本研究使用聚乙二醇與左旋-丙交酯以開環聚合法合成聚乳酸-聚乙二醇-聚乳酸(poly(L-lactide)-poly(ethylene glycol)-poly(L-lactide))(PLLA-PEG-PLLA)三團聯共聚物。將共聚物中的親水鏈段PEG聚合度固定為91，再利用凝膠滲透層析儀(GPC)對共聚物進行分子量的分析，計算出疏水段PLLA聚合度為20、40和75。
使用翻轉試管法測量各共聚物之臨界成膠濃度與溶體-沉澱相變化溫度，發現當共聚物疏水鏈段聚合度上升時，共聚物有利於形成凝膠相以及進行溶體-沉澱相變化。利用流變法測量共聚物在不同濃度下之凝膠-溶體相變化溫度，發現當共聚物濃度上升時，不利於凝膠-溶體相變化。以Flory-Huggins均場理論模型建立相界線並預測相圖，發現無法預測出共聚物水溶液在高溫時的沉澱相，且相界線隨疏水鏈段聚合度上升而向左偏移，臨界點之共聚物與水交互作用參數隨疏水鏈段聚合度的上升，由熵控制轉變為焓控制。由於兩親團聯共聚物會在選擇性溶劑中產生微胞，因此利用螢光探針法測量臨界微胞濃度並計算微胞化自由能，發現隨著疏水鏈段聚合度上升，有利於共聚物微胞之形成。
利用動態光散射法得知共聚物水溶液在趨近無限稀薄濃度時，隨疏水鏈段聚合度上升，相關長度上升，動態相關延遲時間上升，示蹤擴散係數下降。在稀薄濃度與半稀薄濃度時，相關長度隨共聚物濃度上升而上升，與均聚物之相關長度隨濃度上升而下降對比有顯著的差異，推論本實驗之共聚物產生微結構，親水鏈段與疏水鏈段間之排斥力對共聚物與水的交互作用造成了遮蔽的效果。在半稀薄濃度下，利用相關長度對溫度、疏水鏈段聚合度以及濃度之關係計算微胞聚集焓，發現隨疏水鏈段聚合度上升，有利於微胞聚集，且微胞聚集焓小於凝膠-溶體相變化焓，凝膠-溶體相變化焓又小於溶體-沉澱相變化焓，了解共聚物分子在各相變化過程之焓變化。在稀薄濃度與半稀薄濃度時，隨共聚物濃度上升，動態相關延遲時間上升、合作擴散係數下降，與均聚物之合作擴散係數隨濃度上升而上升對比，具有顯著的差異，推論是由於高分子-溶劑間作用力與高分子-溶劑間摩擦力之相對大小不同導致，但隨濃度上升至濃(concentrated)範圍後，共聚物之合作擴散係數隨濃度上升而上升，與均聚物之趨勢相同。發現濃溶液隨溫度上升，相關長度下降，但到了高溫下相關長度反而開始上升，推測是發生了沉澱相變化所導致，最後由濃溶液之相關長度隨濃度與溫度的變化，推測相圖中不同區域之相結構。

In this study, polyethylene glycol and L-lactide were used to synthesize poly(L-lactide)-poly(ethylene glycol)-poly(L-lactide) (PLLA-PEG-PLLA) triblock copolymers by ring-opening polymerization. The degree of polymerization of the hydrophilic segment PEG was fixed at 91. The molecular weight of the copolymers was analyzed by gel permeation chromatography (GPC), and the degree of polymerization of the hydrophobic segment PLLA was calculated to be 20, 40, and 75, respectively.
The critical gelation concentration and the solution-precipitation phase transition temperature of each copolymer were measured by tube-inverting method. It was found that the copolymers favored the formation of a gel phase and possessed for solution-precipitation phase transition when the degree of polymerization of the hydrophobic segment of the copolymer increased. The rheological measurement was used to find the gel-solution phase transition temperature of the copolymers of different concentrations. It was found that copolymer solution was not conducive to the gel to solution phase change when the copolymer concentration was increased. The phase boundary in phase diagram was predicted by the Flory-Huggins mean-field theory. However, the precipitate phase of the copolymers in aqueous solutions at a high temperature could not be predicted. The phase boundary was shifted to the left as the degree of polymerization of the hydrophobic segment increased, and the Flory-Huggins interaction parameter at the critical point between copolymer and water changed from entropy control to enthalpy control as the degree of polymerization of the hydrophobic segment increased. The amphiphilic copolymer formed micelle in a selective solvent. Thus, the critical micelle concentration could be measured by the fluorescent probe and the Gibbs free energy of micellization was calculated. It was found that the copolymers favored the formation of the micelle when the degree of polymerization of the hydrophobic segment of the copolymer increased.
The dynamic light scattering was used to find that in the aqueous solutions of the copolymers at the infinitely dilute concentration, as the degree of polymerization of the hydrophobic segment increased, the correlation length increased, the dynamic correlation delay time increased, and the tracer diffusion coefficient decreased. In dilute and semi-dilute solutions, the correlation length increased as the copolymer concentration increased, whereas oppositely the correlation length decreased as the homopolymer concentration increased. There was a significant difference between the copolymer and the homopolymer. We inferred that triblock copolymer produced the microstructure, and the repulsive force between the hydrophobic segments and the hydrophobic segments caused a shielding effect on copolymer-water interaction. At semi-dilute concentrations, the dependencies of correlation length upon temperature, degree of polymerization of the hydrophobic segment, and concentration were used to calculate the enthalpy of micelle aggregation. It was found that with the degree of polymerization of the hydrophobic segment increased, micelles were conducive to the aggregation. We found the enthalpy of micelle aggregation was smaller than that of gel-solution phase transition, and the enthalpy of gel-solution phase transition was smaller than that of solution-precipitation phase transition. Thus we knew the enthalpy changes of the copolymer molecules during the course of each phase transition. In dilute and semi-dilute solutions, as the concentration increased, the dynamic correlation delay time increased, and the cooperative diffusion coefficient decreased, whereas the cooperative diffusion coefficient of the homopolymer increased with the increase of the concentration. We concluded that this was due to the difference in the relative force between the polymer-solvent thermodynamic interaction and the polymer-solvent friction. However, as the concentration rose to concentrated regime, the cooperative diffusion coefficient of the copolymer increased with increasing concentration, which exhibited the same tendency as the homopolymer. It was also found that the correlation length of the concentrated solutions decreased with temperature, but the correlation length began to rise at higher temperatures, which was supposed to be caused by the sol-precipitation phase transition. Finally, the phase structures of various regions in the phase diagram was inferred from the change of the correlation length with the concentration and temperature in concentrated solutions.

1. L. Yang, Z. Zhao, J. Wei, A. Ghzaoui and S. Li, Micelles formed by self-assembling of polylactide/poly(ethylene glycol) block copolymers in aqueous solutions. Journal of Colloid and Interface Science 314, 470 (2007).

2. A.Vila, A.Sanchez, C. Pérez and M. J. Alonso, PLA‐PEG nanospheres: new carriers for transmucosal delivery of proteins and plasmid DNA. Polymers for Advanced Technologies 13, 851 (2002).

3. M. L. Adams, A.Lavasanifar and G. S. Kwon, Amphiphilic block copolymers for drug delivery. Journal of Pharmaceutical Sciences 92, 1343 (2003).

4. S. Lee, K. Na and Y. H. Bae, Polymeric micelle for tumor pH and folate-mediated targeting. Journal of Controlled Release 91, 103 (2003)

5. Z. Chao, L. Liqiong and G. Shaoqin, Microwave-assisted synthesis of PLLA-PEG-PLLA triblock copolymers. Macromolecular Rapid Communications 28, 422 (2007)

6. T. Riley, S.Stolnik, C. R. Heald, C. D. Xiong, M. C. Garrnett, L. Illum and S. S. Davis, Physicochemical evaluation of nanoparticles assembled from poly(lactic acid)−poly(ethylene glycol) (PLA−PEG) block copolymers as drug delivery vehicles. Langmuir 17, 3168 (2001).

7. S. Hagan, A.Coombes, M. C. Garnett, S.E. Dunn, M. C. Davies, L. Illum and S. S. Davis, Polylactide-poly (ethylene glycol) copolymers as drug delivery systems. 1. characterization of water dispersible micelle-forming systems. Langmuir 12, 2153 (1996).

8. K. S. Ho1 and M. S. Shoichet, Design considerations of polymeric nanoparticle micelles for chemotherapeutic delivery. Current Opinion in Chemical Engineering 2, 53 (2013)

9. S. Li and M. Vert, Synthesis, characterization and stereocomplex-induced gelation of block copolymers prepared by ring-opening polymerization of L(D)-lactide in the presence of poly (ethylene glycol). Macromolecules 36, 8008 (2003).

10. M. J. Rosen, Surfactants and interfacial phenomena, John Wiley & Sons, Inc., New York, Chapter 3 (2004).

11. L. Zhao, M. A. Winnik, G. Riess and M. D. Croucher, Fluorescence probe techniques used to study micelle formation in water-soluble block copolymers. Langmuir 6, 514 (1990).

12. Z. Gao and A. Eisenberg, A model of micellization for block copolymers in solutions. Macromolecules 26, 7353 (1993).

13. K. Kalyanasundaram and J. Thomas, Environmental effects on vibronic band intensities in pyrene monomer fluorescence and their application in studies of micellar systems. Journal of the American Chemical Society 99, 2039 (1977).

14. M. Wilhelm, C. L. Zhao, Y. Wang, R. Xu and M. A. Winnik, Poly(styrene-ethylene oxide) block copolymer micelle formation in water: a fluorescence probe study. Macromolecules 24, 1033 (1991).

15. H. Arimura, Y. Ohya and T. Ouchi, Formation of core−shell type biodegradable polymeric micelles from amphiphilic poly(aspartic acid)-block-polylactide diblock copolymer. Biomacromolecules 6, 720 (2005)

16. E. Raspaud, D. Lairez and M. Adam, Triblock copolymers in a selective solvent. 1. aggregation process in dilute solution. Macromolecules 27, 2956 (1994)

17. U. Zettl, S. Hoffmann, F. Koberling, G. Krausch, J. Enderlein, L.Harnau and M. Ballauff, Self-diffusion and cooperative diffusion in semidilute polymer solutions as measured by fluorescence correlation spectroscopy. Macromolecules 42, 9537 (2009)

18. P. Vidakovic, C. Allain and F. Rondelez, Dynamic correlation length in polymer solutions at the theta temperature. Journal de Physique Lettres 42, 323 (1981)

19. W. Brown and K. Mortensen, Comparison of correlation lengths in semidilute polystyrene solutions in good solvents by quasi-elastic light scattering and small-angle neutron scattering. Macromolecules 21, 420 (1988)

20. K. Mortensen, W. Brown and B. Nordén, Inverse melting transition and evidence of three-dimensional cubatic structure in a block-copolymer micellar system. Physical Review Letters 68, 2340 (1992)

21. M. J. Song, D. S. Lee, J. H. Ahn, D. J. Kim and S. C. Kim, Thermosensitive sol-gel transition behaviors of poly(ethylene oxide)/aliphatic polyester/poly (ethylene oxide) aqueous solutions. Journal of Polymer Science Part A: Polymer Chemistry 42, 772 (2004)

22. S. J. Bae, J. M. Suh, Y. S. Sohn, Y. H. Bae, S. W. Kim and B. Jeong, Thermogelling poly(caprolactone-b-ethylene glycol-b-caprolactone) aqueous solutions. Macromolecules 38, 5260 (2005)

23. S. Lee, M. S. Shim, S. W. Kim, H. Lee, I. Park and T. Y. Chang, Novel thermoreversible gelation of biodegradable PLGA-block-PEO-block-PLGA triblock copolymers in aqueous solution. Macromolecular Rapid Communications 22, 587 (2001)

24. S. J. Lee, B. R. Han, S. Y. Park, D. K. Han and S. C. Kim, Sol-gel transition behavior of biodegradable three-arm and four-arm star-shaped PLGA-PEG block copolymer aqueous solution. Journal of Polymer Science Part A: Polymer Chemistry 44, 888 (2006)

25. J. Byeongmoon, L. D. Sung, S. Jeong-In, B. Y. Han and K. S. Wan, Thermoreversible gelation of poly(ethylene oxide) biodegradable polyester block copolymers. Journal of Polymer Science Part A: Polymer Chemistry 37, 751 (1999)

26. M. S. Kim, H. Hyun, K. S. Seo, Y. H. Cho, J. W. Lee, C. R. Lee, G. Khang and H. B. Lee, Preparation and characterization of MPEG-PCL diblock copolymers with thermo-responsive sol-gel-sol phase transition. Journal of Polymer Science Part A: Polymer Chemistry 44, 5413 (2006)

27. Chenite, C. Chaput, D. Wang, C. Combes, M. D. Buschmann, C. D. Hoemann, J. C. Leroux, B. L. Atkinson, F. Binette and A. Selmani, Novel injectable neutral solutions of chitosan form biodegradable gels in situ. Biomaterials 21, 2155 (2000)

28. M. Malmsten and B. Lindman, Self-assembly in aqueous block copolymer solutions. Macromolecules 25, 5440 (1992)

29. B. Jeong, Y. H. Bae and S. W. Kim, Thermoreversible gelation of PEG−PLGA−PEG triblock copolymer aqueous solutions. Macromolecules 32, 7064 (1999)

30. S. Li, A. E. Ghzaoui, H. Nouailhas and R. Zhuo, Synthesis and gelation properties of PEG-PLA-PEG triblock copolymers obtained by coupling monohydroxylated PEG-PLA with adipoyl chloride. Langmuir 23, 2778 (2007)

31. G. Wanka, H. Hoffmann and W. Ulbricht, Phase diagrams and aggregation behavior of poly(oxyethylene)-poly(oxypropylene)-poly(oxyethylene) triblock copolymers in aqueous solutions. Macromolecules 27, 4145 (1994)

32. R. Shultz and P. J. Flory, Phase equilibria in polymer—solvent systems. Journal of the American Chemical Society 74, 4760 (1952)

33. M. L. Huggins, Solutions of long chain compounds. The Journal of Chemical Physics 9, 440 (1941)

34. C. Qian, S. J. Mumby and B. E. Eichinger, Phase diagrams of binary polymer solutions and blends. Macromolecules 24, 1655 (1991)

35. M. Taylor, P. Tomlins and T. Sahota, Thermoresponsive gels. Gels 3, 4 (2017)

36. 李賢哲, 聚乙二醇單甲醚/左左旋聚乳酸兩性雙團聯共聚物在水中相圖測定：力學與動態光散射方法及Flory-Huggins均場理論的模型, 台灣科技大學碩士論文, 第17、21頁 (2018)

37. B. Jeong, M. R. Kibbey, J. C. Birnbaum, Y.-Y. Won and A. Gutowska, Thermogelling biodegradable polymers with hydrophilic backbones:  PEG-g-PLGA. Macromolecules 33, 8317 (2000)

38. S. Hocine and M. Li, Thermoresponsive self-assembled polymer colloids in wate. Soft Matter 9, 5839 (2013)

39. P. C. Hiemenz and T. P. Lodge, Polymer chemistry second edition, CRC Press, Inc., Boca Raton, Chapter 6 and 7 (2007)

40. M. R. Munch and A. P. Gast, Block copolymers at interface. 1. micelle formation. Macromolecules 21, 1360 (1988)

41. L. Leibler, H. Orland and J.C. Wheeler, Theory of critical micelle concentration for solutions of block copolymers. J. Chem. Phys. 79, 3550 (1983)

42. P. G. de Gennes, Conformations of polymers attached to an interface. Macromolecules 13, 1069 (1980)

43. N. P. Balsara, M. Tirrell and T. P. Lodge, Micelle formation of BAB triblock copolymers in solvents that preferentially dissolve the A block. Macromolecules 24, 1975 (1991)

44. S. Forster, M. Zisenis, E Wenz and M Antonietti, Micellization of strongly segregated block copolymers. J. Chem. Phys. 104, 9956 (1996)

45. 曾駿憲, 聚醚-聚乳酸雙團聯共聚物和四氧化三鐵奈米粒子在水溶液中的共組裝, 台灣科技大學碩士論文, 第18、21頁 (2018)

46. D. C. Dong and M. A. Winnik, The Py scale of solvent polarities. Canadian Journal of Chemistry 62, 2560 (1984)

47. A. Holtzer, Use of the van't Hoff relation in determination of the enthalpy of micelle formation. The Journal of Physical Chemistry 78, 1442 (1974)

48. A. Halperin, Polymeric micelles: a star model. Macromolecules 20, 2943 (1987)

49. S. F. Sun, Physical chemistry of macromolecules. basic principles and issues., John Wiley & Sons, Inc., New York, Chapter 10 (2004)