溶性低容易聚集，具有細胞毒性而且在體內容易被代謝，因此本實驗是利用雙親性嵌段共聚高分子(amphiphilic block copolymers)形成的微胞(micelles)做為光敏劑載體，並且將光敏劑修飾於疏水段末端來解決其水溶性低等問題。另外在高分子親水鏈段末端修飾葉酸(folic acid, FA)，運用葉酸以增強微胞載體其藥物傳輸效率及增進對癌症細胞的專一性。雙親性嵌段共聚高分子的疏水段為生物可分解poly(caprolactone) (PCL)，親水段為具有溫敏性響應的Poly(N-isopropylacrylamide) (PNIPAAm)。高分子FA-PNIPAAm-PCL以click chemistry反應將葉酸修飾於親水鏈段末端。而高分子PNIPAAm-PCL-PpIX以steglich esterification將光敏劑PpIX修飾於疏水鏈段末端。其化學結構及高分子分子量分別由1H-NMR、13C-NMR、DEPT、HMQC、HMBC、FTIR 及GPC鑑定。而雙親性高分子其自組裝形成未包覆及包覆光敏劑PpIX的混合微胞平均粒徑是利用動態光散射儀(DLS)量測各為 48 及60 (nm)。PpIX的單重態氧產生效率則利用9,10- anthracenedipropionic acid （ADPA）鈉鹽作為指示劑，實驗結果証明我們所製備之雙親性嵌段共聚高分子混合微胞，在光源照射下有效地產生單重態氧。細胞毒性實驗顯示此混合微胞具有良好的生物相容性。
並列摘要
Photodynamic therapy is a promising new treatment for cancer that involves using specific light to trigger the photochemical responses of photosensitizers (PS) to generate singlet oxygen (1O2) and reactive oxygen species (ROS) for the effective destruction of tumors. However most photosensitizers are lipophilic leading to aggregation in physiological environment, highly cellular toxicity and easily cleared by mononuclear phagocyte system (MPS) uptake. Polymeric micelles self-assembled form amphiphilic block copolymers are promising candidates as drug carriers to resolve hydrophobicity and cellular toxicity of photosensitizers, and extend circulation in human blood stream. Thus, we prepared a series of amphiphilic block copolymers (ABCs) composed of the same length of hydrophobic poly(ε-caprolactone) (PCL) and different chain length of hydrophilic poly(N-isopropyl- acrylamide) (PNIPAAm) with temperature-responsive property (PNIPAAm-b-PCL). PCL was chosen as hydrophobic block due to its biocompatibility and biodegradability. Then, these synthesized ABCs were divided into two parts. One part of the PNIPAAm-b-PCL was further functionalized with folic acid using click chemistry to enhance the tumor targeting of the polymer micelles. The other part of these ABCs was conjugated with photosensitizers, PpIX. 1H-NMR, FT-IR and GPC were used to characterize the chemical structures and molecular weight of the prepared ABCs. The folic acid modified polymers and PpIX-terminated polymers were mixed with different ratios to form self-assembled micelles in aqueous solution. The diameters of PpIX loaded and unloaded micelles are determined by DLS 56 and 53 nm, respectively. The efficacy of singlet oxygen generation was detected using the disodium salt of 9,10- anthracenedipropionic acid ( ADPA ) as a water-soluble 1O2 indicator. The results showed that mixed micelles could generate singlet oxygen during light irradiation. The cell viability test showed the mixed micelles have good biocompatibility.
參考文獻
延伸閱讀
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