可注射式幾丁聚醣奈米凝膠用於藥物傳輸之研究

Abstract

在此研究中，成功的藉由改質過後的兩性幾丁聚醣高分子合成出具有注射性功能的奈米凝膠。此幾丁聚醣凝膠可經由周遭溫度的改變，而進行sol-to-gel的轉變，4-10 oC下為可流動的液體，當溫度提升到37 oC時，轉變成不可流動的固體，達到可注射的功能。兩性幾丁聚醣高分子在水溶液的環境下會自組裝 (self-assemble) 成為奈米級的膠囊，可作為包覆藥物的藥物載體。在結構分析上，由穿隧電子顯微鏡(TEM)中觀察到，此凝膠具有獨特的多孔洞結構，並在水溶液中會緩慢散布出奈米級的微胞。此外，此凝膠只需加入1 %以上的幾丁聚醣高分子就可具有溫度敏感的特性，因此凝膠內部大部份是由液態所組成，可攜帶大量的藥物。在藥物釋放的探討上，採用抗癲癇藥物 (ESM，親/疏水兩性藥物) 及大腸癌用藥 (CPT，疏水性藥物) 做為模擬藥物，發現此奈米凝膠具有兩階段式的藥物釋放。第一階段是幾丁聚醣膠囊間隙之藥物會先釋放，接著才是包覆於膠囊內部的藥物。此發現可表示在未可將兩種藥物結合應用於單一個奈米凝膠載體上，在同一載體上載入並釋放兩種不同的藥物。作為一醫療材料應具有良好的生物相容性，因此，可注射凝膠也進行了細胞毒性檢測，在本研究中所採用的是表皮細胞(ARPE-19)，結果驗證了此凝膠具有良好的細胞存活率，並在in vitro實驗中進一步的探討與評估。一種具有良好的生物相容性、可進行溫敏型sol-to-gel且可攜帶親/疏水性藥物的可注射式奈米凝膠材料成功的被製作出，並做為一種新穎的藥物傳輸載體。

A novel colloidal injectable nanogel was successfully prepared based on an amphiphilically-modified chitosan prepared previously in this lab, which underwent a thermally-induced sol-to-gel transition upon a temperature change from ambient to physiological environment. Amphiphilic nature of the modified chitosan rendered subsequent self-assembly forming nanocapsules in aqueous solutions. Gelation occurred even with less than 1% nanocapsules upon a change in temperature over reasonable time duration, forming a solid-gel entity in situ. A subsequent application to carry drugs of various degree toward water affinity (from water soluble, ethosuximide (ESM), to water insoluble, CPT), following a controlled drug release in vitro has been systematically investigated. The experimental results indicated a long-term, sustained release profile for both types of drugs were monitored and release kinetics suggested a two-stage profile, suggesting a bimodal release pattern, and has been confirmed to be a result of drug distribution, i.e, within the nanocapsules and inter-capsule regions. This finding implies a dual drug release capability can be designed and fulfilled simultaneously using current nanogel system. Biocompatibility, Sol-to-gel transition, nanostructure, and biocompatibility of the nanogel were characterized, and was considered as a novel water-borne drug delivery system.