惡性腦瘤為一嚴重的慢性疾病，由於其診斷不易以及難以根治，迄今為止仍為十分棘手之疾病。而目前惡性腫瘤主要的治療方式多為外科手術，但由於手術治療可能有傷及周邊組織的風險，無法將病灶切除乾淨，因此術後必須透過化療來抑制並防止腫瘤復發。然而腦部血腦屏障 (Blood-Brain Barrier, BBB) 卻阻擋了大部分的藥物進入，使得藥物治療並沒有達到預期中之效果，導致病程惡化。因此希望能在切除腫瘤後，透過直接性的局部給藥及其藥物緩慢釋放之特性來破壞殘留的腫瘤組織，使藥物不受 BBB 影響，藉以大幅提升化療藥物的治療效能。
為了克服以上在惡性腦瘤治療中所可能產生之問題，本研究開發了一種協同蛋白奈米粒子的溫敏感型水凝膠，作為外科手術後的輔助治療，用以清除殘留之腦瘤組織，並能夠延長在其周圍藥物之釋放。本研究所製作出來的溫敏感型水凝膠具有較低的相轉換度以及很好的凝固效果，當溫度到達 23 ℃ 時便能產生凝固，且在 37 ℃ 的環境下只需 6 s 的時間就能夠完全凝固，且能夠持續釋放藥物長達一週之久，如此一來就可以藉由簡單的注射方式進到腫瘤切除區，並固定在切除區裏頭持續釋放藥物。此外，在細胞毒性測試中證實其細胞毒性低，同時動物實驗中也已經證實當協同蛋白奈米粒子的溫敏感型水凝膠從水膠轉變成凝膠後，能夠固定在特定部位並持續釋放藥物。
本研究的水凝膠輸送系統具有雙藥物輸送的功能，由於兩種藥物的釋放速率不同，因此可以藉由兩種藥物之間的差異互補來提升治療效果，同時可望能夠克服BBB 對於一般藥物經由靜脈注射給藥所產生的障礙，以有效防止術後病灶殘留及腦瘤組織後續可能復發之生長。此外，由於本研究所製作的溫敏感型水凝膠具有核磁共振成像 (Magnetic Resonance Imaging, MRI) 的顯影功能，因此對於往後的追蹤觀察有著極大的幫助。

Malignant brain tumor is a serious disease. Patients treated using surgical resection, radiotherapy and chemotherapy survive, on average, for 6-24 months post-treatment. To date, surgery still is the primary treatment for brain tumor, following with chemotherapy is necessary to prevent the tumor recurrence. However, many potentially effective diagnostic or therapeutic agents are prohibited to deliver into brain by blood-brain barrier (BBB), resulting in the failure of chemotherapy.
To overcome the problems, we develop a BSA nanoparticles-incorporated temperature-sensitive hydrogel to slowly release drugs in the brain tumor. Our data showed that hydrogel could be transferred to gel from solution phase while the temperature was raised higher to 30 ℃ then sustainably released the drugs over one weeks.
This delivery system can be delivery two drug, because the different release rates of the two drugs, so it can be complementary to the difference between the two drugs and improve the therapeutic effect. As a result, it is expected to overcome the BBB, significantly reduce the side-effects and effectively prohibit the growth of residual tumor cells. In addition, the Institute produced a temperature-sensitive hydrogel has development of MRI, so it has a great help to future tracing observation.

目 錄
審定書 i
授權書 ii
致謝 iii
中文摘要 iv
英文摘要 v
目錄 vi
圖次 x
表次 xv
第 一 章 前言 1
1-1 腦癌 (Brain Tumor) 1
1-1-1 概況 1
1-1-2 腦癌的分類 2
1-1-3 腦癌的症狀 6
1-1-4 腦癌的診斷 8
1-1-4-1 電腦斷層掃描 8
1-1-4-2 磁振造影 8
1-1-4-3 正子掃描 9
1-1-5 腦癌的治療 9
1-1-5-1 手術切除 10
1-1-5-2 放射治療13
1-1-5-3 化學治療 14
1-2 奈米粒子 18
1-2-1 金奈米粒子 19
1-2-2 磁性奈米粒子 20
1-2-3 白蛋白 (Albumin) 奈米粒子 21
1-3 敏感型水凝膠 23
1-3-1 pH 值敏感型水凝膠 24
1-3-2 溫敏感型水凝膠 26
1-4 研究動機與目的 29
第 二 章 材料及實驗方法 31
2-1 實驗材料 31
2-2 儀器分析 32
2-2-1 傅里葉轉換紅外光譜 32
2-2-2 示差掃瞄熱量分析儀 33
2-2-3 熱重量分析儀 33
2-2-4 動態光散射儀 33
2-2-5 掃描式電子顯微鏡 33
2-2-6 穿透式電子顯微鏡 33
2-2-7 高效液相色譜儀 34
2-2-8 磁振造影 34
2-3 溫敏感型水凝膠及 BSA NPs 之製作 35
2-3-1 羧甲基纖維素 NH2 官能基修飾 35
2-3-2 溫敏感型水凝膠 35
2-3-3 牛血清白蛋白奈米粒子 ( BSA NPs ) 36
2-3-4 牛血清白蛋白/紫杉醇奈米粒子 ( BSA/PTX NPs ) 36
2-4 溫敏感型水凝膠及 BSA NPs 之基本性質分析 37
2-4-1 溶膠凝膠轉變溫度測試 37
2-4-2 體外溶血試驗 37
2-4-3 包覆率試驗 38
2-4-4 體外抗癌藥物釋放試驗 39
2-4-5 降解性試驗 39
2-4-6 細胞實驗 40
2-4-6-1 細胞培養 40
2-4-6-2 細胞數量計算 40
2-4-6-3 細胞毒性試驗 40
2-4-6-4 細胞影像 41
2-4-7 動物實驗 42
2-4-7-1 體內 MRI 顯影觀察 42
2-4-7-2 體內抑制腫瘤觀察 43
第 三 章 結果與討論 44
3-1 實驗流程 44
3-2 溫敏感型水凝膠、BSA NPs 及 BSA/PTX NPs 之基本結構觀察 45
3-3 藥物包覆率量測 57
3-4 藥物釋放測試 61
3-5 生物相容性測試 64
3-6 體外抑制細胞效果觀察 66
3-7 體內抑制腫瘤觀察 71
第 四 章 結論 74
參考文獻 75
圖　次
圖 1 - 1 血腦屏障 (BBB) 和神經血管單元 (NVU) 之結構示意圖 2
圖 1 - 2 不同年齡層的人之腦轉移發生案例數統計 3
圖 1 - 3 腦腫瘤位置與所引起的常見症狀 6
圖 1 - 4 使用 5-ALA 作為螢光導引手術切除之示意圖 12
圖 1 - 5 血紅素形成途徑及 5-ALA 螢光導引作用原理 12
圖 1 - 6 5-ALA、螢光分子 PpIX 及血紅蛋白之結構示意圖 13
圖 1 - 7 細胞週期 15
圖 1 - 8 EPR 效應之示意圖 18
圖 1 - 9 金奈米粒子之應用示意圖 19
圖 1-10 白蛋白奈米粒子經糖蛋白受器 (gp60) 進到腫瘤細胞周圍之示意圖 22
圖 1-11 Byeon 等人所製作的 HAS 奈米粒子應用於腦癌治療之標靶示意圖 23
圖 1-12 敏感型水凝膠一般常見的給藥方式及部位 24
圖 1-13 pH 值敏感型水凝膠應用在口服胃腸藥的作用示意圖 25
圖 1-14 常見的溫敏感型水凝膠及一般水凝膠疏水鏈鍛之高分子化學結構 27
圖 1-15 溫敏感型水凝膠作用示意圖 27
圖 2 - 1 溫敏感型水凝膠合成示意圖 36
圖 2 - 2 細胞計數器 40
圖 3 - 1 溫敏感型水凝膠協同 BSA/PTX NPs 雙藥物控制釋放系統之示意圖 45
圖 3 - 2 PNIPAM-co-MAA、CMC、改質 CMC 及溫敏感型水凝膠之 FTIR 分析 46
圖 3 - 3 PNIPAM-co-MAA、溫敏感型水凝膠及添加 DTPA-Gd的溫敏感型水凝膠之 TGA 分析 47
圖 3 - 4 溫敏感型水凝膠分別在不同溫度下放置 10 s 之照片，(a, c, e, g) 無添加 DTPA-Gd 之溫敏感水膠，(b, d, f, h) 有添加 DTPA-Gd 之溫敏感水膠；(a, b) 4 ℃，(c, d) 20 ℃，(e, f) 30 ℃，(g, h) 37 ℃ 48
圖 3 - 5 溫敏感型水凝膠之溶膠-凝膠-溶膠相轉換曲線圖 49
圖 3 - 6 溫敏感型水凝膠及添加 DTPA-Gd 的溫敏感型水凝膠之 DSC 分析 50
圖 3 - 7 溫敏感型水凝膠及添加 DTPA-Gd 的溫敏感型水凝膠之 DSC 分析 52
圖 3 - 8 含有 Rhodamine B 之有無添加 DTPA-Gd 的溫敏感型水凝膠在小鼠皮下的凝固效果及 MRI 影像觀察 53
圖 3 - 9 DTPA-Gd 及添加 DTPA-Gd 的溫敏感型水凝膠之MRI 顯影能力比較 54
圖 3-10 溫敏感型水凝膠浸泡在 37 ℃ 的 PBS 環境下之SEM 表面形貌觀察，(A) 未浸泡，(B) 7 day，(C) 14 day 54
圖 3-11 BSA NPs 及 BSA/PTX NPs 之 TEM 照片及粒徑分佈曲線圖 56
圖 3-12 PTX、BSA NPs 及 BSA/ PTX NPs 之 FTIR 分析 56
圖 3-13 BSA/ Rhodamine B NPs 之包覆藥物能力測試曲線圖(n=3) 58
圖 3-14 濃度分別為 0.5、0.25、0.13、0.06 及 0.03 mg/mL 的PTX 溶液之 HPLC 測試曲線 58
圖 3-15 濃度分別為 0.5、0.25、0.13、0.06 及 0.03 mg/mL 的PTX 溶液之 HPLC 標準曲線及線性公式 59
圖 3-16 溫敏感型水凝膠包覆 EPI 之包覆藥物能力測試曲線圖(n=3) 60
圖 3-17 溫敏感型水凝膠同時包覆 EPI 與 BSA/FITC NPs 之包覆藥物能力測試曲線圖 (n=3) 61
圖 3-18 不同 DTPA-Gd 比例的溫敏感型水凝膠之體外釋放曲線圖 (n=3) 62
圖 3-19 不同藥物含量的溫敏感型水凝膠之體外釋放曲線圖(n=3) 63
圖 3-20 BSA/EPI NPs 及溫敏感型水凝膠協同 BSA/EPI NPs 之體外釋放曲線圖 (n=3) 64
圖 3-21 不同溫敏感水膠添加量之溶血率測試 (n=3) 65
圖 3-22 10 μg/mL 之溫敏感型水凝膠及不同添加量的 BSA NPs之體外細胞毒性分析 (n=3) 66
圖 3-23 分別觀察 24、48 及 72 hr 之不同藥物濃度的 EPI、BSA/PTX NPs、含有 EPI 的溫敏感型水凝膠以及同時含有 EPI 和 BSA/PTX NPs 的溫敏感型水凝膠之體外抑制 MBR 614-2 腦癌細胞能力觀察 (n=3) 68
圖 3-24 分別觀察 12、24、36、48、60 及 72 hr 之藥物濃度為 109.8 μM 的 BSA/PTX NPs 之體外抑制 MBR 614-2 腦癌細胞能力觀察 (n=3) 69
圖 3-25 分 別 在 不 疼 時 間 下 觀 察 溫 敏 感 型 水 凝 膠 協 同 BSA/FITC NPs 及 單 純 只 有 抗 癌 藥 物 EPI 進 入 HEK293 細胞之情況，(a, c, e) 單純只有抗癌藥物 EPI，(b, d, f) 溫敏感型水凝膠協同 BSA/FITC NPs；(a, b) 3 hr，(c, d) 7 hr，(e, f) 21 hr 70
圖 3-26 溫敏感型水凝膠在動物體內之腫瘤體積觀察 (n=6) 72
圖 3-27 溫敏感型水凝膠在動物體內之存活率觀察 (n=6) 73
圖 3-28 溫敏感型水凝膠在動物體內之小鼠體重觀察 (n=6) 73
表 次
表 1 -1 轉移性腦癌的原發腫瘤比例 3
表 1 -2 神經膠質瘤分級量表 4
表 1-3 美國腦癌病患於 1995 至 2010 年內之 5 年相對存活率統計 5
表 1-4 腫瘤切除率與病患存活天數之觀察 10
表 1-5 抗癌藥物之分類及作用機制介紹 16
表 2-1 HPLC 之參數設定 34
表 2-2 MRI 掃描之參數 35
表 2-3 細胞毒性試驗之測試材料濃度及體積 41
表 2-4、 MRI 掃描之參數 42
表 3-1 溫敏感型水凝膠在不同溫度下之凝固所需時間量測 51

[1] Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010, 127, 2893-2917.
[2] Shanmugavadivel D, David W, Liu JF, Wilne S. HeadSmart: are you braintumour aware? Paediatr Child Health 2016, 26, 81-86.
[3] Aday S, Cecchelli R, Hallier-Vanuxeem D, Dehouck MP, Ferreira L. Stem CellBased HumanBlood-Brain Barrier Models forDrug Discovery and Delivery. Trends Biotechnol 2016, 34, 382-393.
[4] Abbott NJ, Ronnback L, Hansson E. Astrocyte-endothelial interactions at theblood-brain barrier. Nat Rev Neurosci 2006, 7, 41-53.
[5] Wei X, Chen X, Ying M, Lu W. Brain tumor-targeted drug delivery strategies. Acta Pharm Sinica B 2014, 4, 193-201.
[6] de Boer AG, Gaillard PJ. Drug targeting to the brain. Annu Rev Pharmacol 2007, 47, 323-55.
[7] Wong AD, Ye M, Levy AF, Rothstein JD, Bergles DE, Searson PC. The bloodbrain barrier: an engineering perspective. Front Neuroeng 2013, 6, 7.
[8] Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, TaphoornMJB, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG,Eisenhauer E, Mirimanoff RO. Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma. New Engl J Med 2005, 352, 987-96.
[9] Pabaney A, Kalkanis SN. Chapter 2-The Role of Surgical Resectionfor Metastatic Brain Tumors. Brain Metastases from Primary Tumors 2015, 31-39.
[10] Newton HB, Otero JJ. Chapter 3-Overview of Epidemiology, Pathology, and Treatment of Metastatic Brain Tumors. Epilepsy and Brain Tumors 2015, 29-43.
[11] Wilhelm I, Krizbai IA. Functional Characteristics of Brain Tumor Vascularization. Brain Mapp 2015, 3, 1075-1079.
[12] Sawaya R, Bindal RK, Lang FF, Suki D. Metastatic brain tumors. Brain Tumors 2012, 45, 864-892.
[13] German RB, Karima M, Nadine MD, Delattre JY, Florence LD. Adult Brainstem Gliomas. Oncologist 2012, 17, 388-397.
[14] Selvapandian S, Rajshekhar V, Chandy MJ. Brainstem glioma: comparativestudy of clinico-radiological presentation, pathology and outcome in childrenand adults. Acta Neurochir (Wien) 1999, 141, 721-726.
[15] Guillamo JS, Monjour A, Taillandier L, Devaux B, Varlet P, Haie-Meder C, Defer GL, Maison P, Mazeron JJ, Cornu P, Delattre JY. Brainstem gliomas in adults:prognostic factors and classification. Brain 2001, 124, 2528-2539.
[16] Kleihues P, Louis DN, Scheithauer BW, Rorke LB, Reifenberger G, Burger PC, Cavenee WK. The WHO classification of tumors of the nervous system. J. Neuropathol. Exp Neurol 2002, 61, 215-225.
[17] Holland H, Koschny T, Ahnert P, Meixensberger J, Koschny R. WHO gradespecific comparative genomic hybridization pattern of astrocytoma-A metaanalysis. Pathol Res Pract 2010, 206, 663-668.
[18] Ho VK, Reijneveld JC, Enting RH, Bienfait HP, Robe P, Baumert BG, Visser O Changing incidence and improved survival of gliomas. Eur J Cancer 2014, 50, 2309-2318.
[19] Del Sole A, Moncayo R, Tafuni G, Lucignani G. Position of nuclear medicine techniques in the diagnostic work-up of brain tumors. Q J Nucl Med Mol Imaging 2004, 48, 76-81.
[20] Zimmermann F, Papachristofilou A, Mosna K, Gross MW. Stereotactic Radiation Therapy Planning. Comprehensive Biomedical Physics 2014, 9, 383-393.
[21] Essig M, Weber MA, von Tengg-Kobligk H, Knopp MV, Yuh WT, Giesel FL. Contrast-enhanced magnetic resonance imaging of central nervous system tumors: Agents, mechanisms, and applications. Top Magn Reson Imaging 2006, 17, 89-106.
[22] Warburg O. On the origin of cancer cells. Science 1956, 123, 309-314.
[23] Beyer T, Townsend DW, Brun T, Kinahan PE, Charron M, Roddy R, Jerin J, Young J, Byars L, Nutt R. A combined PET/CT scanner for clinical oncology. J Nucl Med 2000, 41, 1369-1379.
[24] Wechalekar K, Sharma B, Cook G. PET/CT in oncology-A major advance. Clin Radiol 2005, 60, 1143-1155.
[25] Saif MW, Tzannou I, Makrilia N, Syrigos K. Role and cost effectiveness of PET/CT in management of patients with cancer. Yale J Biol Med 2010, 83, 53-65.
[26] Kato T, Shinoda J, Nakayama N, Miwa K, Okumura A, Yano H, Yoshimura S, Maruyama T, Muragaki Y, Iwama T. Metabolic assessment of gliomas using 11C-methionine, [18F] fluorodeoxyglucose, and 11C-choline positronemission tomography. Am J Neuroradiol 2008, 29, 1176-1182.
[27] Pauleit D, Stoffels G, Bachofner A, Floeth FW, Sabel M, Herzog H, Tellmann L, Jansen P, Reifenberger G, Hamacher K, Coenen HH, Langen KJ. Comparison of (18)F-FET and (18)F-FDG PET in brain tumors. Nucl Med Biol 2009, 36, 779-787
[28] F Mu, Lucas JT, Watts JM, Johnson AJ, Bourland JD, Laxton AW, Chan MD, Tatter SB. Tumor resection with carmustine wafer placement as salvage therapy after local failure of radiosurgery for brain metastasis. J Clin Neurosci 2015, 22, 561-565.
[29] Miglierini P, Bouchekoua M, Rousseau B, Hieu PD, Malhaire JP, Pradier O. Impact of the per-operatory application of GLIADEL wafers (BCNU, carmustine) in combination with temozolomide and radiotherapy in patients with glioblastoma multiforme: Efficacy and toxicity. Clin Neurol 2012, 114, 1222-1225.
[30] Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJB, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO. 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 2009, 10, 459-466.
[31] McGirt MJ, Chaichana KL, Gathinji M, Attenello FJ, Than K, Olivi A, Weingart JD, Brem H, Quiñones-Hinojosa AR. Independent association of extent of resection with survival in patients with malignant brain astrocytoma. J Neurosurg 2009, 110, 156-162.
[32] Dea N, Fournier-Gosselin MP, Mathieu D, Goffaux P, Fortin D. Does Extent of Resection Impact Survivalin Patients Bearing Glioblastoma? Can J Neurol Sci 2012, 39, 632-637.
[33] Roder C, Bisdas S, Ebner FH, Honegger J, Naegele T, Ernemann U, Tatagiba M. Maximizing the extent of resection and survival benefit of patients in glioblastoma surgery: High-field iMRI versus conventional and 5-ALAassisted surgery. Eur J Surg Oncol 2014, 40, 297-304.
[34] Potapov AA, Usachev DJ, Loshakov AV, Cherekaev VA, Kornienko VN, Pronin IN, Kobiakov GL, KalininPL, GavrilovAG, Stummer W, Golbin DA, Zelenkov PV. First experience in 5-ALA fluorescence-guided and endoscopically assistedmicrosurgery of brain tumors. Med Laser Appl 2008, 23, 202-208.
[35] Colditz MJ, van Leyen K, Jeffree RL. Aminolevulinic acid (ALA)-protoporphyrin IX fluorescence guided tumourresection. Part 2: Theoretical, biochemical and practical aspects. J Clin Neurosic 2012, 19, 1611-1616.
[36] Ishizuka M, Abe F, Sano Y, Takahashi K, Inoue K, Nakajima M, Kohda T, Komatsu N, Ogura S, Tanaka T. Novel development of 5-aminolevurinic acid (ALA) in cancer diagnoses and therapy. Int Immunopharmacol 2011, 11, 358-365.
[37] Semwal MK, Singh S, Sarin A, Bhatnagar S, Pathak HC. Comparative clinical dosimetry with X-knife and gamma knife. Phys Medica 2012, 28, 269-272.
[38] Larson E, Peterson H, Lamoreaux W. Clnical outcomes followingsalvage Gamma Knife radiosurgery for recurrent glioblastoma. World J Clin Oncol 2014, 5, 142-148.
[39] Halasz LM, Bussière MR, Dennis ER, Niemierko A, Chapman PH, Loeffler JS, Shih HA. Proton Stereotactic Radiosurgery for the Treatment of Benign Meningiomas. Int J Radiat Oncol Biol Phys 2011, 81, 1428-1435.
[40] Kim JA, Åberg C, Salvati A, Dawson KA. Role of cell cycle on the cellular uptake and dilution of nanoparticles in a cell population. Nat Nanotechnol 2012, 7, 62-68.
[41] Estanqueiro M, Amaral MH, Conceic J, Lobo JMS. Nanotechnological carriers for cancer chemotherapy:The state of the art. Colloids Surf., B 2015, 126, 631-648.
[42] Nagasawa DT, Chow F, Yew A, Kim W, Cremer N, Yang I. Temozolomide and other potential agents for the treatment of glioblastoma multiforme. Neurosurg Clin N Am 2012, 23, 307-322.
[43] Virmani P, Chung E, Thomas AA, Mellinghoff IK, Marchetti MA. Cutaneous adverse drug reaction associated with oral temozolomide presenting as dermal and subcutaneous plaques and nodules. Jaad Case Reports 2015, 1, 286-288.
[44] Berrocal A, Perez SP, Gil M, Balaña C, Garcia LJ, Yaya R, Rodríguez J, Reynes G, Gallego O, Iglesias L. Extended-schedule dose-dense temozolomide in refractorygliomas. J Neurooncol 2010, 96, 417-422.
[45] Hua MY, Liu HL, Yang HW, Chen PY, Tsai RY, Huang CY, Tseng IC, Lyu LA, Ma CC, Tang HJ, Yen TC, Wei KC. The effectiveness of a magnetic nanoparticle-based delivery system for BCNU in the treatment of gliomas. Biomaterials 2011, 32, 516-527.
[46] Cao TM, Negrin RS, Stockerl-Goldstein KE, Johnston LJ, Shizuru JA, Taylor TL, Rizk NW, Wong RM, Blume KG, Hu WW. Pulmonary Toxicity Syndrome in Breast Cancer Patients Undergoing BCNU-Containing High-Dose Chemotherapy and Autologous Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant 2000, 6, 387-394.
[47] Brem H, Piantadosi S, Burger PC, Walker M, Selker R, Vick NA, Black K, Sisti M, Brem S, Mohr G. Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas. Lancet 1995, 345, 1008-1012.
[48] Westphal M, Hilt DC, Bortey E, Delavault P, Olivares R, Warnke PC, Whittle IR, Jääskeläinen J, Ram Z. A phase 3 trial of local chemotherapy with biodegradable carmustine (BCNU) wafer (Gliadel wafers) in patients with primary malignant glioma. Neuro Oncol 2003, 5, 79-88.
[49] Lawson HC, Sampath P, Bohan E, Park MC, Hussain N, Olivi A, Weingart J, Kleinberg L, Brem H. Interstitial chemotherapy for malignant gliomas: the Johns Hopkins experience. J Neurooncol 2007, 83, 61-67.
[50] Sabel M, Giese A. Safety profile of carmustine wafers in malignant glioma: a review of controlled trials and a decade of clinical experience. Curr Med Res Opin 2008, 24, 3239-3257.
[51] Ghosh P, Han G, De M, Kim CK, Rotello VM. Gold nanoparticles in delivery applications. Adv Drug Deliv Rev 2008, 60, 1307-1315.
[52] Dobson J. Magnetic nanoparticles for drug delivery. Drug Dev Res 2006, 67, 55-60.
[53] Elsadek B, Kratz F. Impact of albumin on drug delivery-new applications on the horizon. J Control Release 2012, 157, 4-28.
[54] Fang J, Nakamura H, Maeda H. The EPR effect: unique features of tumor blood vessels for drug delivery, factors involved, and limitations and augmentation of the effect. Adv Drug Deliv Rev 2011, 63, 136-151.
[55] de Oliveira AM, Jäger E, Jäger A, Stepánek P, Giacomelli FC. Physicochemical aspects behind the size of biodegradable polymericnanoparticles: a step forward, Adv Colloid Interface Sci 2013, 436 , 1092-1102.
[56] Libutti SK, Paciotti GF, Byrnes AA, Alexander HR Jr, Gannon WE, Walker M, Seidel GD, Yuldasheva N, Tamarkin L. Phase I and pharmacokinetic studies of CYT-6091, a novel PEGylated colloidal gold-rhTNF nanomedicine. Clin Cancer Res 2010, 16, 6139-6149.
[57] Chen D, Li B, Cai S, Wang P, Peng S, Sheng Y, He Y, Gu Y, Chen H. Dual targeting luminescent gold nanoclusters for tumor imaging and deep tissue therapy. Biomaterials 2016, 18, 1-16.
[58] Huang X, El-Sayed MA. Plasmonic photo-thermal therapy (PPTT). Alexandria Journal of Medicine 2011, 47, 1-9.
[59] Dhamecha D, Jalalpure S, Jadhav K. Doxorubicin functionalized gold nanoparticles: Characterization and activity against human cancer cell lines. Process Biochem 2015, 50, 2298-2306.
[60] Lee J, Chatterjee DK, Lee MH, Krishnan S. Gold nanoparticles in breast cancer treatment: Promise and potential pitfalls. Cancer Lett 2014, 347, 46-53.
[61] Zhang X, Teodoro JG, Nadeau JL. Intratumoral gold-doxorubicin is effective in treating melanoma in mice. Nanomed Nanotech Biol Med 2015, 11, 1365-1375.
[62] Alexiou C, Arnold W, Klein RJ, Parak FG, Hulin P, Bergemann C, Erhardt W,Wagenpfeil S, Lübbe AS. Locoregional cancer treatment with magnetic drugtargeting. Cancer Res 2000, 60, 6641-6648.
[63] Lübbe AS, Bergemann C, Huhnt W, Fricke T, Riess H, Brock JW, Huhn D. Preclinical experiences with magnetic drug targeting: tolerance and efficacy. Cancer Res 1996, 56, 4694-4701.
[64] McConnell HL, Schwartz DL, Richardson BE, Woltjer RL, Muldoon LL, Neuwelt EA. Ferumoxytol nanoparticle uptake in brain during acute neuroinflammation is cell-specific. Nanomed Nanotech Biol Med 2016, 12, 1535-1542.
[65] Chertok B, David AE, Yang VC. Polyethyleneimine-modified iron oxide nanoparticles for brain tumor drug delivery using magnetic targeting and intra-carotid administration. Biomaterials 2010, 31, 6317-6324.
[66] Park K. Albumin: a versatile carrier for drug delivery. J Control Release 2012, 157, 3.
[67] Kratz F. Albumin as a drug carrier: design of prodrugs, drug conjugates and nanoparticles. J Control Release 2008, 132, 171-183.
[68] Elzoghby AO, Samy WM, Elgindy NA. Albumin-based nanoparticles as potential controlled release drug delivery systems. J Control Release 2012, 157, 168-182.
[69] Livney YD. Milk proteins as vehicles for bioactives. Curr Opin Colloid Interface Sci 2010, 15, 73-83.
[70] Gradishar WJ, Krasnojon D, Cheporov S, Makhson AN, Manikhas GM, Clawson A, Bhar P. Significantly longer progression-free survival with nabpaclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer. J Clin Oncol 2009, 27, 3611-3619.
[71] Byeon HJ, Thao LQ, Lee S, Min SY, Lee ES, Shin BS, Choi HG, Youn YS. Doxorubicin-loaded nanoparticles consisted of cationic- and mannosemodified-albumins for dual-targeting in brain tumors. J Control Release 2016, 225, 301-313.
[72] Gandhi A, Paul A, Sen SO, Sen KK. Studies on thermoresponsive polymers: Phase behaviour, drug delivery and biomedical applications. A J Pharm Sci 2015, 10, 99-107.
[73] Yong Q, Kinam P. Environment-sensitive hydrogels for drug delivery. Adv Drug Deliv Rev 2012, 64, 49-60.
[74] Hoare TR, Kohane DS. Hydrogels in drug delivery: Progress and challenges. Polymer 2008, 49, 1993-2007.
[75] Gupta P, Vermani K, Garg S. Hydrogels: from controlled release to pHresponsive drug delivery. Drug Discov Today 2002, 7, 569-576.
[76] Peppas NA, Bures P, Leobandung W, Ichikawa H. Hydrogels in pharmaceutical formulations. Eur J Pharm Biopharm 2000, 50, 27-46.
[77] Watkins KA, Chen R. pH-responsive, lysine-based hydrogels for the oral delivery of a wide size range of molecules. Int J Pharm 2015, 478, 496-503.
[78] Yang K, Wan S, Chen B, Gao W, Chen J, Liu M, He B, Wu H. Dual pH and temperature responsive hydrogels based on β-cyclodextrin derivatives for atorvastatin delivery. Carbohydr Polym 2016, 136, 300-306.
[79] Yu L, Ci T, Zhou S, Zeng W, Ding J. The thermogelling PLGA-PEG-PLGA block copolymer as a sustained release matrix of doxorubicin. Biomater Sci 2013, 1, 411-420.
[80] Gong CY, Shi S, Dong PW, Kan B, Gou ML, Wang XH, Li XY, Luo F, Zhao X, Wei YQ, Qian ZY. Synthesis and characterization of PEG-PCL-PEG thermosensitive hydrogel. Int J Pharm 2009, 365, 89-99.
[81] Floyd JA, Galperin A, Ratner BD. Drug encapsulated aerosolized microspheres as a biodegradable, intelligent glioma therapy. J Biomed Mater Res Part A 2016, 104, 544-552.
[82] Xie B, Jin L, Luo Z, Yu J, Shi S, Zhang Z, Shen M, Chen H, Li X, Song Z. An injectable thermosensitive polymeric hydrogel for sustained release of Avastin® to treat posterior segment disease. Int J Pharm 2015, 490, 375-383.
[83] Floyd JA, Galperin A, Ratner BD. Drug encapsulated polymeric microspheres for intracranial tumor therapy: A review of the literature. Adv Drug Deliv Rev 2015, 9, 23-37.
[84] Krukiewicz K, Zak JK. Biomaterial-based regional chemotherapy: Local anticancer drug delivery to enhance chemotherapy and minimize its sideeffects. Mat Sci Eng C 2016, 62, 927-942.
[85] Gandhi A, Paul A, Sen SO, Sen KK. Studies on thermoresponsive polymers: Phase behaviour, drug delivery and biomedical applications. Asian J Pharmacol Sci 2015, 10, 99-107.
[86] Bischofberger I, Trappe V. New aspects in the phase behaviour of poly-Nisopropyl acrylamide: systematic temperature dependent shrinking of PNiPAM assemblies well beyond the LCST. Sci Rep 2015, 5, 15520-15529.
[87] Naraharisetti PK, Ong BYS, Xie JW, Lee TKY, Wang CH, Sahinidis NV. In vivo performance of implantable biodegradable preparations delivering Paclitaxel and Etanidazole for the treatment of glioma. Biomaterials 2007, 28, 886-894.
[88] Li KW, Dang WB, Tyler BM, Troiano G, Tihan T, Brem H, Walter KA. Polilactofate microspheres for paclitaxel delivery to central nervous system malignancies. Clin Cancer Res 2003, 9, 3441-3447.
[89] Minotti G, Licata S, Saponiero A, Menna P, Calafiore AM, Di Giammarco G, Liberi G, Animati F, Cipollone A, ManziniS, Maggi CA. Anthracycline Metabolism and Toxicity in Human Myocardium: Comparisons between Doxorubicin,Epirubicin, and a Novel Disaccharide Analogue with a Reduced Level of Formation and [4Fe-4S] Reactivity of ItsSecondary Alcohol Metabolite. Chem Res Toxicol 2000, 13, 1336-1341.
[90] JN Vieira, JJ Posada, RA Rezende, MA Sabino. Starch and chitosan oligosaccharides as interpenetrating phases in poly(N-isopropylacrylamide) injectable gels. Mat Sci Eng C 2014, 37, 20-27.
[91] B Mukherjee, S Chakraborty, L Mondal, BS Satapathy, S Sengupta, L Dutta, A Choudhury, D Mandal. Multifunctional drug nanocarriers facilitate more specific entry of therapeutic payload into tumors and control multiple drug resistance in cancer. J Biomed Nanotechnol 2016, 7, 203-251.
[92] Wang CF, Mäkilä EM, Kaasalainen MH, Hagström MV, Salonen JJ, Hirvonen JT, Santos HA. Dual-drug delivery by porous silicon nanoparticles for improved cellular uptake, sustained release, and combination therapy. Acta Biomater 2015, 16, 206-214.
[93] Zhou HY, Zhang YP, Zhang WF, Chen XG. Biocompatibility and characteristics of injectable chitosan-based thermosensitive hydrogel for drug delivery. Carbohyd Polym 2011, 83, 1643-1651.
[94] Chaterji S, Kwon K, Park K. Smart polymeric gels: redefining the limits of biomedical devices. Prog Polym Sci 2007, 32, 1083-1122.
[95] Vieiraa JN, Posadaa JJ, Rezendeb RA, Sabino MA. Starch and chitosan oligosaccharides as interpenetrating phases in poly(N-isopropylacrylamide) injectable gels. Mat Sci Eng C 2014, 37, 20-27.
[96] Wei W, Hu X, Qi X, Yu H, Liu Y, Li J, Zhang J, Dong W. A novel thermoresponsive hydrogel based on salecan and poly(N-isopropylacrylamide): Synthesis and characterization. Colloids Surf, B 2015, 125, 1-11.
[97] Asmal Rani MS, Rudhziah S, Ahmad A. Nor Sabirin Mohamed. Biopolymer Electrolyte Based on Derivatives of Cellulose from Kenaf Bast Fiber. Polymers 2014, 6, 2371-2385.
[98] Luztonó LA, Donates YC, Ramirez LGG, Palomo AG, Silva DZ, Katime I. Polymeric Nanohydrogels of Poly(N-Isopropylacrylamide) Combined with Others Functionalized Monomers: Synthesis and Characterization. J Biomater Nanobiotechnol 2014, 5, 31-38.
[99] Qi XM, Liu SY, Chu FB, Pang S, Liang YR, Guan Y, Peng F, Sun RC. Preparation and Characterization of Blended Films from Quaternized Hemicelluloses and Carboxymethyl Cellulose. Materials 2016, 9, 4.
[100] Haldorai Y, Shim JJ. Chemo-responsive bilayer actuator film: fabrication, characterization and actuator response. New J Chem 2014, 38, 2653-2659.
[101] Weber C, Hoogenboom R, Schubert US. Temperature responsive biocompatible polymers based on poly(ethylene oxide) and poly(2-oxazoline)s. Prog Polym Sci 2012, 37, 686-714.
[102] Schmaljohann D. Thermo- and pH-responsive polymers in drug delivery. Adv Drug Deliv Rev 2006, 58, 1655-1670.
[103] Yu L, Ci T, Zhou S, Zeng W, Ding J. The thermogelling PLGA-PEG-PLGA block copolymer as a sustained release matrix of doxorubicin. Biomater Sci 2013, 1, 411-420.
[104] Battogtokh G, Kang JH, Ko YT. Long-circulating self-assembled cholesteryl albumin nanoparticles enhance tumor accumulation of hydrophobic anticancer drug. Eur J Pharm 2015, 96 , 96-105.
[105] Hua MY, Yang HW, Chuang CK, Tsai RY, Chen WJ, Chuang KL, Chang YH, Chuang HC, Pang ST. Magnetic-nanoparticle-modified paclitaxel for targeted therapy for prostate cancer. Biomaterials 2010, 31, 7355-7363.
[106] Sripriyalakshmi S, Anjali CH, George Priya DC, Rajith B, Aswathy R. BSA Nanoparticle Loaded Atorvastatin Calcium - A New Facet for an Old Drug. Plos One 2014, 9, 86317-86326.
[107] Xu S, Wang W, Li X, Liu J, Dong A, Deng L. Sustained release of PTXincorporated nanoparticles synergized by burst release of DOX·HCl from thermosensitive modified PEG/PCL hydrogel to improve anti-tumor efficiency. Eur J Pharm Sci 2014, 62, 267-273.
[108] Gong CY, Wang C, Wang YJ, Wu QJ, Zhang DD, Luo F, Qian ZY. Efficient inhibition of colorectal peritoneal carcinomatosis by drug loaded micelles in thermosensitive hydrogel composites. Nanoscale 2012, 4, 3095-3104.
[109] Xu Y, Jia Y, Wang Z, Wang Z. Mathematical Modeling and Finite Element Simulation of Slow Release of Drugs Using Hydrogels as Carriers with Various Drug Concentration Distributions. J Pharm Sci-Us 2013, 102, 1532-1543.
[110] Xu X, Chen X, Xu X, Lu T, Wang X, Yang L, Jing X. BCNU-loaded PEGPLLA ultrafine fibers and their in vitro antitumor activity against Glioma C6 cells. J Control Release 2006, 114, 307-316.
[111] Schiff PB, Fant J, Horwitz SB. Promotion of microtubule assembly in vitro by Taxol. Nature 1979, 277, 665-667.
[112] Jensen PB, Sørensen BS, Sehested M, Demant EJ, Kjeldsen E, Friche E, Hansen HH. Different modes of anthracycline interaction with topoisomerase II: Separate structures critical for DNA-cleavage, and for overcoming topoisomerase II-related drug resistance. Biochem Pharmacol 1993, 45, 2025-2035.
[113] Osheroff N. Eukaryotic Topoisomerase II: characterisation of enzyme turnover. J Biol Chem 1986, 261, 9944-9950.