結合PLGA與微流體晶片發展一套藥物包覆、輸送暨釋放系統

Abstract

本研究致力於發展一套藥物輸送及釋放系統，選用聚乳酸與乙醇酸之共聚物(PLGA)為素材並製成可攜帶疏水性藥物之藥球，以期達到保護藥物、藥物於人體內的長效、緩慢釋放及控制藥物釋放的目標，藉由加入海藻酸鈉(alginate)，使得藥球可同時攜帶多種藥物，具有藥物階段性釋放之功能。 本研究結合微流體操控技術及溶劑揮發法發展一種藥球製造方法，設計三種液珠式微流體晶片，生成尺寸可操控及高尺寸均勻度之液珠，並以溶劑揮發法去除液珠內的二氯甲烷而製成攜帶藥物的PLGA藥球，藥球尺寸約為34 μm，變異係數為6.39%，代表藥球尺寸均勻度非常高，藥球的尺寸可由PLGA的濃度及液珠尺寸調控。本研究選用薑黃素，包覆於PLGA藥球內，由於薑黃素於二氯甲烷內的溶解度低於PLGA，使得薑黃素在PLGA藥球內有分佈不均勻的現象；將薑黃素藥球與心肌細胞共同培養，薑黃素藥球與細胞不具排斥性，可藉由薑黃素藥球建立使用化療藥物時減少其心臟毒性與協同作用的藥物策略。除了藥球的尺寸之外，藥球的結構亦是一種操控藥物釋放的因子，本研究選用碳酸氫鈉作為致孔劑，利用碳酸氫鈉分解並產生二氧化碳氣體的特性而形成孔洞的結構，高濃度的碳酸氫鈉溶液所製成的多孔藥球，膨脹率較高且尺寸較大(100 μm)，孔洞的數量較多及孔洞尺寸也較高，形狀也趨向不規則，機械強度也較弱。以多孔藥球為基礎上，將海藻酸鈉填入藥球的孔洞內，除了可增強藥球的機械強度之外，可讓海藻酸鈉攜帶親水性藥物，讓藥球可同時攜帶兩類或多種類藥物。由於海藻酸鈉的降解速率高於PLGA，本研究使用油溶及水溶性染劑替代藥物並進行染劑釋放實驗，可知只有水溶性染劑在短時間內釋放，初步證明含有海藻酸鈉的PLGA藥球具有藥物階段性釋放的潛力。

In our study, a PLGA-based drug delivery system was developed. PLGA (Poly Lactic-co-Glycolic Acid) microsphere having the ability to carry hydrophobic drugs was fabricated to achieve the goals of protecting drugs, sustaining drug release and controlling drug release in vivo. Alginate, a hydrophilic polymer, was combined with PLGA microsphere to enhance its functions. Alginate-PLGA microsphere can simultaneously carry hydrophilic and hydrophobic drugs and release drugs in different stages. We combined droplet-based microfluidics and solvent evaporation to fabricate size-controllable and monodisperse PLGA microspheres. The mean diameter was 34 μm and coefficient of variance was 6.39%. Size of PLGA microsphere was regulated by concentration of PLGA and diameter of droplet produced by microfluidic device. We chose curcumin as the model drug, examining possibility of carrying hydrophobic drugs. Curcumin was successfully covered in PLGA microspheres. However, the difference of solubility between PLGA and curcumin caused the space distribution of curcumin in PLGA microsphere was non-uniform. We seeded H9c3 cells with curcumin-PLGA microspheres. The cells had a tendency to grow nearby the microspheres and exhibited no significant cytotoxity. On this basis, we could develop a strategy to decreased cardiotoxity induced by chemotherapeutic drugs and synergistic interaction of chemicals and curcumin-PLGA microsphere in cancer cells. In order to add a factor of influencing drug release in vivo, we chose sodium hydrocarbonate as porogen to make porous PLGA microsphere. The higher concentration of sodium hydrocoarbinate caused the higher expansion (100 μm) of porous PLGA microsphere and the numbers of pores and their size were also larger. Numbers and size could effectively control drug release rate. On the basis of porous microsphere, alginate was filled in the pores to form alginate-PLGA microsphere. Hydrophilic and hydrophobic dyes were replaced as drugs. Alginate-PLGA microsphere could simultaneously carry hydrophilic and hydrophobic dyes and had the ability to release hydrophilic dye (blue) in the first stage and hydrophobic dye (red) in the second stage. It proved that alginate-PLGA microsphere had potential to release the drugs in different stages.