臺灣博碩士論文加值系統

神經膠質母細胞瘤(Glioblastoma Multiforme；GBM)是腦癌中最盛行及死亡率最高的癌症，其癌細胞為異質群體(heterogeneous population)導致目前臨床治療預後不佳。儘管奈米系統的發展已成功改善藥物和基因治療方式，但由於大腦組織是一個多種細胞形式的器官，因此如何在癌組織以及健康的腦細胞之間進行安全和成功的治療便顯得重要及迫切的課題。本研究成功開發一種新穎的治療方式，透過二氧化矽-金複合奈米粒子(HAc-Au@SiO2)搭配5ALA(5-Aminolevulinic Acid)光敏劑，並結合聲動力和低劑量的放射治療，能夠有效保護正常細胞而毒殺癌細胞且細胞毒殺比也高達4倍，也能在GBM細胞產生大量活性氧化物質(Reactive Oxygen Species；ROS)，使粒線體膜電位(mitochondrial membrane potential, MMP))喪失並使生成 ATP 能力受損，進而活化p53路徑促進Cytochrome c的釋放並活化Caspase-3，造成細胞傷害而走向細胞凋亡的命運，也促使細胞週期停滯在G2/M期。另外我們也成功建立冷光報告基因的穩定細胞株，以利後續可以透過非侵入式活體分子影像系統(Non Invasion In Vivo Imaging System；IVIS)來偵測腫瘤區的訊號，在初步動物實驗中，載體搭配治療能有效降低腫瘤生長。此治療方式提供一個非侵入性、低劑量放射治療以及更有效殺死癌細胞來降低腫瘤的復發機率並保護周圍正常組織，進而大大降低副作用，期望我們的研究成果，將為腦癌腫瘤治療提供一種新的治療策略。

Glioblastoma Multiforme (GBM) is the most common and the most malignant glia tumors in brain cancer. The tumor is composed heterogeneous population cancer cells that make the healing progress after the treatment slow. Although the development of nanoscale systems has successfully improved the way of drug and gene therapy, brain is a complicated multi-cell organ that it is important to have safe and efficacy treatments between cancer tissues and healthy brain cells. The main purpose of this study is to invent a novel treatment by utilizing the silica-gold composite nanoparticles with 5ALA photosensitizer, which is able to combine sonodynamic therapy with low dose radiation therapy to protect healthy cells and cancer cells effectively. The GBM/Astrocyte kill ratio elevates 4 times compare to control group. Follow by this novel treatment, GBM cells produce numbers of reactive oxygen species (ROS) that lead to a decline of mitochondrial membrane potential (MMP). Therefore, cells are fail to generate ATP which can activate the p53 pathway to promote the release of Cytochrome C and then activate Caspase-3. Activation of Caspase-3 not only causes cell damage and may lead to cell apoptosis, but also promote cell cycle arrest in G2 / M period. In addition, we have successfully established a stable cell line of luciferase (Luc) reporter gene to facilitate the subsequent detection of the signal of the tumor area through the non-invasion in vivo imaging system (IVIS). In the preliminary animal experiment, Combined with vehicle and treatment can effectively reduce tumor growth.This is a non-invasive treatment that require only low-dosage radiotherapy, and is more effective at killing cancer cells. In addition, this novel treatment is able to reduce the chance of recurrence and protect the surrounding healthy tissue to reduce side effects significantly. Hence, we expect our findings as a new strategy to treat brain cancer.

目錄
致謝 I
中文摘要 IV
Abstract V
目錄 VI
圖目錄 IX
表目錄 XII
第一章 緒論 1
第二章 文獻回顧 4
2-1神經膠質母細胞瘤病理及目前治療方式 4
2-2放射治療 7
2-3金奈米粒子應用於放射治療 10
2-4 金奈米粒子應用於放射治療(IR, 6MeV) 12
2-5 金奈米粒子放射增敏的物理學機制 13
2-6 金奈米粒子放射增敏的生物學機制 15
2-6-1 ROS及氧化壓力 15
2-6-2 細胞週期影響 17
2-7 二氧化矽在生物醫學上的應用 21
2-7-1二氧化矽應用於放射治療 24
2-8 5-ALA應用於神經膠質母細胞瘤手術導引與轉化機制 25
2-8-1 5-ALA誘導光動力治療應用與限制 27
2-8-2 5-ALA是放射增敏劑 29
2-9聲動力治療原理及機制 30
2-9-1聲動力學治療機制 30
2-9-2 聲動力治療生物機制 33
2-9-3聲敏物質 34
2-10 玻尿酸（Hyaluronic Acid）與神經膠質母細胞瘤 36
第三章 材料與方法 37
3-1實驗設計 37
3-2 材料和儀器 38
3-2-1化學合成材料 38
3-2-2生物實驗材料和試劑 39
3-2-3儀器 41
3-3材料合成方法 42
3-3-1 Au@SiO2載體材料合成 42
3-3-2螢光染劑參雜Au@SiO2載體 42
3-3-3玻尿酸接枝Au@SiO2載體 43
3-4材料性質測試 44
3-4-1穿透式顯微鏡(TEM) 44
3-4-2粒徑與表面電性測試(DLS & Zeta Potential) 44
3-4-3載體材料官能基測定(傅里葉轉換紅外光譜；FTIR) 44
3-4-4可見光紫外光分光光譜儀(UV-vis) 44
3-4-5 Sonodynamic Therapy 實驗裝置及參數 45
3-5分生實驗 46
3-5-1重組 plasmid DNA 46
3-5-2細菌培養/細菌放大DNA 47
3-5-3小量質體DNA 萃取以及DNA Retardation Assay 電泳系統 47
3-5-4質體DNA轉染(Plasmid DNA Transfection) 47
3-5-5建立Stable Cell Line 47
3-6體外細胞實驗(in vitro) 48
3-6-1細胞實驗 48
3-6-2 5-ALA-PpIX 培養時間及濃度測定 48
3-6-3 細胞存活率測試 49
3-6-4載體經US/XR治療後細胞毒性測試 49
3-6-5 胞內ROS probe (Cellular Reactive Oxygen Species Detection Assay) 50
3-6-6 細胞週期測定 50
3-6-7共軛焦顯微鏡樣品製備 51
3-6-8 西方點墨法(Western blot) 51
3-6-9 DNA double-strand breaks (Gamma H2AX Pharmacodynamic Assay) 52
3-7 動物實驗(in vivo) 53
3-7-1腫瘤誘導 53
3-7-2 非侵入式活體分子影像系統(Non Invasion In Vivo Imaging System, IVIS) 54
3-7-3腦組織固定以及切片 54
第四章 結果與討論 55
4-1 HAc-Au@SiO2形貌觀察及性質分析 55
4-1-1載體外觀及粒徑分析 55
4-1-2 FTIR之鑑定 57
4-1-3 Zeta potential之鑑定 58
4-1-4 UV-vis之鑑定 59
4-2 HAc-Au@SiO2 細胞實驗 60
4-2-1載體及5ALA細胞毒性測試 60
4-2-2. 5ALA-PpIX培養時間以及螢光強度測定 63
4-2-3. PpIX與粒線體共位 65
4-2-4. PpIX與HAc-Au@SiO2載體共位 66
4-2-5. HAc-Au@SiO2載體在正常與癌細胞細胞吞噬差異 67
4-2-6. US/XR治療誘導細胞毒性 69
4-2-6. 正常細胞、癌細胞與癌幹細胞治療後毒殺差異性 71
4-2-7. 胞內活性氧 (Reactive Oxygen Species；ROS) 測定 74
4-2-8. US/XR治療後GBM細胞週期改變 76
4-2-9. 治療處理後粒線體以及細胞凋亡影響 80
4-3 動物實驗 84
4-3-1 建立冷光報告基因的穩定細胞株 84
4-3-2 建立原位腦癌模型 86
4-3-3 初步動物實驗結果 88
第五章 結論 90
第六章 參考文獻 92


圖目錄
Figure 2-1. Development and progression of astrocytic tumours. 5
Figure 2-2. New approaches to brain tumor therapies. 6
Figure 2-3. Depth-dose curves normalized at the depth of maximum for 100 kV, 250 kV and 6 MeV beams 7
Figure 2-4. Photon mass energy absorption coefficients of soft tissue and gold. 8
Figure 2-5. Comparison of predicted and observed values of dose enhancement for gold nanoparticles at both megavoltage and kilovoltage energies. 9
Figure 2-6. Summary of various approaches for enhancing the radiosensitization in cancer cells. 10
Figure 2-7. Versatility of Gold Nanoparticles. GNPs can be tunable to various shapes and sizes, functionalized with various biomolecules, and are generally safe and nontoxic in vitro and in vivo. 11
Figure 2-8. Interactions of X-rays with NPs result directly or indirectly in the production of secondary species: photons, electrons and later ROS. 14
Figure 2-9. Schematic representation of radiation interactions with gold nanoparticles relating to downstream applications in radiation research. 14
Figure 2-10. Possible reactive oxygen species (ROS)-mediated mechanisms associated with nanoparticle toxicity. 16
Figure 2-11. Changes of cell sensitivity and cell cycle arrest after radiotherapy. 18
Figure 2-12. Basic outline of Radiotherapy effects of cell DNA. 19
Figure 2-13. DNA double strand breaks cause γH2AX formation and subsequent repair mechanisms. 20
Figure 2-14. Mesoporous silica nanoparticle (MSN) morphology, functionalization, and bio-distribution/elimination 22
Figure 2-15. Representation of the intact and degraded structures of silica NPs along with the mechanisms and regulating factors of the degradation. 23
Figure 2-16. 5-ALA-induced tumor fluorescence. 25
Figure 2-17. The porphyrin-heme biosynthetic pathway and putative mitochondrial transporters. 26
Figure 2-18. Schematic representation of diagnostics and PDT of 5-ALA for glioma cells. 5-ALA is converted to PpIX in malignant gliomas via an oral-intake of exogenous 5-ALA. 28
Figure 2-19. Mechanism of Sonodynamic Therapy. 30
Figure 2-20. Response of bubbles to acoustic pressure. 32
Figure 2-21. Possible mechanisms of SDT. 33
Figure 2-22. Mechanism of HA-induced glioma invasion and motility. 36
Figure 3-1. Graphics Abstract 37
Figure 3-2. A schematic representation of the one-pot formation procedure of the core–shell HAc-Au@SiO2. 43
Figure 3-3. In vitro experimental schemes. The gap between the culture dish and the probe was filled with degassed water. 45
Figure 3-4. Orthotopic mouse glioma model. GBM-luc tumor using burr hole as guidance for tumor location. 53
Figure 3-5. Mechanism of Firefly Luciferase Reporter Assay. 54
Figure 4-1. TEM image and particle-size distribution of HAc-Au@SiO2 nanoparticles. 56
Figure 4-2. FTIR spectrum of Au-CTAB, Au@SiO2 with CTAB, Au@SiO2 without CTAB and HAc-Au@SiO2-APTES. 57
Figure 4-3. Zeta potential of Au-CTAB, Au@SiO2 with CTAB, Au@SiO2 without CTAB, Au@SiO2-APTES and HAc-Au@SiO2-APTES. 58
Figure 4-4. UV-Vis extinction spectra of the synthesized Au-CTAB, Au@SiO2 and HAc- Au@SiO2. (4000–500 nm) 59
Figure 4-5. The cytotoxicity of Astrocyte (normal cells) and GBM (Cancer cell) were incubated with different concentrations (0 - 800 μg/ml) of Au@SiO2, HAc-Au@SiO2, and 5ALA for 24 hours at 37℃. 62
Figure 4-6. Intracellular PpIX fluorescence in GBM cells using flow cytometric and Multimode microplate readers analyses. 64
Figure 4-7. Mitochondria co-localization of PpIX in GBM cells. 65
Figure 4-8. HAc-Au@SiO2 naoparticles co-localization of PpIX in GBM cells. 66
Figure 4-9. Cellular uptake of HAc-Au@SiO2 nanoparticles into GBM and Astrocyte cells. 68
Figure 4-10. Cytotoxicity of 100 μg/ml HAc-Au@SiO2 in GBM cells combined with 5ALA and US/XR therapy in 24 hr. 70
Figure 4-11. Cytotoxicity of 100 μg/ml HAc-Au@SiO2 in Astrocyte cells, GBM cells and GSC cells combined with 5ALA and US/XR therapy in 24 hr. 73
Figure 4-12. Intracellular production of reactive oxygen species (ROS) after ionizing irradiation in GBM cells using flow cytometric analyses . 75
Figure 4-13. Cell cycle distributions of HAc-Au@SiO2/5ALA-treated GBM cells in ionizing radiation (IR)/ ultrasound bombardment (US)-induced G2/M phase arrest by flow cytometric analysis. 78
Figure 4-14. Effects of US/XR treatments on mitochondria damage and apoptosis of normal and cancer cell. 83
Figure 4-15. Diagram illustrating steps required for bioluminescence imaging (BLI) to Monitor Tumor Growth and Response to Therapy. 85
Figure 4-16. Stereotactic intracranial implantation and in vivo bioluminescent imaging of tumor xenografts in a mouse model system of glioblastoma multiforme. 87
Figure 4-17. HAc-Au@SiO2 /5ALA plus radiation therapy (RT) and Sonodynamic Therapy (SDT) cures mice with intracranial GBM-luc tumors. 89
Figure 4-18 The molecular mechanism of treatment 91

 
表目錄
Table 1. According to the World Health Organization (WHO) to develop glioma grading system 5
Table 2. Application of gold nanoparticles in 6MeV radiotherapy 12

[1] W.M. Pardridge, Blood-brain barrier drug targeting: the future of brain drug development, Molecular interventions 3(2) (2003) 90.
[2] W.M. Pardridge, The blood-brain barrier: bottleneck in brain drug development, NeuroRx 2(1) (2005) 3-14.
[3] W.M. Pardridge, Molecular Trojan horses for blood–brain barrier drug delivery, Current opinion in pharmacology 6(5) (2006) 494-500.
[4] B.T. Hawkins, T.P. Davis, The blood-brain barrier/neurovascular unit in health and disease, Pharmacological reviews 57(2) (2005) 173-185.
[5] S. Ohtsuki, T. Terasaki, Contribution of carrier-mediated transport systems to the blood–brain barrier as a supporting and protecting interface for the brain; importance for CNS drug discovery and development, Pharmaceutical research 24(9) (2007) 1745-1758.
[6] M. Eckley, K.A. Wargo, A review of glioblastoma multiforme, US Pharm 35(5) (2010) 3-10.
[7] I.D. M. Herold, CC Stobbe, RV Iyer, JD Chapman, D, Gold microspheres: a selective technique for producing biologically effective dose enhancement, International journal of radiation biology 76(10) (2000) 1357-1364.
[8] J.H. Hubbell, S.M. Seltzer, Tables of x-ray mass attenuation coefficients and mass energy-absorption coefficients 1 keV to 20 MeV for elements Z= 1 to 92 and 48 additional substances of dosimetric interest, National Inst. of Standards and Technology-PL, Gaithersburg, MD (United States). Ionizing Radiation Div., 1995.
[9] M.-C. Daniel, D. Astruc, Gold nanoparticles: assembly, supramolecular chemistry, quantum-size-related properties, and applications toward biology, catalysis, and nanotechnology, Chemical reviews 104(1) (2004) 293-346.
[10] J. Takahashi, M. Misawa, M. Murakami, T. Mori, K. Nomura, H. Iwahashi, 5-Aminolevulinic acid enhances cancer radiotherapy in a mouse tumor model, SpringerPlus 2(1) (2013) 602.
[11] A.P. McHale, J.F. Callan, N. Nomikou, C. Fowley, B. Callan, Sonodynamic therapy: concept, mechanism and application to cancer treatment, Therapeutic Ultrasound, Springer2016, pp. 429-450.
[12] M. Bailey, V. Khokhlova, O. Sapozhnikov, S. Kargl, L. Crum, Physical mechanisms of the therapeutic effect of ultrasound, Acoust. Phys 49(4) (2003) 437-464.
[13] J.A. Schwartzbaum, J.L. Fisher, K.D. Aldape, M. Wrensch, Epidemiology and molecular pathology of glioma, Nature clinical practice Neurology 2(9) (2006) 494-503.
[14] S. Agnihotri, K.E. Burrell, A. Wolf, S. Jalali, C. Hawkins, J.T. Rutka, G. Zadeh, Glioblastoma, a brief review of history, molecular genetics, animal models and novel therapeutic strategies, Archivum immunologiae et therapiae experimentalis 61(1) (2013) 25-41.
[15] A. Messali, R. Villacorta, J.W. Hay, A review of the economic burden of glioblastoma and the cost effectiveness of pharmacologic treatments, Pharmacoeconomics 32(12) (2014) 1201-1212.
[16] M.S. Lesniak, H. Brem, Targeted therapy for brain tumours, Nature reviews Drug discovery 3(6) (2004) 499-508.
[17] F.B. Furnari, T. Fenton, R.M. Bachoo, A. Mukasa, J.M. Stommel, A. Stegh, W.C. Hahn, K.L. Ligon, D.N. Louis, C. Brennan, Malignant astrocytic glioma: genetics, biology, and paths to treatment, Genes & development 21(21) (2007) 2683-2710.
[18] D.N. Louis, H. Ohgaki, O.D. Wiestler, W.K. Cavenee, P.C. Burger, A. Jouvet, B.W. Scheithauer, P. Kleihues, The 2007 WHO classification of tumours of the central nervous system, Acta neuropathologica 114(2) (2007) 97-109.
[19] I. Jovčevska, N. Kočevar, R. Komel, Glioma and glioblastoma‑how much do we (not) know?(Review), Molecular and clinical oncology 1(6) (2013) 935-941.
[20] D.G. Pfister, D.H. Johnson, C.G. Azzoli, W. Sause, T.J. Smith, S. Baker Jr, J. Olak, D. Stover, J.R. Strawn, A.T. Turrisi, American Society of Clinical Oncology treatment of unresectable non–small-cell lung cancer guideline: Update 2003, Journal of Clinical Oncology 22(2) (2004) 330-353.
[21] M.M. Mrugala, Advances and challenges in the treatment of glioblastoma: a clinician’s perspective, Discovery medicine 15(83) (2013) 221-230.
[22] S. Kesari, Understanding glioblastoma tumor biology: the potential to improve current diagnosis and treatments, Seminars in oncology, Elsevier, 2011, pp. S2-S10.
[23] G. Iacob, E.B. Dinca, Current data and strategy in glioblastoma multiforme, J Med Life 2(4) (2009) 386-393.
[24] J.E. Chang, D. Khuntia, H.I. Robins, M.P. Mehta, Radiotherapy and radiosensitizers in the treatment of glioblastoma multiforme, Clin Adv Hematol Oncol 5(11) (2007) 894-902.
[25] A.D. Norden, P.Y. Wen, Glioma therapy in adults, The neurologist 12(6) (2006) 279-292.
[26] T. Reithmeier, E. Graf, T. Piroth, M. Trippel, M.O. Pinsker, G. Nikkhah, BCNU for recurrent glioblastoma multiforme: efficacy, toxicity and prognostic factors, BMC cancer 10(1) (2010) 30.
[27] A. Brandes, A. Tosoni, P. Amista, L. Nicolardi, D. Grosso, F. Berti, M. Ermani, How effective is BCNU in recurrent glioblastoma in the modern era? A phase II trial, Neurology 63(7) (2004) 1281-1284.
[28] K. Jain, Use of nanoparticles for drug delivery in glioblastoma multiforme, Expert review of neurotherapeutics 7(4) (2007) 363-372.
[29] G.F. Woodworth, G.P. Dunn, E.A. Nance, J. Hanes, H. Brem, Emerging insights into barriers to effective brain tumor therapeutics, Frontiers in oncology 4 (2014) 126.
[30] P. Retif, S. Pinel, M. Toussaint, C. Frochot, R. Chouikrat, T. Bastogne, M. Barberi-Heyob, Nanoparticles for radiation therapy enhancement: the key parameters, Theranostics 5(9) (2015) 1030.
[31] S. Jain, J.A. Coulter, A.R. Hounsell, K.T. Butterworth, S.J. McMahon, W.B. Hyland, M.F. Muir, G.R. Dickson, K.M. Prise, F.J. Currell, Cell-specific radiosensitization by gold nanoparticles at megavoltage radiation energies, International Journal of Radiation Oncology* Biology* Physics 79(2) (2011) 531-539.
[32] D. Kwatra, A. Venugopal, S. Anant, Nanoparticles in radiation therapy: a summary of various approaches to enhance radiosensitization in cancer, Translational Cancer Research 2(4) (2013) 330-342.
[33] B. Jeremic, A.R. Aguerri, N. Filipovic, Radiosensitization by gold nanoparticles, Clinical and Translational Oncology 15(8) (2013) 593-601.
[34] J.F. Dorsey, L. Sun, D.Y. Joh, A. Witztum, G.D. Kao, M. Alonso-Basanta, S. Avery, S.M. Hahn, A. Al Zaki, A. Tsourkas, Gold nanoparticles in radiation research: potential applications for imaging and radiosensitization, Translational cancer research 2(4) (2013) 280.
[35] M.Y. Chang, A.L. Shiau, Y.H. Chen, C.J. Chang, H.H.W. Chen, C.L. Wu, Increased apoptotic potential and dose‐enhancing effect of gold nanoparticles in combination with single‐dose clinical electron beams on tumor‐bearing mice, Cancer science 99(7) (2008) 1479-1484.
[36] W.N. Rahman, N. Bishara, T. Ackerly, C.F. He, P. Jackson, C. Wong, R. Davidson, M. Geso, Enhancement of radiation effects by gold nanoparticles for superficial radiation therapy, Nanomedicine: Nanotechnology, Biology and Medicine 5(2) (2009) 136-142.
[37] C. Chien, C. Wang, T. Hua, P. Tseng, T. Yang, Y. Hwu, Y. Chen, K. Chung, J. Je, G. Margaritondo, Synchrotron X‐Ray Synthesized Gold Nanoparticles for Tumor Therapy, AIP Conference Proceedings, AIP, 2007, pp. 1908-1911.
[38] C.-J. Liu, C.-H. Wang, S.-T. Chen, H.-H. Chen, W.-H. Leng, C.-C. Chien, C.-L. Wang, I.M. Kempson, Y. Hwu, T.-C. Lai, Enhancement of cell radiation sensitivity by pegylated gold nanoparticles, Physics in medicine and biology 55(4) (2010) 931.
[39] J.N. Kavanagh, K.M. Redmond, G. Schettino, K.M. Prise, DNA double strand break repair: a radiation perspective, Antioxidants & redox signaling 18(18) (2013) 2458-2472.
[40] E.I. Azzam, J.-P. Jay-Gerin, D. Pain, Ionizing radiation-induced metabolic oxidative stress and prolonged cell injury, Cancer letters 327(1) (2012) 48-60.
[41] R.I. Berbeco, H. Korideck, W. Ngwa, R. Kumar, J. Patel, S. Sridhar, S. Johnson, B.D. Price, A. Kimmelman, G.M. Makrigiorgos, DNA damage enhancement from gold nanoparticles for clinical MV photon beams, Radiation research 178(6) (2012) 604-608.
[42] D. Regulla, E. Schmid, W. Friedland, W. Panzer, U. Heinzmann, D. Harder, Enhanced values of the RBE and H ratio for cytogenetic effects induced by secondary electrons from an X-irradiated gold surface, Radiation research 158(4) (2002) 505-515.
[43] S.J. McMahon, H. Paganetti, K.M. Prise, Optimising element choice for nanoparticle radiosensitisers, Nanoscale 8(1) (2016) 581-589.
[44] K.T. Butterworth, S.J. McMahon, F.J. Currell, K.M. Prise, Physical basis and biological mechanisms of gold nanoparticle radiosensitization, Nanoscale 4(16) (2012) 4830-4838.
[45] K.T. Butterworth, S.J. McMahon, L.E. Taggart, K.M. Prise, Radiosensitization by gold nanoparticles: effective at megavoltage energies and potential role of oxidative stress, Translational Cancer Research 2(4) (2013) 269-279.
[46] T.K. Hei, H. Zhou, V.N. Ivanov, M. Hong, H.B. Lieberman, D.J. Brenner, S.A. Amundson, C.R. Geard, Mechanism of radiation‐induced bystander effects: a unifying model, Journal of Pharmacy and Pharmacology 60(8) (2008) 943-950.
[47] N. Sanvicens, M.P. Marco, Multifunctional nanoparticles–properties and prospects for their use in human medicine, Trends in biotechnology 26(8) (2008) 425-433.
[48] Z. Zhang, A. Berg, H. Levanon, R.W. Fessenden, D. Meisel, On the interactions of free radicals with gold nanoparticles, Journal of the American Chemical Society 125(26) (2003) 7959-7963.
[49] J.A. Coulter, S. Jain, K.T. Butterworth, L.E. Taggart, G.R. Dickson, S.J. McMahon, W.B. Hyland, M.F. Muir, C. Trainor, A.R. Hounsell, Cell type-dependent uptake, localization, and cytotoxicity of 1.9 nm gold nanoparticles, Int J Nanomedicine 7(1) (2012) 2673-85.
[50] R. Wahab, S. Dwivedi, F. Khan, Y.K. Mishra, I. Hwang, H.-S. Shin, J. Musarrat, A.A. Al-Khedhairy, Statistical analysis of gold nanoparticle-induced oxidative stress and apoptosis in myoblast (C2C12) cells, Colloids and Surfaces B: Biointerfaces 123 (2014) 664-672.
[51] J.K. Fard, S. Jafari, M.A. Eghbal, A review of molecular mechanisms involved in toxicity of nanoparticles, Advanced pharmaceutical bulletin 5(4) (2015) 447.
[52] G.M. Cooper, R.E. Hausman, The cell, Sinauer Associates Sunderland2000.
[53] M.T. Madigan, J.M. Martinko, J. Parker, Brock biology of microorganisms, prentice hall Upper Saddle River, NJ1997.
[54] H. Kitano, Systems biology: a brief overview, Science 295(5560) (2002) 1662-1664.
[55] H. Lodish, D. Baltimore, A. Berk, S.L. Zipursky, P. Matsudaira, J. Darnell, Molecular cell biology, Scientific American Books New York1995.
[56] T.M. Pawlik, K. Keyomarsi, Role of cell cycle in mediating sensitivity to radiotherapy, International Journal of Radiation Oncology* Biology* Physics 59(4) (2004) 928-942.
[57] T.Y. Seiwert, J.K. Salama, E.E. Vokes, The concurrent chemoradiation paradigm—general principles, Nature clinical practice Oncology 4(2) (2007) 86-100.
[58] M.B. Kastan, J. Bartek, Cell-cycle checkpoints and cancer, Nature 432(7015) (2004) 316-323.
[59] W. Roa, X. Zhang, L. Guo, A. Shaw, X. Hu, Y. Xiong, S. Gulavita, S. Patel, X. Sun, J. Chen, Gold nanoparticle sensitize radiotherapy of prostate cancer cells by regulation of the cell cycle, Nanotechnology 20(37) (2009) 375101.
[60] A. Choudhury, A. Cuddihy, R.G. Bristow, Radiation and new molecular agents part I: targeting ATM-ATR checkpoints, DNA repair, and the proteasome, Seminars in radiation oncology, Elsevier, 2006, pp. 51-58.
[61] L.B. Harrison, M. Chadha, R.J. Hill, K. Hu, D. Shasha, Impact of tumor hypoxia and anemia on radiation therapy outcomes, The oncologist 7(6) (2002) 492-508.
[62] W.M. Bonner, C.E. Redon, J.S. Dickey, A.J. Nakamura, O.A. Sedelnikova, S. Solier, Y. Pommier, γH2AX and cancer, Nature Reviews Cancer 8(12) (2008) 957-967.
[63] E.P. Rogakou, D.R. Pilch, A.H. Orr, V.S. Ivanova, W.M. Bonner, DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139, Journal of biological chemistry 273(10) (1998) 5858-5868.
[64] D.B. Chithrani, S. Jelveh, F. Jalali, M. van Prooijen, C. Allen, R.G. Bristow, R.P. Hill, D.A. Jaffray, Gold nanoparticles as radiation sensitizers in cancer therapy, Radiation research 173(6) (2010) 719-728.
[65] J.P. Banáth, P.L. Olive, Expression of phosphorylated histone H2AX as a surrogate of cell killing by drugs that create DNA double-strand breaks, Cancer Research 63(15) (2003) 4347-4350.
[66] L.J. Kuo, L.-X. Yang, γ-H2AX-a novel biomarker for DNA double-strand breaks, In vivo 22(3) (2008) 305-309.
[67] C.E. Redon, A.J. Nakamura, Y.-W. Zhang, J.J. Ji, W.M. Bonner, R.J. Kinders, R.E. Parchment, J.H. Doroshow, Y. Pommier, Histone γH2AX and poly (ADP-ribose) as clinical pharmacodynamic biomarkers, Clinical cancer research 16(18) (2010) 4532-4542.
[68] S. Kwon, R.K. Singh, R.A. Perez, E.A. Abou Neel, H.-W. Kim, W. Chrzanowski, Silica-based mesoporous nanoparticles for controlled drug delivery, Journal of tissue engineering 4 (2013) 2041731413503357.
[69] C. Bharti, U. Nagaich, A.K. Pal, N. Gulati, Mesoporous silica nanoparticles in target drug delivery system: a review, International journal of pharmaceutical investigation 5(3) (2015) 124.
[70] C. Tourne-Peteilh, S. Begu, D.A. Lerner, A. Galarneau, U. Lafont, J.-M. Devoisselle, Sol–gel one-pot synthesis in soft conditions of mesoporous silica materials ready for drug delivery system, Journal of sol-gel science and technology 61(3) (2012) 455-462.
[71] M. Liong, J. Lu, M. Kovochich, T. Xia, S.G. Ruehm, A.E. Nel, F. Tamanoi, J.I. Zink, Multifunctional inorganic nanoparticles for imaging, targeting, and drug delivery, ACS nano 2(5) (2008) 889-896.
[72] H. Chen, Z. Zhen, W. Tang, T. Todd, Y.-J. Chuang, L. Wang, Z. Pan, J. Xie, Label-free luminescent mesoporous silica nanoparticles for imaging and drug delivery, Theranostics 3(9) (2013) 650.
[73] J. Xie, S. Lee, X. Chen, Nanoparticle-based theranostic agents, Advanced drug delivery reviews 62(11) (2010) 1064-1079.
[74] X. Lin, J. Xie, G. Niu, F. Zhang, H. Gao, M. Yang, Q. Quan, M.A. Aronova, G. Zhang, S. Lee, Chimeric ferritin nanocages for multiple function loading and multimodal imaging, Nano letters 11(2) (2011) 814-819.
[75] N.-T. Chen, S.-H. Cheng, J.S. Souris, C.-T. Chen, C.-Y. Mou, L.-W. Lo, Theranostic applications of mesoporous silica nanoparticles and their organic/inorganic hybrids, Journal of Materials Chemistry B 1(25) (2013) 3128-3135.
[76] K.P. Tamarov, L.A. Osminkina, S.V. Zinovyev, K.A. Maximova, J.V. Kargina, M.B. Gongalsky, Y. Ryabchikov, A. Al-Kattan, A.P. Sviridov, M. Sentis, Radio frequency radiation-induced hyperthermia using Si nanoparticle-based sensitizers for mild cancer therapy, Scientific reports 4 (2014).
[77] L.T. Canham, Bioactive silicon structure fabrication through nanoetching techniques, Advanced Materials 7(12) (1995) 1033-1037.
[78] J.G. Croissant, Y. Fatieiev, N.M. Khashab, Degradability and clearance of silicon, organosilica, silsesquioxane, silica mixed oxide, and mesoporous silica nanoparticles, Advanced Materials (2017).
[79] J.-H. Park, L. Gu, G. Von Maltzahn, E. Ruoslahti, S.N. Bhatia, M.J. Sailor, Biodegradable luminescent porous silicon nanoparticles for in vivo applications, Nature materials 8(4) (2009) 331-336.
[80] E. Gross, D. Kovalev, N. Künzner, J. Diener, F. Koch, V.Y. Timoshenko, M. Fujii, Spectrally resolved electronic energy transfer from silicon nanocrystals to molecular oxygen mediated by direct electron exchange, Physical Review B 68(11) (2003) 115405.
[81] C. Lee, H. Kim, C. Hong, M. Kim, S. Hong, D. Lee, W.I. Lee, Porous silicon as an agent for cancer thermotherapy based on near-infrared light irradiation, Journal of Materials Chemistry 18(40) (2008) 4790-4795.
[82] S. Shen, H. Tang, X. Zhang, J. Ren, Z. Pang, D. Wang, H. Gao, Y. Qian, X. Jiang, W. Yang, Targeting mesoporous silica-encapsulated gold nanorods for chemo-photothermal therapy with near-infrared radiation, Biomaterials 34(12) (2013) 3150-3158.
[83] N. Zhao, Z. Yang, B. Li, J. Meng, Z. Shi, P. Li, S. Fu, RGD-conjugated mesoporous silica-encapsulated gold nanorods enhance the sensitization of triple-negative breast cancer to megavoltage radiation therapy, International journal of nanomedicine 11 (2016) 5595.
[84] P. Huang, L. Bao, C. Zhang, J. Lin, T. Luo, D. Yang, M. He, Z. Li, G. Gao, B. Gao, Folic acid-conjugated silica-modified gold nanorods for X-ray/CT imaging-guided dual-mode radiation and photo-thermal therapy, Biomaterials 32(36) (2011) 9796-9809.
[85] W. Stummer, A. Novotny, H. Stepp, C. Goetz, K. Bise, H.J. Reulen, Fluorescence-guided resection of glioblastoma multiforme utilizing 5-ALA-induced porphyrins: a prospective study in 52 consecutive patients, Journal of neurosurgery 93(6) (2000) 1003-1013.
[86] W. Stummer, U. Pichlmeier, T. Meinel, O.D. Wiestler, F. Zanella, H.-J. Reulen, A.-G.S. Group, Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial, The lancet oncology 7(5) (2006) 392-401.
[87] W. Stummer, J.-C. Tonn, C. Goetz, W. Ullrich, H. Stepp, A. Bink, T. Pietsch, U. Pichlmeier, 5-Aminolevulinic acid-derived tumor fluorescence: the diagnostic accuracy of visible fluorescence qualities as corroborated by spectrometry and histology and postoperative imaging, Neurosurgery 74(3) (2013) 310-320.
[88] M.S. Eljamel, C. Goodman, H. Moseley, ALA and Photofrin® Fluorescence-guided resection and repetitive PDT in glioblastoma multiforme: a single centre Phase III randomised controlled trial, Lasers in medical science 23(4) (2008) 361-367.
[89] Q. Peng, T. Warloe, K. Berg, J. Moan, M. Kongshaug, K.E. Giercksky, J.M. Nesland, 5‐Aminolevulinic acid‐based photodynamic therapy, Cancer 79(12) (1997) 2282-2308.
[90] M. Toda, Intraoperative navigation and fluorescence imagings in malignant glioma surgery, The Keio journal of medicine 57(3) (2008) 155-161.
[91] K. Takahashi, N. Ikeda, N. Nonoguchi, Y. Kajimoto, S.-I. Miyatake, Y. Hagiya, S.-I. Ogura, H. Nakagawa, T. Ishikawa, T. Kuroiwa, Enhanced expression of coproporphyrinogen oxidase in malignant brain tumors: CPOX expression and 5-ALA–induced fluorescence, Neuro-oncology 13(11) (2011) 1234-1243.
[92] W. Stummer, H. Reulen, A. Novotny, H. Stepp, J. Tonn, Fluorescence-guided resections of malignant gliomas--an overview, Acta Neurochirurgica-Supplements only (88) (2003) 9-12.
[93] L. Teng, M. Nakada, Y. Hayashi, T. Yoneyama, S.-G. Zhao, J.-I. Hamada, Current applications of 5-ALA in glioma diagnostics and therapy, Clinical Management and Evolving Novel Therapeutic Strategies for Patients with Brain Tumors, InTech2013.
[94] E. Buytaert, M. Dewaele, P. Agostinis, Molecular effectors of multiple cell death pathways initiated by photodynamic therapy, Biochimica et Biophysica Acta (BBA)-Reviews on Cancer 1776(1) (2007) 86-107.
[95] I.J. Macdonald, T.J. Dougherty, Basic principles of photodynamic therapy, Journal of Porphyrins and Phthalocyanines 5(02) (2001) 105-129.
[96] N.L. Oleinick, R.L. Morris, I. Belichenko, The role of apoptosis in response to photodynamic therapy: what, where, why, and how, Photochemical & Photobiological Sciences 1(1) (2002) 1-21.
[97] G. Iacob, E.B. Dinca, Current data and strategy in glioblastoma multiforme, Journal of medicine and life 2(4) (2009) 386.
[98] S. Karmakar, N.L. Banik, S.J. Patel, S.K. Ray, 5-Aminolevulinic acid-based photodynamic therapy suppressed survival factors and activated proteases for apoptosis in human glioblastoma U87MG cells, Neuroscience letters 415(3) (2007) 242-247.
[99] L. Teng, M. Nakada, S. Zhao, Y. Endo, N. Furuyama, E. Nambu, I. Pyko, Y. Hayashi, J. Hamada, Silencing of ferrochelatase enhances 5-aminolevulinic acid-based fluorescence and photodynamic therapy efficacy, British journal of cancer 104(5) (2011) 798-807.
[100] A. Nabavi, H. Thurm, B. Zountsas, T. Pietsch, H. Lanfermann, U. Pichlmeier, M. Mehdorn, Five-aminolevulinic acid for fluorescence-guided resection of recurrent malignant gliomas: a phase II study, Neurosurgery 65(6) (2009) 1070-1077.
[101] Z. Mohammadi, A. Sazgarnia, O. Rajabi, M. Seilanian Toosi, Comparative study of X-ray treatment and photodynamic therapy by using 5-aminolevulinic acid conjugated gold nanoparticles in a melanoma cell line, Artificial cells, nanomedicine, and biotechnology 45(3) (2017) 467-473.
[102] B. Wang, D. Cvetkovic, R. Gupta, L. Chen, C. Ma, Q. Zhang, J. Zeng, Radiation Therapy Combined With 5-Aminolevulinic Acid: A Preliminary Study With an In Vivo Mouse Model Implanted With Human PC-3 Tumor Cells, International Journal of Radiation Oncology• Biology• Physics 93(3) (2015) E522.
[103] J. Takahashi, M. Misawa, H. Iwahashi, Transcriptome analysis of porphyrin-accumulated and x-ray-irradiated cell cultures under limited proliferation and non-lethal conditions, Microarrays 4(1) (2015) 25-40.
[104] T. Kitagawa, J. Yamamoto, T. Tanaka, Y. Nakano, D. Akiba, K. Ueta, S. Nishizawa, 5-Aminolevulinic acid strongly enhances delayed intracellular production of reactive oxygen species (ROS) generated by ionizing irradiation: Quantitative analyses and visualization of intracellular ROS production in glioma cells in vitro, Oncology reports 33(2) (2015) 583-590.
[105] M. Trendowski, G. Yu, V. Wong, C. Acquafondata, T. Christen, T.P. Fondy, The real deal: using cytochalasin B in sonodynamic therapy to preferentially damage leukemia cells, Anticancer research 34(5) (2014) 2195-2202.
[106] X. Wang, Y. Wang, P. Wang, X. Cheng, Q. Liu, Sonodynamically induced anti-tumor effect with protoporphyrin IX on hepatoma-22 solid tumor, Ultrasonics 51(5) (2011) 539-546.
[107] I. Rosenthal, J.Z. Sostaric, P. Riesz, Sonodynamic therapy––a review of the synergistic effects of drugs and ultrasound, Ultrasonics sonochemistry 11(6) (2004) 349-363.
[108] L. Lagneaux, E.C. de Meulenaer, A. Delforge, M. Dejeneffe, M. Massy, C. Moerman, B. Hannecart, Y. Canivet, M.-F. Lepeltier, D. Bron, Ultrasonic low-energy treatment: a novel approach to induce apoptosis in human leukemic cells, Experimental hematology 30(11) (2002) 1293-1301.
[109] X. Wang, Q. Liu, Z. Wang, P. Wang, P. Zhao, X. Zhao, L. Yang, Y. Li, Role of autophagy in sonodynamic therapy-induced cytotoxicity in S180 cells, Ultrasound in medicine & biology 36(11) (2010) 1933-1946.
[110] D. Song, W. Yue, Z. Li, J. Li, J. Zhao, N. Zhang, Study of the mechanism of sonodynamic therapy in a rat glioma model, OncoTargets and therapy 7 (2014) 1801.
[111] T. Yoshida, T. Kondo, R. Ogawa, L.B. Feril Jr, Q.-L. Zhao, A. Watanabe, K. Tsukada, Combination of doxorubicin and low-intensity ultrasound causes a synergistic enhancement in cell killing and an additive enhancement in apoptosis induction in human lymphoma U937 cells, Cancer chemotherapy and pharmacology 61(4) (2008) 559-567.
[112] F.W. Kremkau, J.S. Kaufmann, M.M. Walker, P.G. Burch, C.L. Spurr, Ultrasonic enhancement of nitrogen mustard cytotoxicity in mouse leukemia, Cancer 37(4) (1976) 1643-1647.
[113] M.J. Povey, T.J. Mason, Ultrasound in food processing, Springer Science & Business Media1998.
[114] V. MišÍk, P. Riesz, Free radical intermediates in sonodynamic therapy, Annals of the New York Academy of Sciences 899(1) (2000) 335-348.
[115] K. Byun, K.Y. Kim, H. Kwak, Sonoluminescence characteristics from micron and submicron bubbles, JOURNAL-KOREAN PHYSICAL SOCIETY 47(6) (2005) 1010.
[116] D. Kessel, J. Lo, R. Jeffers, J.B. Fowlkes, C. Cain, Modes of photodynamic vs. sonodynamic cytotoxicity, Journal of Photochemistry and Photobiology B: Biology 28(3) (1995) 219-221.
[117] G.-Y. Wan, Y. Liu, B.-W. Chen, Y.-Y. Liu, Y.-S. Wang, N. Zhang, Recent advances of sonodynamic therapy in cancer treatment, Cancer biology & medicine 13(3) (2016) 325.
[118] Q. Liu, X. Wang, P. Wang, L. Xiao, Q. Hao, Comparison between sonodynamic effect with protoporphyrin IX and hematoporphyrin on sarcoma 180, Cancer chemotherapy and pharmacology 60(5) (2007) 671-680.
[119] M.S. Eljamel, New light on the brain: the role of photosensitizing agents and laser light in the management of invasive intracranial tumors, Technology in cancer research & treatment 2(4) (2003) 303-309.
[120] S.J. Madsen, E. Angell‐Petersen, S. Spetalen, S.W. Carper, S.A. Ziegler, H. Hirschberg, Photodynamic therapy of newly implanted glioma cells in the rat brain, Lasers in surgery and medicine 38(5) (2006) 540-548.
[121] F. Fry, Intense focused ultrasound in medicine: some practical guiding physical principles from sound source to focal site in tissue, European urology 23 (1993) 2-7.
[122] T. Ohmura, T. Fukushima, H. Shibaguchi, S. Yoshizawa, T. Inoue, M. Kuroki, K. Sasaki, S.-I. Umemura, Sonodynamic therapy with 5-aminolevulinic acid and focused ultrasound for deep-seated intracranial glioma in rat, Anticancer research 31(7) (2011) 2527-2533.
[123] L. Osminkina, E. Luckyanova, M. Gongalsky, A. Kudryavtsev, A.K. Gaydarova, R. Poltavtseva, P. Kashkarov, V.Y. Timoshenko, G. Sukhikh, Effects of nanostructurized silicon on proliferation of stem and cancer cell, Bulletin of experimental biology and medicine 151(1) (2011) 79-83.
[124] A. Sviridov, V. Andreev, E. Ivanova, L. Osminkina, K. Tamarov, V.Y. Timoshenko, Porous silicon nanoparticles as sensitizers for ultrasonic hyperthermia, Applied Physics Letters 103(19) (2013) 193110.
[125] L. Osminkina, A. Nikolaev, A. Sviridov, N. Andronova, K. Tamarov, M. Gongalsky, A. Kudryavtsev, H. Treshalina, V.Y. Timoshenko, Porous silicon nanoparticles as efficient sensitizers for sonodynamic therapy of cancer, Microporous and Mesoporous Materials 210 (2015) 169-175.
[126] P. Auvinen, R. Tammi, V.M. Kosma, R. Sironen, Y. Soini, A. Mannermaa, R. Tumelius, E. Uljas, M. Tammi, Increased hyaluronan content and stromal cell CD44 associate with HER2 positivity and poor prognosis in human breast cancer, International journal of cancer 132(3) (2013) 531-539.
[127] J.M. Louderbough, J.A. Schroeder, Understanding the dual nature of CD44 in breast cancer progression, Molecular Cancer Research 9(12) (2011) 1573-1586.
[128] M. Dohadwala, J. Luo, L. Zhu, Y. Lin, G.J. Dougherty, S. Sharma, M. Huang, M. Põld, R.K. Batra, S.M. Dubinett, Non-small cell lung cancer cyclooxygenase-2-dependent invasion is mediated by CD44, Journal of Biological Chemistry 276(24) (2001) 20809-20812.
[129] V.J. Wielenga, K.-H. Heider, G. Johan, A. Offerhaus, G.R. Adolf, F.M. van den Berg, H. Ponta, P. Herrlich, S.T. Pals, Expression of CD44 variant proteins in human colorectal cancer is related to tumor progression, Cancer Research 53(20) (1993) 4754-4756.
[130] S. Arpicco, G. De Rosa, E. Fattal, Lipid-based nanovectors for targeting of CD44-overexpressing tumor cells, Journal of drug delivery 2013 (2013).
[131] K.Y. Choi, G. Saravanakumar, J.H. Park, K. Park, Hyaluronic acid-based nanocarriers for intracellular targeting: interfacial interactions with proteins in cancer, Colloids and Surfaces B: Biointerfaces 99 (2012) 82-94.
[132] R. Asher, A. Bignami, Hyaluronate binding and CD44 expression in human glioblastoma cells and astrocytes, Experimental cell research 203(1) (1992) 80-90.
[133] T. Yoshida, Y. Matsuda, Z. Naito, T. Ishiwata, CD44 in human glioma correlates with histopathological grade and cell migration, Pathology international 62(7) (2012) 463-470.
[134] A. Merzak, S. Koocheckpour, G.J. Pilkington, CD44 mediates human glioma cell adhesion and invasion in vitro, Cancer Research 54(15) (1994) 3988-3992.
[135] J.B. Park, H.-J. Kwak, S.-H. Lee, Role of hyaluronan in glioma invasion, Cell adhesion & migration 2(3) (2008) 202-207.
[136] X. Qian, X.-H. Peng, D.O. Ansari, Q. Yin-Goen, G.Z. Chen, D.M. Shin, L. Yang, A.N. Young, M.D. Wang, S. Nie, In vivo tumor targeting and spectroscopic detection with surface-enhanced Raman nanoparticle tags, Nature biotechnology 26(1) (2008) 83.
[137] C. Zhang, D. Ni, Y. Liu, H. Yao, W. Bu, J. Shi, Magnesium silicide nanoparticles as a deoxygenation agent for cancer starvation therapy, Nature nanotechnology 12(4) (2017) 378-386.
[138] E. Eruslanov, S. Kusmartsev, Identification of ROS using oxidized DCFDA and flow-cytometry, Advanced protocols in oxidative stress II (2010) 57-72.
[139] R.M. Day, Y.J. Suzuki, Cell proliferation, reactive oxygen and cellular glutathione, Dose-Response 3(3) (2005) 425.
[140] W.K. Kaufmann, R.S. Paules, DNA damage and cell cycle checkpoints, The FASEB Journal 10(2) (1996) 238-247.
[141] M. Moroni, D. Maeda, M.H. Whitnall, W.M. Bonner, C.E. Redon, Evaluation of the gamma-H2AX assay for radiation biodosimetry in a swine model, International journal of molecular sciences 14(7) (2013) 14119-14135.
[142] A.P. Castano, T.N. Demidova, M.R. Hamblin, Mechanisms in photodynamic therapy: part two—cellular signaling, cell metabolism and modes of cell death, Photodiagnosis and photodynamic therapy 2(1) (2005) 1-23.