有機修飾二氧化矽凝膠體作為疏水性藥物載體的研究

Abstract

本論文主要發展一種生物可降解的多孔性二氧化矽凝膠體(xerogel)，經由有機分子部份修飾，調整二氧化矽凝膠體親水性的特性，可作為包覆水難溶藥物的載體。此有機修飾凝膠體可藉由製程參數的調控，進一步改變凝膠體微結構，達到藥物控制釋放的目的。甘油的添加，形成二氧化矽網狀間含有甘油分子鏈段的混成結構，會加速縮合反應進行，導致凝膠體孔隙度提高。IBU藥物包覆效率隨甘油提高而大幅提升，導因於甘油分子與藥物間形成多個氫鍵，可有效將藥物攜載於載體中。調控不同有機甘油的比例，可得到多樣的微結構，進一步造成藥物釋放行為的不同。另外，調控溶凝膠過程的化學環境，由於直接影響水解縮合反應，故對結構亦產生很大的影響，pH=2時為溶凝膠反應等電位點，整個反應過程較完全，加上甘油的修飾作用，形成最大孔隙結構，孔隙度高達44%，藥物釋放速率相對較快。因此，利用不同甘油添加量與製程化學環境的調控，可有效操控藥物釋放速率。 第二部份導入有機二甲基亞楓(DMSO)，成功發展出一種親水性的凝膠載體，內含許多充滿DMSO溶劑的微孔隙，這些疏水性微孔結構，將有效攜載難溶於水的抗癌藥物小紅莓(DOX)。且由於DMSO會影響溶凝膠反應過程，故導致凝膠體結構發生改變，也改變藥物的釋放行為，結果顯示隨DMSO添加量的增加，藥物釋放量越多。此實驗結果將有助於二氧化矽凝膠體應用在包覆疏水性藥物的研究上，並可以達到控制釋放的目的，以提高其應用性。

Biocompatible and biodegradable nano-hybrids are becoming increasingly important as drug-loaded implants and drug-eluting coatings for biomedical devices. The key successful point of the drug-loaded implantable devices for biomedical application is not only the sufficient encapsulation efficiency for clinical use, but also the controlled release of bioactive agents to exert therapeutic effect. However, the surface of silica xerogel exhibits a hydrophilic character which is unfavorable for the encapsulation of hydrophobic agents. On this basis, a novel organically modified SiO2/glycerol hybrid with biodegradable nature was successfully fabricated and employed as a vehicle to encapsulate amphiphilic bioactive agent, i.e., ibuprofen (IBU). The IBU loading efficiency and release behaviors from the novel SiO2/glycerol hybrid was investigated in terms of glycerol content and the pH value in the synthetic process. Preliminary results showed that both two synthetic parameters significantly affected the porosity, pore size and micro-environment of the nanostructure of the SiO2/glycerol hybrid. Subsequently, drug encapsulation efficiency and release behaviors were altered. Moreover, the glycerol reacted with SiO2 to form SiO2-glycerol complex demonstrating a weakly cross-linked structure, which significantly altered the nanostructure and subsequent drug release behaviors of the modified SiO2 xerogel. A novel chemically modified SiO2/glycerol/DMSO nano-hybrid was successful synthesized by incorporating various content of DMSO in the sol-gel process, and proposed to encapsulate a partially hydrophobic anti-tumor drug, such as doxorubicin (DOX). The DOX encapsulation efficiency of the hybrid xerogel was higher than that of pristine SiO2 xerogel. In addition, the polar aprotic solvent, DMSO significantly affected the nanostructure of the SiO2/glycerol/DMSO nano-hybrid, resulting in various drug release behaviors. Interestingly, the SiO2/glycerol/DMSO nano-hybrid demonstrated a flexible characteristic which is suitable for the drug-eluted coating employed for stent. These results demonstrate that the newly organically modified SiO2 xerogel showed an enhanced encapsulation efficiency of hydrophobic agents, and a variety of drug controlled release behaviors.