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研究生:曾安安
研究生(外文):Ann-Shireen Chan
論文名稱:聚己內酯與聚麩胺酸團聯共聚物之合成與搭載阿黴素之奈米微胞對人類乳癌細胞之細胞毒性
論文名稱(外文):Synthesis of Poly(ε-caprolactone)-Poly(γ-glutamic acid)(PCL-PGA) Block Copolymer as Doxorubicin Nanomicellefor Human Breast Cancer Cells
指導教授:謝明發謝明發引用關係
指導教授(外文):Ming-Fa Hsieh
學位類別:碩士
校院名稱:中原大學
系所名稱:醫學工程研究所
學門:工程學門
學類:綜合工程學類
論文種類:學術論文
論文出版年:2009
畢業學年度:97
語文別:英文
論文頁數:184
中文關鍵詞:聚己內酯聚麩胺酸乳癌奈米粒子藥物釋放
外文關鍵詞:drug deliverypoly(γ-glutamic acid)breast cancernanoparticlepoly(ε-caprolactone)pH-dependent
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本研究中,以單甲基聚乙二醇-雙聚己內酯聚麩胺酸嵌段共聚合物搭
載抗癌藥物艾黴素餵食野生種人類乳癌細胞(MCF-7/wt)。聚麩胺酸為一生物
可分解且無毒性之高分子聚合物,與聚己內酯共聚合搭載疏水性抗癌藥物
艾黴素,以延長在血液中之半衰期。使用紅外線光譜儀、氫質子核磁共振
儀、示差掃描熱分析儀及動態散射粒徑儀鑑定聚己內酯聚麩胺酸化學結
構;以螢光探針DPH 觀察其微胞形成之行為。微胞的粒徑大小與聚合物組
成、溫度及酸鹼值有關,尺寸介於90 至200 奈米之間。隨著聚麩胺酸鏈長
增加,微胞尺寸隨之下降。相對於高酸鹼質的環境時,在低酸鹼質環境所
形成微胞的尺寸較大,其臨界微胞濃度為6.3 至10.7 重量百分比(63-107 毫
克/升)。單甲基聚乙二醇-雙聚己內酯聚麩胺酸微胞對藥物的承載量及承載
率分別為12.14% 與97.22%。體外細胞實驗結果顯示,單甲基聚乙二醇-
雙聚己內酯聚麩胺酸未搭載藥物之微胞濃度為50 毫克/毫升時並未造成
MCF-7/WT 細胞形態改變,而細胞存活率結果顯示未搭載藥物之微胞具有
極小的毒性。搭載艾黴素之微胞其半致死劑量為6.73 @g/mL,低於單純添
加艾黴素。其藥物釋放速率在酸鹼值為7.4 時高於酸鹼值為5.0 時。添加搭
載藥物微胞與MCF-7/WT 細胞培養後可由螢光顯微鏡發現,搭載藥物微胞
有聚集的現象,證明微胞在溶脢體的酸性環境中。在藥物擴散進入細胞內
之前,藥物累積於細胞質中。初步的動物實驗結果顯示注射雌激素並未影
響BALB/c nu mouse 之體重,但會促進其雌性性徵的表現。卵巢完全切除
IV
之老鼠其腫瘤成長速率在實驗初期不如未切除卵巢之老鼠;然而,完全切
除卵巢之老鼠其腫瘤成長速率會以倍數增加。組織學方面,H&E 染色結果
指出,位於卵巢完全切除老鼠之乳腺脂肪墊下方之細胞為乳癌腫瘤細胞。
本研究至此,成功的合成並分析單甲基聚乙二醇-雙聚己內酯聚麩胺酸共聚
物,並且完成細胞毒性測試。未來預期完成此共聚合物的應用。
In this paper, a poly(γ-glutamic acid)-poly(ε-caprolactone)-poly(γ-glutamic acid)
[PEG-(PCL-PGA)2] triblock copolymer was synthesized for the encapsulation of doxorubicin
(Dox) drug in the treatment of wild type (MCF-7/wt) human breast cancer cells. Because
γ-PGA is a natural food substance, it is non-toxic and readily biodegradable. This was
copolymerized with PCL to extend its lifetime when it is circulated in blood pool and to hold
the hydrophobic doxorubicin drug. The copolymer PEG-(PCL-PGA)2 was characterized using
fourier transform infrared spectroscopy (FTIR), 1H nuclear magnetic resonance (1H NMR),
differential scanning calorimetry (DSC) and dynamic light scattering (DLS). The copolymer
micelle diameters were found to be dependent on copolymer composition, pH and time. The
particle sizes ranged from 90-200 nm. As the length of the PGA increased, the size of the
micelles decreased. In contrast, as the length of the PCL increased, the size of the micelles
increased. The micelles formed larger particle sizes at low pH compared to high pH. Changes
in the turbidity of the solution which were not reflected as changes in the particle sizes
indicated possible pH-dependent morphological changes. The micelles formed at a critical
micelle concentration in the range of 6.3-10.7 wt% (63-107 mg/L) with DPH in methanol. In
vitro studies involved plasma stability, cytotoxicity of blank micelles, drug loading and
release, cytotoxicity of Dox-loaded micelles and fluorescence microscopy. It was found that
copolymers which had short length PGA and PCL chains proved to be stable in plasma.
Furthermore, the PEG-(PCL-PGA)2 copolymer micelles did not cause any significant
morphological changes in MCF-7/wt cells up to an amount of 0.50 mg of
PEG-(PCL10-PGA7.5)2. An MTT assay of PEG-(PCL5-PGA8)2 and PEG-(PCL5-PGA2.9)2
showed minimal cytotoxicity of the blank micelles and some degree of membrane disruption.
After drug loading, it was found that the DLC and DLE using PEG-(PCL5–PGA2.9)2 were
12.14% and 97.22% respectively. The cytotoxicity of Dox-loaded micelles against MCF-7/wt
cells was lower with an IC50 of 1.17 @g/mL, than free dox with an IC50 of 0.065 @g/mL. On
II
the other hand, the IC50 against MCF-7/Adr was 10 @g/mL and 1.11 @g/mL for Dox-loaded
micelles and free Dox, respectively. Drug release was higher at pH 7.4 than at pH 5 but the
overall, the system exhibited slow sustained release. Fluorescence microscopy of MCF-7/wt
cells incubated with Dox-loaded micelles showed that the micelles can aggregate, indicating
contact with the acidic environment of the lysosomes. The drug was also initially present in
the cytoplasm before becoming diffuse all throughout the cells. Lastly, preliminary studies in
vivo studies were done on a BALB/c nu mouse model showed that estradiol did not have any
significant effect on the weight of the mice but that it increased the manifestation of female
characteristics. Mice that were ovariectomized grew multiple tumors at a slower rate than
mice with intact ovaries. However, the mice that did not undergo overiectomization exhibited
a faster growth rate of tumor at the beginning of the study. Histological H and E staining
showed that the tumor grown on the lower mammary fat pad of overiectomized mouse is a
breast cancer tumor tissue. In conclusion, PEG-(PCL-PGA)2 amphiphilic copolymers were
synthesized, characterized and tested for cytotoxicity to target cells. Doxorubicin drug was
effectively encapsulated into the micelles. Further studies can be done to characterize the
conformational changes, in vivo characteristics and broader applications of this micelle
system.
Table of Contents
Abstract
摘要
Acknowledgments
List of Abbreviations
Table of Contents
List of Figures
List of Tables
List of Schemes

Chapter 1: Background and Motivation of the Study
Chapter 2: Review of Related Literature
2.1 An overview of cancer and chemotherapy
2.1.1 Cancer as a disease
2.1.2 Trends in the incidence and treatment of cancer
2.2. Types of breast cancer and breast cancer therapies
2.3. Drug resistance
2.3.1 Metabolic effects and growth factors
2.3.2 Multi-drug resistance gene and MDR effect
2.3.3 Strategies to overcome drug resistance effect
2.4. Doxorubicin
2.4.1 A chemotherapeutic drug
2.4.2 Dosage-related toxicity
2.5 Polymeric drug carriers for chemotherapy
2.5.1 General requirements of a polymeric drug carrier system
2.5.2 Nanoparticle drug carriers for chemotherapy
2.6 Poly(γ-glutamic acid) (PGA) as a material for drug carrier
2.6.1 Natural source and applications
2.6.2 Applications in drug delivery
2.7 Poly(ε-caprolactone) (PCL) as a material for drug carrier
2.7.1 Characteristics and applications
2.7.2 Applications for drug delivery
2.8 pH-controlled drug delivery systems
2.8.1 Physico-chemical characteristics of pH-controllable polymers
2.8.2 Micelle formation
2.8.3 Drug delivery applications
Chapter 3 Materials and Methods
3.1 Research structure
3.2 Materials
3.2.1 Equipment list
3.2.2 Reagents list
3.3 Hydrolysis of γ-PGA
3.4 Dilute solution viscometry
3.5 Synthesis and Activation of PEG-(PCL-OH)2
3.6 Conjugation of PCL to PGA
3.7 Solubility tests
3.8 Formation of copolymer nanoparticles
3.9 Measurement of Critical Micelle Concentration (CMC)
3.10 pH and time-dependent changes in particle size
3.11 Doxorubicin loading in PCL-PGA micelles
3.12 Cell culture of MCF-7/wt and MCF-7/Adr
3.13 Cytotoxicity of the PCL-PGA material to MCF-7/ wt
3.14 Inoculation of MCF-7/wt into BALB/c nu mice
Chapter 4 Results
4.1 Hydrolysis of NaPGA to HPGA
4.1.1 Physical appearance and solubility of HPGA
4.1.2 FTIR and 1H NMR
4.1.3 Dilute solution viscometry
4.2 Characterization of activated PEG-(PCL-OH)2: PEG-(PCL-COOH)2 and
PEG-(PCL-OSu)2
4.3 Characterization of PEG-(PCL-PGA)2 copolymer
4.3.1 Synthesis and structural analysis
4.3.2 Solubility of PEG-(PCL-PGA)2 copolymer
4.3.3 Thermal properties of the copolymer
4.4 Properties of the nanoparticles
4.4.1 Critical micelle concentration (CMC)
4.4.2 pH and time-dependent changes in particle size
4.4.3 Stability of micelles in rabbit plasma
4.5 In vitro cytotoxicity of PEG-(PCL-PGA)2 nanoparticles
4.6 Properties of the Dox-loaded nanoparticles
4.7 In vitro application of the Dox-loaded micelles
4.7.1 MTT assay of the Dox-loaded micelles
4.7.2 Cell morphology and Dox-loaded micelle uptake
4.8 Inoculation of MCF-7/wt into BALB/c nu mice
Chapter 5 Discussion
Chapter 6 Conclusion and Future Work
References

List of Figures
Figure 1 Annual Age-adjusted Cancer Incidence Rates* for Selected Cancers by Sex, United
States, 1975 to 2004.[1]
Figure 2 Mechanism of P-gp action (a) pump mechanism, (b) flippase mechanism [19] Figure 3 Doxorubicin and Daunorubicin
Figure 4 Release of adriamycin from PEG-Glu(Adr)-G4
Figure 5 Typical drug level vs. time profile. (a) Standard oral does; (b) oral overdose; (c) i.v. injection; (d) Controlled release ideal dose [31]
Figure 6 A schematic diagram of a nanoparticle with targeting ligands [35]
Figure 7 Enhanced Permeability and Retention effect
Figure 8 Stereochemically different γ-PGA
Figure 9 Morphological changes that occur with pH change for PEG-PLLA-PLGA [45]
Figure 10 Common methods of drug loading into micelles [60]
Figure 11 a) PEI–PBLG unimolecular micelle in a good solvent; b) Micelle in aqueous solution
Figure 12 Flower-like pH-sensitive micelles from PLA-b-PEG-b-poly(His)
Figure 13 Research structure
Figure 14 FTIR of salt form PGA (NaPGA) and different hydrolysis
Figure 15 1H NMR of HPGA 0.15meq base
Figure 16 Dilute solution viscometry of HPGA hydrolyzed with 0.15 meq base
Figure 17 Dilute solution viscometry of HPGA with 0.30 meq base
Figure 18 Dilute solution viscometry of HPGA hydrolyzed with 2.5 meq base
Figure 19 Effect of molar equivalent of base on hydrolysis of PGA
Figure 20 1H NMR of PEG-(PCL10-COOH)2
Figure 22 1H NMR of PEG-(PCL5-OSu)2
Figure 23 1H NMR of PEG-(PCL3.5-OSu)2
Figure 24 Comparison of a selected 1H NMR region for PEG-(PCL-OSu)2
Figure 25 FTIR of various PEG-(PCL-PGA)2 copolymers
Figure 26 FTIR of PEG-(PCL5-PGA8)2 in comparison with HPGA and PEG-(PCL5-OSu)2
Figure 27 FTIR of PEG-(PCL5-PGA2.9)2 in comparison with HPGA and PEG-(PCL5-OSu)2
Figure 28 1H NMR of PEG-(PCL10-PGA7.5)2 in d-DMSO
Figure 29 1H NMR of PEG-(PCL5-PGA2.9)2 in CDCl3
Figure 30 1H NMR of PEG-(PCL5-PGA8)2 in CDCl3
Figure 31 1H NMR of PEG-(PCL5-PGA2.9)2 in D2O
Figure 32 1H NMR of PEG-(PCL3.5-PGA8)2 in a) d-DMSO/Na2CO3 in D2O and b) d-DMSO
Figure 33 1H NMR of PEG-(PCL3.5-PGA2.9)2 in a) d-DMSO/Na2CO3 in D2O and b) d-DMSO
Figure 34 1H NMR of PEG-(PCL10-PGA7.5)2 in CDCl3 and d-DMSO co-solvent
Figure 351H NMR of PEG-(PCL5-PGA8)2 in CDCl3 and d-DMSO co-solvent
Figure 36 1H NMR of PEG-(PCL5-PGA2.9)2 in CDCl3 and d-DMSO co-solvent
Figure 37 Transmittance relative to blank for PEG-(PCL10-PGA7.5)2 in DMSO/chloroform co-solvent
Figure 38 Transmittance relative to blank for PEG-(PCL5-PGA2.9)2 in DMSO/chloroform co-solvent
Figure 39 Transmittance relative to blank for PEG-(PCL5-PGA8)2 in DMSO/chloroform co-solvent
Figure 40 Transmittance relative to blank for PEG-(PCL3.5-PGA8)2 in DMSO/chloroform co-solvent
Figure 41 Transmittance relative to blank for PEG-(PCL3.5-PGA2.9)2 in DMSO/chloroform co-solvent
Figure 42 (L-R) 2.9 kDa HPGA in chloroform, 8 kDa HPGA in chloroform, 2.9 kDa HPGA in DMSO and 8 kDa HPGA in DMSO
Figure 43 DSC secondary heating curve of HPGA
Figure 44 DSC secondary heating curves for PEG-(PCL-OSu)2 and PEG-(PCL-PGA)2
Figure 45 a) Before washing with water; b) after washing with water
Figure 46 (from top to bottom of each set) Cooling, first heating, and secondary heating curves of various PEG-(PCL-PGA)2 copolymers
Figure 47 Comparison of CMC measurements according to different methods
Figure 48 CMC measurement of PEG-(PCL10-PGA7.5)2
Figure 49 CMC measurement of PEG-(PCL5-PGA8)2
Figure 50 CMC measurement of PEG-(PCL3.5-PGA8)2
Figure 51 CMC measurement of PEG-(PCL5-PGA2.9)2
Figure 52 CMC measurement of PEG-(PCL3.5-PGA2.9)2
Figure 53 Particle sizes across various pH at 0-48 h for PEG-(PCL10-PGA7.5)2
Figure 54 Transmittance of aqueous solutions of PEG-(PCL10-PGA7.5)2 incubated in PBS with varying pH
Figure 55 Particle sizes across various pH at 0-48 h for PEG-(PCL5-PGA8)2
Figure 56 Transmittance of aqueous solutions of PEG-(PCL5-PGA8)2 incubated in PBS with varying pH
Figure 57 Particle sizes across various pH at 0-48 h for PEG-(PCL5-PGA2.9)2
Figure 58 Transmittance of aqueous solutions of PEG-(PCL5-PGA2.9)2 incubated in PBS with varying pH
Figure 59 Particle sizes across various pH at 0-48 h for PEG-(PCL3.5-PGA8)2
Figure 60 Transmittance of aqueous solutions of PEG-(PCL3.5-PGA8)2 incubated in PBS with varying pH
Figure 61 Particle sizes across various pH at 0-48 h for PEG-(PCL3.5-PGA2.9)2
Figure 62 Transmittance of aqueous solutions of PEG-(PCL3.5-PGA2.9)2 incubated in PBS with varying pH
Figure 63 Stability of various copolymer micelles in 10 % plasma with PBS over a 24 h observation period
Figure 64 Comparison of particle size of PEG-(PCL3.5-PGA8)2 in PBS at pH 5 (a) and at pH 6 (b) and in 10% plasma at 0 h (c) and 12 h (d); with the particle size of PEG-(PCL3.5-PGA2.9)2 in PBS at pH 5 (e) and at pH 7.4 and in 10% plasma at 0 h (g) and 24 h (h)
Figure 65 Microscopic images of MCF-7/wt cells after a 24-hour incubation time with
PEG-(PCL10-PGA7.5)2
Figure 66 Microscopic images of MCF-7/wt cells after 24-hour incubation with
PEG-(PCL10-PGA7.5)2 (from top left, amount per well) (a) 0.01 mg, (b) 0.10 mg, (c) 0.50 mg, (d) 1 mg
Figure 67 Cytotoxicity of blank PEG-(PCL5-PGA8)2 using MTT assay
Figure 68 Cytotoxicity of blank PEG-(PCL5-PGA2.9)2 using MTT assay
Figure 69 Drug release profile of Dox-loaded micelle from PEG-(PCL5-PGA2.9)2
Figure 70 Cytotoxicity of Dox-loaded micelles against MCF-7/wt cells with seeding density: 5x10^3
Figure 71 Cytotoxicity of Dox-loaded micelles against MCF-7/Adr with seeding density: 5x10^3
Figure 72 Cytotoxicity of free Dox and Dox-loaded micelles against MCF-7/wt and
MCF-7/Adr with seeding density: 1x10^3
Figure 73 Microscope images of MCF-7/wt at 48 h: a) control; b) blank
Figure 74 Microscope images of MCF-7/wt with Dox-loaded micelles at 2 days: (a,c and e) fluorescence image; (b,d and f) optical image
Figure 75 Microscope images of MCF-7/wt at 3 days control
Figure 76 Microscope images of MCF-7/wt at 3 days: a) blank fluorescence; b) blank optical microscope image; (c, e and g) fluorescent images with Dox-loaded micelles; (d, f and h) optical images with Dox-loaded micelles
Figure 77 Enlarged view of MCF-7/wt cells incubated with Dox-loaded micelle samples at 3 days
Figure 78 Microscope images of MCF-7/wt at 5 days: (a, c and e) fluorescent images with Dox-loaded micelles; (b, d and f) optical images with Dox-loaded micelles
Figure 79 Effects of estradiol on the weight of BALB/c nu mice
Figure 80 BALB/c nu mice 1 day after inoculation of MCF-7/wt cells
Figure 81 BALB/c nu mice 5 weeks after inoculation of MCF-7/wt cells
Figure 82 Tumor size in BALB/c nu mice inocculated with MCF-7/wt cells
Figure 83 H and E stain on tumor tissue harvested from ovariectomized BALB/c nu mouse
Figure 84 Proposed mechanism of Dox interaction with PEG-(PCL-PGA)2 micelles during change of pH

List of Tables
Table 1 Estimated Female Breast Cancer Cases and Deaths by Race/Ethnicity in the United States, 2006 [12]
Table 2 Sources and Characteristics of Natural γ-PGA [5]
Table 3 Specifications for the Synthesis of PCL
Table 4 Solubility Tests at concentration of 1 mg/mL
Table 5 FTIR peak values for HPGA
Table 6 1H NMR peak shifts and integration of hydrolyzed PGA
Table 7 Molecular weight of PGA determined by dilute solution viscometry
Table 8 1H NMR peak shifts and integration of PEG-(PCL10-COOH)2
Table 9 1H NMR peak shifts and integration for PEG-(PCL-OSu)2
Table 10 FTIR peaks of the PEG-(PCL-PGA)2 copolymer
Table 11 FTIR peaks of the PEG-(PCL5-PGA8)2 copolymer
Table 12 FTIR peaks of the PEG-(PCL5-PGA2.9)2 copolymer
Table 13 1H NMR peak shifts and integration for PEG-(PCL-PGA)2 in separate solvent systems
Table 14 Theoretical and Actual peak ratio of PGA:PCL
Table 15 1H NMR peak shifts and integration for PEG-(PCL-PGA)2
Table 16 Comparison of melting temperature (Tm) before and after conjugation
Table 17 CMC measurements of the copolymers in PBS
Table 18 Dox-loading Optimization Data
Table 19 IC50 from MTT of MCF-7/wt cells
Table 20 In vitro cytotoxicity of free Dox and Dox-loaded micelles against MCF-7/wt and MCF-7/Adr
Table 21 Comparison of CMC of various amphiphilic polymer systems
Table 22 Comparison of DLC for different systems
List of Schemes
Scheme 1 Mechanism of polymerization [46]
Scheme 2 Timeline of observation
Scheme 3 Synthesis of PEG-(PCL-PGA)2
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