本研究成功合成出具有高度靈敏光響應能力的多枝鏈聚乙二醇-聚己內酯嵌段式共聚高分子，此材料能在水溶液中自發性地自組裝形成奈米尺寸的微胞，且具有優異的藥物負載能力、可調控的藥物包覆量以及在正常生理條件下優異的藥物包封穩定性和低細胞毒性。在施加紫外光照10秒的條件下，體外實驗不僅成功證實能有效控制藥物釋放的行為，更能觀測到藥物胞吞的過程，此材料不僅賦予可控的藥物傳載及釋放能力，且未來極有機會拓展至體內皮膚癌治療的發展潛力。

This work has successfully developed a multi-armed polyethylene glycol-polycaprolactone with ultrasensitive photoresponsive ability. This material can spontaneously self-assemble into nanosized micelles in aqueous solution that exhibits excellent drug-loading efficiency and adjustable drug-loading capacity, as well as the long-term stability of drug entrapment and low cytotoxicity under normal physiological conditions. When exposed to ultraviolet radiation for 10 seconds, in vitro studies show that the drug release behavior could be effectively controlled and drug-loaded micelles could be efficiently endocytosed into cancer cells, which indicates that this newly-developed micelle not only provide controlled transport / release of drug but can also potentially be applied for in vivo skin cancer treatment.

[1] Defining Cancer. (2014, 10 June). National Cancer Institute.
[2] Alberts, B., Johnson, A., Lewis, J., Raff, M., Roberts, K., & Walter, P. (2002). Molecular Biology of the Cell. New York: Garland Science. B. AlbertsA. JohnsonJ. LewisM. RaffK. Roberts2002Molecular Biology of the CellNew YorkGarland Science.
[3] Cancer Fact sheet N°297. (2014, February). World Health Organization.
[4] Jemal, A., Bray, F., Center, M. M., Ferlay, J., Ward, E., & Forman, D. (2011).
Global cancer statistics. CA: a cancer journal for clinicians, 61(2), 69-90.
[5] Kufe, D. W., Pollock, R. E., & Weichselbaum, R. R. Holland-Frei Cancer
Medicine, ISBN-10: 1-55009-213-8. 2003, BC Decker Inc. Chapter 86. Head
and Neck Cancer. People's Medical Publishing House USA.
[6] 101年癌症登記年報 (2015). 行政院衛生福利部國民健康署
[7] Liu, G. Y., Chen, C. J., Li, D. D., Wang, S. S., & Ji, J. (2012). Near-infrared
light-sensitive micelles for enhanced intracellular drug delivery. Journal of Materials Chemistry, 22(33), 16865-16871.
[8] Fornari, F. A., Randolph, J. K., Yalowich, J. C., Ritke, M. K., & Gewirtz, D. A. (1994). Interference by doxorubicin with DNA unwinding in MCF-7 breast tumor cells. Molecular pharmacology, 45(4), 649-656.
[9] Momparler, R. L., Karon, M., Siegel, S. E., & Avila, F. (1976). Effect of adriamycin on DNA, RNA, and protein synthesis in cell-free systems and intact cells. Cancer research, 36(8), 2891-2895.
[10] Taiwan Clinical Oncology Research Foundation, Anti cancer new drug micro fat body-Doxorubicin
[11] Singal, P. K., & Iliskovic, N. (1998). Doxorubicin-induced cardiomyopathy. New England Journal of Medicine, 339(13), 900-905.
[12] Vert, M. (2009). Degradable and bioresorbable polymers in surgery and in pharmacology: beliefs and facts. Journal of Materials Science: Materials in Medicine, 20(2), 437-446.
[13] Vert, M. (2007). Polymeric biomaterials: strategies of the past vs. strategies of the future. Progress in Polymer Science, 32(8-9), 755-761.
[14] French, A. C., Thompson, A. L., & Davis, B. G. (2009). High‐Purity Discrete
PEG‐Oligomer Crystals Allow Structural Insight. Angewandte Chemie, 121(7), 1274-1278.
[15] Ferrari, M. (2005). Cancer nanotechnology: opportunities and challenges. Nature reviews cancer, 5(3), 161.
[16] Wiradharma, N., Zhang, Y., Venkataraman, S., Hedrick, J. L., & Yang, Y. Y.
(2009). Self-assembled polymer nanostructures for delivery of anticancer therapeutics. Nano Today, 4(4), 302-317.
[17] Bae, Y., & Kataoka, K. (2009). Intelligent polymeric micelles from functional
poly (ethylene glycol)-poly (amino acid) block copolymers. Advanced drug
delivery reviews, 61(10), 768-784.
[18] Davis, M. E., Chen, Z., & Shin, D. M. (2010). Nanoparticle therapeutics: an
emerging treatment modality for cancer. In Nanoscience And Technology: A Collection of Reviews from Nature Journals (pp. 239-250).
[19] Lutz, J. F. Sci., Part A: Polym. Chem. 2008, 46, 3459.
[20] Inkinen, S., Hakkarainen, M., Albertsson, A. C., & Södergård, A. (2011). From
lactic acid to poly (lactic acid)(PLA): characterization and analysis of PLA and
its precursors. Biomacromolecules, 12(3), 523-532.
[21] Oh, J. K. (2011). Polylactide (PLA)-based amphiphilic block copolymers:
synthesis, self-assembly, and biomedical applications. Soft Matter, 7(11), 5096-
5108.
[22] Torchilin, V. (2011). Tumor delivery of macromolecular drugs based on the EPR
effect. Advanced drug delivery reviews, 63(3), 131-135.
[23] Kolb, H. C., Finn, M. G., & Sharpless, K. B. (2001). Click chemistry: diverse
chemical function from a few good reactions. Angewandte Chemie
International Edition, 40(11), 2004-2021.
[24] Evans, R. A. (2007). The rise of azide–alkyne 1, 3-dipolar ‘click’cycloaddition
and its application to polymer science and surface modification. Australian
Journal of Chemistry, 60(6), 384-395.
[25] Hein, J. E., & Fokin, V. V. (2010). Copper-catalyzed azide–alkyne cycloaddition
(CuAAC) and beyond: new reactivity of copper (I) acetylides. Chemical Society
Reviews, 39(4), 1302-1315.
[26] Author, A. (1961). Proceedings of the Chemical Society. October
1961. Proceedings of the Chemical Society, 1961(October), 357-396.
[27] Liang, J. (2014). Science online. Click Chemistry.
[28] Wang, H., Zhou, F., Ren, G., Zheng, Q., Chen, H., Gao, B., ... & Lu, J. (2017).
SuFEx‐Based Polysulfonate Formation from Ethenesulfonyl Fluoride–Amine
Adducts. Angewandte Chemie, 129(37), 11355-11360.
[29] Diels, O., & Alder, K. (1928). Synthesen in der hydroaromatischen
Reihe. Justus Liebigs Annalen der Chemie, 460(1), 98-122.
[30] Carey, Part B. ,pp. 474-526.
[31] Dewar, M. J., Olivella, S., & Stewart, J. J. (1986). Mechanism of the Diels-
Alder reaction: reactions of butadiene with ethylene and
cyanoethylenes. Journal of the American Chemical Society, 108(19), 5771-
5779.
[32] Ripoll, J. L., Rouessac, A., & Rouessac, F. (1978). Applications récentes de la
réaction de retro-Diels-Alder en synthèse organique. Tetrahedron, 34(1), 19-40.
[33] Inglis, A. J., & Barner‐Kowollik, C. (2010). Ultra rapid approaches to mild
macromolecular conjugation. Macromolecular rapid communications, 31(14),
1247-1266.
[34] Kwon, G. S., & Kataoka, K. (1995). Block copolymer micelles as long-
circulating drug vehicles. Advanced drug delivery reviews, 16(2-3), 295-309.
[35] Kwon, G. S., & Okano, T. (1996). Polymeric micelles as new drug
carriers. Advanced Drug Delivery Reviews, 21(2), 107-116.
[36] Hrubý, M., Koňák, Č., & Ulbrich, K. (2005). Polymeric micellar pH-sensitive
drug delivery system for doxorubicin. Journal of Controlled Release, 103(1),
137-148.
[37] Gao, Z., & Eisenberg, A. (1993). A model of micellization for block copolymers
in solutions. Macromolecules, 26(26), 7353-7360.
[38] Malmsten, M., & Lindman, B. (1992). Self-assembly in aqueous block
copolymer solutions. Macromolecules, 25(20), 5440-5445.
[39] Dayananda, K., He, C., Park, D. K., Park, T. G., & Lee, D. S. (2008). pH-and
temperature-sensitive multiblock copolymer hydrogels composed of poly
(ethylene glycol) and poly (amino urethane). Polymer, 49(23), 4968-4973.
[40] Reddy, T. T., Kano, A., Maruyama, A., Hadano, M., & Takahara, A. (2008).
Thermosensitive transparent semi-interpenetrating polymer networks for
wound dressing and cell adhesion control. Biomacromolecules, 9(4), 1313-1321.
[41] Miyata, K., Christie, R. J., & Kataoka, K. (2011). Polymeric micelles for nano-
scale drug delivery. Reactive and Functional Polymers, 71(3), 227-234.
[42] Jones, M. C., & Leroux, J. C. (1999). Polymeric micelles–a new generation of
colloidal drug carriers. European journal of pharmaceutics and
biopharmaceutics, 48(2), 101-111.
[43] Shuai, X., Ai, H., Nasongkla, N., Kim, S., & Gao, J. (2004). Micellar carriers
based on block copolymers of poly (ε-caprolactone) and poly (ethylene glycol)
for doxorubicin delivery. Journal of Controlled Release, 98(3), 415-426.
[44] van Nostrum, C. F. (2004). Polymeric micelles to deliver photosensitizers for
photodynamic therapy. Advanced drug delivery reviews, 56(1), 9-16.
[45] Husseini, G. A., El-Fayoumi, R. I., O'Neill, K. L., Rapoport, N. Y., & Pitt, W. G.
(2000). DNA damage induced by micellar-delivered doxorubicin and ultrasound:
comet assay study. Cancer letters, 154(2), 211-216.
[46] Marin, A., Muniruzzaman, M., & Rapoport, N. (2001). Mechanism of the
ultrasonic activation of micellar drug delivery. Journal of controlled
release, 75(1-2), 69-81.
[47] Liu, X. M., & Wang, L. S. (2004). A one-pot synthesis of oleic acid end-capped
temperature-and pH-sensitive amphiphilic polymers. Biomaterials, 25(10),
1929-1936.
[48] Modi, S., Swetha, M. G., Goswami, D., Gupta, G. D., Mayor, S., & Krishnan,
Y. (2009). A DNA nanomachine that maps spatial and temporal pH changes
inside living cells. Nature nanotechnology, 4(5), 325.
[49] Langer, R. (1998). Drug delivery and targeting. NATURE-LONDON-, 5-10.
[50] Kopecek, J., Kopecková, P., & Konák, C. (1997). Biorecognizable polymers:
design, structure, and bioactivity. Journal of Macromolecular Science, Part A:
Pure and Applied Chemistry, 34(10), 2103-2117.
[51] Nasongkla, N., Bey, E., Ren, J., Ai, H., Khemtong, C., Guthi, J. S., ... & Gao, J.
(2006). Multifunctional polymeric micelles as cancer-targeted, MRI-
ultrasensitive drug delivery systems. Nano letters, 6(11), 2427-2430.
[52] Rapoport, N. (2007). Physical stimuli-responsive polymeric micelles for anti-
cancer drug delivery. Progress in Polymer Science, 32(8-9), 962-990.
[53] Gref, R., Minamitake, Y., Peracchia, M. T., Trubetskoy, V., Torchilin, V., &
Langer, R. (1994). Biodegradable long-circulating polymeric
nanospheres. Science, 263(5153), 1600-1603.
[54] Soppimath, K. S., Aminabhavi, T. M., Kulkarni, A. R., & Rudzinski, W. E.
(2001). Biodegradable polymeric nanoparticles as drug delivery
devices. Journal of controlled release, 70(1-2), 1-20.
[55] Lü, J. M., Wang, X., Marin-Muller, C., Wang, H., Lin, P. H., Yao, Q., & Chen,
C. (2009). Current advances in research and clinical applications of PLGA-
based nanotechnology. Expert review of molecular diagnostics, 9(4), 325-341.
[56] Tian, H., Tang, Z., Zhuang, X., Chen, X., & Jing, X. (2012). Biodegradable
synthetic polymers: preparation, functionalization and biomedical
application. Progress in Polymer Science, 37(2), 237-280.
[57] Alexandridis, P., & Lindman, B. (2000). Amphiphilic block copolymers: self-
assembly and applications. Elsevier.
[58] Wei, H., Cheng, S. X., Zhang, X. Z., & Zhuo, R. X. (2009). Thermo-sensitive
polymeric micelles based on poly (N-isopropylacrylamide) as drug
carriers. Progress in Polymer Science, 34(9), 893-910.
[59] Dai, J., Lin, S., Cheng, D., Zou, S., & Shuai, X. (2011). Interlayer‐crosslinked
micelle with partially hydrated core showing reduction and pH dual sensitivity
for pinpointed intracellular drug release. Angewandte Chemie International
Edition, 50(40), 9404-9408.
[60] Wei, M., Gao, Y., Li, X., & Serpe, M. J. (2017). Stimuli-responsive polymers
and their applications. Polymer Chemistry, 8(1), 127-143.
[61] Roggan, A., Friebel, M., Dörschel, K., Hahn, A., & Mueller, G. J. (1999).
Optical properties of circulating human blood in the wavelength range 400-2500
nm. Journal of biomedical optics, 4(1), 36-47.
[62] Qiu, Y., & Park, K. (2001). Environment-sensitive hydrogels for drug
delivery. Advanced drug delivery reviews, 53(3), 321-339.
[63] Haba, Y., Harada, A., Takagishi, T., & Kono, K. (2004). Rendering poly
(amidoamine) or poly (propylenimine) dendrimers temperature
sensitive. Journal of the American Chemical Society, 126(40), 12760-12761.
[64] Wang, L. J., Zhou, X. J., Zhang, X. H., & Du, B. Y. (2015). Enhanced
mechanophore activation within micelles. Macromolecules, 49(1), 98-104.
[65] Anal, A. K. (2007). Stimuli-induced pulsatile or triggered release delivery
systems for bioactive compounds. Recent Patents on Endocrine, Metabolic &
Immune Drug Discovery, 1(1), 83-90.
[66] Mendes, P. M. (2008). Stimuli-responsive surfaces for bio-
applications. Chemical Society Reviews, 37(11), 2512-2529.
[67] Park, S. Y., & Bae, Y. H. (1999). Novel pH‐sensitive polymers containing
sulfonamide groups. Macromolecular rapid communications, 20(5), 269-273.
[68] Li, Y. L., Zhu, L., Liu, Z., Cheng, R., Meng, F., Cui, J. H., ... & Zhong, Z. (2009).
Reversibly stabilized multifunctional dextran nanoparticles efficiently deliver
doxorubicin into the nuclei of cancer cells. Angewandte Chemie, 121(52),
10098-10102.
[69] Ma, N., Li, Y., Xu, H., Wang, Z., & Zhang, X. (2009). Dual redox responsive
assemblies formed from diselenide block copolymers. Journal of the American
Chemical Society, 132(2), 442-443.
[70] Yu, S., Ding, J., He, C., Cao, Y., Xu, W., & Chen, X. (2014). Disulfide cross‐
linked polyurethane micelles as a reduction‐triggered drug delivery system for
cancer therapy. Advanced healthcare materials, 3(5), 752-760.
[71] Li, X. Q., Wen, H. Y., Dong, H. Q., Xue, W. M., Pauletti, G. M., Cai, X. J., ... &
Li, Y. Y. (2011). Self-assembling nanomicelles of a novel camptothecin prodrug
engineered with a redox-responsive release mechanism. Chemical
Communications, 47(30), 8647-8649.
[72] Dissemond, J., Witthoff, M., Brauns, T. C., Haberer, D., & Goos, M. (2003).
PH-Wert des milieus chronischer wunden. Der Hautarzt, 54(10), 959-965.
[73] Rofstad, E. K., Mathiesen, B., Kindem, K., & Galappathi, K. (2006). Acidic
extracellular pH promotes experimental metastasis of human melanoma cells in
athymic nude mice. Cancer research, 66(13), 6699-6707.
[74] Vaupel, P., Kallinowski, F., & Okunieff, P. (1989). Blood flow, oxygen and
nutrient supply, and metabolic microenvironment of human tumors: a
review. Cancer research, 49(23), 6449-6465.
[75] Li, J., Liu, F., Shao, Q., Min, Y., Costa, M., Yeow, E. K., & Xing, B. (2014).
Enzyme‐Responsive Cell‐Penetrating Peptide Conjugated Mesoporous Silica
Quantum Dot Nanocarriers for Controlled Release of Nucleus‐Targeted Drug
Molecules and Real‐Time Intracellular Fluorescence Imaging of Tumor
Cells. Advanced healthcare materials, 3(8), 1230-1239.
[76] Azagarsamy, M. A., Sokkalingam, P., & Thayumanavan, S. (2009). Enzyme-
triggered disassembly of dendrimer-based amphiphilic nanocontainers. Journal
of the American Chemical Society, 131(40), 14184-14185.
[77] Rapoport, N. (2007). Physical stimuli-responsive polymeric micelles for anti-
cancer drug delivery. Progress in Polymer Science, 32(8-9), 962-990.
[78] Ganta, S., Devalapally, H., Shahiwala, A., & Amiji, M. (2008). A review of
stimuli-responsive nanocarriers for drug and gene delivery. Journal of
controlled release, 126(3), 187-204.
[79] Qiu, Y., & Park, K. (2001). Environment-sensitive hydrogels for drug
delivery. Advanced drug delivery reviews, 53(3), 321-339.
[80] Mura, S., Nicolas, J., & Couvreur, P. (2013). Stimuli-responsive nanocarriers
for drug delivery. Nature materials, 12(11), 991.
[81] Rofstad, E. K., Mathiesen, B., Kindem, K., & Galappathi, K. (2006). Acidic
extracellular pH promotes experimental metastasis of human melanoma cells in
athymic nude mice. Cancer research, 66(13), 6699-6707.
[82] Vaupel, P., Kallinowski, F., & Okunieff, P. (1989). Blood flow, oxygen and
nutrient supply, and metabolic microenvironment of human tumors: a
review. Cancer research, 49(23), 6449-6465.