癌症的發生率與死之率在全球逐漸增加，在年齡七十歲以下的死亡病例中，癌症為第二大主因。治療癌症的方法有很多種，其中化學治療是一種傳統的方法，缺點為非標靶治療且會產生許多副作用。近年研究顯示出腫瘤細胞與正常細胞所在的地方環境非常不同，腫瘤的微環境特徵包含缺氧、酸性與高濃度的活性氧化物質。因此治療癌症可以利用這些特殊的腫瘤微環境特徵發展標靶治療，利用抗癌藥物載體對此微環境應答的反應進行藥物的傳遞。標靶藥物傳遞系統擁有許多優點，包含藥物可以直達病灶以減少有害的副作用。
本論文主要合成一種以PEG-b-PCL為基底的高分子藥物載體，在PCL鏈中加載具電荷反轉特性的酸性不穩定的β-羧酸醯胺鏈段，其可將載體所形成奈米粒子的表面電荷由負轉為正，以利貼附具負電性的細胞膜，增加其被細胞內化的作用，以及利用具活性氧化物質（Reactive Oxygen Species, ROS）應答的π-共軛硫縮酮連接PEG與PCL。由於π-共軛硫縮酮與抗癌藥阿黴素（doxorubicin, DOX）之間的π–π重疊作用，使DOX在載體所形成之奈米粒子中包覆率與包覆效率分別提高至6.58%與63.67%。由DOX藥物釋放結果顯示，在模擬腫瘤酸性為環境中（pH 6.2）加上ROS的條件下，在24小時釋放抗癌藥物DOX所得的累積釋放量為10.61%，72小時後增加至40.5%。體外細胞毒性測試結果顯示，未加載藥物的高分子奈米粒子與海拉細胞（腫瘤細胞）與纖維母細胞（正常細胞）共存24小時後，細胞存活率皆大於80%，亦即高分子奈米粒子有良好的生物相容性，而加載抗癌藥物的高分子奈米粒子與海拉細胞共存24小時後，細胞存活率下降至50%，表明藥物載體具有較佳抗癌的活性。細胞攝取的結果顯示，加載抗癌藥物的高分子奈米粒子與海拉細胞共存1小時後，細胞核內DOX螢光強度高，而在12小時後細胞型態改變且逐漸凋亡，亦即加載抗癌藥物的高分子奈米粒子擁有表面電荷反轉的特性，因此可大幅提高藥物粒子被內化的能力。

Stimuli-drug delivery system has been considered as a potential anti-cancer therapy strategy because of cancer cells’ tumor microenvironment (TME) characterizations, including hypoxia, acidic environment, and high reactive oxygen species (ROS). A number of carriers can be employed in drug vehicles. Particularly, polymeric nanoparticles (PNPs) composed of biopolymers have attracted extensive attention due to their small size and versatile structure design, making them promising drug carriers.
Herein, in this thesis, a novel PNP, BA-P(CL-co-DCL)-9FTK-mPEG drug carrier was synthesized and investigated for TME-stimuli release of the anti-cancer drug, doxorubicin (DOX). The designed amphiphilic polymer consisted of methoxy poly(ethylene glycol) (mPEG) hydrophilic block and poly(ε-caprolactone) (PCL) hydrophobic block, linked with a π-conjugated thioketal ROS-responsive linker, for responding to overproduced ROS in cancer tumor cells. A pH-sensitive segment, β-carboxylic amides was introduced into copolymer structure to control charge reversal for improving cell internalization effect.
The successful preparation of the BA-P(CL-co-DCL)-9FTK-mPEG polymer was confirmed by 1H-NMR, FT-IR, and GPC. BA-P(CL-co-DCL)-9FTK-mPEG can self-assemble into PNPs, and encapsulate DOX. The DOX-loaded PNPs were assessed by DLS and SEM with the average size of 163 nm. The drug loading content (DLC) and drug loading efficiency (DLE) were improved to 6.58% and 63.67%, respectively, due to the π-π interaction between ROS-responsive linker and DOX. The surface charge of the designed PNPs converted from -3 mV at the physiological environment (pH 7.4) to +4 mV after 4 hours under mimicked tumor acidic condition (pH 6.2), indicating the pH sensitivity of the designed PNP due to the hydrolysis of β-carboxylic amides. In addition, the ROS-responsive property was demonstrated that by the oxidation of π-conjugated thioketal under 50 mM H2O2 leading to PNPs particles degradation. DOX release profiles showed that cumulative release of DOX significantly increased to 40% in the presence of pH 6.2 and 50 mM H2O2 after 72 hours. The designed polymer was highly biocompatible with more than 80% cell viability when incubated with Hela cancer cells and L929 normal cells for 24 hours. It was found that the cell viability of Hela cells decreased to 50% after treated with DOX-loaded designed PNPs indicating efficient anti-cancer activity. The cellular uptake study presented that the residual DOX in cytoplasm of Hela cells was observed, and cells tend to apoptosis after 12 hours, which indicated that the designed polymer had better cell internalization. All together, the results suggest that the BA-P(CL-co-DCL)-9FTK-mPEG designed polymer could serve as a drug carrier for TME-stimuli drug delivery for enhancing the effectiveness of anticancer therapy.

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