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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 何佳安 | |
| dc.contributor.author | Chih-Wen Yang | en |
| dc.contributor.author | 楊智雯 | zh_TW |
| dc.date.accessioned | 2021-07-10T21:34:45Z | - |
| dc.date.available | 2021-07-10T21:34:45Z | - |
| dc.date.copyright | 2016-11-02 | |
| dc.date.issued | 2016 | |
| dc.date.submitted | 2016-08-19 | |
| dc.identifier.citation | (1) Holohan, C.; Van Schaeybroeck, S.; Longley, D. B.; Johnston, P. G. 'Cancer drug resistance: an evolving paradigm.' Nat Rev Cancer 2013, 13, 714-726.
(2) Wesarg, E.; Hoffarth, S.; Wiewrodt, R.; Kroll, M.; Biesterfeld, S.; Huber, C.; Schuler, M. 'Targeting BCL-2 family proteins to overcome drug resistance in non-small cell lung cancer.' Int J Cancer 2007, 121, 2387-2394. (3) Kreuter, J. 'Nanoparticles--a historical perspective.' Int J Pharm 2007, 331, 1-10. (4) Neuse, E. W. 'Synthetic polymers as drug-delivery vehicles in medicine.' Met Based Drugs 2008, 2008, 469531. (5) Obenauf, A. C.; Massague, J. 'Surviving at a distance: organ specific metastasis.' Trends Cancer 2015, 1, 76-91. (6) Torre, L. A.; Bray, F.; Siegel, R. L.; Ferlay, J.; Lortet-Tieulent, J.; Jemal, A. 'Global cancer statistics, 2012.' CA Cancer J Clin 2015, 65, 87-108. (7) Popat, K.; McQueen, K.; Feeley, T. W. 'The global burden of cancer.' Best Pract Res Clin Anaesthesiol 2013, 27, 399-408. (8) Lavi, O. 'Redundancy: a critical obstacle to improving cancer therapy.' Cancer Res 2015, 75, 808-812. (9) Hajdu, S. I. 'A note from history: landmarks in history of cancer, part 1.' Cancer 2011, 117, 1097-1102. (10) Sudhakar, A. 'History of Cancer, Ancient and Modern Treatment Methods.' J Cancer Sci Ther 2009, 1, 1-4. (11) Weinberg, R. A. 'The molecular basis of oncogenes and tumor suppressor genes.' Ann N Y Acad Sci 1995, 758, 331-338. (12) Levine, A. J.; Perry, M. E.; Chang, A.; Silver, A.; Dittmer, D.; Wu, M.; Welsh, D. 'The 1993 Walter Hubert Lecture: the role of the p53 tumour-suppressor gene in tumorigenesis.' Br J Cancer 1994, 69, 409-416. (13) Bieging, K. T.; Mello, S. S.; Attardi, L. D. 'Unravelling mechanisms of p53-mediated tumour suppression.' Nat Rev Cancer 2014, 14, 359-370. (14) Pavlova, N. N.; Thompson, C. B. 'The Emerging Hallmarks of Cancer Metabolism.' Cell Metab 2016, 23, 27-47. (15) Robey, I. F.; Lien, A. D.; Welsh, S. J.; Baggett, B. K.; Gillies, R. J. 'Hypoxia-inducible factor-1alpha and the glycolytic phenotype in tumors.' Neoplasia 2005, 7, 324-330. (16) Sonveaux, P.; Copetti, T.; De Saedeleer, C. J.; Vegran, F.; Verrax, J.; Kennedy, K. M.; Moon, E. J.; Dhup, S.; Danhier, P.; Frerart, F.; Gallez, B.; Ribeiro, A.; Michiels, C.; Dewhirst, M. W.; Feron, O. 'Targeting the lactate transporter MCT1 in endothelial cells inhibits lactate-induced HIF-1 activation and tumor angiogenesis.' PLoS One 2012, 7, e33418. (17) Goetze, K.; Walenta, S.; Ksiazkiewicz, M.; Kunz-Schughart, L. A.; Mueller-Klieser, W. 'Lactate enhances motility of tumor cells and inhibits monocyte migration and cytokine release.' Int J Oncol 2011, 39, 453-463. (18) Valastyan, S.; Weinberg, R. A. 'Tumor metastasis: molecular insights and evolving paradigms.' Cell 2011, 147, 275-292. (19) Hanahan, D.; Weinberg, R. A. 'Hallmarks of cancer: the next generation.' Cell 2011, 144, 646-674. (20) Cosentino, K.; Garcia-Saez, A. J. 'Mitochondrial alterations in apoptosis.' Chem Phys Lipids 2014, 181, 62-75. (21) Neupert, W.; Herrmann, J. M. 'Translocation of proteins into mitochondria.' Annu Rev Biochem 2007, 76, 723-749. (22) DuBoff, B.; Feany, M.; Gotz, J. 'Why size matters - balancing mitochondrial dynamics in Alzheimer's disease ' Trends Neurosci 2013, 36, 325-335. (23) Turner, W. 'The Cell Theory, Past and Present.' J Anat Physiol 1890, 24, 253-287. (24) Verschoor, M. L.; Ungard, R.; Harbottle, A.; Jakupciak, J. P.; Parr, R. L.; Singh, G. 'Mitochondria and cancer: past, present, and future.' Biomed Res Int 2013, 2013, 612369. (25) Benard, G.; Bellance, N.; James, D.; Parrone, P.; Fernandez, H.; Letellier, T.; Rossignol, R. 'Mitochondrial bioenergetics and structural network organization.' J Cell Sci 2007, 120, 838-848. (26) Ernster, L.; Schatz, G. 'Mitochondria: a historical review.' J Cell Biol 1981, 91, 227s-255s. (27) Warburg, O. H. 'The classic: The chemical constitution of respiration ferment.' Clin Orthop Relat Res 2010, 468, 2833-2839. (28) Slater, E. C. 'Keilin, cytochrome, and the respiratory chain.' J Biol Chem 2003, 278, 16455-16461. (29) Hogeboom, G. H.; Claude, A.; Hotch-Kiss, R. D. 'The distribution of cytochrome oxidase and succinoxidase in the cytoplasm of the mammalian liver cell.' J Biol Chem 1946, 165, 615-629. (30) Sabatini, D. D. 'Philip Siekevitz: Bridging biochemistry and cell biology.' J Cell Biol 2010, 189, 3-5. (31) Ow, Y. P.; Green, D. R.; Hao, Z.; Mak, T. W. 'Cytochrome c: functions beyond respiration.' Nat Rev Mol Cell Biol 2008, 9, 532-542. (32) Chen, L. B. 'Mitochondrial membrane potential in living cells.' Annu Rev Cell Biol 1988, 4, 155-181. (33) Perry, S. W.; Norman, J. P.; Barbieri, J.; Brown, E. B.; Gelbard, H. A. 'Mitochondrial membrane potential probes and the proton gradient: a practical usage guide.' Biotechniques 2011, 50, 98-115. (34) Duque-Parra, J. E. 'Note on the origin and history of the term 'apoptosis'.' Anat Rec B New Anat 2005, 283, 2-4. (35) Maghsoudi, N.; Zakeri, Z.; Lockshin, R. A. 'Programmed cell death and apoptosis--where it came from and where it is going: from Elie Metchnikoff to the control of caspases.' Exp Oncol 2012, 34, 146-152. (36) Ameisen, J. C. 'On the origin, evolution, and nature of programmed cell death: a timeline of four billion years.' Cell Death Differ 2002, 9, 367-393. (37) Zhuang, H.; Tian, W.; Li, W.; Zhang, X.; Wang, J.; Yang, Y.; Liu, X.; Xia, Z.; Feng, D.; Zhang, L. 'Autophagic Cell Death and Apoptosis Jointly Mediate Cisatracurium Besylate-Induced Cell Injury.' Int J Mol Sci 2016, 17. (38) Roos, W. P.; Kaina, B. 'DNA damage-induced cell death: from specific DNA lesions to the DNA damage response and apoptosis.' Cancer Lett 2013, 332, 237-248. (39) Favaloro, B.; Allocati, N.; Graziano, V.; Di Ilio, C.; De Laurenzi, V. 'Role of apoptosis in disease.' Aging (Albany NY) 2012, 4, 330-349. (40) Kaczanowski, S. 'Apoptosis: its origin, history, maintenance and the medical implications for cancer and aging.' Phys Biol 2016, 13, 031001. (41) Yuan, J.; Shaham, S.; Ledoux, S.; Ellis, H. M.; Horvitz, H. R. 'The C. elegans cell death gene ced-3 encodes a protein similar to mammalian interleukin-1 beta-converting enzyme.' Cell 1993, 75, 641-652. (42) Hengartner, M. O.; Horvitz, H. R. 'C. elegans cell survival gene ced-9 encodes a functional homolog of the mammalian proto-oncogene bcl-2.' Cell 1994, 76, 665-676. (43) Conradt, B.; Horvitz, H. R. 'The C. elegans protein EGL-1 is required for programmed cell death and interacts with the Bcl-2-like protein CED-9.' Cell 1998, 93, 519-529. (44) Nehme, R.; Conradt, B. 'egl-1: a key activator of apoptotic cell death in C. elegans.' Oncogene 2008, 27 Suppl 1, S30-40. (45) Cecconi, F.; Alvarez-Bolado, G.; Meyer, B. I.; Roth, K. A.; Gruss, P. 'Apaf1 (CED-4 homolog) regulates programmed cell death in mammalian development.' Cell 1998, 94, 727-737. (46) Tait, S. W.; Green, D. R. 'Mitochondria and cell death: outer membrane permeabilization and beyond.' Nat Rev Mol Cell Biol 2010, 11, 621-632. (47) Portt, L.; Norman, G.; Clapp, C.; Greenwood, M.; Greenwood, M. T. 'Anti-apoptosis and cell survival: a review.' Biochim Biophys Acta 2011, 1813, 238-259. (48) Lewis, M. R.; Lewis, W. H. 'Mitochondria in Tissue Culture.' Science 1914, 39, 330-333. (49) Johnson, L. V.; Walsh, M. L.; Bockus, B. J.; Chen, L. B. 'Monitoring of relative mitochondrial membrane potential in living cells by fluorescence microscopy.' J Cell Biol 1981, 88, 526-535. (50) Bereiter-Hahn, J.; Voth, M. 'Dynamics of mitochondria in living cells: shape changes, dislocations, fusion, and fission of mitochondria.' Microsc Res Tech 1994, 27, 198-219. (51) Mishra, P.; Chan, D. C. 'Mitochondrial dynamics and inheritance during cell division, development and disease.' Nat Rev Mol Cell Biol 2014, 15, 634-646. (52) Wai, T.; Langer, T. 'Mitochondrial Dynamics and Metabolic Regulation.' Trends Endocrinol Metab 2016, 27, 105-117. (53) Santel, A.; Frank, S.; Gaume, B.; Herrler, M.; Youle, R. J.; Fuller, M. T. 'Mitofusin-1 protein is a generally expressed mediator of mitochondrial fusion in mammalian cells.' J Cell Sci 2003, 116, 2763-2774. (54) Kluge, M. A.; Fetterman, J. L.; Vita, J. A. 'Mitochondria and endothelial function.' Circ Res 2013, 112, 1171-1188. (55) Ni, H. M.; Williams, J. A.; Ding, W. X. 'Mitochondrial dynamics and mitochondrial quality control.' Redox Biol 2015, 4, 6-13. (56) Chipuk, J. E.; Green, D. R. 'How do BCL-2 proteins induce mitochondrial outer membrane permeabilization?' Trends Cell Biol 2008, 18, 157-164. (57) Youle, R. J.; van der Bliek, A. M. 'Mitochondrial fission, fusion, and stress.' Science 2012, 337, 1062-1065. (58) Gao, L.; Laude, K.; Cai, H. 'Mitochondrial pathophysiology, reactive oxygen species, and cardiovascular diseases.' Vet Clin North Am Small Anim Pract 2008, 38, 137-155, vi. (59) Pon, J. R.; Marra, M. A. 'Driver and passenger mutations in cancer.' Annu Rev Pathol 2015, 10, 25-50. (60) van Gisbergen, M. W.; Voets, A. M.; Starmans, M. H.; de Coo, I. F.; Yadak, R.; Hoffmann, R. F.; Boutros, P. C.; Smeets, H. J.; Dubois, L.; Lambin, P. 'How do changes in the mtDNA and mitochondrial dysfunction influence cancer and cancer therapy? Challenges, opportunities and models.' Mutat Res Rev Mutat Res 2015, 764, 16-30. (61) Chatterjee, A.; Mambo, E.; Sidransky, D. 'Mitochondrial DNA mutations in human cancer.' Oncogene 2006, 25, 4663-4674. (62) Schon, E. A.; DiMauro, S.; Hirano, M. 'Human mitochondrial DNA: roles of inherited and somatic mutations.' Nat Rev Genet 2012, 13, 878-890. (63) Ishikawa, K.; Takenaga, K.; Akimoto, M.; Koshikawa, N.; Yamaguchi, A.; Imanishi, H.; Nakada, K.; Honma, Y.; Hayashi, J. 'ROS-generating mitochondrial DNA mutations can regulate tumor cell metastasis.' Science 2008, 320, 661-664. (64) Singh, K. K.; Russell, J.; Sigala, B.; Zhang, Y.; Williams, J.; Keshav, K. F. 'Mitochondrial DNA determines the cellular response to cancer therapeutic agents.' Oncogene 1999, 18, 6641-6646. (65) Warburg, O. 'On the origin of cancer cells.' Science 1956, 123, 309-314. (66) Tait, S. W.; Ichim, G.; Green, D. R. 'Die another way--non-apoptotic mechanisms of cell death.' J Cell Sci 2014, 127, 2135-2144. (67) Lopez, J.; Tait, S. W. 'Mitochondrial apoptosis: killing cancer using the enemy within.' Br J Cancer 2015, 112, 957-962. (68) Hsu, C. C.; Tseng, L. M.; Lee, H. C. 'Role of mitochondrial dysfunction in cancer progression.' Exp Biol Med 2016, 241, 1281-1295. (69) Apostolova, N.; Victor, V. M. 'Molecular strategies for targeting antioxidants to mitochondria: therapeutic implications.' Antioxid Redox Signal 2015, 22, 686-729. (70) Smith, R. A.; Hartley, R. C.; Murphy, M. P. 'Mitochondria-targeted small molecule therapeutics and probes.' Antioxid Redox Signal 2011, 15, 3021-3038. (71) Zhang, B. B.; Wang, D. G.; Guo, F. F.; Xuan, C. 'Mitochondrial membrane potential and reactive oxygen species in cancer stem cells.' Fam Cancer 2015, 14, 19-23. (72) Murphy, M. P.; Smith, R. A. 'Drug delivery to mitochondria: the key to mitochondrial medicine.' Adv Drug Deliv Rev 2000, 41, 235-250. (73) Wong, R. S. 'Apoptosis in cancer: from pathogenesis to treatment.' J Exp Clin Cancer Res 2011, 30, 87. (74) Ramsay, E. E.; Hogg, P. J.; Dilda, P. J. 'Mitochondrial metabolism inhibitors for cancer therapy.' Pharm Res 2011, 28, 2731-2744. (75) Marchetti, P.; Guerreschi, P.; Mortier, L.; Kluza, J. 'Integration of Mitochondrial Targeting for Molecular Cancer Therapeutics.' Int J Cell Biol 2015, 2015, 283145. (76) Paalzow, L. K. 'Torsten Teorell, the father of pharmacokinetics.' Ups J Med Sci 1995, 100, 41-46. (77) Coelho, J. F.; Ferreira, P. C.; Alves, P.; Cordeiro, R.; Fonseca, A. C.; Gois, J. R.; Gil, M. H. 'Drug delivery systems: Advanced technologies potentially applicable in personalized treatments.' EPMA J 2010, 1, 164-209. (78) Jacobson, P. D.; Parmet, W. E. 'A new era of unapproved drugs: the case of Abigail Alliance v Von Eschenbach.' JAMA 2007, 297, 205-208. (79) Zhang, S.; Gao, H.; Bao, G. 'Physical Principles of Nanoparticle Cellular Endocytosis.' ACS Nano 2015, 9, 8655-8671. (80) Wohlfart, S.; Gelperina, S.; Kreuter, J. 'Transport of drugs across the blood-brain barrier by nanoparticles.' J Control Release 2012, 161, 264-273. (81) Davis, M. E.; Chen, Z. G.; Shin, D. M. 'Nanoparticle therapeutics: an emerging treatment modality for cancer.' Nat Rev Drug Discov 2008, 7, 771-782. (82) Barenholz, Y. 'Doxil(R)--the first FDA-approved nano-drug: lessons learned.' J Control Release 2012, 160, 117-134. (83) Gregoriadis, G.; Ryman, B. E. 'Liposomes as carriers of enzymes or drugs: a new approach to the treatment of storage diseases.' Biochem J 1971, 124, 58P. (84) Gabizon, A.; Papahadjopoulos, D. 'Liposome formulations with prolonged circulation time in blood and enhanced uptake by tumors.' Proc Natl Acad Sci U S A 1988, 85, 6949-6953. (85) Redondo-Morata, L.; Giannotti, M. I.; Sanz, F. 'Influence of cholesterol on the phase transition of lipid bilayers: a temperature-controlled force spectroscopy study.' Langmuir 2012, 28, 12851-12860. (86) Fukasawa, M.; Adachi, H.; Hirota, K.; Tsujimoto, M.; Arai, H.; Inoue, K. 'SRB1, a class B scavenger receptor, recognizes both negatively charged liposomes and apoptotic cells.' Exp Cell Res 1996, 222, 246-250. (87) Blume, G.; Cevc, G. 'Liposomes for the sustained drug release in vivo.' Biochim Biophys Acta 1990, 1029, 91-97. (88) Milla, P.; Dosio, F.; Cattel, L. 'PEGylation of proteins and liposomes: a powerful and flexible strategy to improve the drug delivery.' Curr Drug Metab 2012, 13, 105-119. (89) Bala, I.; Hariharan, S.; Kumar, M. N. 'PLGA nanoparticles in drug delivery: the state of the art.' Crit Rev Ther Drug Carrier Syst 2004, 21, 387-422. (90) Makadia, H. K.; Siegel, S. J. 'Poly Lactic-co-Glycolic Acid (PLGA) as Biodegradable Controlled Drug Delivery Carrier.' Polymers (Basel) 2011, 3, 1377-1397. (91) Ramoneda, X. A.; Ponce-Cevallos, P. A.; del Pilar Buera, M.; Elizalde, B. E. 'Degradation of beta-carotene in amorphous polymer matrices. Effect of water sorption properties and physical state.' J Sci Food Agric 2011, 91, 2587-2593. (92) Gref, R.; Minamitake, Y.; Peracchia, M. T.; Trubetskoy, V.; Torchilin, V.; Langer, R. 'Biodegradable long-circulating polymeric nanospheres.' Science 1994, 263, 1600-1603. (93) Mandal, B.; Bhattacharjee, H.; Mittal, N.; Sah, H.; Balabathula, P.; Thoma, L. A.; Wood, G. C. 'Core-shell-type lipid-polymer hybrid nanoparticles as a drug delivery platform.' Nanomedicine 2013, 9, 474-491. (94) Taluja, A.; Youn, Y. S.; Bae, Y. H. 'Novel approaches in microparticulate PLGA delivery systems encapsulating proteins.' J Mater Chem 2007, 17, 4002-4014. (95) Marchetti, C.; Palaia, I.; Giorgini, M.; De Medici, C.; Iadarola, R.; Vertechy, L.; Domenici, L.; Di Donato, V.; Tomao, F.; Muzii, L.; Benedetti Panici, P. 'Targeted drug delivery via folate receptors in recurrent ovarian cancer: a review.' Onco Targets Ther 2014, 7, 1223-1236. (96) Chahibi, Y.; Akyildiz, I. F.; Sang Ok, S. 'Antibody-based molecular communication for targeted drug delivery systems.' Conf Proc IEEE Eng Med Biol Soc 2014, 2014, 5707-5710. (97) Gilboa, E.; Berezhnoy, A.; Schrand, B. 'Reducing Toxicity of Immune Therapy Using Aptamer-Targeted Drug Delivery.' Cancer Immunol Res 2015, 3, 1195-1200. (98) Jin, Y.; Huang, Y.; Yang, H.; Liu, G.; Zhao, R. 'A peptide-based pH-sensitive drug delivery system for targeted ablation of cancer cells.' Chem Commun (Camb) 2015, 51, 14454-14457. (99) Carmeliet, P. 'VEGF as a key mediator of angiogenesis in cancer.' Oncology 2005, 69 Suppl 3, 4-10. (100) Hashizume, H.; Baluk, P.; Morikawa, S.; McLean, J. W.; Thurston, G.; Roberge, S.; Jain, R. K.; McDonald, D. M. 'Openings between defective endothelial cells explain tumor vessel leakiness.' Am J Pathol 2000, 156, 1363-1380. (101) Peer, D.; Karp, J. M.; Hong, S.; Farokhzad, O. C.; Margalit, R.; Langer, R. 'Nanocarriers as an emerging platform for cancer therapy.' Nat Nanotechnol 2007, 2, 751-760. (102) Bertrand, N.; Wu, J.; Xu, X.; Kamaly, N.; Farokhzad, O. C. 'Cancer nanotechnology: the impact of passive and active targeting in the era of modern cancer biology.' Adv Drug Deliv Rev 2014, 66, 2-25. (103) Rajendran, L.; Knolker, H. J.; Simons, K. 'Subcellular targeting strategies for drug design and delivery.' Nat Rev Drug Discov 2010, 9, 29-42. (104) Sakhrani, N. M.; Padh, H. 'Organelle targeting: third level of drug targeting.' Drug Des Devel Ther 2013, 7, 585-599. (105) Noble, G. T.; Stefanick, J. F.; Ashley, J. D.; Kiziltepe, T.; Bilgicer, B. 'Ligand-targeted liposome design: challenges and fundamental considerations.' Trends Biotechnol 2014, 32, 32-45. (106) Biswas, S.; Torchilin, V. P. 'Nanopreparations for organelle-specific delivery in cancer.' Adv Drug Deliv Rev 2014, 66, 26-41. (107) Pathak, R. K.; Kolishetti, N.; Dhar, S. 'Targeted nanoparticles in mitochondrial medicine.' Wiley Interdiscip Rev Nanomed Nanobiotechnol 2015, 7, 315-329. (108) Senft, D.; Ronai, Z. A. 'Regulators of mitochondrial dynamics in cancer.' Curr Opin Cell Biol 2016, 39, 43-52. (109) Gelderblom, H.; Verweij, J.; Nooter, K.; Sparreboom, A. 'Cremophor EL: the drawbacks and advantages of vehicle selection for drug formulation.' Eur J Cancer 2001, 37, 1590-1598. (110) Wen, R.; Banik, B.; Pathak, R. K.; Kumar, A.; Kolishetti, N.; Dhar, S. 'Nanotechnology inspired tools for mitochondrial dysfunction related diseases.' Adv Drug Deliv Rev 2016, 99, 52-69. (111) Hastings, T. G. 'The role of dopamine oxidation in mitochondrial dysfunction: implications for Parkinson's disease.' J Bioenerg Biomembr 2009, 41, 469-472. (112) Marrache, S.; Pathak, R. K.; Dhar, S. 'Detouring of cisplatin to access mitochondrial genome for overcoming resistance.' Proc Natl Acad Sci U S A 2014, 111, 10444-10449. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/76666 | - |
| dc.description.abstract | 粒線體標靶藥物對癌症治療是個新興的策略；被稱為能量工廠的粒線體，除了供應細胞生長的能量，它在細胞凋亡機制中也扮演重要的角色。在粒線體內分佈許多訊息傳遞分子，調控細胞凋亡路徑，維持人體內環境的平衡。在癌化的細胞中，藉由特定分子的異常表現，使細胞凋亡機制失調，讓癌細胞能夠輕易逃脫細胞凋亡的途徑，不斷增生，也讓癌症治療效果不彰。因此藉著誘導粒線體凋亡訊息，重新啟動癌細胞凋亡機制的概念，有潛力成為癌症治療方法。過去研究指出，親脂性陽離子Triphenylphosphonium (TPP)因細胞膜電位為負電位(Δψ p)因素，容易進入細胞，細胞內的TPP分子可增加五到十倍，相較於細胞外。而細胞內粒線體胞器膜的負電位更高，理論上可使TPP分子更大量累積在粒線體中，若與細胞質之TPP含量相比，可增加到一百到五百倍。因此，在本論文研究中，運用TPP為靶向配體，開發具有粒線體標靶功能的新型奈米藥物傳遞系統並應用於癌症治療。在載體設計上，首先合成修飾TPP分子的磷脂質(Lipid-TPP)，並將之使用於製備具有TPP靶向配體之金奈米粒子，在確定修飾有Lipid-TPP分子的金奈米粒子具有細線體標靶的能力後，我們接著將Lipid-TPP與生物可降解性的Poly(Lactide-co-Glycolide)高分子作結合，並包覆紫杉醇製備成為奈米藥物劑型，探討此奈米藥物對粒線體標靶性能與藥物傳遞的效率。從我們的實驗結果得知，奈米藥物系統與TPP分子結合可以選擇性累積在粒線體的位置，並將藥物更有效率傳送到粒線體胞器內，致使毒殺癌細胞效果增加。此外，本論文更深入探討癌細胞死亡機制，發現此奈米藥物系統，會影響細胞內粒線體的膜電位，改變粒線體的動態平衡調控。 | zh_TW |
| dc.description.abstract | Targeting mitochondria as a therapeutic objective for cancer treatment has become an emerging approach in recent years. Mitochondria are referred to the cells' powerhouses, and also the suicidal weapon stores. Dozens of lethal signal transduction pathways that converge on mitochondria, indicating that the mitochondria play pivotal roles in cell death and survival signaling. However, the tumor-specific alterations that protect themselves from apoptosis lead to cell death escape. Strategies on activating cell death machinery in cancer cells by regulating the mitochondrial biofunctions could therefore be promising therapeutic approaches. Herein we report triphenylphosphonium (TPP)-decorated nanosystems that selectively target the mitochondria. The lipophilic cation TPP enhanced cytosolic nanosystem accumulation by 5- to 10-fold from extracellular environment via negative membrane potential (Δψp), and further enhanced nanosystem in the mitochondrial matrix over 100- to 500-fold through negative potential (Δψm). The TPP-sensitized AuNP@lipid hybrid nanoparticles were first fabricated to examine their mitochondria-targeting capability. Next the mitochondria-targeting concept was demonstrated on the biodegradable PLGA@lipid hybrid nanosystems (PLGA = poly(D,L-lactide-co-glycolide)) encapsulating the drug paclitaxel (Taxol) to study their efficiency in targeting and intracellular drug delivery. Based on our preliminary results, TPP decoration onto nanosystems potentially improves their selective accumulation in mitochondria. Intracellular drug delivery performance also demonstrated that the cytotoxicity of the used anticancer drug increased due to the efficient drug delivery into mitochondria. In addition, our design of the nanosystem was found to cause the change in the mitochondrial dynamic and mitochondrial depolarization behaviors. | en |
| dc.description.provenance | Made available in DSpace on 2021-07-10T21:34:45Z (GMT). No. of bitstreams: 1 ntu-105-R02b22032-1.pdf: 4275803 bytes, checksum: ce6a06d677de2177d60339cd266ad81a (MD5) Previous issue date: 2016 | en |
| dc.description.tableofcontents | 誌謝………………………………………………………………………………………I
摘要……………………………………………………………….......…………………II Abstract…………………………………………………………………...…………….III 目錄…………………………………………………………………………………….IV 圖目錄…………………………………………………………………….…...……….VI 表目錄……………………………………………………………….……………….VIII 第一章 緒論 1.1 前言…………………………………………………………………………..1 1.2癌症………………………………………..……………………………….…2 1.2.1癌症生成……………………………..………………………….…….…2 1.3粒線體……………………………………………………………….…….….5 1.3.1粒線體與細胞凋亡………………………………………………………7 1.3.2粒線體動態平衡調控………………….…………………………….…10 1.3.3粒線體與癌症…………………………………………………….….…13 1.3.4粒線體標靶小分子藥物與癌症治療……………………….……….…18 1.4藥物傳遞系統…………………………………………………….…………21 1.4.1奈米藥物傳遞系統………………………………………..……………23 1.4.1.1微脂體………………………………………………………….…25 1.4.1.2 PLGA……………………………………………………...………27 1.4.2標靶藥物傳遞系統……………………………..………………………29 1.4.2.1粒線體標靶藥物藥物傳遞系統………….………………………31 1.5研究動機………………………………………………...…………………..32 第二章 實驗材料與儀器 2.1 實驗藥品……………………………………………………………………33 2.2 細胞株………………………………………………………………………35 2.3 抗體…………………………………………………………………………35 2.4 實驗儀器…………………………………………………..………………..36 第三章 實驗方法 3.1 DSPE-PEG-TPP 材料合成……………………..…………………………..37 3.2載體製備與包覆藥物……………………………………………………….39 3.3奈米載體藥物定量…………………………….……………………………41 3.4細胞培養…………………………………………….………………………42 3.5細胞毒性測試…………………………………………….…………………43 3.6粒線體活性測試………………………………………….…………………44 3.7蛋白質膠體電泳分析………………….……………………………………45 3.7.1蛋白質萃取……………………………………………..………………45 3.7.2蛋白質定量………………………………………..……………………46 3.7.3蛋白質膠體電泳…………………………………..……………………46 3.7.4蛋白質轉印(Electrotransfer) …………………………...………………48 3.7.5免疫墨點法(Immunoblotting) …………………………….……………48 3.8 粒線體蛋白質萃取…………………………………………………...…….50 第四章 實驗結果與討論 4.1 DSPE-PEG2000-TPP鑑定………………………………………….………51 4.2磷脂質包覆PLGA奈米微粒粒徑大小與介面電性……………….………52 4.3奈米載體藥物定量…………………………………………………..………55 4.4細胞攝取奈米載體及奈米載體標靶粒線體現象………………….…….…57 4.5粒線體標靶奈米藥物對癌細胞毒殺能力……………………….…….……60 4.6粒線體標靶奈米藥物對粒線體活性影響………………………….…….…62 4.7粒線體標靶奈米藥物對粒線體膜電位影響…………………….……….…64 4.8粒線體標靶奈米藥物對粒線體動態平衡的影響……………….…….……66 4.9結論…………………………………………………………….……….……68 第五章 未來展望………………………………………………………...……………69 參考文獻……………………………………………………………………….………70 | |
| dc.language.iso | zh-TW | |
| dc.subject | 奈米藥物傳遞系統 | zh_TW |
| dc.subject | 癌症治療 | zh_TW |
| dc.subject | 粒線體標靶 | zh_TW |
| dc.subject | cancer therapy | en |
| dc.subject | mitochondrial targeting | en |
| dc.subject | nanodrug delivery system | en |
| dc.title | 開發細胞胞器標靶奈米藥物技術為新型癌症治療策略 | zh_TW |
| dc.title | Development of subcellular-targeting nanodrug for cancer therapeutic strategy | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 104-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.coadvisor | 蕭寧馨 | |
| dc.contributor.oralexamcommittee | 陳平,鄭建中,吳立真,徐士蘭,楊家銘 | |
| dc.subject.keyword | 癌症治療,粒線體標靶,奈米藥物傳遞系統, | zh_TW |
| dc.subject.keyword | cancer therapy,mitochondrial targeting,nanodrug delivery system, | en |
| dc.relation.page | 81 | |
| dc.identifier.doi | 10.6342/NTU201602987 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2016-08-19 | |
| dc.contributor.author-college | 生命科學院 | zh_TW |
| dc.contributor.author-dept | 生化科技學系 | zh_TW |
| 顯示於系所單位： | 生化科技學系 | |
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