分子疊層堆積於自組裝幾丁聚醣奈米載體應用於抗癌藥物釋放之研究

Abstract

本論文分為兩部份進行探討，第一部份是探討兩性分子其動態自組裝行為及不同參數對自組裝過程之影響，以本實驗室先前已研究出兩性幾丁聚醣(CHC)作為模型進行研究。首先探討載體濃度對其包覆藥物能力及緩慢釋放之效果的影響，再來，在不同參數下，例如：載體濃度、外界環境溫度等，研究在特定時間下兩性分子其動態自組裝過程。 而本論文第二部份為主要發展一種可長期釋放、低漏藥率之疏水性抗癌藥物之載體為目標。利用本實驗室先前已研究出具有生物相容性之兩性幾丁聚醣(CHC)作為藥物載體以包覆疏水性藥物喜樹鹼( Camptothecin, CPT )，然後運用層接層( layer-by-layer )技術在已形成自組裝奈米膠囊之CHC表面覆蓋上聚苯乙烯磺酸鈉 ( poly(sodium 4-styrene sulfonate ) , PSS )而利用靜電作用力以製備出層接層(layer-by-layer, LBL)自組裝奈米膠囊CHC@PSS。本奈米膠囊可藉由外層覆蓋上PSS以更有效控制藥物釋放速率，降低其漏藥率及一開始藥物釋放時Burst release現象，可增加藥物之有效使用率。層接層自組裝奈米膠囊經由電子顯微鏡之微觀觀察及DLS測量下，可發現在CHC表面覆蓋PSS前後其粒徑大小有所不同，以及Zeta potential測定得到其電性有所變化，進而證實PSS確實覆蓋於CHC之表面形成core-shell結構。然後，經由不同吸附比例以調控CHC@PSS其藥物釋放速率。而CHC@PSS與未進行表面覆蓋的CHC能更有效遲緩藥物釋放之速率，因此，適合作為攜帶疏水性藥物之載體，以達長期釋放之目的。

This study was divided into two main research directions. The first part of this study mainly investigated the dynamic of self-assembly of amphiphilic molecules. During this study, we used a novel, modified amphiphilic chitosan as model molecule. Chitosan has been demonstrated to be able to self-assemble well into a nanocapsule-structure due to hydrophobic interaction. Carboxy- methyl hexanoyl chitosan (CHC) was found to have varying self-assembly behavior at different concentration and temperature levels. Lastly, the in vitro release data of CHC nanocarriers revealed that such vector were able to control the CPT release in a precise manner under different study parameters. Second part of the study mainly focused on the preparation of a better and more efficient multilayer drug delivery vector. Poly- (sodium 4-styrene sulfonate) ( PSS) was used as the first shell material on the surface of CHC core. Coating of PSS onto CHC core was accomplished via electrostatic interaction, which formed a layer-by-layer (LBL) self-assembly nanocapsule (CHC@PSS). The addition of PSS shell would serve as a physical barrier to protect the drug and prolong drug release. The measurement of the zeta-potential indicated that the charge of the nanocarrier was changed from positive to negative and the size of it increased after coating PSS. Additional study of the CHC:PSS ratio on the nanocapsules and drug release rate revealed that CHC:PSS ratio could indeed manipulate the rate of drug release. In this thesis, we proved that CHC@PSS nanoparticles had significantly enhanced CPT retention rate when compared to CHC-only nanocarriers. It could therefore be concluded that the CHC@PSS device could potentially be an effective nanocarrier in high-efficient drug system for future clinical practices.