利用腫瘤趨向性脂肪幹細胞攜帶智慧型奈米微粒對膠質母細胞瘤進行靶向傳遞及化學治療

簡易檢索 / 詳目顯示

回結果列表

研究生：	林意文 Lin, Yi-Wen
論文名稱：	利用腫瘤趨向性脂肪幹細胞攜帶智慧型奈米微粒對膠質母細胞瘤進行靶向傳遞及化學治療 Tumortropic Adipose-Derived Stem Cells Carrying Smart Therapeutic Nanoparticles for Targeting Delivery and Chemotherapy of Glioblastoma
指導教授：	邱信程 Chiu, Hsin-Cheng
口試委員:	江啟勳 Chiang, Chi-Shiun 張建文 Chang, Chien-Wen 許源宏 Hsu,Yuan-Hung
學位類別：	碩士 Master
系所名稱：	原子科學院 - 生醫工程與環境科學系 Department of Biomedical Engineering and Environmental Sciences
論文出版年：	2014
畢業學年度：	102
語文別：	中文
論文頁數：	93
中文關鍵詞：	脂肪幹細胞、奈米粒子、抗癌藥物、細胞型傳遞系統
外文關鍵詞：	Adipose-derived stem cells, Nanoparticles, Anti-cancer drugs, Cell-based drug delivery systems
相關次數：	點閱：4 下載：0
分享至:	分享至facebook 分享至twitter

查詢本校圖書館目錄查詢臺灣博碩士論文知識加值系統勘誤回報

本研究的目標是利用具腫瘤趨向性的脂肪幹細胞作為智慧型奈米載藥微粒的傳遞媒介，將化療藥物主動靶向輸送至惡性腦瘤，再透過施加高頻交流磁場(high frequency magnetic field, HFMF)觸發載藥奈米微粒釋放藥物以達成精準有效的腦瘤化學治療。智慧型奈米載藥微粒的核心是由疏水poly(lactic-co-glycolic acid) (PLGA)鏈段聚集所構成，可同時裝載化療藥物paclitaxel (PTX)與oleic acid-coated superparamagnetic iron oxide nanoparticles (SPIONs)。為了提升載藥微粒的結構穩定性，透過疏水定錨方式將雙性生物可降解高分子poly(γ-glutamic acid-co-distearin glutamate) (poly(γ-GA-co-DSGA))與疏水PLGA核心相結合。實驗分析結果顯示奈米載藥微粒之粒徑與粒徑分布(polydispersity index, PDI)分別為106.5 nm與0.11，其藥物包覆效率及裝載量可達91.9%及8.4 wt%。體外細胞實驗結果證實，奈米微粒緊密的疏水核心可穩定包覆藥物且避免洩漏；因此吞噬奈米載藥微粒的幹細胞不僅能維持良好的細胞存活率亦保有良好的腫瘤趨向性。活體內分布及腫瘤生長抑制實驗數據說明:相較於由小鼠尾靜脈僅注射載藥微粒，將載藥幹細胞注射入帶有原位腦癌腫瘤ALTS1C1的小鼠能大幅提升奈米微粒於腦瘤的累積程度，再透過體外施加高頻交流磁場產生磁-熱效應觸發藥物釋放可有效造成癌細胞的壞死凋亡進而延長小鼠的存活時間。此外，於小鼠之皮下ALTS1C1腫瘤動物實驗中亦可觀察到結合載藥幹細胞與高頻交流磁場的治療模式的確能有效抑制腫瘤生長。綜合上述成果，我們證實結合智慧型奈米載藥微粒與腫瘤趨向性幹細胞能有效將藥物傳遞至對傳統化療療效不彰的腦瘤區域，再搭配體外磁場操控藥物釋放可大幅抑制腦瘤生長，相信此一方法的建立能開啟對腦癌治療的新契機。

To improve the therapeutic efficacy of solid brain tumors by promoting tumor-targeted chemotherapy delivery and triggering drug release upon external alternating magnetic field, the tumor-tropic adipose-derived stem cells were exploited as a vehicle to carry the superparamagnetic iron oxide nanoparticles (SPION)/ paclitaxel (PTX) -loaded nanoparticles. The PTX and oleic acid-coated SPIONs were hydrophobically entrapped in the poly(lactic-co-glycolic acid)-based cores stabilized by amphiphilic lipid-containing copolymer, poly(γ-glutamic acid-co-distearin glutamate).While the particle size and polydispersity index were evaluated to be ca 106 nm and 0.11, respectively, the SPION / PTX -loaded nanoparticles were featured with a high drug loading efficiency (91.9%), corresponding to a loading capacity of 8.4 wt%. The in vitro results demonstrate that the SPION / PTX -loaded nanoparticles after being engulfed by stem cells are benign to the cellular host, thereby allowing the host to retain their innate tumor tropism. The in vivo fluorescence images reveal that the Cy5.5-labeled nanoparticles transported by tumor-homing stem cells display the considerably enhanced accumulation in the brain tumor of the ALTS1C1 intracranial tumor-bearing mice. Notably, the survival rate of the ALTS1C1 intracranial tumor-bearing mice subjected to the payload-containing stem cells via tail vein injection and high frequency magnetic field (HFMF) was significantly enhanced as compared to that of tumor-bearing mice receiving SPION / PTX -loaded nanoparticles alone. Furthermore, the treatment combining payload-containing stem cells and HFMF stimulus exhibited the superior capability of inhibiting tumor growth of the ALTS1C1 subcutaneous tumor-bearing mice. Based on the above results, the use of tumor-tropic stem cells to deliver therapeutic nanoparticles combined with the external remotely-controlled drug release shows the great potential for brain tumor treatment.

摘要....................................................II
Abstract...............................................III
致謝...................................................    IV
表目錄...................................................X
圖目錄...................................................XI
中英文對照表..............................    ................XV
一. 緒論    ............................................... 1
1 前言    .............................. ................ 1
2 研究動機及目的.......................................    2
二.文獻回顧.............................................    4
1 腫瘤微環境...........................................    4
1.1 腫瘤微環境介紹.......................................4
1.2 腫瘤血管新生    ........................................5
2 惡性腦瘤Brain tumor..................................6
2.1 多形性膠質母細胞瘤【Glioblastoma Multiforme ,GBM】....    7
2.2 血腦屏障 (Blood-brain barrier , BBB)...............    7
2.3 血腦屏障的藥物運送..................................    10
2.4 腦瘤治療..........................................    12
2.5 腦瘤治療瓶頸.......................................    13
3 現代高分子載體作為腫瘤治療之概況.........................    14
3.1 高分子藥物載體傳輸系統【Drug delivery system】........    15
3.2 藥物標的方式.......................................    16
3.3 高分子微粒    ........................................18
3.4 高分子微粒製備與包藥方式.............................    19
3.5 γ-聚麩胺酸簡介【γ-Poly (glutamic acid)：γ-PGA】.....    20
3.5.1 γ-聚麩胺酸......................................    20
3.5.2 γ-聚麩胺酸的化學結構特性[60].......................    21
4 細胞載具............................................    21
4.1 幹細胞之特性......................................    21
4.1.1 幹細胞的腫瘤趨向性...............................    22
4.2 細胞調控藥物傳遞系統 【Cell-mediated drug delivery system】...............................................    23
4.3 化學治療藥物paclitaxel (PTX)之介紹..................    24
4.3.1 研究背景    ........................................24
4.3.2 作用機轉.........................................    25
5 磁性奈米微粒作為藥物傳遞之應用    ........................26
5.1 磁性奈米微粒的特性    ................................26.
5.2 氧化鐵特性.........................................    27
5.3 以liposomes/micelles 形式包覆磁性奈米粒子............    27
5.4 磁熱效應...........................................    28
5.5 超順磁奈米氧化鐵於腫瘤治療之應用.......................    29
三.實驗方法與步驟    ........................................31
1 高分子合成與性質鑑定...................................    31
1.1 高分子聚麩胺酸(-PGA)的水解..........................    31
1.2 二硬酯酸甘油脂修飾聚麩胺酸高分子之合成...................    31
1.2.1 無水有機溶劑之製備    ................................31
1.2.2 活化聚麩胺酸......................................    31
1.2.3 聚麩胺酸修飾distearin............................    32
1.2.4 二硬酯酸甘油脂修飾聚麩胺酸高分子之組成鑑定.............    32
2 超順磁氧化鐵奈米微粒(superparamagnetic iron oxide nanoparticles, SPIONs)之製備............................    32
3 超順磁氧化鐵奈米微粒性質鑑定...........................    33
3.1 F e 3O 4 之X射線繞射分析儀分析(X-Ray Diffractometer , XRD)...................................................    33
3.2 氧化鐵奈米微粒之超導量子干涉儀........................    34
3.3 氧化鐵奈米微粒之熱重分析儀量測    ........................34
4 高分子載體製備與特性分析    ................................35
4.1 高分子奈米微粒的製備.................................    35
4.2 高分子奈米微粒粒徑分析...............................    36
4.2.1 奈米微粒型態分析..................................    36
4.2.2 奈米微粒利用動態光散射儀(Dynamic light scattering,DLS)粒徑分析...................................................    36
4.3 奈米載體之穩定性測試................................    37
4.4 載藥高分子奈米微粒之藥物包覆效率與包覆含量測定...........    37
4.5 高分子載藥奈米微粒體外(in vitro)釋放實驗與分析.........    37
4.6 高分子載藥奈米微粒經高頻磁場升溫測試...................    38
5 體外細胞實驗........................................    39
5.1 細胞來源及適合之培養條件..............................    39
5.2 細胞培養..........................................    39.
5.3 脂肪衍生幹細胞分離(ADSCs) [94, 95]..................    40
5.4 幹細胞的分化與鑑定[94].............................    40
5.5 小鼠脂肪幹細胞對高分子粒子之吞噬情形...................    40
5.5.1 流式細胞儀分析..................................    40
5.5.2 螢光顯微鏡觀察..................................    41
5.6 細胞毒性分析    ........................................41
5.6.1 高分子奈米載體對脂肪幹細胞之毒性分析..................    41
5.7 脂肪幹細胞對高分子奈米載體(SPION/PTX-loaded NPs)的裝載.    42
5.7.1 細胞內藥物吞噬含量評估.............................    42
5.7.2 細胞內超順磁奈米氧化鐵吞噬能力評估...................    42
5.8 脂肪幹細胞吞噬奈米載體後之移動能力測試..................    44
5.8.1 條件培養液製備...................................    44
5.8.2 幹細胞移動能力測試................................    44
5.9 高頻交流磁場對癌細胞之體外毒性評估......................    45
6 動物實驗.............................................    46
6.1 動物來源..........................................    46
6.2 腫瘤模型建立    ........................................46
6.3 高分子載體於小鼠體內累積分布情形.......................    47
6.4 腫瘤抑制生長評估....................................    48
6.5 幹細胞尾靜脈注射...................................    48
6.6 動物犧牲與腫瘤組織包埋    ................................49
6.7 組織切片...........................................    49
6.7.1 腫瘤組織切片Hematoxylin and eosin (H&E)染色.......    49
6.7.2 組織切片免疫螢光染色..............................    50
7數據統計............................................    50
四.結果與討論...........................................    51
1 二硬酯酸甘油脂修飾聚麩胺酸高分子組成分析.................    51
2 奈米超順磁氧化鐵之性質分析............................    52
3 高分子載體之性質分析.................................    54
3.1 高分子組成對奈米微粒尺寸影響........................    54
3.2 載藥奈米微粒的特性分析    ................................56
4 高分子載體中的PTX含量分析.............................    57
5 藥物傳遞及藥物控制釋放分析.............................    58
6 高分子載體的磁熱效應....................................59
7 細胞實驗.............................................    60
7.1 幹細胞吞噬SPION/PTX-loaded NPs的特性分析............    60
7.2 裝載SPION/PTX-loaded NPs之幹細胞的螢光顯微鏡觀察.......    62
8 Prussian blue assay    ................................63
9 裝載SPION/PTX-loaded NPs之幹細胞體外治療評估............    65
10 細胞遷移能力分析.....................................    66
11 動物實驗...........................................    69
11.1 皮下腫瘤以靜脈注射給藥.............................    70
11.1.1 高分子載體於動物體內之累積情形......................    70
11.1.2 藥物傳遞系統於腫瘤生長抑制之成效....................    71
11.2 腫瘤組織切片觀察及免疫染色分析........................    73
11.3 原位腫瘤以靜脈注射給藥..............................    76
11.3.1 動物體內藥物累積分佈.............................    76
11.3.2 老鼠體重及存活率評估.............................    78
11.3.3 腫瘤組織切片免疫螢光及H&E染色......................    79
五.結論    .................................................83
六.參考文獻...............................................84



                                

[1]M. Roger, A. Clavreul, M. C. Venier-Julienne, C. Passirani, C. Montero-Menei, and P. Menei, "The potential of combinations of drug-loaded nanoparticle systems and adult stem cells for glioma therapy," Biomaterials, vol. 32, pp. 2106-16, Mar 2011.
[2]R. Stupp, M. E. Hegi, W. P. Mason, M. J. van den Bent, M. J. Taphoorn, R. C. Janzer, et al., "Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial," Lancet Oncol, vol. 10, pp. 459-66, May 2009.
[3]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.
[4]X. Ying, H. Wen, W. L. Lu, J. Du, J. Guo, W. Tian, et al., "Dual-targeting daunorubicin liposomes improve the therapeutic efficacy of brain glioma in animals," J Control Release, vol. 141, pp. 183-92, Jan 25 2010.
[5]K. Feng, J. Yan, X. Li, F. Xia, K. Ma, S. Wang, et al., "A randomized controlled trial of radiofrequency ablation and surgical resection in the treatment of small hepatocellular carcinoma," J Hepatol, vol. 57, pp. 794-802, Oct 2012.
[6]S. Mitragotri, "Healing sound: the use of ultrasound in drug delivery and other therapeutic applications," Nat Rev Drug Discov, vol. 4, pp. 255-60, Mar 2005.
[7]Y. Ma, S. Tong, G. Bao, C. Gao, and Z. Dai, "Indocyanine green loaded SPIO nanoparticles with phospholipid-PEG coating for dual-modal imaging and photothermal therapy," Biomaterials, vol. 34, pp. 7706-14, Oct 2013.
[8]M. Zheng, C. Yue, Y. Ma, P. Gong, P. Zhao, C. Zheng, et al., "Single-step assembly of DOX/ICG loaded lipid--polymer nanoparticles for highly effective chemo-photothermal combination therapy," ACS Nano, vol. 7, pp. 2056-67, Mar 26 2013.
[9]T. Jiang, Z. Zhang, Y. Zhang, H. Lv, J. Zhou, C. Li, et al., "Dual-functional liposomes based on pH-responsive cell-penetrating peptide and hyaluronic acid for tumor-targeted anticancer drug delivery," Biomaterials, vol. 33, pp. 9246-58, Dec 2012.
[10]E. K. Lim, Y. M. Huh, J. Yang, K. Lee, J. S. Suh, and S. Haam, "pH-triggered drug-releasing magnetic nanoparticles for cancer therapy guided by molecular imaging by MRI," Adv Mater, vol. 23, pp. 2436-42, Jun 3 2011.
[11]H. F. Dvorak, V. M. Weaver, T. D. Tlsty, and G. Bergers, "Tumor microenvironment and progression," J Surg Oncol, vol. 103, pp. 468-74, May 1 2011.
[12]M. K. Danquah, X. A. Zhang, and R. I. Mahato, "Extravasation of polymeric nanomedicines across tumor vasculature," Adv Drug Deliv Rev, vol. 63, pp. 623-39, Jul 18 2011.
[13]F. Nussenbaum and I. M. Herman, "Tumor angiogenesis: insights and innovations," J Oncol, vol. 2010, p. 132641, 2010.
[14]P. Baluk, L. C. Yao, J. Feng, T. Romano, S. S. Jung, J. L. Schreiter, et al., "TNF-alpha drives remodeling of blood vessels and lymphatics in sustained airway inflammation in mice," J Clin Invest, vol. 119, pp. 2954-64, Oct 2009.
[15]E. M. Conway, D. Collen, and P. Carmeliet, "Molecular mechanisms of blood vessel growth," Cardiovasc Res, vol. 49, pp. 507-21, Feb 16 2001.
[16]P. Carmeliet and R. K. Jain, "Angiogenesis in cancer and other diseases," Nature, vol. 407, pp. 249-57, Sep 14 2000.
[17]E. di Tomaso, M. Snuderl, W. S. Kamoun, D. G. Duda, P. K. Auluck, L. Fazlollahi, et al., "Glioblastoma recurrence after cediranib therapy in patients: lack of "rebound" revascularization as mode of escape," Cancer Res, vol. 71, pp. 19-28, Jan 1 2011.
[18]H. Gerhardt and C. Betsholtz, "Endothelial-pericyte interactions in angiogenesis," Cell Tissue Res, vol. 314, pp. 15-23, Oct 2003.
[19]S. S. Brem, P. J. Bierman, H. Brem, N. Butowski, M. C. Chamberlain, E. A. Chiocca, et al., "Central nervous system cancers," J Natl Compr Canc Netw, vol. 9, pp. 352-400, Apr 2011.
[20]R. K. Bindal, R. Sawaya, M. E. Leavens, and J. J. Lee, "Surgical treatment of multiple brain metastases," J Neurosurg, vol. 79, pp. 210-6, Aug 1993.
[21]D. Kondziolka, A. Patel, L. D. Lunsford, A. Kassam, and J. C. Flickinger, "Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain metastases," Int J Radiat Oncol Biol Phys, vol. 45, pp. 427-34, Sep 1 1999.
[22]E. S. Nussbaum, H. R. Djalilian, K. H. Cho, and W. A. Hall, "Brain metastases. Histology, multiplicity, surgery, and survival," Cancer, vol. 78, pp. 1781-8, Oct 15 1996.
[23]A. F. Eichler and J. S. Loeffler, "Multidisciplinary management of brain metastases," Oncologist, vol. 12, pp. 884-98, Jul 2007.
[24]D. N. Louis, H. Ohgaki, O. D. Wiestler, W. K. Cavenee, P. C. Burger, A. Jouvet, et al., "The 2007 WHO classification of tumours of the central nervous system," Acta Neuropathol, vol. 114, pp. 97-109, Aug 2007.
[25]"Cancer registry annual report,Taiwan," 行政院衛生署國民健康局癌症登記報告,, 2007.
[26]A. Jemal, R. Siegel, J. Xu, and E. Ward, "Cancer statistics, 2010," CA Cancer J Clin, vol. 60, pp. 277-300, Sep-Oct 2010.
[27]L. Arko, I. Katsyv, G. E. Park, W. P. Luan, and J. K. Park, "Experimental approaches for the treatment of malignant gliomas," Pharmacol Ther, vol. 128, pp. 1-36, Oct 2010.
[28]E. I. Fomchenko and E. C. Holland, "Stem cells and brain cancer," Exp Cell Res, vol. 306, pp. 323-9, Jun 10 2005.
[29]J. T. Huse and E. C. Holland, "Targeting brain cancer: advances in the molecular pathology of malignant glioma and medulloblastoma," Nat Rev Cancer, vol. 10, pp. 319-31, May 2010.
[30]A. Jemal, R. Siegel, E. Ward, T. Murray, J. Xu, C. Smigal, et al., "Cancer statistics, 2006," CA Cancer J Clin, vol. 56, pp. 106-30, Mar-Apr 2006.
[31]C. Kang, X. Yuan, Y. Zhong, P. Pu, Y. Guo, A. Albadany, et al., "Growth inhibition against intracranial C6 glioma cells by stereotactic delivery of BCNU by controlled release from poly(D,L-lactic acid) nanoparticles," Technol Cancer Res Treat, vol. 8, pp. 61-70, Feb 2009.
[32]L. L. Rubin and J. M. Staddon, "The cell biology of the blood-brain barrier," Annu Rev Neurosci, vol. 22, pp. 11-28, 1999.
[33]Y. Chen and L. Liu, "Modern methods for delivery of drugs across the blood-brain barrier," Adv Drug Deliv Rev, vol. 64, pp. 640-65, May 15 2012.
[34]F. Wang, Y. Cheng, J. Mei, Y. Song, Y. Q. Yang, Y. Liu, et al., "Focused ultrasound microbubble destruction-mediated changes in blood-brain barrier permeability assessed by contrast-enhanced magnetic resonance imaging," J Ultrasound Med, vol. 28, pp. 1501-9, Nov 2009.
[35]N. Vykhodtseva, N. McDannold, and K. Hynynen, "Progress and problems in the application of focused ultrasound for blood-brain barrier disruption," Ultrasonics, vol. 48, pp. 279-96, Aug 2008.
[36]W. M. Pardridge, "The blood-brain barrier: bottleneck in brain drug development," NeuroRx, vol. 2, pp. 3-14, Jan 2005.
[37]F. Y. Yang, W. M. Fu, R. S. Yang, H. C. Liou, K. H. Kang, and W. L. Lin, "Quantitative evaluation of focused ultrasound with a contrast agent on blood-brain barrier disruption," Ultrasound Med Biol, vol. 33, pp. 1421-7, Sep 2007.
[38]W. M. Pardridge, "Blood-brain barrier drug targeting: the future of brain drug development," Mol Interv, vol. 3, pp. 90-105, 51, Mar 2003.
[39]N. J. Abbott, "Blood-brain barrier structure and function and the challenges for CNS drug delivery," J Inherit Metab Dis, vol. 36, pp. 437-49, May 2013.
[40]N. J. Abbott, L. Ronnback, and E. Hansson, "Astrocyte-endothelial interactions at the blood-brain barrier," Nat Rev Neurosci, vol. 7, pp. 41-53, Jan 2006.
[41]J. R. Less, M. C. Posner, Y. Boucher, D. Borochovitz, N. Wolmark, and R. K. Jain, "Interstitial hypertension in human breast and colorectal tumors," Cancer Res, vol. 52, pp. 6371-4, Nov 15 1992.
[42]S. D. Nathanson and L. Nelson, "Interstitial fluid pressure in breast cancer, benign breast conditions, and breast parenchyma," Ann Surg Oncol, vol. 1, pp. 333-8, Jul 1994.
[43]B. D. Curti, W. J. Urba, W. G. Alvord, J. E. Janik, J. W. Smith, 2nd, K. Madara, et al., "Interstitial pressure of subcutaneous nodules in melanoma and lymphoma patients: changes during treatment," Cancer Res, vol. 53, pp. 2204-7, May 15 1993.
[44]R. Gutmann, M. Leunig, J. Feyh, A. E. Goetz, K. Messmer, E. Kastenbauer, et al., "Interstitial hypertension in head and neck tumors in patients: correlation with tumor size," Cancer Res, vol. 52, pp. 1993-5, Apr 1 1992.
[45]M. S. Khil, A. Kolozsvary, M. Apple, and J. H. Kim, "Increased tumor cures using combined radiosurgery and BCNU in the treatment of 9l glioma in the rat brain," Int J Radiat Oncol Biol Phys, vol. 47, pp. 511-6, May 1 2000.
[46]W. Vogelhuber, T. Spruss, G. Bernhardt, A. Buschauer, and A. Gopferich, "Efficacy of BCNU and paclitaxel loaded subcutaneous implants in the interstitial chemotherapy of U-87 MG human glioblastoma xenografts," Int J Pharm, vol. 238, pp. 111-21, May 15 2002.
[47]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.
[48]H. H. Engelhard, "The role of interstitial BCNU chemotherapy in the treatment of malignant glioma," Surg Neurol, vol. 53, pp. 458-64, May 2000.
[49]J. S. Lee, T. K. An, G. S. Chae, J. K. Jeong, S. H. Cho, H. B. Lee, et al., "Evaluation of in vitro and in vivo antitumor activity of BCNU-loaded PLGA wafer against 9L gliosarcoma," Eur J Pharm Biopharm, vol. 59, pp. 169-75, Jan 2005.
[50]G. Y. Kim, B. M. Tyler, M. M. Tupper, J. M. Karp, R. S. Langer, H. Brem, et al., "Resorbable polymer microchips releasing BCNU inhibit tumor growth in the rat 9L flank model," J Control Release, vol. 123, pp. 172-8, Nov 6 2007.
[51]J. Shi, A. R. Votruba, O. C. Farokhzad, and R. Langer, "Nanotechnology in drug delivery and tissue engineering: from discovery to applications," Nano Lett, vol. 10, pp. 3223-30, Sep 8 2010.
[52]R. T. Liggins and H. M. Burt, "Polyether-polyester diblock copolymers for the preparation of paclitaxel loaded polymeric micelle formulations," Adv Drug Deliv Rev, vol. 54, pp. 191-202, Feb 21 2002.
[53]D. R. Luke, B. L. Kasiske, G. R. Matzke, W. M. Awni, and W.F. Keane, "Effects of cyclosporine on the isolated perfused rat kidney," Transplantation, vol. 43, pp. 795-9, Jun 1987.
[54]N. Onetto, R. Canetta, B. Winograd, R. Catane, M. Dougan, J. Grechko, et al., "Overview of Taxol safety," J Natl Cancer Inst Monogr, pp. 131-9, 1993.
[55]M. Ferrari, "Cancer nanotechnology: opportunities and challenges," Nat Rev Cancer, vol. 5, pp. 161-71, Mar 2005.
[56]C. Loo, A. Lowery, N. Halas, J. West, and R. Drezek, "Immunotargeted nanoshells for integrated cancer imaging and therapy," Nano Lett, vol. 5, pp. 709-11, Apr 2005.
[57]C. H. Heldin, K. Rubin, K. Pietras, and A. Ostman, "High interstitial fluid pressure - an obstacle in cancer therapy," Nat Rev Cancer, vol. 4, pp. 806-13, Oct 2004.
[58]D. Peer, J. M. Karp, S. Hong, O. C. FaroKHzad, R. Margalit, and R. Langer, "Nanocarriers as an emerging platform for cancer therapy," Nature Nanotechnology, vol. 2, pp. 751-760, Dec 2007.
[59]N. Kumar, M. N. Ravikumar, and A. J. Domb, "Biodegradable block copolymers," Adv Drug Deliv Rev, vol. 53, pp. 23-44, Dec 3 2001.
[60]G.-H. H., "γ-Polyglutamic Acid(γ-PGA)：Structural Charateristics and Chemical Properties.," Chemical Monthly, 2006.
[61]A. I. Caplan and S. P. Bruder, "Mesenchymal stem cells: building blocks for molecular medicine in the 21st century," Trends Mol Med, vol. 7, pp. 259-64, Jun 2001.
[62]M. V. Risbud and M. Sittinger, "Tissue engineering: advances in in vitro cartilage generation," Trends Biotechnol, vol. 20, pp. 351-6, Aug 2002.
[63]K. Le Blanc and O. Ringden, "Immunobiology of human mesenchymal stem cells and future use in hematopoietic stem cell transplantation," Biol Blood Marrow Transplant, vol. 11, pp. 321-34, May 2005.
[64]K. Le Blanc, "Immunomodulatory effects of fetal and adult mesenchymal stem cells," Cytotherapy, vol. 5, pp. 485-9, 2003.
[65]M. Krampera, L. Cosmi, R. Angeli, A. Pasini, F. Liotta, A. Andreini, et al., "Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells," Stem Cells, vol. 24, pp. 386-98, Feb 2006.
[66]A. Garcia-Lora, I. Algarra, and F. Garrido, "MHC class I antigens, immune surveillance, and tumor immune escape," J Cell Physiol, vol. 195, pp. 346-55, Jun 2003.
[67]S. J. Baek, S. K. Kang, and J. C. Ra, "In vitro migration capacity of human adipose tissue-derived mesenchymal stem cells reflects their expression of receptors for chemokines and growth factors," Exp Mol Med, vol. 43, pp. 596-603, Oct 31 2011.
[68]E. Spaeth, A. Klopp, J. Dembinski, M. Andreeff, and F. Marini, "Inflammation and tumor microenvironments: defining the migratory itinerary of mesenchymal stem cells," Gene Ther, vol. 15, pp. 730-8, May 2008.
[69]Y. L. Hu, Y. H. Fu, Y. Tabata, and J. Q. Gao, "Mesenchymal stem cells: a promising targeted-delivery vehicle in cancer gene therapy," J Control Release, vol. 147, pp. 154-62, Oct 15 2010.
[70]M. Hashida, M. Nishikawa, and Y. Takakura, "Receptor-mediated cell specific delivery of drugs to the liver and kidney," Advanced Biomaterials in Biomedical Engineering and Drug Delivery Systems, pp. 86-90, 1996.
[71]B. Burke, S. Sumner, N. Maitland, and C. E. Lewis, "Macrophages in gene therapy: cellular delivery vehicles and in vivo targets," Journal of Leukocyte Biology, vol. 72, pp. 417-428, Sep 2002.
[72]U. Steinfeld, C. Pauli, N. Kaltz, C. Bergemann, and H. H. Lee, "T lymphocytes as potential therapeutic drug carrier for cancer treatment," International Journal of Pharmaceutics, vol. 311, pp. 229-236, Mar 27 2006.
[73]L. G. Menon, K. Kelly, H. W. Yang, S. K. Kim, P. M. Black, and R. S. Carroll, "Human Bone Marrow-Derived Mesenchymal Stromal Cells Expressing S-TRAIL as a Cellular Delivery Vehicle for Human Glioma Therapy," Stem Cells, vol. 27, pp. 2320-2330, 2009.
[74]M. Studeny, F. C. Marini, J. L. Dembinski, C. Zompetta, M. Cabreira-Hansen, B. N. Bekele, et al., "Mesenchymal stem cells: Potential precursors for tumor stroma and targeted-delivery vehicles for anticancer agents," Journal of the National Cancer Institute, vol. 96, pp. 1593-1603, Nov 3 2004.
[75]A. Nakamizo, F. Marini, T. Amano, A. Khan, M. Studeny, J. Gumin, et al., "Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas," Cancer Research, vol. 65, pp. 3307-3318, Apr 15 2005.
[76]M. A. Stoff-Khalili, A. A. Rivera, J. M. Mathis, N. S. Banerjee, A. S. Moon, A. Hess, et al., "Mesenchymal stem cells as a vehicle for targeted delivery of CRAds to lung metastases of breast carcinoma," Breast Cancer Research and Treatment, vol. 105, pp. 157-167, Oct 2007.
[77]A. M. Sonabend, I. V. Ulasov, M. A. Tyler, A. A. Rivera, J. M. Mathis, and M. S. Lesniak, "Mesenchymal stem cells effectively deliver an oncolytic adenovirus to intracranial glioma," Stem Cells, vol. 26, pp. 831-841, 2008.
[78]H. Cheng, C. J. Kastrup, R. Ramanathan, D. J. Siegwart, M. L. Ma, S. R. Bogatyrev, et al., "Nanoparticulate Cellular Patches for Cell-Mediated Tumoritropic Delivery," Acs Nano, vol. 4, pp. 625-631, Feb 2010.
[79]G. P. Wang, Y. S. Guan, X. R. Jin, S. S. Jiang, Z. J. Lu, Y. Wu, et al., "Development of novel 5-fluorouracil carrier erythrocyte with pharmacokinetics and potent antitumor activity in mice bearing malignant ascites," Journal of Gastroenterology and Hepatology, vol. 25, pp. 985-990, May 2010.
[80]M. Chokri, M. Lopez, C. Oleron, A. Girard, C. Martinache, S. Canepa, et al., "Production of human macrophages with potent antitumor properties (MAK) by culture of monocytes in the presence of GM-CSF and 1,25-dihydroxy vitamin D3," Anticancer Res, vol. 12, pp. 2257-60, Nov-Dec 1992.
[81]M. R. Choi, K. J. Stanton-Maxey, J. K. Stanley, C. S. Levin, R. Bardhan, D. Akin, et al., "A cellular Trojan horse for delivery of therapeutic nanoparticles into tumors," Nano Letters, vol. 7, pp. 3759-3765, Dec 2007.
[82]Y. Ikehara, T. Niwa, L. Biao, S. K. Ikehara, N. Ohashi, T. Kobayashi, et al., "A carbohydrate recognition-based drug delivery and controlled release system using intraperitoneal macrophages as a cellular vehicle," Cancer Research, vol. 66, pp. 8740-8748, Sep 1 2006.
[83]B. Zarabi, A. Nan, J. Zhuo, R. Gullapalli, and H. Ghandehari, "Macrophage targeted N-(2-hydroxypropyl)methacrylamide conjugates for magnetic resonance imaging," Mol Pharm, vol. 3, pp. 550-7, Sep-Oct 2006.
[84]M. C. Wani, H. L. Taylor, M. E. Wall, P. Coggon, and A. T. McPhail, "Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia," J Am Chem Soc, vol. 93, pp. 2325-7, May 5 1971.
[85]E. K. Rowinsky and R. C. Donehower, "Paclitaxel (taxol)," N Engl J Med, vol. 332, pp. 1004-14, Apr 13 1995.
[86]J. J. Manfredi and S. B. Horwitz, "Taxol: an antimitotic agent with a new mechanism of action," Pharmacol Ther, vol. 25, pp. 83-125, 1984.
[87]P. B. Schiff, J. Fant, and S. B. Horwitz, "Promotion of microtubule assembly in vitro by taxol," Nature, vol. 277, pp. 665-7, Feb 22 1979.
[88]B. Monsarrat, P. Alvinerie, M. Wright, J. Dubois, F. Gueritte-Voegelein, D. Guenard, et al., "Hepatic metabolism and biliary excretion of Taxol in rats and humans," J Natl Cancer Inst Monogr, pp. 39-46, 1993.
[89]M. S. Martina, J. P. Fortin, C. Menager, O. Clement, G. Barratt, C. Grabielle-Madelmont, et al., "Generation of superparamagnetic liposomes revealed as highly efficient MRI contrast agents for in vivo imaging," J Am Chem Soc, vol. 127, pp. 10676-85, Aug 3 2005.
[90]N. Nasongkla, E. Bey, J. Ren, H. Ai, C. Khemtong, J. S. Guthi, et al., "Multifunctional polymeric micelles as cancer-targeted, MRI-ultrasensitive drug delivery systems," Nano Lett, vol. 6, pp. 2427-30, Nov 2006.
[91]!!! INVALID CITATION !!!
[92]D. Yoo, J. H. Lee, T. H. Shin, and J. Cheon, "Theranostic magnetic nanoparticles," Acc Chem Res, vol. 44, pp. 863-74, Oct 18 2011.
[93]S. Laurent, D. Forge, M. Port, A. Roch, C. Robic, L. Vander Elst, et al., "Magnetic iron oxide nanoparticles: synthesis, stabilization, vectorization, physicochemical characterizations, and biological applications," Chem Rev, vol. 108, pp. 2064-110, Jun 2008.
[94]B. A. Bunnell, M. Flaat, C. Gagliardi, B. Patel, and C. Ripoll, "Adipose-derived stem cells: isolation, expansion and differentiation," Methods, vol. 45, pp. 115-20, Jun 2008.
[95]J. H. Sung, H. M. Yang, J. B. Park, G. S. Choi, J. W. Joh, C. H. Kwon, et al., "Isolation and characterization of mouse mesenchymal stem cells," Transplant Proc, vol. 40, pp. 2649-54, Oct 2008.
[96]C. C. Liang, A. Y. Park, and J. L. Guan, "In vitro scratch assay: a convenient and inexpensive method for analysis of cell migration in vitro," Nat Protoc, vol. 2, pp. 329-33, 2007.
[97]M. Y. M. Shinkai, "Intracellular hyperthermia for cancer using magnetite cationic liposomes," Magnetism and Magnetic Materials, vol. 194, pp. 176-184, 1999.

全文公開日期本全文未授權公開 (校內網路)
全文公開日期本全文未授權公開 (校外網路)

簡易檢索 / 詳目顯示

相關論文