本研究主要探討不同共聚物組成對兩性共聚物於藥物輸送系統
之影響。實驗利用開環聚合反應製備mPEG-PLGA兩團聯共聚物，其中[PLGA]/[mPEG]之比例由1.46至3.10，並分別以分子量350、550和750之methoxy poly(ethylene glycol)(mPEG)作為親水鏈段。結果顯示，除了mPEG350系列及[PLGA]/[mPEG]比例為3.10之共聚物不溶於水，其他兩團聯共聚物水溶液皆可形成奈米微胞，臨界微胞濃度低於1×10-2 mg/ml。mPEG550與mPEG750系列共聚物具有溫度敏感性，以mPEG-PLGA(550-1405)共聚物的成膠範圍最廣。此外，mPEG750系列共聚物成膠溫度較高，故不適用於人體體內。降解機制以mPEG與酯鍵鍵結處先被水解，接著為PLGA疏水鏈段降解，尤其以GA鍵結處(G-G, G-L)易先水解，較疏水的LA鍵結處(L-L)則較慢降解。細胞毒性及溶血試驗證實，此材料具有良好生物相容性。藥物釋放初期無突釋現象，能持續穩定釋放藥物Teicoplanin，以水膠濃度15wt% mPEG-PLGA(550-1405)為最適化藥物輸送系統，可釋放藥物達31天。藥物釋放前九天以水膠濃度15wt%之系統釋放最快，20wt%次之，25wt%最慢；九天後則以25wt%釋放最快，15wt%最慢，乃因水膠降解之寡聚物產生結晶行為所致。動物實驗結果顯示，此藥物輸送系統能有效治療患有骨髓炎的紐西蘭兔。本研究不僅探討不同組成對藥物輸送系統之影響，並證實此藥物輸送系統應用於局部抗生素釋放治療骨髓炎之可行性。

The purpose of this study is to understand the effect of copolymer composition on the drug delivery system. A series of biodegradable mPEG-PLGA diblock copolymers, [PLGA]/[mPEG] ratio from 1.46 to 3.01, were synthesized by ring-opening polymerization. Methoxy poly(ethylene glycol)(mPEG) of 350, 550 and 750, were used as the hydrophilic segment. Our results showed that copolymers of mPEG350 series and [PLGA]/[mPEG] at 3.01 were insoluble in water. The other copolymers in aqueous solution formed nanoparticles with critical micelle concentrations below 1×10-2 mg/ml. mPEG550 and mPEG750 series copolymers had thermosensitive properties with mPEG-PLGA(550-1405) having a wider gelation window. However, the gelation temperatures of mPEG750 series copolymers were above body temperature. Initially, hydrolysis occurred at the ester linkage of mPEG, which was followed by PLGA degradation occurring preferentially in GA unit rather than LA unit due to their hydrophobicity. Cytotoxicity and hemolysis test indicated that mPEG-PLGA diblock copolymers were biocompatible. Drug release study showed no initial burst and 15 wt% mPEG-PLGA(550-1405) hydrogel had the optimal drug release behavior. Before day9, drug release rate decreased as the concentration of copolymer aqueous solution increased. But this relationship inverted after day9. We inferred that this was due to the crystallization of degraded oligomer in the hydrogel. In vivo study showed that implantation of the mPEG-PLGA hydrogel containing Teicoplanin was effective in treating osteomyelitis in rabbits. The effect of copolymer composition on the drug delivery system was elucidated in this study. The use of mPEG-PLGA-based biodegradable hydrogels may hold great promise as a therapeutic strategy for osteomyelitis.

1 Wichterle, O. & Lim, D. Hydrophilic gels for biological use. Nature 185, 117-118 (1960).
2 Hamidi, M., Azadi, A. & Rafiei, P. Hydrogel nanoparticles in drug delivery. Advanced Drug Delivery Reviews 60, 1638-1649 (2008).
3 Bajpai, A. K., Shukla, K. S., Bhanu, S. & Kankane, S. Responsive polymers in controlled drug delivery. Progress in Polymer Science 33, 1088-1118 (2008).
4 Pillai, O. & Panchagnula, R. Polymers in drug delivery. Current Opinion in Chemical Biology 5, 447-451 (2001).
5 Qiu, Y. & Park, K. Environment-sensitive hydrogels for drug delivery. Advanced Drug Delivery Reviews 53, 321-339 (2001).
6 Jeong, B., Kim, S. W. & Bae, Y. H. Thermosensitive sol-gel reversible hydrogels. Advanced Drug Delivery Reviews 54, 37-51 (2002).
7 Ruel-Gariepy, E. & Leroux, J. C. In situ-forming hydrogels - review of temperature-sensitive systems. European Journal of Pharmaceutics and Biopharmaceutics 58, 409-426 (2004).
8 Jeong, B., Bae, Y. H. & Kim, S. W. Biodegradable thermosensitive micelles of PEG-PLGA-PEG triblock copolymers. Colloids and Surfaces B-Biointerfaces 16, 185-193 (1999).
9 Jeong, B., Bae, Y. H. & Kim, S. W. Thermoreversible gelation of PEG-PLGA-PEG triblock copolymer aqueous solutions. Macromolecules 32, 7064-7069 (1999).
10 Jeong, B., Bae, Y. H. & Kim, S. W. Drug release from biodegradable injectable thermosensitive hydrogel of PEG-PLGA-PEG triblock copolymers. Journal of Controlled Release 63, 155-163 (2000).
11 Jeong, B., Bae, Y. H. & Kim, S. W. In situ gelation of PEG-PLGA-PEG triblock copolymer aqueous solutions and degradation thereof. Journal of Biomedical Materials Research 50, 171-177 (2000).
12 Yu, L., Chang, G. T., Zhang, H. & Ding, J. D. Temperature-induced spontaneous sol-gel transitions of poly(D,L-lactic acid-co-glycolic acid)-b-poly(ethylene glycol)-b-poly(D,L-lactic acid-co-glycolic acid) triblock copolymers and their end-capped derivatives in water. Journal of Polymer Science Part a-Polymer Chemistry 45, 1122-1133 (2007).
13 Qiao, M. X., Chen, D. W., Ma, X. C. & Liu, Y. J. Injectable biodegradable temperature-responsive PLGA-PEG-PLGA copolymers: Synthesis and effect of copolymer composition on the drug release from the copolymer-based hydrogels. International Journal of Pharmaceutics 294, 103-112 (2005).
14 Zentner, G. M. et al. Biodegradable block copolymers for delivery of proteins and water-insoluble drugs. Journal of Controlled Release 72, 203-215 (2001).
15 Kim, M. S., Seo, K. S., Khang, G., Cho, S. H. & Lee, H. B. Preparation of methoxy poly(ethylene glycol)/polyester diblock copolymers and examination of the gel-to-sol transition. Journal of Polymer Science Part a-Polymer Chemistry 42, 5784-5793 (2004).
16 Kim, M. S. et al. In vivo osteogenic differentiation of rat bone marrow stromal cells in thermosensitive MPEG-PCL diblock copolymer gels. Tissue Engineering 12, 2863-2873 (2006).
17 Hyun, H. et al. In vitro and in vivo release of albumin using a biodegradable MPEG-PCL diblock copolymer as an in situ gel-forming carrier. Biomacromolecules 8, 1093-1100 (2007).
18 Mortensen, K. & Pedersen, J. S. Structural Study on the Micelle Formation of Poly(Ethylene Oxide) Poly(Propylene Oxide) Poly(Ethylene Oxide) Triblock Copolymer in Aqueous-Solution. Macromolecules 26, 805-812 (1993).
19 Vasanthan, N. & Ly, O. Effect of microstructure on hydrolytic degradation studies of poly (l-lactic acid) by FTIR spectroscopy and differential scanning calorimetry. Polymer Degradation and Stability 94, 1364-1372 (2009).
20 Bostman, O. M. Absorbable Implants for the Fixation of Fractures. Journal of Bone and Joint Surgery-American Volume 73A, 148-153 (1991).
21 Branco, M. C. & Schneider, J. P. Self-assembling materials for therapeutic delivery. Acta Biomaterialia 5, 817-831 (2009).
22 Lin, C. C. & Metters, A. T. Hydrogels in controlled release formulations: Network design and mathematical modeling. Advanced Drug Delivery Reviews 58, 1379-1408 (2006).
23 Sia, I. G. & Berbari, E. F. Osteomyelitis. Best Practice & Research in Clinical Rheumatology 20, 1065-1081 (2006).
24 Sener, M. et al. Comparison of various surgical methods in the treatment of implant-related infection. International Orthopaedics 34, 419-423 (2010).
25 Roeder, B., Van Gils, C. C. & Maling, S. Antibiotic beads in the treatment of diabetic pedal osteomyelitis. The Journal of Foot and Ankle Surgery 39, 124-130 (2000).
26 Zalavras, C. G., Patzakis, M. J. & Holtom, P. Local antibiotic therapy in the treatment of open fractures and osteomyelitis. Clinical Orthopaedics and Related Research, 86-93 (2004).
27 Ward, T. J. & Farris, A. B. Chiral separations using the macrocyclic antibiotics: a review. Journal of Chromatography A 906, 73-89 (2001).
28 Parenti, F., Beretta, G., Berti, M. & Arioli, V. Teichomycins, new antibiotics from actinoplanes-teichomyceticus-nov-sp .1. descriotion of producer strain, fermentation studies and biological properties J. Antibiot. 31, 276-283 (1978).
29 Hunt, A. H., Molloy, R. M., Occolowitz, J. L., Marconi, G. G. & Debono, M. Structure of the major glycopeptide of the teicoplanin complex. Journal of the American Chemical Society 106, 4891-4895 (1984).
30 D'Acquarica, I. et al. Direct chromatographic resolution of carnitine and O-acylcarnitine enantiomers on a teicoplanin-bonded chiral stationary phase. Journal of Chromatography A 857, 145-155 (1999).
31 Berthod, A., Liu, Y. B., Bagwill, C. & Armstrong, D. W. Facile liquid chromatographic enantioresolution of native amino acids and peptides using a teicoplanin chiral stationary phase. Journal of Chromatography A 731, 123-137 (1996).
32 Rowland, M. Clinical pharmacokinetics of teicoplanin. Clinical Pharmacokinetics 18, 184-209 (1990).
33 Malabarba, A., Ferrari, P., Gallo, G. G., Kettenring, J. & Cavalleri, B. Teicoplanin, antibiotics from actinoplanes-teichomyceticus nov-sp .7. preparation and NMR characteristics of the aglycone of teicoplanin J. Antibiot. 39, 1430-1442 (1986).
34 Schafer, M., Schneider, T. R. & Sheldrick, G. M. Crystal structure of vancomycin. Structure 4, 1509-1515 (1996).
35 Jones, R. A. L. Soft Condensed Matter (2002).
36 Alexandridis, P., Holzwarth, J. F. & Hatton, T. A. Micellizaton of poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) triblock copolymers in aqueous-solutions-thermodynamics of copolymer association Macromolecules 27, 2414-2425 (1994).
37 Pople, J. A. et al. Ordered phases in aqueous solutions of diblock oxyethylene/oxybutylene copolymers investigated by simultaneous small-angle X-ray scattering and rheology. Macromolecules 30, 5721-5728 (1997).
38 Han, C. K. & Bae, Y. H. Inverse thermally-reversible gelation of aqueous N-isopropylacrylamide copolymer solutions. polymer 39, 2809-2814 (1998).
39 Habas, J. P., Pavie, E., Lapp, A. & Peyrelasse, J. Understanding the complex rheological behavior of PEO-PPO-PEO copolymers in aqueous solution. Journal of Rheology 48, 1-21 (2004).
40 Park, M. J., Char, K., Bang, J. & Lodge, T. P. Order-disorder transition and critical micelle temperature in concentrated block copolymer solutions. Macromolecules 38, 2449-2459 (2005).
41 McCann, S. J., White, L. O. & Keevil, B. Assay of teicoplanin in serum: comparison of high-performance liquid chromatography and fluorescence polarization immunoassay. Journal of Antimicrobial Chemotherapy 50, 107-110 (2002).
42 Monzen, M., Kawakatsu, T., Doi, M. & Hasegawa, R. Micelle formation in triblock copolymer solutions. Computational and Theoretical Polymer Science 10, 275-280 (2000).
43 Zhao, X. L., Liu, W. G., Chen, D. Y., Lin, X. Z. & Lu, W. W. Effect of block order of ABA- and BAB-type NIPAAm/HEMA triblock copolymers on thermoresponsive Behavior of solutions. Macromolecular Chemistry and Physics 208, 1773-1781 (2007).
44 Altinok, H. et al. Effect of block architecture on the self-assembly of copolymers of ethylene oxide and propylene oxide in aqueous solution. Langmuir 13, 5837-5848 (1997).
45 Booth, C. & Attwood, D. Effects of block architecture and composition on the association properties of poly(oxyalkylene) copolymers in aqueous solution. Macromolecular Rapid Communications 21, 501-527 (2000).
46 Linse, P. Micellization of poly(ethylene oxide)-poly(propylene oxide) block-copolymers in aqueous-solutionI. Macromolecules 26, 4437-4449 (1993).
47 Alexandridis, P., Zhou, D. L. & Khan, A. Lyotropic liquid crystallinity in amphiphilic block copolymers: Temperature effects on phase behavior and structure for poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide) copolymers of different composition. Langmuir 12, 2690-2700 (1996).
48 Kim, S. Y. et al. Reverse thermal gelling PEG-PTMC diblock copolymer aqueous solution. Macromolecules 40, 5519-5525 (2007).
49 Brown, W., Schillen, K. & Hvidt, S. Triblock copolymers in aqueous-solution studied by static and dynamic light-scattering and oscillatory shear measurements-influence of relative block sizes. Journal of Physical Chemistry 96, 6038-6044 (1992).
50 Jeong, B., Kibbey, M. R., Birnbaum, J. C., Won, Y. Y. & Gutowska, A. Thermogelling biodegradable polymers with hydrophilic backbones: PEG-g-PLGA. Macromolecules 33, 8317-8322, doi:10.1021/ma000638v (2000).
51 Li, Y., Volland, C. & Kissel, T. In-vitro degradation and bovine serum albumin release of the ABA triblock copolymers consisting of poly (L(+) lactic acid), or poly(L(+) lactic acid-co-glycolic acid) A-blocks attached to central polyoxyethylene B-blocks. Journal of Controlled Release 32, 121-128 (1994).
52 Shah, S. S., Zhu, K. J. & Pitt, C. G. Poly--DL-lactic acid-polyethylene-glycol block-copolymers-the influence of polyethylene-glycol on the degradation of poly-DL-lactic acid. J. Biomater. Sci.-Polym. Ed. 5, 421-431 (1994).
53 Hakkarainen, M., Albertsson, A. C. & Karlsson, S. Weight losses and molecular weight changes correlated with the evolution of hydroxyacids in simulated in vivo degradation of homo- and copolymers of PLA and PGA. Polymer Degradation and Stability 52, 283-291 (1996).
54 King, E. & Cameron, R. E. Effect of hydrolytic degradation and dehydration on the microstructure of 50 : 50 poly(glycolide-co-D,L-lactide). Polymer International 45, 313-320 (1998).
55 Li, S. M., Garreau, H. & Vert, M. Structure property relationships in the case of the degradation of massive poly(alpha-hydroxy acids) in aqueous-media .2. degradation of lactide-glycolide copolymers-PLA37.5GA25 and PLA75GA25 Journal of Materials Science-Materials in Medicine 1, 131-139 (1990).
56 Park, T. G. Degradation of poly(lactic-co-glycolic acid) microspheres-effect of copolymer composition. Biomaterials 16, 1123-1130 (1995).
57 Loh, X. J., Goh, S. H. & Li, J. Hydrolytic degradation and protein release studies of thermogelling polyurethane copolymers consisting of poly[(R)-3-hydroxybutyrate], poly(ethylene glycol), and poly(propylene glycol). Biomaterials 28, 4113-4123 (2007).
58 Chen, S. B., Pieper, R., Webster, D. C. & Singh, J. Triblock copolymers: synthesis, characterization, and delivery of a model protein. International Journal of Pharmaceutics 288, 207-218 (2005).
59 Singh, S., Webster, D. C. & Singh, J. Thermosensitive polymers: Synthesis, characterization, and delivery of proteins. International Journal of Pharmaceutics 341, 68-77 (2007).
60 Li, S. M. & Vert, M. Crystalline oligomeric stereocomplex as an intermediate compound in racemic poly(DL-lactide acid) degradation. Polymer International 33, 37-41 (1994).
61 Li, S. M. & Vert, M. Morphological-changes resulting from the hydrolytic degradation of stereocopolymers derived from L-lactides and DL-lactides. Macromolecules 27, 3107-3110 (1994).
62 Peng, K.-T. et al. Treatment of osteomyelitis with teicoplanin-encapsulated biodegradable thermosensitive hydrogel nanoparticles. Biomaterials 31, 5227-5236 (2010).
63 Gong, C. et al. Biodegradable in situ gel-forming controlled drug delivery system based on thermosensitive PCL-PEG-PCL hydrogel. Part 2: Sol-gel-sol transition and drug delivery behavior. Acta Biomaterialia 5, 3358-3370 (2009).
64 Liu, C. B. et al. Thermo reversible gel-sol behavior of biodegradable PCL-PEG-PCL triblock copolymer in aqueous solutions. Journal of Biomedical Materials Research Part B-Applied Biomaterials 84B, 165-175 (2008).
65 Mortensen, K. Structural properties of self-assembled polymeric aggregates in aqueous solutions. Polymers for Advanced Technologies 12, 2-22 (2001).
66 Jiang, Z. Q., You, Y. J., Deng, X. M. & Hao, J. Y. Injectable hydrogels of poly(epsilon-caprolactone-co-glycolide)-poly(ethylene glycol)-poly(epsilon-caprolactone-co-glycolide) triblock copolymer aqueous solutions. polymer 48, 4786-4792 (2007).
67 Loh, X. J., Goh, S. H. & Li, J. New biodegradable thermogelling copolymers having very low gelation concentrations. Biomacromolecules 8, 585-593 (2007).
68 Molina, I., Li, S., Martinez, M. B. & Vert, M. Protein release from physically crosslinked hydrogels of the PLA/PEO/PLA triblock copolymer-type. Biomaterials 22, 363-369 (2001).