請用此 Handle URI 來引用此文件:
http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/60403
完整後設資料紀錄
DC 欄位 | 值 | 語言 |
---|---|---|
dc.contributor.advisor | 林文澧(Win-Li Lin) | |
dc.contributor.author | Hsiao-Hsuan Hung | en |
dc.contributor.author | 洪筱媗 | zh_TW |
dc.date.accessioned | 2021-06-16T10:17:19Z | - |
dc.date.available | 2016-08-20 | |
dc.date.copyright | 2013-08-20 | |
dc.date.issued | 2013 | |
dc.date.submitted | 2013-08-17 | |
dc.identifier.citation | [1] L. A. Gloeckler Ries, M. E. Reichman, D. R. Lewis, B. F. Hankey, and B. K. Edwards, 'Cancer survival and incidence from the Surveillance, Epidemiology, and End Results (SEER) program,' Oncologist, vol. 8, pp. 541-52, 2003.
[2] F. J. Lagerwaard, P. C. Levendag, P. J. Nowak, W. M. Eijkenboom, P. E. Hanssens, and P. I. Schmitz, 'Identification of prognostic factors in patients with brain metastases: a review of 1292 patients,' Int J Radiat Oncol Biol Phys, vol. 43, pp. 795-803, Mar 1 1999. [3] T. S. Surawicz, F. Davis, S. Freels, E. R. Laws, Jr., and H. R. Menck, 'Brain tumor survival: results from the National Cancer Data Base,' J Neurooncol, vol. 40, pp. 151-60, Nov 1998. [4] M. D. Walker, E. Alexander, Jr., W. E. Hunt, C. S. MacCarty, M. S. Mahaley, Jr., J. Mealey, Jr., et al., 'Evaluation of BCNU and/or radiotherapy in the treatment of anaplastic gliomas. A cooperative clinical trial,' J Neurosurg, vol. 49, pp. 333-43, Sep 1978. [5] L. M. DeAngelis, 'Brain tumors,' N Engl J Med, vol. 344, pp. 114-23, Jan 11 2001. [6] A. Hirano and T. Matsui, 'Vascular structures in brain tumors,' Hum Pathol, vol. 6, pp. 611-21, Sep 1975. [7] J. D. Waggener and J. L. Beggs, 'Vasculature of Neural Neoplasms,' Adv Neurol, vol. 15, pp. 27-49, 1976. [8] D. W. Caley and D. S. Maxwell, 'Development of the blood vessels and extracellular spaces during postnatal maturation of rat cerebral cortex,' J Comp Neurol, vol. 138, pp. 31-47, Jan 1970. [9] R. Wellenreuther, J. A. Kraus, D. Lenartz, A. G. Menon, J. Schramm, D. N. Louis, et al., 'Analysis of the neurofibromatosis 2 gene reveals molecular variants of meningioma,' Am J Pathol, vol. 146, pp. 827-32, Apr 1995. [10] T. Hoshino, J. J. Townsend, I. Muraoka, and C. B. Wilson, 'An autoradiographic study of human gliomas: growth kinetics of anaplastic astrocytoma and glioblastoma multiforme,' Brain, vol. 103, pp. 967-84, Dec 1980. [11] D. R. Groothuis, J. M. Fischer, N. A. Vick, and D. D. Bigner, 'Experimental gliomas: an autoradiographic study of the endothelial component,' Neurology, vol. 30, pp. 297-301, Mar 1980. [12] D. Schiffer, A. Chio, M. T. Giordana, A. Mauro, A. Migheli, and M. C. Vigliani, 'The vascular response to tumor infiltration in malignant gliomas. Morphometric and reconstruction study,' Acta Neuropathol, vol. 77, pp. 369-78, 1989. [13] J. Folkman, 'Angiogenesis: initiation and control,' Ann N Y Acad Sci, vol. 401, pp. 212-27, 1982. [14] M. Greenblatt and P. Shubi, 'Tumor angiogenesis: transfilter diffusion studies in the hamster by the transparent chamber technique,' J Natl Cancer Inst, vol. 41, pp. 111-24, Jul 1968. [15] P. J. Kelly, R. L. Suddith, H. T. Hutchison, K. Werrbach, and B. Haber, 'Endothelial growth factor present in tissue culture of CNS tumors,' J Neurosurg, vol. 44, pp. 342-6, Mar 1976. [16] N. Ferrara and W. J. Henzel, 'Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells,' Biochem Biophys Res Commun, vol. 161, pp. 851-8, Jun 15 1989. [17] W. T. Monacci, M. J. Merrill, and E. H. Oldfield, 'Expression of vascular permeability factor/vascular endothelial growth factor in normal rat tissues,' Am J Physiol, vol. 264, pp. C995-1002, Apr 1993. [18] K. H. Plate, G. Breier, H. A. Weich, H. D. Mennel, and W. Risau, 'Vascular endothelial growth factor and glioma angiogenesis: coordinate induction of VEGF receptors, distribution of VEGF protein and possible in vivo regulatory mechanisms,' Int J Cancer, vol. 59, pp. 520-9, Nov 15 1994. [19] D. Shweiki, A. Itin, D. Soffer, and E. Keshet, 'Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis,' Nature, vol. 359, pp. 843-5, Oct 29 1992. [20] H. F. Dvorak, T. M. Sioussat, L. F. Brown, B. Berse, J. A. Nagy, A. Sotrel, et al., 'Distribution of vascular permeability factor (vascular endothelial growth factor) in tumors: concentration in tumor blood vessels,' J Exp Med, vol. 174, pp. 1275-8, Nov 1 1991. [21] T. Reya, S. J. Morrison, M. F. Clarke, and I. L. Weissman, 'Stem cells, cancer, and cancer stem cells,' Nature, vol. 414, pp. 105-11, Nov 1 2001. [22] S. K. Singh, C. Hawkins, I. D. Clarke, J. A. Squire, J. Bayani, T. Hide, et al., 'Identification of human brain tumour initiating cells,' Nature, vol. 432, pp. 396-401, Nov 18 2004. [23] D. Corbeil, K. Roper, A. Weigmann, and W. B. Huttner, 'AC133 hematopoietic stem cell antigen: human homologue of mouse kidney prominin or distinct member of a novel protein family?,' Blood, vol. 91, pp. 2625-6, Apr 1 1998. [24] S. Corbeil, G. Kurath, and S. E. LaPatra, 'Fish DNA vaccine against infectious hematopoietic necrosis virus: efficacy of various routes of immunisation,' Fish Shellfish Immunol, vol. 10, pp. 711-23, Nov 2000. [25] Y. Uchida, Y. Fujimori, H. Ohsawa, J. Hirose, H. Noike, K. Tokuhiro, et al., 'Angioscopic evaluation of stabilizing effects of bezafibrate on coronary plaques in patients with coronary artery disease,' Diagn Ther Endosc, vol. 7, pp. 21-7, 2000. [26] S. K. Singh, I. D. Clarke, M. Terasaki, V. E. Bonn, C. Hawkins, J. Squire, et al., 'Identification of a cancer stem cell in human brain tumors,' Cancer Res, vol. 63, pp. 5821-8, Sep 15 2003. [27] W. M. Pardridge, 'Blood-brain barrier delivery,' Drug Discov ToDay, vol. 12, pp. 54-61, Jan 2007. [28] M. W. Brightman, 'Morphology of blood-brain interfaces,' Exp Eye Res, vol. 25 Suppl, pp. 1-25, 1977. [29] L. L. Rubin and J. M. Staddon, 'The cell biology of the blood-brain barrier,' Annu Rev Neurosci, vol. 22, pp. 11-28, 1999. [30] D. Fukumura and R. K. Jain, 'Tumor microenvironment abnormalities: causes, consequences, and strategies to normalize,' J Cell Biochem, vol. 101, pp. 937-49, Jul 1 2007. [31] D. Fukumura and R. K. Jain, 'Tumor microvasculature and microenvironment: targets for anti-angiogenesis and normalization,' Microvasc Res, vol. 74, pp. 72-84, Sep-Nov 2007. [32] S. Paku and N. Paweletz, 'First steps of tumor-related angiogenesis,' Lab Invest, vol. 65, pp. 334-46, Sep 1991. [33] H. F. Dvorak, J. A. Nagy, J. T. Dvorak, and A. M. Dvorak, 'Identification and characterization of the blood vessels of solid tumors that are leaky to circulating macromolecules,' Am J Pathol, vol. 133, pp. 95-109, Oct 1988. [34] A. Eberhard, S. Kahlert, V. Goede, B. Hemmerlein, K. H. Plate, and H. G. Augustin, 'Heterogeneity of angiogenesis and blood vessel maturation in human tumors: implications for antiangiogenic tumor therapies,' Cancer Res, vol. 60, pp. 1388-93, Mar 1 2000. [35] J. W. Baish and R. K. Jain, 'Fractals and cancer,' Cancer Res, vol. 60, pp. 3683-8, Jul 15 2000. [36] K. L. Black and N. S. Ningaraj, 'Modulation of brain tumor capillaries for enhanced drug delivery selectively to brain tumor,' Cancer Control, vol. 11, pp. 165-73, May-Jun 2004. [37] R. Stupp, W. P. Mason, M. J. van den Bent, M. Weller, B. Fisher, M. J. Taphoorn, et al., 'Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma,' N Engl J Med, vol. 352, pp. 987-96, Mar 10 2005. [38] S. B. Tatter, 'Recurrent malignant glioma in adults,' Curr Treat Options Oncol, vol. 3, pp. 509-24, Dec 2002. [39] M. Westphal, D. C. Hilt, E. Bortey, P. Delavault, R. Olivares, P. C. Warnke, et al., 'A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafers (Gliadel wafers) in patients with primary malignant glioma,' Neuro Oncol, vol. 5, pp. 79-88, Apr 2003. [40] D. Fortin, A. Desjardins, A. Benko, T. Niyonsega, and M. Boudrias, 'Enhanced chemotherapy delivery by intraarterial infusion and blood-brain barrier disruption in malignant brain tumors: the Sherbrooke experience,' Cancer, vol. 103, pp. 2606-15, Jun 15 2005. [41] Z. Lidar, Y. Mardor, T. Jonas, R. Pfeffer, M. Faibel, D. Nass, et al., 'Convection-enhanced delivery of paclitaxel for the treatment of recurrent malignant glioma: a phase I/II clinical study,' J Neurosurg, vol. 100, pp. 472-9, Mar 2004. [42] M. K. N. Gummerloch, E. A., Physiology and Pharmacology of the Blood-Brain Barrier vol. 103, 1992. [43] W. M. Pardridge, J. L. Buciak, and P. M. Friden, 'Selective transport of an anti-transferrin receptor antibody through the blood-brain barrier in vivo,' J Pharmacol Exp Ther, vol. 259, pp. 66-70, Oct 1991. [44] D. Chen and K. H. Lee, 'Biodistribution of calcitonin encapsulated in liposomes in mice with particular reference to the central nervous system,' Biochim Biophys Acta, vol. 1158, pp. 244-50, Nov 28 1993. [45] X. Zhou and L. Huang, 'DNA transfection mediated by cationic liposomes containing lipopolylysine: characterization and mechanism of action,' Biochim Biophys Acta, vol. 1189, pp. 195-203, Jan 19 1994. [46] J. Huwyler, D. Wu, and W. M. Pardridge, 'Brain drug delivery of small molecules using immunoliposomes,' Proc Natl Acad Sci U S A, vol. 93, pp. 14164-9, Nov 26 1996. [47] N. D. Doolittle, M. E. Miner, W. A. Hall, T. Siegal, E. Jerome, E. Osztie, et al., 'Safety and efficacy of a multicenter study using intraarterial chemotherapy in conjunction with osmotic opening of the blood-brain barrier for the treatment of patients with malignant brain tumors,' Cancer, vol. 88, pp. 637-47, Feb 1 2000. [48] C. Guerin, A. Olivi, J. D. Weingart, H. C. Lawson, and H. Brem, 'Recent advances in brain tumor therapy: local intracerebral drug delivery by polymers,' Invest New Drugs, vol. 22, pp. 27-37, Jan 2004. [49] R. A. Kroll and E. A. Neuwelt, 'Outwitting the blood-brain barrier for therapeutic purposes: osmotic opening and other means,' Neurosurgery, vol. 42, pp. 1083-99; discussion 1099-100, May 1998. [50] H. Maeda, J. Wu, T. Sawa, Y. Matsumura, and K. Hori, 'Tumor vascular permeability and the EPR effect in macromolecular therapeutics: a review,' J Control Release, vol. 65, pp. 271-84, Mar 1 2000. [51] R. K. Jain, 'Barriers to drug delivery in solid tumors,' Sci Am, vol. 271, pp. 58-65, Jul 1994. [52] R. K. Jain, 'Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy,' Science, vol. 307, pp. 58-62, Jan 7 2005. [53] R. K. Jain, 'Transport of molecules in the tumor interstitium: a review,' Cancer Res, vol. 47, pp. 3039-51, Jun 15 1987. [54] Y. H. Bae and K. Park, 'Targeted drug delivery to tumors: myths, reality and possibility,' J Control Release, vol. 153, pp. 198-205, Aug 10 2011. [55] A. S. Hoffman, 'The origins and evolution of 'controlled' drug delivery systems,' J Control Release, vol. 132, pp. 153-63, Dec 18 2008. [56] Z. G. Gao, L. Tian, J. Hu, I. S. Park, and Y. H. Bae, 'Prevention of metastasis in a 4T1 murine breast cancer model by doxorubicin carried by folate conjugated pH sensitive polymeric micelles,' J Control Release, vol. 152, pp. 84-9, May 30 2011. [57] R. K. Jain and T. Stylianopoulos, 'Delivering nanomedicine to solid tumors,' Nat Rev Clin Oncol, vol. 7, pp. 653-64, Nov 2010. [58] K. Hynynen, N. McDannold, N. Vykhodtseva, and F. A. Jolesz, 'Noninvasive MR imaging-guided focal opening of the blood-brain barrier in rabbits,' Radiology, vol. 220, pp. 640-6, Sep 2001. [59] C. Y. Lin, Y. L. Huang, J. R. Li, F. H. Chang, and W. L. Lin, 'Effects of focused ultrasound and microbubbles on the vascular permeability of nanoparticles delivered into mouse tumors,' Ultrasound Med Biol, vol. 36, pp. 1460-9, Sep 2010. [60] C. Y. Lin, J. R. Li, H. C. Tseng, M. F. Wu, and W. L. Lin, 'Enhancement of focused ultrasound with microbubbles on the treatments of anticancer nanodrug in mouse tumors,' Nanomedicine, vol. 8, pp. 900-7, Aug 2012. [61] K. Hynynen, N. McDannold, N. Vykhodtseva, and F. A. Jolesz, 'Non-invasive opening of BBB by focused ultrasound,' Acta Neurochir Suppl, vol. 86, pp. 555-8, 2003. [62] N. Sheikov, N. McDannold, S. Sharma, and K. Hynynen, 'Effect of focused ultrasound applied with an ultrasound contrast agent on the tight junctional integrity of the brain microvascular endothelium,' Ultrasound Med Biol, vol. 34, pp. 1093-104, Jul 2008. [63] N. Sheikov, N. McDannold, N. Vykhodtseva, F. Jolesz, and K. Hynynen, 'Cellular mechanisms of the blood-brain barrier opening induced by ultrasound in presence of microbubbles,' Ultrasound Med Biol, vol. 30, pp. 979-89, Jul 2004. [64] N. McDannold, N. Vykhodtseva, and K. Hynynen, 'Targeted disruption of the blood-brain barrier with focused ultrasound: association with cavitation activity,' Phys Med Biol, vol. 51, pp. 793-807, Feb 21 2006. [65] N. J. McDannold, N. I. Vykhodtseva, and K. Hynynen, 'Microbubble contrast agent with focused ultrasound to create brain lesions at low power levels: MR imaging and histologic study in rabbits,' Radiology, vol. 241, pp. 95-106, Oct 2006. [66] L. H. Treat, N. McDannold, N. Vykhodtseva, Y. Zhang, K. Tam, and K. Hynynen, 'Targeted delivery of doxorubicin to the rat brain at therapeutic levels using MRI-guided focused ultrasound,' Int J Cancer, vol. 121, pp. 901-7, Aug 15 2007. [67] H. L. Liu, M. Y. Hua, P. Y. Chen, P. C. Chu, C. H. Pan, H. W. Yang, et al., 'Blood-brain barrier disruption with focused ultrasound enhances delivery of chemotherapeutic drugs for glioblastoma treatment,' Radiology, vol. 255, pp. 415-25, May 2010. [68] S. Voulgaris, M. Partheni, M. Karamouzis, P. Dimopoulos, N. Papadakis, and H. P. Kalofonos, 'Intratumoral doxorubicin in patients with malignant brain gliomas,' Am J Clin Oncol, vol. 25, pp. 60-4, Feb 2002. [69] K. A. Walter, R. J. Tamargo, A. Olivi, P. C. Burger, and H. Brem, 'Intratumoral chemotherapy,' Neurosurgery, vol. 37, pp. 1128-45, Dec 1995. [70] A. C. Stan, S. Casares, D. Radu, G. F. Walter, and T. D. Brumeanu, 'Doxorubicin-induced cell death in highly invasive human gliomas,' Anticancer Res, vol. 19, pp. 941-50, Mar-Apr 1999. [71] L. H. Treat, N. McDannold, Y. Zhang, N. Vykhodtseva, and K. Hynynen, 'Improved anti-tumor effect of liposomal doxorubicin after targeted blood-brain barrier disruption by MRI-guided focused ultrasound in rat glioma,' Ultrasound Med Biol, vol. 38, pp. 1716-25, Oct 2012. [72] H. von Holst, E. Knochenhauer, H. Blomgren, V. P. Collins, L. Ehn, M. Lindquist, et al., 'Uptake of adriamycin in tumour and surrounding brain tissue in patients with malignant gliomas,' Acta Neurochir (Wien), vol. 104, pp. 13-6, 1990. [73] N. Uchida, D. W. Buck, D. He, M. J. Reitsma, M. Masek, T. V. Phan, et al., 'Direct isolation of human central nervous system stem cells,' Proc Natl Acad Sci U S A, vol. 97, pp. 14720-5, Dec 19 2000. [74] A. H. Yin, S. Miraglia, E. D. Zanjani, G. Almeida-Porada, M. Ogawa, A. G. Leary, et al., 'AC133, a novel marker for human hematopoietic stem and progenitor cells,' Blood, vol. 90, pp. 5002-12, Dec 15 1997. [75] S. Miraglia, W. Godfrey, A. H. Yin, K. Atkins, R. Warnke, J. T. Holden, et al., 'A novel five-transmembrane hematopoietic stem cell antigen: isolation, characterization, and molecular cloning,' Blood, vol. 90, pp. 5013-21, Dec 15 1997. [76] Y. Boucher, M. Leunig, and R. K. Jain, 'Tumor angiogenesis and interstitial hypertension,' Cancer Res, vol. 56, pp. 4264-6, Sep 15 1996. [77] N. Sheikov, N. McDannold, F. Jolesz, Y. Z. Zhang, K. Tam, and K. Hynynen, 'Brain arterioles show more active vesicular transport of blood-borne tracer molecules than capillaries and venules after focused ultrasound-evoked opening of the blood-brain barrier,' Ultrasound Med Biol, vol. 32, pp. 1399-409, Sep 2006. [78] S. P. Leon, R. D. Folkerth, and P. M. Black, 'Microvessel density is a prognostic indicator for patients with astroglial brain tumors,' Cancer, vol. 77, pp. 362-72, Jan 15 1996. [79] F. Zeppernick, R. Ahmadi, B. Campos, C. Dictus, B. M. Helmke, N. Becker, et al., 'Stem cell marker CD133 affects clinical outcome in glioma patients,' Clin Cancer Res, vol. 14, pp. 123-9, Jan 1 2008. [80] S. Warrier, P. Pavanram, D. Raina, and M. Arvind, 'Study of chemoresistant CD133+ cancer stem cells from human glioblastoma cell line U138MG using multiple assays,' Cell Biol Int, vol. 36, pp. 1137-43, 2012. | |
dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/60403 | - |
dc.description.abstract | 目的:聚焦式超音波搭配微氣泡,可強化奈米抗癌藥物微脂體在大鼠腦腫瘤組織的累積量及療效。本研究欲探討在不同成長階段的大鼠腦腫瘤,其在有無搭配聚焦式超音波搭配微氣泡所造成的藥物在腫瘤組織累積量的差異、藥物抑制腫瘤生長的效果差異,以及在微觀下的特殊組織染色分析腫瘤組織的差異。
方法與材料:本實驗的超音波參數頻率為0.5 MHz,壓力為0.5 MPa,微氣泡劑量為100 ul/kg;奈米抗癌藥物微脂體劑量為6 mg/kg。使用神經膠質瘤細胞C6 glioma cells (106 cells) 植入右半腦以及相同體積的生理食鹽水植入左半腦。奈米抗癌藥物微脂體在腫瘤細胞植入後第8天、第11天或第14天經尾靜脈注射,分別代表早期、中期和晚期階段腫瘤;另外設計一組分別在第8天和第11天都施藥;除此之外,分為有無施打聚焦式超音波搭配微氣泡。一半的老鼠在奈米抗癌藥物微脂體注射入體內後24小時犧牲做酵素免疫分析法定量腫瘤組織內藥物,另外一半的老鼠會在第16天犧牲評估腫瘤治療效果,組織樣本會做特殊免疫染色:H&E、CD31、CD133、VEGF,以及螢光染色。我們會在第15天注射Evans blue (EB, 100 mg/kg),老鼠總共為136隻。 結果:奈米抗癌藥物微脂體的萃取量隨著腫瘤的生長其藥物在組織中的萃取濃度越高,而且經過施打聚焦式超音波搭配微氣泡有顯著的差異,在第8天的強化成效較第11天以及第14天顯著。除此之外,治療方面,腫瘤生長體積在第16天的結果,發現奈米抗癌藥物微脂體結合聚焦式超音波搭配微氣泡比只有施打奈米抗癌藥物有顯著的抑制效果;單次治療組別,在第8天施打奈米抗癌藥物微脂體結合聚焦式超音波搭配微氣泡其腫瘤生長抑制效果較在第11天做治療顯著;相較於其他治療組別,兩次治療分別在第8天和第11天施打奈米抗癌藥物微脂體結合聚焦式超音波搭配微氣泡有最顯著的抑制腫瘤生長效果。在組織染色的部份,隨著腫瘤生長時間增加,細胞分佈越濃密,特殊組織染色分析結果也越明顯;比較治療後第16天的腦腫瘤組織,其細胞核變異性,細胞數,特殊蛋白表現較控制組第16天的腦腫瘤組織細胞核單一性,細胞數少量,特殊組織染色分析結果降低,尤其是治療兩次施打奈米抗癌藥物微脂體結合聚焦式超音波搭配微氣泡的組別。 結論:就奈米化療藥物累積量的結果來看,得知晚期的腫瘤組織通透性較早期的腫瘤組織佳,原因或許可以從CD31、VEGF的特殊組織染色分析結果其表現量增加而推出晚期腫瘤組織具備較多的血管,也就是說在中期與晚期階段的腫瘤組織其血管通透性較好,在早期第8天其腫瘤組織的血管通透性較差,另外隨著腫瘤體積增加其血腦屏障的完整性可能被腫瘤組織破壞,因此聚焦式超音波搭配微氣泡強化奈米藥物累積,雖有其顯著強化效果,但尤其是對早期腫瘤組織特別顯著。就腫瘤治療結果來看,治療兩次施打奈米抗癌藥物微脂體結合聚焦式超音波搭配微氣泡腫瘤生長抑制效果最為顯著,歸因於其具有較高藥物濃度的累積,而其抑制效果除了腫瘤體積減少,腫瘤細胞數減少,其CD133的表現量也減少,也就是所殘存的腫瘤細胞其抗藥性和再分化能力降低。所以藥物注射入體內後利用聚焦式超音波搭配微氣泡以提昇腦腫瘤組織內累積量達到藥物毒殺細胞效率進而抑制腫瘤的生長的效果,特別是在早期階段性治療以及多次治療具備更好的抑制效果。 | zh_TW |
dc.description.abstract | Purpose: Focused ultrasound (FUS) with microbubbles (MB) could enhance the delivery of nanodrug into brain tumors in rodent model. In this study, we investigated the difference of PEGylated liposomal doxorubicin (PLD) accumulation, tumor growth response after treatment and immunohistochemistry in different stages of brain tumor tissue-bearing with or without FUS/MBs.
Methods and Materials: The ultrasound frequency and peak pressure at the focal zone were 0.5 MHz and 0.5 MPa, respectively. The doses of MB and PLD through IV injection were 100 ul/kg, and 6 mg/kg, respectively. C6 glioma cells (106 cells) were injected into the right hemisphere and same volume of saline were into the left hemisphere (sham). PLD solution was injected on Day 8, Day 11, or Day 14 after tumor inoculation for the early-, medium-, or late-staged tumors, respectively, and a shot on both Day 8 and Day 11 was also studied for both with and without FUS/MBs. A half of the rats were sacrificed 24 hours after PLD injection to quantify the amount of PLD accumulated in tumor tissues by ELISA and the other half were sacrificed on Day 16 to evaluate the tumor growth response. Some tissue samples were analyzed by immunohistochemistry, CD31, VEGF and CD133, and immunofluorescence assay. We also injected Evan blue (EB, 100 mg/kg) on Day 15 and N was equal to 6 for each group. Results: The result of PLD accumulation shows that there was higher concentration of doxorubicin in later staged tumor tissue with or without sonication, FUS/MBs sonication could significantly enhance the amount of PLD accumulated in tumor tissues on Day 8 but not so drastically enhanced by sonication on Day 11 or Day 14. In addition, the tumor size of the PLD+MBs+FUS group was significantly smaller than the PLD groups on Day 16; in the groups with one treatment, we found the tumors size of the PLD+MBs+FUS groups treated on Day 8 was significantly smaller than that of group treated on Day 11and Day 14; and an additional PLD+MBs+FUS treatment causes a significantly further inhibition. Furthermore, the immunochemistry analysis of brain tumor tissues on Day 16 showed that (1) the nuclei were more pleomorphic and the cell distribution was more condensed in the control groups, and the responses of CD31, VEGF, and CD133 in brain tumor tissues were stronger in different stages; (2) these above phenomena were decreased in the treated groups, especially in the group with two PLD+MBs+FUS treatment. Conclusion: The result of nanodrug accumulation shows that there was a higher concentration of doxorubicin in a later staged tumor tissue, due to the compromised BBB with tumor growth, and the responses of CD31 and VEGF immunochemistry for a later-staged tumor tissue were stronger, indicating a high vascular permeability for medium- and late-staged tumors but a low permeability for the early-staged tumor. Therefore FUS/MBs is able to enhance the delivery of nanodrug into brain tumors, especially in early staged tumors. The result of tumor therapy shows an additional PLD+MBs+FUS strategy could successfully inhibit tumor growth due to a high concentration of nanodrug accumulation. The strategy decreases not only tumor volume and tumor cells but also CD133 immunochemistry response, displaying that abilities of drug resistance and differentiation of tumor cells would decrease. As a results, FUS/MBs can enhance the delivery of nanodrug and then achieve a greater cytotoxic ability of nanodrug to achieve an effective inhibition for tumor growth. A better hinder for early-staged tumors can be seen and multiple treatment of PLD+MBs+FUS can further damage the tumor. | en |
dc.description.provenance | Made available in DSpace on 2021-06-16T10:17:19Z (GMT). No. of bitstreams: 1 ntu-102-R00548029-1.pdf: 6801133 bytes, checksum: 8d2b88cb5547a4df2380e7c6f7d79673 (MD5) Previous issue date: 2013 | en |
dc.description.tableofcontents | 口試委員會審定書 #
誌謝 i 中文摘要 ii ABSTRACT iv CONTENTS vii LIST OF FIGURES ix LIST OF TABLES x Chapter 1 INTRODUCTION 1 1.1 Problems of brain tumor therapy 1 1.2 Blood vessel architecture and angiogenesis in glioma 1 1.3 Cancer stem cell markers 3 1.4 Blood-brain barrier (BBB) and blood brain-tumor barrier (BTB) 3 1.5 Biologic therapy for malignant glioma 4 1.6 Delivery strategies across the BBB 5 1.7 Disadvantages of passive targeting 5 1.8 BBB disruption via focused ultrasound combined with microbubbles 6 1.9 PEGylated Liposomal Doxorubicin (PLD) 7 1.10 Specific Aim 7 Chapter 2 MATERIALS AND METHODS 8 2.1 Cell culture 8 2.2 Animals 8 2.3 Tumor implantation 8 2.4 Study design 9 2.5 Ultrasound 10 2.6 Chemotherapy 11 2.7 Quantification 11 2.8 Immunofluorescence analysis 12 2.9 Immunohistochemistry 12 2.10 Statistical Analysis 13 Chapter 3 RESULTS 17 3.1 Tumor growth and blood brain-tumor barrier (BTB) 17 3.2 Effect of burst length of FUS sonication on nanodrug delivery and tissue damage 17 3.3 PLD accumulation in tumor tissues related to FUS sonication and tumor stages 18 3.4 Influence of FUS sonication times with MBs on tumor growth response for chemotherapy with anticancer nanodrug 19 3.5 Immunohistochemistry 19 Chapter 4 DISCUSSIONS 28 Chapter 5 CONCLUSIONS 32 REFERENCES 33 | |
dc.language.iso | en | |
dc.title | 在不同腦腫瘤生長階段下施打聚焦式超音波搭配微氣泡強化奈米抗癌藥物在腫瘤組織的累積量及療效 | zh_TW |
dc.title | Focused Ultrasound with Microbubbles
Enhances the Accumulation and Efficacy of Anticancer Nanodrug in Different Stages of Brain Tumors | en |
dc.type | Thesis | |
dc.date.schoolyear | 101-2 | |
dc.description.degree | 碩士 | |
dc.contributor.oralexamcommittee | 張富雄(Fu-Hsiung Chang),謝銘鈞(Ming-Jium Shieh) | |
dc.subject.keyword | 聚焦式超音波,奈米抗癌藥物微脂體,神經膠質瘤細胞,奈米藥物, | zh_TW |
dc.subject.keyword | focused ultrasound,microbubbles,PEGylated liposomal doxorubicin,glioma,nanodrug,tumor stages, | en |
dc.relation.page | 38 | |
dc.rights.note | 有償授權 | |
dc.date.accepted | 2013-08-17 | |
dc.contributor.author-college | 工學院 | zh_TW |
dc.contributor.author-dept | 醫學工程學研究所 | zh_TW |
顯示於系所單位: | 醫學工程學研究所 |
文件中的檔案:
檔案 | 大小 | 格式 | |
---|---|---|---|
ntu-102-1.pdf 目前未授權公開取用 | 6.64 MB | Adobe PDF |
系統中的文件,除了特別指名其著作權條款之外,均受到著作權保護,並且保留所有的權利。