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

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研究生：	陳盈宇 Chen, Ying-Yu
論文名稱：	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
指導教授：	王子威 Wang, Tzu-Wei
口試委員:	孫瑞昇董國忠
學位類別：	碩士 Master
系所名稱：	工學院 - 材料科學工程學系 Materials Science and Engineering
論文出版年：	2011
畢業學年度：	100
語文別：	英文
論文頁數：	75
中文關鍵詞：	注射式水膠、溫感性、Pluronic F127 、透明質酸、藥物釋放載體
外文關鍵詞：	injectable hydrogel, thermosensitive, Pluronic F127, hyaluronic acid, drug delivery carrier
相關次數：	點閱：1 下載：0
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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。

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.

CONTENTS
ABSTRACT....................................................................................................................I
中文摘要......................................................................................................................III
CONTENTS..................................................................................................................V
FIGURE INDEX.........................................................................................................VII
TABLE INDEX............................................................................................................Ⅹ
CHAPTER 1  INTRODUCTION................................................................................1
1.1 Introduction of biomaterials.............................................................................1
1.2 Smart hydrogels................................................................................................4
1.2.1. Introduction of hydrogels.....................................................................4
        1.2.2. Temperature-sensitive hydrogels.........................................................5
        1.2.3. pH-sensitive hydrogels.........................................................................6
        1.2.4. Photo-sensitive hydrogels....................................................................7
        1.2.5. The rheological properties of hydrogels...............................................9
1.3. Pluronic block copolymer (PEO-PPO-PEO).................................................12
     1.3.1. The structure of Pluronic block copolymer........................................12
     1.3.2. Nomenclature of Pluronic block copolymer......................................13
     1.3.3. The gelation mechanism of Pluronic block copolymer in aqueous
 solutions.............................................................................................14
     1.3.4. The toxicity of Pluronic block copolymer..........................................16
1.4. Hyaluronic acid (HA)....................................................................................18
1.5. The purpose of this study..............................................................................20
CHAPTER 2  MATERIALS AND METHODS........................................................22
2.1. Experimental reagents and instruments.........................................................22
2.2. Synthesize hexamethylene diisocyanate -Pluronic F127(HDI-PF127)
          copolymer.....................................................................................................24
2.3. Hexamethylene diisocyanate -Pluronic F127/hyaluronic acid
 (HDI-PF127/HA) composite hydrogel...........................................................25
2.4. Characterization of HDI-PF127 copolymers.................................................26
2.4.1. Fourier transform infrared spectroscopy (FT-IR)..............................26
2.4.2. 1H NMR……......................................................................................26
2.4.3. Gel permeation chromatography (GPC)….........................................26
2.4.4. Transmission electron microscopy (TEM)….....................................26
2.4.5. Dynamic light scattering (DLS)…………….....................................27
2.4.6. The stability of micelles composed of Pluronic copolymers….........27
2.5. Characteristics of HDI-PF127/HA composite hydrogels………..................29
2.5.1. Sol-gel phase transition diagram…....................................................29
2.5.2. The evaluation of rheological behavior…..........................................29
2.5.3. Degradation in vitro….......................................................................29
2.5.4. In vitro biocompatibility test of HDI-PF127/HA composite
 hydrogels…........................................................................................31
2.6. Assessments of drug release in vitro and anti-tumor effect…......................34
2.6.1. In vitro release of bovine serum albumin (BSA)...............................34
2.6.2. In vitro release of doxorubicin...........................................................36
2.6.3. In vitro release of paclitaxol...............................................................37
2.6.4. Evaluation of the effect that inhibit the proliferation of tumor
cell......................................................................................................38
CHAPTER 3  RESULTS……………………….......................................................41
3.1. Characterization of HDI-PF127 copolymers.................................................41
3.2. Characteristics of HDI-PF127/HA composite hydrogels..............................50
3.3. Assessments of drug release in vitro and anti-tumor effect of
HDI-PF127/HA hydrogels…………………………………………….........58
CHAPTER 4  DISCUSSION.....................................................................................66
CHAPTER 5  CONCLUSION...................................................................................71
REFERENCE...............................................................................................................72

FIGURE INDEX
Figure 1-1 Polymer with lower critical solution temperature........................................5
Figure 1-2 Chemical formulas of polymers with thermosensitive property..................6
Figure 1-3 pH-dependent ionization of polyelectrolytes................................................7
Figure 1-4 Two mechanisms of photoinitiation (A) radical photopolymerization by photocleavage (B) Radical photopolymerization by hydrogen abstraction...................9
Figure 1-5 Typical stress response for different materials during oscillatory measurements..............................................................................................................10.
Figure 1-6 Equations representing the synthesis of the Pluronic copolymers and the structure of Pluronic copolymers.................................................................................13
Figure 1-7 The diagram of Pluronic grid......................................................................14
Figure 1-8 The gelation mechanism of Pluronic in aqueous solutions........................16
Figure 1-9 The chemical structure of hyaluronic acid.................................................19
Figure 1-10 Experimental flow chart...........................................................................21
Figure 2-1 Chain extension of Pluronic F127 with hexamethylene diisocyanate........24
Figure 2-2 The thermosensitive behavior of HDI-PF127/HA composite hydrogel. The solution form of HDI-PF127/HA at 4℃ (a) and the gel form at 37℃ (b).................. 25
Figure 2-3 The standard curve of D-glucuronic acid...................................................31
Figure 2-4 The mechanism of WST-1 assay................................................................32
Figure 2-5 The mechanism of LDH assay....................................................................33
Figure. 2-6 The diagram of reaction for Bradford assay..............................................35
Figure 2-7 The standard curve of bovine serum albumin............................................36
Figure 2-8 The standard curve of doxorubicin.............................................................37
Figure 2-9 The standard curve of paclitaxol................................................................38
Figure 2-10 The layout of experimental groups for evaluating the effect of drug released from hydrogels…………...............................................................................39
Figure 3-1 FT-IR spectra of (a) Pluronic F127 and (b) HDI-Pluronic F127................41
Figure 3-2 1H NMR spectra of (a) PF127 and (b) HDI-PF127 in CDCl3....................43
Figure 3-3 TEM images of PF127 (a) x35000 (b) x60000 (c) x100000 (d) x125000 and HDI-PF127 (e) x35000 (f) x60000 (g) x100000 (h) x125000...............................45
Figure 3-4 Micellar size distribution of (a) PF127 and (b) HDI-PF127......................46
Figure 3-5 The fluorescence spectrums of DPH with different (a) PF127 and
(b) HDI-PF127 concentration.......................................................................................48
Figure 3-6 The absorbance of DPH which was incorporated into PF127 and HDI-PF127 with different temperature........................................................................49
Figure 3-7 The sol-gel phase transition diagram of PF127 and HDI-PF127/HA........51
Figure 3-8 The storage modulus (G’) and loss modulus (G’’) of the (a) 20% PF127 and (b) 20%/0.5% (c) 15%/0.5% (d) 10%/0.5% and (e) 5%/0.5% HDI-PF127/HA hydrogels in PBS..........................................................................................................54
Figure 3-9 The diagram of strain versus G’ value........................................................55
Figure 3-10 Degradation of 16 wt % PF127 and HDI-PF127/HA composite hydrogels in PBS at 37℃ (n=3, HDI-PF127/HA-1: 7.5% HDI-PF127 and 0.5% HA; HDI-PF127-2: 10% HDI-PF127 and 0.5% HA)..........................................................56
Figure 3-11 The evaluation of cell viability by WST-1 assay (n=3)............................57
Figure 3-12 The evaluation of cell toxicity by LDH assay (n=3) ...............................57
Figure 3-13 Release profile of BSA from HDI-PF127/HA composite hydrogels in PBS at 37℃ (n=3)…………………………………………………............................58
Figure 3-14 Release profile of (a) DOX and (b) PTX from HDI-PF127/HA composite
hydrogels in PBS at 37℃ (n=3)………………...........................................................60
Figure 3-15 The evaluation of inhibition of cell proliferation by WST-1 assay (n=3)..……………………………...............................................................................61
Figure 3-16 The evaluation of inhibition of cell proliferation by LDH assay (n=3,* p < 0.05) …………………………….................................................................................61
Figure 3-17 OM images of the cell morphology and numbers of MCF-7 cultured with and without DOX for 1, 3 and 7 days. (a), (c), (e): MCF-7 cultured on dish for 1, 3 and 7 days, respectively. (b), (d), (f): MCF-7 cultured with HDI-PF127/HA hydrogel containing DOX for 1, 3 and 7 days, respectively…………………….......................63
Figure 3-18 The images of LIVE&DEAD. (a), (b), (c): MCF-7 cultured on dish for 1, 3 and 7 days, respectively. (d), (e), (f): MCF-7 cultured with HDI-PF127/HA hydrogel containing DOX for 1, 3 and 7 days, respectively.......................................................65
Figure 4-1 The hypothesized schematic diagram for intermicellar interaction of PF127 and HDI-PF127 copolymers…………………………………………….....................67
Figure 4-2 The hypothesis of HDI-PF127/HA hydrogel with different HDI-PF127 concentration endure the deformation………………..................................................69

TABLE INDEX
Table 1-1 Metals commonly used in biomedical applications………………...............2
Table 1-2 Ceramics commonly used in biomedical applications………………...........2
Table 1-3 Synthetic and naturally derived polymer commonly used in biomedical applications……………….............................................................................................3
Table 2-1 The formulations of HDI-PF127/HA composite hydrogels……………….25
Table 3-1 Molecular characteristics of triblock copolymer PF127 and the multiblock copolymers………………...........................................................................................44
Table 3-2 Average diameter of (a) PF127 and (b) HDI-PF127 by DLS.......................47

                                

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