臨床局部熱治療有具侵入性的治療過程、無法對腫瘤均勻加熱以及對正常組織造成熱損傷等問題，以奈米載體配合近紅外光進行光熱治療除了可以降低治療過程的侵入性外，奈米載體能專一的累積在腫瘤處，實現對腫瘤細胞均勻熱治療。因此本研究開發了具pH應答能力的SATAT胜肽修飾奈米微胞，並希望藉由核標靶進一步提升光熱治療效果。此系統利用鍵結TAT胜肽的Poly（ethylene glycol） methyl ether-block-poly（lactide-co-glycolide），經由自組裝形成包覆光熱治療試劑IR780的奈米微胞─PPT@IR780。為了利用TAT的核標靶能力與避免因其非專一的穿膜效果造成正常細胞的攝取，因此在PPT@IR780上修飾succinic anhydride（SA），簡稱PPST/IR780。PPST/IR780之粒徑與表面電位分別為77.67±1.01 nm與 -11.3 mV。TEM影像顯示微胞分散性良好且粒徑均一，和DLS鑑定結果相符。以Fluorescamine assay測定TAT的鍵結效率及SA的修飾效率，分別為71.23%與85.3%。微胞在DI H2O、PBS與DMEM+10%CCS中展現良好的穩定性。而且於PBS環境下，24小時內的藥物洩漏量低於5%，微包內的IR780有80%以上吸收值沒有衰減，這說明微胞能穩定地包覆IR780並維持其光學活性。升溫效率測試證實micelle/IR780能經由雷射觸發升溫。另外，在初步的光熱治療實驗中micelle/IR780展現對腫瘤細胞的毒殺效果。在pH7.4環境下進行的細胞攝取實驗，驗證了（1）因修飾SA而降低TAT的穿膜能力，導致PPST/IR780比PPT/IR780有較低的攝取量 （2）經由PB （pH=5）前處理後，SA展現pH應答能力而脫落，回復TAT活性，進而使PPST/IR780和PPT/IR780有等量的細胞攝取。最後藉由DiI系統，給予細胞等量DiI的PPST/DiI與PPM/DiI攝取兩小時，再經過四小時作用後，以螢光顯微鏡觀察到PPST/DiI相較於PPM/DiI在細胞核有較高累積。綜合以上結果，PPST/IR780成功展現pH應答性，並具有能的對腫瘤進行核標靶光熱治療的潛力。

Combining nanocarriers and near infrared light for photothermal therapy could solve the difficulties in local hyperthermia, such as invasive procedure, non-uniform heating on tumor site and non-selectivity heating. Consequently, we developed the pH-responsive SATAT conjugated micelles via nuclear targeting for better photothermal therapy. （the nanocarriers were abbreviated in PPST/IR780） To take advantage of nuclear targeting and to prevent from non-specific penetrating, we modified TAT with succinic anhydride（SA） to make it respond to acidic pH. During blood circulation （pH 7.4） SA would inhibit nonspecific interactions of TAT, once inside the lysosomes（pH~5） SA would drop out from TAT. The unshielded TAT could help micelles escape from lysosomes and achieve nuclear targeting. Particle size and surface potential of PPST/IR780 were 77.67 nm and -11.3 mV, respectively. TEM images showed the micelles were dispersing and had uniform diameters, which was in accordance with DLS measurements. The TAT conjugation efficiency was 71.23% and SA modification efficiency was 85.3% by means of fluorescamine assay. The micelles displayed well stability in DI H2O, PBS and DMEM+10% CCS within 24-hour incubation. We found that the IR780 leakage percentage was less than 5% and only about 15% IR780 decayed in micelles after 24-hour PBS dispersing. Taken together, the micelles could not only stable encapsulate IR780 but also remain its activity. The heating efficiency test confirmed micelle/IR780 possesses heat generating triggered by laser. The preliminary in vitro experiment demonstrated the heat killing effect on cancer cells. Under pH 7.4 condition, PPST/IR780 had lower cellular uptake amount resulted from the inhibition of SA. After pretreated in pH5 PB, reactivated TAT would lead to PPST/IR780 had the same cellular uptake amount as PPT/IR780. Finally, we observed that PPST/DiI accumulated more than PPM/DiI in nucleus through fluorescence microscope. In summary, PPST/IR780 successfully demonstrated the pH-responsive ability and had the potential to be applied in nuclear targeting photothermal therapy.

摘要 1
目錄 4
圖目錄 7
表目錄 9
1. 緒論 10
1.1 前言 10
1.2研究背景與動機 10
第二章、文獻回顧 13
2.1 癌症治療近況 13
2.2癌症熱治療 13
2.2.1 癌症熱治療的生理機制 14
2.2.2 癌症熱治療的臨床應用 15
2.3 光熱治療 16
2.3.1光熱治療試劑-金屬奈米粒子 17
2.3.2光熱治療試劑-近紅外光染劑 19
2.4奈米載體傳遞系統 21
2.4.1 奈米載體 21
2.4.2奈米載體特性與優勢 23
2.5 奈米載體傳遞策略 24
2.5.1奈米載體的入胞機制 24
2.5.2主動標靶（active targeting） 26
2.5.3細胞胞器靶向（subcellular targeting） 30
2.5.4細胞核靶向 31
2.5.5細胞穿膜肽（cell penetrating peptides, CPPs）介導傳遞 33
第三章、載體製備與分析方法 39
3.1實驗材料 39
3.2載體製備與分析方法 40
3.2.1製備PLGA-PEG-TAT（PPT） 40
3.2.2微胞製備方法 40
3.2.3製備PPST/IR780 40
3.3基本物化性質分析 41
3.3.1 PLGA-PEG-TAT定性分析 41
3.3.2 PLGA-PEG-TAT定量分析 41
3.3.3 micelle/IR780粒徑大小、表面電位與穩定性測試 42
3.3.4 micelle/IR780光學性質分析 42
3.3.5 micelle/IR780型態與分散性分析 42
3.3.6 micelle/IR780之E.E、L.E與產率測定 42
3.3.7 micelle包覆IR780包覆穩定性測試 42
3.3.8 micelle/IR780光熱升溫性質測試 43
3.3.9 Succinic anhydride修飾效率分析 43
3.4藥物載體之體外細胞測試 43
3.4.1細胞培養 43
3.4.2細胞攝取藥物載體實驗 43
3.4.3藥物載體毒性實驗 44
3.4.4細胞攝取抑制劑毒性實驗 44
3.4.5 細胞攝取藥物載體機制探討 44
3.4.6 藥物載體光熱毒殺實驗 44
3.4.7 藥物載體經攝取後於細胞內之分布 45
第四章、實驗結果與討論 46
4.1 載體製備及物化特性分析 46
4.1.1 PLGA-PEG-TAT定性分析 46
4.1.2 PLGA-PEG-TAT定量分析 47
4.1.3 奈米微胞 （micelle）製備 47
4.1.4 Succinic anhydride 修飾效率測定 48
4.1.5 micelle/IR780粒徑大小、電位與分散性 49
4.1.6 micelle/IR780之光學特性分析 51
4.1.7 micelle/IR780之E.E、L.E與產率測定 52
4.1.8 micelle/IR780之光學穩定性測試 52
4.1.9 micelle/IR780穩定性測試 53
4.1.10 micelle包覆IR780包覆穩定性測試 55
4.1.11 micelle/IR780光熱升溫性質測試 55
4.2 體外細胞測試 57
4.2.1 TAT於微胞系統上活性確認實驗 57
4.2.2 細胞攝取機制探討 58
4.2.3 SA抑制TAT能力與pH應答性測試 61
4.2.4 初步光熱毒殺實驗 63
4.2.5 PPST/IR780攝取濃度調整實驗 64
4.2.6 藥物載體經攝取後於細胞內之分布 66
第五章、結論與未來展望 67
第六章、參考文獻 68

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