利用溫感型水膠材料以關節內注射的方式輸送抗發炎藥物槲皮素達到治療骨關節炎的目的

The Use of Thermo-Sensitive Hydrogel Methoxy-Poly (ethylene glycol)-Poly (ʟ-alanine)-ʟ-Lysine for Intra-Articular Delivery of Quercetin to Treat Osteoarthritis

丁立慈(Li-Tzu Ting)

指導教授 ： 朱一民

國立清華大學/工學院/化學工程學系/碩士(2018年)

摘要

骨關節炎是一種慢性退化的關節疾病，其所伴隨的疼痛感是患者行動不便的主要原因，然而目前的藥物治療方法，例如口服抗發炎藥或注射糖皮質激素、中樞鎮痛劑等，皆需要頻繁的投遞藥物，才能暫緩關節炎症狀，但也伴隨著顯著的副作用如腸胃不適、心血管疾病或使病患產生成癮性。而槲皮素為一種天然的生物性類黃酮，具有良好的抗氧化性、抗發炎作用與極高的生物相容性，因而在近期被廣泛的研究用來作為治療骨關節炎的藥物。在本研究中，我們設計了一種高生物相容性的溫度敏感型正電荷胺基酸水膠材料Methoxy-Poly (ethylene glycol)-Poly (ʟ-alanine)-ʟ-Lysine (簡稱mPAL)來包覆槲皮素，期望透過關節腔注射液態mPAL水膠材料，透過其溫度敏感性而在原位成膠。隨著水膠穩定降解，達到緩釋槲皮素的治療作用，不僅延長藥物滯留時間，也能減少投藥的頻率。研究透過核磁共振氫譜來鑑定所合成的共聚高分子結構，並且利用動態光散射儀、穿透式電子顯微鏡、掃描式電子顯微鏡、全反射傅立葉轉換紅外線光譜儀、流變儀等設備來觀測此水膠的成膠機制與膠體性質，再透過調整水膠藥物載體配方來達到較好的藥物包覆效果，同時也進行水膠載體的藥物釋放與生物毒性測試。初步的研究結果證實我們所合成的mPAL水膠材料搭配槲皮素的藥物載體配方是具有相當大的潛力來作為注射型的緩釋藥物劑型。

關鍵字

胺基酸水膠 ； 藥物控制釋放系統 ； 關節內注射 ； 骨關節炎 ； 槲皮素 ； 溫度敏感 ； 正電荷

並列摘要

Osteoarthritis is a chronic degenerative joint disease and one of the leading causes of disability. However, the recommended treatments, such as oral administrations of analgesics or intra-articular injections of corticosteroids can only provide temporary pain alleviation and are accompanied with undesirable side effects, such as gastrointestinal discomfort or cardiovascular diseases. Quercetin is a natural flavonoid with anti-inflammatory and anti-oxidative functions. Furthermore, owing to its minimal side effects, there are a growing number of studies performed on quercetin as treatments for osteoarthritis. In this study, a positively charged thermo-sensitive hydrogel, Methoxy-Poly (ethylene glycol)-Poly (ʟ-alanine)-ʟ-Lysine, abbreviated as mPAL, is synthesized sequentially by ring opening polymerization of a series of alanine-NCA and lysine-NCA initiated by amine-terminated mPEG. With the encapsulation of quercetin, we design a drug delivery system for intra-articular injection and expect this highly biocompatible and biodegradable peptide-based hydrogel could perform in situ gelation and stable drug release to enhance the efficiency of drug delivery. To examine the properties of mPAL copolymer, it was thoroughly analyzed by 1H NMR, FTIR, DLS, TEM, SEM, and rheometer. Additionally, examinations were also conducted on quercetin loaded mPAL hydrogel, which include the release profile of quercetin and the in vitro cytotoxicity test. Ultimately, the preliminary results indicate that mPAL copolymer could be a potential drug carrier for intra-articular injection in osteoarthritis treatment.

並列關鍵字

Peptide-based hydrogel ； Drug delivery system ； Intra-articular injection ； Osteoarthritis ； Quercetin ； Thermo-sensitive ； Positively charged

參考文獻

1. T. R. Hoare, D. S. Kohane, Hydrogels in drug delivery: Progress and challenges. Polymer, 2008. 49(8): p. 1993-2007.

2. E. Caló, V. V. Khutoryanskiy, Biomedical applications of hydrogels: A review of patents and commercial products. Eur Polym J., 2015. 65: p. 252-267.

3. J. L. Drury, D. J. Mooney, Hydrogels for tissue engineering: Scaffold design variables and applications. Biomaterials, 2003. 24(24): p. 4337-4351.

4. O. Wichterle, D. LÍM, Hydrophilic gels for biological use. Nature, 1960. 185: p. 117-118.

5. D. A. Gyles, L. D. Castro, J. O. C. Silva, M. Roseane, A review of the designs and prominent biomedical advances of natural and synthetic hydrogel formulations. Eur Polym J., 2017. 88: p. 373-392.