本研究成功合成出具備高度酸鹼應答能力的聚胺酯共聚高分子，此材料不僅能在水溶液中自組裝形成奈米尺寸的微胞，且具有優異的藥物負載能力及可調控的藥物包覆量，於長效測試中亦呈現出高度微胞穩定性。在小鼠巨噬細胞(Raw 264.7)的體外實驗，不僅能成功透過環境酸鹼值控制藥物釋放的行為，更能在微酸環境條件下(pH = 6.0)觀測到藥物胞吞作用(Endocytosis)的過程，證實此材料不僅有極優越的藥物釋放能力，且有機會拓展至人體抗癌治療的發展潛力。

This work has successfully constructed a polyurethane containing Ultrasensitive pH-Responsive ability. The new material can not only perform self-assembly of nano-scale micelles in aqueous solution, but also possess excellent drug-loading capability and adjustable drug-loading capacity. Besides, in the test of a long period of time, the micelles still represent highly durability and stability. In vitro test of the Macrophages (Raw 264.7), the behavior of the drug release can be well controlled by the pH value of the environment. Moreover, under weak acidic conditions (pH = 6.0), endocytosis was observed, which prove that this material not only shows promising drug release ability, but also has potentials in expanding to the anti-cancer therapies in human bodies.

[1.] Matsudaira, Paul T.; Lodish, Harvey F.; Arnold Berk; Kaiser, Chris; Monty Krieger; Matthew P Scott; Anthony Bretscher; Hidde Ploegh. Molecular Cell Biology. W.H.Freeman & Co Ltd. 2007. ISBN 1-4292-0314-5.
[2.] Alberts, Bruce. Molecular biology of the Cell. New York, 2002: Garland Science. ISBN 0-8153-3218-1.
[3.] Cancer Fact sheet N°297. World Health Organization. February 2014
[4.] World Cancer Report 2014.. World Health Organization. 2014: Chapter 1.1. ISBN 9283204298.
[5.] The top 10 causes of death Fact sheet N°310. WHO. May 2014 [10 June 2014].
[6.] Frei, Emil; Kufe, Donald W.; Holland, James F. Cancer medicine 6. Hamilton, Ont, 2003: BC Decker. ISBN 1-55009-213-8.
[7.] 101年癌症登記年報.行政院衛生福利部國民健康署,2015
[8.] R. Cheng, F. Meng, C. Deng,H. A. Klok, Z. Zhong, Biomaterials 2013, 34, 3647.
[9.] S. Mura, J. Nicolas, P. Couvreur, Nat. Mater. 2013, 12, 991.
[10.] D. Le Garrec, J. Taillefer, J. E. Van Lier, J.-C. Leroux, J. Drug Target. 2002, 10, 429.
[11.] N. Kang, M. È. Perron, R. E. Prud’Homme, Y. Zhang, G. Gaucher, J. C. Leroux, Nano Lett. 2005, 5, 315.
[12.] C. Yang, A. B. Attia, J. P. Tan, X. Ke, S. Gao, J. L. Hedrick, Y. Y. Yang, Biomaterials 2012, 33, 2971.
[13.] Taiwan Clinical Oncology Research Foundation, Anti cancer new drug micro fat body-Doxorubicin
[14.] Current Concepts: Doxorubicin-Induced Cardiomyopathy. Singal, Pawan K.; Iliskovic, Natasha. N Engl J Med 1998 Sep 24;339(13):900-5
[15.] Penczek P, Frisch KC, Szczepaniak B, Rudnik E. J polym Sci Chem 1993;31:1211.
[16.] Kidane, A. G. ; Burriesci, G. ; Edirisinghe, M. ; Ghanbari, H. ; Bonhoeffer, P. ; Seifalian, A. M. Acta Biomater. 2009, 5, 2409–2417.
[17.] Xue, L.; Greisler, H. P. J. Vasc. Surg. 2003, 37, 472–480.
[18.] Rosenheck, S.; Sharon, Z.; Leibowitz, D. Europace 2000, 2, 60–65.
[19.] Lawrence, E. L.; Turner, I. G. Med. Eng. Phys. 2005, 27, 443–453.
[20.] Yang, M. J.; Den, X. Y.; Zhang, Z.; Julien, M.; Pelletier, F.; Desaulniers, D.; Cossette, R.; Teijeira, F. J.; Laroche, G.; Guidoin, R. Artif. Organs. 1997, 21, 121–130.
[21.] Gisselfalt, K.; Edberg, B.; Flodin, P. Biomacromolecules 2002, 3, 951–958.
[22.] (a) Zhang, C. H.; Wen, X. J.; Vyavahare, N. R.; Boland, T. Biomaterials 2008, 29, 3781–3791. (b) Rockwood, D. N.; Akins, R. E.; Parrag, I. C. ; Woodhouse, K. A.; Rabolt, J. F. Biomaterials 2008, 29, 4783–4791.
[23.] Adhikari,R.;Gunatillake,P.A.;Griffiths,I.;Tatai,L.;Wickramaratna,M.; Houshyar, S.; Moore, T. ; Mayadunne, R. T. M.; Field, J.; Mcgee, M. ; Carbone, T. Biomaterials 2008, 29, 3762–3770.
[24.] Jeong,B.;Bae,Y.H.;Lee,D. S.;Kim,S.W. Nature 1997, 388, 860–862.
[25.] Mequanint, K.; Patel, A.; Bezuidenhout, D. Biomacromolecules 2006, 7, 883–891.
[26.] Loh, X. J.; Sng, K. B. C.; Li, J. Biomaterials 2008, 29, 3185–3194.
[27.] Knight, P. T.; Lee, K. M.; Qin, H.; Mather, P. T. Biomacromolecules 2008, 9, 2458–2467.
[28.] Lee, E. S.; Na, K.; Bae, Y. H. Nano Lett. 2005, 5, 325–329.
[29.] Lee, E. S.; Na, K.; Bae, Y. H. J. Controlled Release 2003, 91, 103–113.

[30.] High Purity Discrete PEG Oligomer Crystals Allow Structural Insight". A.C. French, A.L. Thompson, B.G. Davis. Angew. Chem. Intl Ed. 2009, 48, 1248-1252.
[31.] Ferrari, M. Nat. Nanotechnol. 2007, 2, 37–47.
[32.] N. Wiradharma, Y. Zhang, S. Venkataraman, J.L. Hedrick, Y.Y. Yang, Self-assembled polymer nanostructures for delivery of anticancer therapeutics, Nano Today 4 (2009) 302–317.
[33.] Y. Bae, K. Kataoka, Intelligent polymeric micelles from functional poly(ethylene glycol)-poly(amino acid) block copolymers, Adv. Drug Deliv. Rev. 61. 2009 768–784.
[34.] M.E. Davis, Z. Chen, D.M. Shin, Nanoparticle therapeutics: an emerging treatment modality for cancer, Nat. Rev. Drug Discov. 7. 2008 771–782.
[35.] J. F. Lutz, J. Polym. Sci., Part A: Polym. Chem. 2008, 46, 3459
[36.] S. Inkinen, M. Hakkarainen, A. C. Albertsson, A. Sodergard, Biomacromolecules 2011, 12, 523.
[37.] J. K. Oh, Soft Matter 2011, 7, 5096.
[38.] V. Torchilin, Tumor delivery of macromolecular drugs based on the EPR effect, Adv. Drug Deliv. Rev. 63. 2011 131–135.
[39.] H. C. Kolb, M. G. Finn and K. B. Sharpless .2001. "Click Chemistry: Diverse Chemical Function from a Few Good Reactions". Angewandte Chemie International Edition 40 : 2004–2021.
[40.] R. A. Evans. The Rise of Azide–Alkyne 1,3-Dipolar 'Click' Cycloaddition and its Application to Polymer Science and Surface Modification. Australian Journal of Chemistry. 2007, 60 : 384–395.
[41.] Heina, J. E.; Fokin, V. V. Chem. Soc. Rev., 2010, 39, 1302-1315.
[42.] Huisgen, R. Proc. Chem. Soc., 1961, 357-396.
[43.] J.r. LIANG. Science online.Click Chemistry 2014
[44.] G. S. Kwon, K. Kataoka, Adv.Drug Deliv.Res., 16(1995) , p295
[45.] G. S. Kwon, T. Okano, Adv.Drug Deliv.Res., 2(1996) , p107
[46.] M. Hruby , C. Konak , K.Ulbrich , J. Control. Release, 103 (2005) , p137
[47.] Z. Gao, A Eisenberg, Macromolecules, 26 (1993) , p7353
[48.] M. Malmesten, B. Londman, Macromolecules, 25 (1992) , p5440
[49.] Dayananda, K.; He, C.; Park, D. K.; Park, T. G.; Lee, D. S. Polymer 2008, 49, 4968–4973.
[50.] Reddy, T. T.; Kano, A.; Maruyama, A.; Hadano, M.; Takahara, A. Biomacromolecules 2008, 9, 1313–1321.
[51.] K. Kataoka, G. S. Kwon, M.Yokoyama, T. Okano, Y. Sakurai, J.Control.Release, 24 1993 , p119
[52.] M.C. Jones, J.C. Leroux, J.Europ.Pharm.Biopharm., (1999), p101
[53.] X. Shuai, H. Ai, N. Nasongkla, S. Kim, J. Gao, J.Control. Release, 98. 2004 , p415
[54.] Cornelus.F.van Nostrum, Adv.Drug Deliv.Res., 56 2004 , p9
[55.] G. A. Husseini, R. I. EL Fayoumi, K. L. ONeill, N. Y. Rapoport, W. G.Pitt , Cancer Lett., 154(2000) , p211
[56.] A. Marin, M. Muniruzzaman, N. Rapoport, J.Control. Release,75. 2001 , p69
[57.] X. M. Liu, L.S. Wang, Biomaterials, 25 2004 , p1929
[58.] Modi, S.; Swetha, M. G.; Goswami, D.; Gupta, G. D.; Mayor, S.; Krishnan, Y. A DNA Nanomachine That Maps Spatial and Temporal pH Changes Inside Living Cells. Nat. Nanotechnol. 2009, 4, 325–330.
[59.] Langer, R. Nature 1998, 392, 5–10.
[60.] Bader H, Ringsdorf H, Schmidt B, Angew. Chem.,123/124,457(1984)
[61.] N. Nasongkla , E. Bey , J. Ren , H. Ai , C. Khemtong , J. S. Guthi , S. F. Chin , A. D. Sherry , D. A. Boothman , J. Gao , Nano Lett. 2006 , 6 , 2427.
[62.] N. Rapoport , Prog. Polym. Sci. 2007 , 32 , 962.
[63.] K. S. Soppimath, T. M. Aminabhavi, A. R. Kulkarni, W. E. Rudzinski, J. Controll. Rel. 2001, 70, 1.
[64.] J. M. Lü, X. W. Wang, C. Marin-Muller, H. Wang, P. H. Lin, Expert Rev. Mol. Diagn. 2009, 9, 325
[65.] H. Tian, Z. Tang, X. Zhuang, X. Chen, X. Jing, Prog. Polym. Sci. 2012, 37, 237.
[66.] H. Wei , S.-X. Cheng , X.-Z. Zhang , R.-X. Zhuo , Prog. Polym. Sci. 2009 , 34 , 893.
[67.] C.-L. Lo , S.-J. Lin , H.-C. Tsai , C.-H. D. Cheng , G.-H. Hsiue , Biomaterials 2009 , 30 , 3961.
[68.] J. Y. Ko , S. Park , H. Lee , H. Koo , M. S. Kim , K. Choi , I. C. Kwon ,S. Y. Jeong , K. Kim , D. S. Lee , Small 2010 , 6 , 2539.
[69.] J. Y. Ko , S. Park , H. Lee , H. Koo , M. S. Kim , K. Choi , I. C. Kwon , S. Y. Jeong , K. Kim , D. S. Lee , Small 2010 , 6 , 2539.
[70.] M. I. Giannotti , O. Esteban , M. Oliva , M. F. Garcia-Parajo , F. Sanz , Biomacromolecules 2011 , 12 , 2524.
[71.] M. Motornov , Y. Roiter , I. Tokarev , S. Minko , Prog. Polym. Sci. 2010 , 35 , 174 .
[72.] Q. Sun , D. Cheng , X. Yu , Z. Zhang , J. Dai , H. Li , B. Liang , X. Shuai , J. Mater. Chem. 2011 , 21 , 15316 .
[73.] J. Li , F. Liu , Q. Shao , Y. Min , M. Costa , E. K. Yeow , B. Xing , Adv. Healthcare Mater. 2014 , 3 , 1230 .
[74.] M. A. Azagarsamy , P. Sokkalingam , S. Thayumanavan , J. Am. Chem. Soc. 2009 , 131 , 14184 .
[75.] Y. L. Li , L. Zhu , Z. Liu , R. Cheng , F. Meng , J. H. Cui , S. J. Ji , Z. Zhong , Angew. Chem. Int. Ed. 2009 , 48 , 9914 .
[76.] N. Ma , Y. Li , H. Xu , Z. Wang , X. Zhang , J. Am. Chem. Soc. 2010 , 132 , 442 .
[77.] S. Yu , J. Ding , C. He , Y. Cao , W. Xu , X. Chen , Adv. Healthcare Mater. 2014 , 3 , 752 .
[78.] X. Q. Li , H. Y. Wen , H. Q. Dong , W. M. Xue , G. M. Pauletti , X. J. Cai , W. J. Xia , D. Shi , Y. Y. Li , Chem. Commun. 2011 , 47 , 8647 .
[79.] J. Dai , S. Lin , D. Cheng , S. Zou , X. Shuai , Angew. Chem. Int. Ed. 2011 , 50 , 9404 .
[80.] N. Rapoport, Prog. Polym. Sci. 2007, 32, 962;
[81.] S. Ganta, H. Devalapally, A. Shahiwala, M. Amiji, J. Controll. Rel. 2008, 126, 187;
[82.] Y. Qiu, K. Park, Adv. Drug Delivery Rev. 2012, 64, 49;
[83.] S. Mura, J. Nicolas, P. Couvreur, Nat. Mater. 2013, 12, 991.
[84.] W. Gao , J. M. Chan , O. C. Farokhzad , Mol. Pharm. 2010 , 7 , 1913 .
[85.] Y. Huang , Z. Tang , X. Zhang , H. Yu , H. Sun , X. Pang , X. Chen , Biomacromolecules 2013 , 14 , 2023 .