開發HDI-PF127/HA溫感性注射式水膠系統作為抗癌藥物載體之研究

Development of HDI-PF127/HA thermo-sensitive injectable hydrogel system for anti-cancer drug delivery

陳盈宇(Ying-Yu Chen)

指導教授 ： 王子威

國立清華大學/工學院/材料科學工程學系/碩士(2011年)

https://doi.org/10.6843/NTHU.2011.00342

摘要

注射式水膠是一種新穎的智慧型材料，在生理環境刺激下能由液態轉變為凝膠態。在藥物釋放應用領域，可用來作為藥物載體，藉由生理環境的變化控制藥物釋放的情形；在組織工程方面也可應用為生物支架材料，利用注射的方法將支架材料打入人體，達到減少手術傷口大小而降低患者術後其他併發症的可能性。因此，注射式水膠無論在藥物釋放或組織工程領域上，都具有極大的應用價值。Pluronic F127是一種可利用溫度來控制成膠性質的智慧型高分子，但受限於Pluronic F127所形成的水膠本身機械強度不佳，因而降低Pluronic F127水膠在工程上的應用性。而透明質酸是一種由雙醣類組成富含於細胞外間質的天然高分子，近年來由於其良好的生物相容性廣泛的被應用在美容、食品保健和醫藥等用途上。本研究的目的是希望利用Pluronic F127/HA製備出溫感性的水膠，並擁有較佳的機械穩定性與生物相容性，當作藥物釋放載體應用在癌症治療上。
實驗發現利用hexamethylene diisocyanate (HDI) 將Pluronic F127的高分子鏈跟鏈末端做連結，會使得Pluronic F127在成膠時所具有的微胞結構更加穩定，經由流變特性分析証實HDI-Pluronic F127 (HDI-PF127) 仍然具有隨溫度變化進行液態/凝膠態相轉換的能力而且其臨界成膠濃度約為5 % (w/w)左右，相較於Pluronic F127臨界成膠濃度需在15% (w/w)大為降低許多，可減少毒性產生。細胞毒性分析結果也顯示此複合水膠材料具有良好生物相容性。本研究除了探討此複合型溫感性水膠物理和化學特性之外，也實際利用此水膠包覆抗癌藥物，例如：Doxorubicin和Paclitaxol，觀察其在藥物包覆上的廣度並觀察其藥物釋放的情況作為癌症治療上的應用。結果顯示，此水膠包覆藥物系統，可達到緩慢釋放的效果，使抗癌藥物的釋放時間延長為一個月以上，並能有效的抑制乳癌細胞的增生。未來依據需要可藉由調整水膠的濃度大小控制其釋放速率。
總合整體實驗，於本研究中所製備的HDI-Pluronic F127/hyaluronic acid (HDI-PF127/HA) 水膠可在低溫維持液態，並藉由控制濃度使其能在接近人體體溫時形成凝膠態且具有生物相容性。此外，HDI-PF127/HA水膠具緩慢的降解速率，能夠將包覆的抗癌藥物維持長時間穩定釋放速率。未來此水膠可局部注射並侷限在需要治療的腫瘤位置，減少藥物毒性並達到緩慢釋放的抗癌治療效果。因此，此複合型溫感性水膠在藥物釋放與組織工程領域上具有相當應用潛力。

關鍵字

注射式水膠 ； 溫感性 ； Pluronic F127 ； 透明質酸 ； 藥物釋放載體

並列摘要

Injectable hydrogel is a novel smart material which can undergo sol-gel phase transition by the stimulation of physiological factors or environmental stimuli. In the field of pharmaceutics, it can be used as a drug carrier that can control the drug release rate by the alteration of physiological environment; in the field of tissue engineering, it can be applied as a scaffold that can be implanted into the defect site by the method of injection. Pluronic F127 is a smart polymer which has the property of sol-gel in transition response to temperature but was limited by the weak mechanical strength. Hyaluronic acid is a linear natural polymer composed of repeating disaccharides found in the extracellular matrix and broadly applied in the field of cosmetology, health food, and medicine. The purpose of this study is to develop a thermosensitive hydrogel composed of Pluronic F127 and hyaluronic acid with improved mechanical stability and biocompatibility as a controlled drug delivery carrier for cancer therapy.
The results showed that the introduction of hexamethylene diisocyanate (HDI) as the extender for Pluronic F127 polymer chains made the micelles more stable. Furthermore, HDI-Pluronic F127 still maintained sol-gel transition property with broader temperature range and the critical gelation concentration was also decreased. The cell viability test showed the HDI-Pluronic F127/ hyaluronic acid hydrogel had favorable biocompatibility. With appropriate physical and chemical properties of this thermosensitive hydrogel, anticancer drugs such as doxorubicin and paclitaxol were incorporated to investigate the drug release profile and anticancer treatment effect. The results showed that the slow controlled release of anticancer drugs can be achieved over one month and significantly inhibit the proliferation of human breast tumor cells. By adjusting the concentration of hydrogels, the release profile can also be manipulated if desired.
In brief, the HDI-Pluronic F127/hyaluronic acid composite hydrogel prepared in this study can maintain solution form at low temperature and become gelation as the temperature increase to body temperature. It was found that the hydrogel was biocompatible and had the slow release property for anticancer drugs. Therefore, the HDI-Pluronic F127/hyaluronic acid hydrogel has considerable potential applications in the field of controlled drug delivery in the future.

並列關鍵字

injectable hydrogel ； thermosensitive ； Pluronic F127 ； hyaluronic acid ； drug delivery carrier

參考文獻

1. Temenoff, J.S. and A.G. Mikos, Biomaterials: The Intersection of Biology and Materials Science. 2008.

2. Wichterle, O. and D. Lim, Hydrophilic Gels for Biological Use. Nature, 1960. 185(4706): p. 117-118.

3. Kuo, C.K. and P.X. Ma, Ionically crosslinked alginate hydrogels as scaffolds for tissue engineering: Part 1. Structure, gelation rate and mechanical properties. Biomaterials, 2001. 22(6): p. 511-521.

4. Kim, M.R. and T.G. Park, Temperature-responsive and degradable hyaluronic acid/Pluronic composite hydrogels for controlled release of human growth hormone. Journal of Controlled Release, 2002. 80(1-3): p. 69-77.

5. Jia, X., et al., Synthesis and Characterization of in Situ Cross-Linkable Hyaluronic Acid-Based Hydrogels with Potential Application for Vocal Fold Regeneration. Macromolecules, 2004. 37(9): p. 3239-3248.