多功能微氣泡配合聚焦式超音波於腦腫瘤之診斷治療研究

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研究生：	范景翔 Fan, Ching-Hsiang
論文名稱：	多功能微氣泡配合聚焦式超音波於腦腫瘤之診斷治療研究 Multifunctional microbubbles with focused ultrasound for the theranostics of brain tumor
指導教授：	葉秩光 Yeh, Chih-Kuang
口試委員:	葉秩光劉浩澧楊逢羿廖愛禾謝清河
學位類別：	博士 Doctor
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：	2013
畢業學年度：	101
語文別：	英文
論文頁數：	169
中文關鍵詞：	微氣泡、聚焦式超音波、血腦屏障、穴蝕效應、化學治療、標靶治療
外文關鍵詞：	microbubble, focused ultrasound, blood-brain barrier, cavitation, chemotherapy, targeting therapy
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血腦屏障為中樞神經系統中特化的保護性結構，其功能為維持腦內平衡並保護腦組織不受外來物質的侵害，但同時也限制了腦部治療藥物或造影用藥等無法順利流入腦內達成其功效。近年來，聚焦式超音波配合微氣泡已被證實能短暫性開起局部血腦屏障，增加藥物遞送進入腦組織的機會。本論文以聚焦式超音波配合自製多功能微氣泡於小動物模型引發血腦屏障開啟，研究主題包含過程中安全性評估及藥物遞送之應用。安全性評估可分為兩個面向：第一面向主要陳述於第二章，從影像處理端的角度出發，以即時超音波成像技術監測腦部接受聚焦式超音波照射後之生理變化，其結果發現當聚焦式超音波的能量過大時會引發腦出血及局部缺血的現象，而這些現象可分別以高頻造影超音波B-mode影像及對比增強影像偵測，進而為日後利用聚焦式超音波與微氣泡誘發血腦屏障開啟之安全性的研究提供一項即時可靠的評估工具。第二面向則陳述於第三章，為從物理端的角度提出使用匹配頻率之聚焦式超音波及微氣泡，企圖在血腦屏障開啟的過程中抑制慣性穴蝕效應的發生。其結果證實此方式確實有良好開啟血腦屏障的效果並可有效抑制慣性穴蝕效應的發生，進而避免血腦屏障開啟過程中所產生的腦出血或是腦組織傷害，將可進一步提升使用聚焦式超音波配合微氣泡此技術開啟血腦屏障之安全性。第四章則著重於以聚焦式超音波配合多功能微氣泡進行腦部藥物遞送，本研究以自製的微氣泡包覆脂溶性的化療舊藥亞硝氮芥(BCNU)，再於包覆BCNU微氣泡(BCNU-MB)外殼修飾血管新生因子的抗體，作為新型的標靶性藥物載體。由於腦瘤的血管新生因子表現豐富，因此該微氣泡將主動並大量吸附至腫瘤內部血管的血管新生因子受器周圍，配合聚焦式超音波的照射，不僅可局部開啟血腦屏障，同時可將微氣泡擊破，精準地將微氣泡內包覆的BCNU釋放至腫瘤內，達到標靶治療的目的。另外此微氣泡會大量累積於腫瘤區域，因此可在超音波造影下提供良好的腫瘤位置偵測效果。將該微氣泡配合聚焦式超音波進一步應用至大鼠腦瘤模型進行治療，其抑制腫瘤生長的效果相當明顯。此研究結果將可提供重要資訊應用於未來腦部藥物輸送及診斷治療合一之藥物載體設計。

The blood brain barrier (BBB) is a specialized protective structure in central nervous system, which is critical for maintaining brain homeostasis and low permeability that controls the passage of molecules from the circulation into the brain parenchyma and the efflux from the brain. However, the BBB also hinders the transportation of therapeutic agents and contrast agents from blood into brain tissue, lowering the treatment efficiency. Recently, focused ultrasound (FUS) sonication in the presence of microbubbles (MBs) has been proved to transiently open the BBB, allowing the penetration of administered agents into the brain. This thesis tried to induce blood-brain barrier disruption by selfmade multifunctional microbubbles and focused ultrasound (MB-FUS-BBBD) in small animal model, and focused on its safety issue and drug delivery application. The safety issue can be divided to two certain parts. The first part described in chapter 2 investigated the feasibility of using real-time ultrasound imaging to monitor the histological alterations of brain after receiving MB-FUS-BBBD process. We found that when FUS was over-excited, the MB-FUS-BBBD process accompanied extensive intracerebral hemorrhage (ICH) and blood flow shortage. In addition, the hemorrhage pattern and the location of blood flow shortage were represented by high-frequency ultrasound B-mode images and contrast-enhanced ultrasound images, respectively. The second part presented in chapter 3 attempted to use submicron bubbles and on-resonant frequency FUS synergistically to inhibit the occurrence of inertial cavitation during MB-FUS-BBBD. The results demonstrated that when submicron bubbles were exposed to resonant-frequency matched FUS, inertial cavitation could be reduced, avoiding the risk of ICH and brain damage. Feasibility of combined-use of multifunctional MBs with FUS for brain drug delivery was described in chapter 4. A 1,3-bis(2-chloroethyl)-1-nitrosoure (BCNU)-loaded and VEGF-A ligand conjugated MB (VEGF-BCNU-MB) was developed as a novel targeting drug carrier. These VEGF-BCNU-MBs accumulated actively in the brain tumor vasculatures where overactive angiogenesis was marked by overexpression of VEGF-R2 receptor. Sonicated by FUS, VEGF-BCNU-MBs not only opened the BBB but also released chemotherapeutic agent into tumor sites, thus achieving the goal of targeting therapy. Furthermore, these abundantly accumulated targeting bubbles had the potential to serve as tools for molecular ultrasound imaging for tumor detection. Further applied the combination of FUS exposure and VEGF-BCNU-MBs in a rat glioblastoma multiforme (GBM) model, obvious tumor growth suppression was found. Our ﬁndings gave the information for future MB design aimed at targeted brain tumor therapy or extending the application of MBs to theragnostic applications.

中文摘要    vii
Abstract    ix
致謝    xi
List of Symbols    xiii
List of Figures    xiv
List of Tables    xix

Chapter 1 
Introduction 
1 Brain tumor    1
1.1 Glioblastoma Multiforme (GBM)    1
1.2 Angiogenesis of GBM    1
1.3 Treatment Strategies of GBM    3
1.3.1 Surgical Resection and Radiation Therapy    3
1.3.2 Traditional Chemotherapy    3
1.3.2.1 BCNU     3
2 Blood-Brain Barrier (BBB)    5
2.1 The Concept of BBB    5
2.2 The Structure of BBB    5
2.3 The BBB in Brain Tumor    6
2.4 Methods for Increasing BBB Permeability    7
3 Microbubble (MB)    8
3.1 Diagnostic Application    8
3.2 Therapeutic Application     9
3.3 Concept of Novel Multifunctional MBs    10
3.4 Drug-loaded MBs    12
3.5 Targeted MBs    16
4 Ultrasound    16
4.1 Diagnostic Application    16
4.1.1 Contrast-Enhanced Ultrasound Imaging (CEUS)    17
4.2 Therapeutic Effect of FUS    18
4.2.1 Thermal Effect    18
4.2.2 Cavitation Effect    19
4.3 Interaction between FUS and MBs within Brain Tissue    20
4.3.1 Concepts of Combing MBs and FUS Induced BBBD for CNS Drug Delivery    20
4.3.2 The influence of FUS sonication and MBs parameters on BBBD     22
4.3.3 Cellular Mechanisms of MB-FUS-BBBD    25
4.3.4 Acoustic Emission Signals of MBs during MB-FUS-BBBD    26
4.3.5 Bioeffects of FUS and MBs    27
4.3.6 MB-FUS-BBBD for Enhancing Delivery of Agents into Brain      28
5 Scope and Organization of This Dissertation    30

Chapter 2 
Detection of ICH and Transient Blood-Supply Shortage in FUS-Induced BBBD by Ultrasound Imaging
1 Introduction    38
2 Method    39
2.1 Animal Preparation    39
2.2 Experimental Set-Up    40
2.3 Preparation of MBs    42
2.4 FUS Generation, Calibration and Sonication    43
2.5 CEUS Imaging Protocol    44
2.6 Histology    45
2.7 B-Mode Gray-Level Intensity    46
2.8 CEUS Imaging and Intensity Contributed by MBs    46
3 Result    48
4 Summary    54

Chapter 3
FUS with Submicron Bubbles Producing Inertial Cavitation Suppression in BBBD Application
1 Introduction    55
2 Method    57
2.1 Submicron Bubble Preparation    57
2.2 Estimation of Submicron Bubbles Resonance Frequency    58
2.3 Animal Preparation    61
2.4 Experimental Setup    61
2.5 FUS Calibration and Sonication    63
2.6 Acquisition and Analysis of Passive Cavitation Detection (PCD)    65
2.7 Evaluation of BBBD    67
2.8 Magnetic resonance imaging (MRI) Examination    68
2.9 Brain Damage Evaluation    69
2.10 Synthesis of Submicron-Sized BCNU-Loaded Bubbles    69
2.11 Quantitative Determination of BCNU Accumulation in Brain Tissue    70
2.12 Quantitation of BCNU Accumulation in Brain Tissue    71
2.13 Statistical Analysis    72
3 Result    72
3.1 In Vivo Cavitation Detection    72
3.2 Safety Assessment    75
3.3 Repetitive and Transcranial FUS Treatment for Enhancing Delivery of Encapsulated Drugs      78
4 Summary    80

Chapter 4 
Antiangiogenic-Targeting Drug-Carrying MBs Combined with FUS for Glioma Treatment
1 Introduction    82
2 Method    83
2.1 Preparation of Drug-Loaded and Antiangiogenic-Targeting MBs    83
2.1.1 Preparation of Biotinylated Drug-Loaded MBs    83
2.1.2 Preparation of Antiangiogenic-Targeting Drug-Loaded MBs    83
2.2 Characterization of Antiangiogenic-Targeting Drug-Loaded MBs    84
2.2.1 Size Distribution, Concentration and Drug Loading Efficiency    84
2.2.2 Estimation of Conjugation Efficiency    84
2.3 In Vitro Affinity and Cytotoxicity Test of VEGF-BCNU-MBs    84
2.3.1 Cell Culture and In Vitro Binding Test    84
2.3.2 Flow Cytometry    85
2.3.3 In Vitro Ultrasound-Triggered Drug Release Experiment Setup    86
2.3.4 In Vitro Cytotoxicity Measurement    86
2.4 In Vivo Glioma Animal Treatment    87
2.4.1 Brain Glioma Tumor Model    87
2.4.2 In Vivo MB Targeting Test Using Immunofluorescence Imaging    88
2.4.3 In Vivo MB Binding Affinity Test Using Small-Animal Ultrasonic Imaging    89
2.4.4 Sonogram-Guided MB-FUS-BBBD    90
2.4.5 Confirmation and Quantification of VEGF-BCNU-MB-Enhanced FUS-BBBD    90
2.4.6 In vivo BCNU Quantification after VEGF-BCNU-MB -Enhanced FUS-BBBD    91
2.5 Evaluation of VEGF-BCNU-MB-Facilitated BBBD for Glioma Treatment    92
2.5.1 Glioma Treatment Experimental Design    92
2.5.2 MRI    93
2.5.3 Statistical Analysis    93
3 Result    94
3.1 Characterization of VEGF-BCNU-MBs    94
3.2 In vitro Targeting and Toxicity Test    95
3.3 Tumor Immunofluorescence Staining    97
3.4 In Vivo Ultrasound Imaging    98
3.5 In Vivo FUS-Induced BBBD and EB Release    101
3.6 In Vivo Drug Release and Liver Deposition    102
3.7 In Vivo Antitumor Efficacy and Animal Survival    103
4 Summary    108

Chapter 5 
Discussion
1 Detection of ICH and Transient Blood-Supply Shortage in FUS-Induced  BBBD by Ultrasound Imaging    109
2 FUS with Submicron Bubbles Producing Inertial Cavitation Suppression in  BBBD Application    112
3 Antiangiogenic-Targeting Drug-Carrying MBs Combined With FUS for  Glioma Treatment     115
3.1 Clinical Implications of Antiangiogenic-Targeting, Drug-Loaded MBs    115
3.2 Roles of Angiogenesis and Vasculogenesis in Targeting of Drug-Loaded       MBs in a Glioma Model    116
3.3 Biophysical Features of Antiangiogenic-Targeting MBs    117
3.4 Multimodality of Antiangiogenic-Targeting MBs    118
Chapter 6 
Conclusion and Future Work    120

References     123

Author Biography     165

Publication List     165

                                

[1] P.Y. Wen and S. Kesari, “Malignant gliomas in adults,” N Engl J Med., vol. 359, pp. 492–507, 2008.
[2] D.N. Louis, H Ohgaki, O.D. Wiestler, W.K. Cavenee, P.C. Burger and A. Jouvet, “The 2007 WHO classification of tumours of the central nervous system,” Acta Neuropathol., vol. 114, pp. 97–109, 2007.
[3] A. Jemal, R. Siegel, E. Ward, T. Murray, J. Xu, C. Smigal and M.J. Thun, “Cancer statistics, 2006,” CA Cancer J Clin., vol. 56, pp. 106–130, 2006
[4] E.C. Holland, “Glioblastoma multiforme: the terminator,” Proc Natl Acad Sci USA., vol. 97, pp. 6242–6244, 2000.
[5] A. Behin, K. Hoang-Xuan, A.F. Carpentier and J.Y. Delattre, “Primary brain tumours in adults,” Lancet. vol. 361, pp. 323–331, 2003.
[6] S.A. Grossman and L.K. Norris, “Adjuvant and neoadjuvant treatment for primary brain tumors in adults,” Semin Oncol., vol. 22, pp.530–539, 1995.
[7] H.H. Engelhard, “The role of interstitial BCNU chemotherapy in the treatment of malignant glioma,” Surg Neurol., vol. 53, pp. 458–464, 2000.
[8] Y. Li, H.L. Ho Duc, B. Tyler, T. Williams, M. Tupper, R. Langer, H. Brem and M.J.
Cima, “In vivo delivery of BCNU from a MEMS device to a tumor model,” J Control
Release., vol. 106, pp. 138–145, 2005.
[9] W.M. Pardridge, “Drug and gene delivery to the brain: the vascular route,” Neuron., vol. 36, pp. 555–558, 2002
[10] J. Folkman, “How is blood vessel growth regulated in normal and neoplastic tissue? G.H.A. Clowes memorial Award lecture,” Cancer Res., vol. 46, pp. 467–473, 1986
[11] E.R. Gerstner, T.T. Batchelor, “Antiangiogenic therapy for glioblastoma,” Cancer J., vol. 18, pp. 45–50, 2012
[12] J.J. Verhoeff, O. van Tellingen, A. Claes, L.J. Stalpers, M.E. van Linde, D.J. Richel, W.P. Leenders and W.R. van Furth, “Concerns about anti-angiogenic treatment in patients with glioblastoma multiforme,” BMC Cancer., vol. 9, pp. 444, 2009.
[13] K. Holmes, O.L. Roberts, A.M. Thomas and M.J. Cross, “Vascular endothelial growth factor receptor-2: structure, function, intracellular signalling and therapeutic
inhibition,” Cell Signal., vol. 19, pp. 2003–2012, 2007.
[14] K.H. Plate, G. Breier, B. Millauer, A. Ullrich and W. Risau, “Up-regulation of vascular endothelial growth factor and its cognate receptors in a rat glioma model of
tumor angiogenesis,” Cancer Res., vol. 53, pp. 5822–5827, 1993.
[15] J. Folkman, “Tumor angiogenesis: therapeutic implications,” N. Engl. J. Med., vol. 285, pp. 1182–1186, 1971.
[16] S. Kanno, N. Oda, M. Abe, Y. Terai, M. Ito, K. Shitara, K. Tabayashi, M. Shibuya and Y. Sato, “Roles of two VEGF receptors, Flt-1 and KDR, in the signal transduction of VEGF effects in human vascular endothelial cells,” Oncogene., vol. 19, pp. 2138–2146, 2000.
[17] J. Folkman, “Angiogenesis,” Annu Rev Med., vol. 57, pp. 1–18, 2006.
[18] N. Ferrara, K.J. Hillan and W. Novotny, “Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy,” Biochem Biophys Res Commun., vol. 333, pp. 328–335, 2005.
[19] J.M. Saul, A. Annapragada, J.V. Natarajan and R.V. Bellamkonda, “Controlled targeting of liposomal doxorubicin via the folate receptor in vitro,” J Control Release., vol. 19, pp. 49–67, 2003.
[20] A.Giese, and M. Westphal, “Glioma invasion in the central nervous
system,” Neurosurgery., vol. 39, pp. 235–252, 1996.
[21] D.F. Deen, A. Chiarodo, E.A. Grimm, J.R. Fike, M.A. Israel, L.E. Kun, V.A. Levin, L.J. Marton, R.J. Packer, A.E. Pegg, M.L. Rosenblum, H.D. Suit, M.D. Walker, C.J. Wikstrand, C.B. Wilson, A.J. Wong and W.K. Yung, “Brain tumor working group
report on the 9th international conference on brain tumor research and therapy. Organ System Program, National Cancer Institute,” J Neurooncol., vol. 16, pp. 243–272, 1993.
[22] C. Kang, X. Yuan, Y. Zhong, P. Pu, Y. Guo, A. Albadany, S. Yu, Z. Zhang, Y. Li, J. Chang and J. Sheng, “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, 2009.
[23] P.Y. Chen, H.L. Liu, M.Y. Hua, H.W. Yang, C.Y. Huang, P.C. Chu, L.A. Lyu, I.C. Tseng, L.Y. Feng, H.C. Tsai, S.M. Chen, Y.J. Lu, J.J. Wang, T.C. Yen, Y.H. Ma, T. Wu, J.P. Chen, J.I. Chuang, J.W. Shin, C. Hsueh and K.C. Wei, “Novel magnetic/ultrasound focusing system enhances nanoparticle drug delivery for glioma
treatment,” Neuro Oncol., vol. 12, pp. 1050–1060, 2010.
[24] M.D. Walker, S.B. Green, D.P. Byar, E. J.r. Alexander, U. Batzdorf, W.H. Brooks, et al., “Randomized comparisons of radiotherapy and nitrosoureas for the treatment of malignant glioma after surgery,” N. Engl. J. Med., vol. 303, pp. 1323–1329, 1980.
[25] S.A. Grossman and J.F. Batara, “Current management of glioblastoma multiforme,” Semin Oncol., vol. 31, pp. 635–644, 2004.
[26] E.R. Barnhart, B.B. Huff, “Physicians’ Desk Reference,” (edition 48), Medical Economics Company, Oradell, NJ, 1988.
[27] M. Westphal, D.C. Hilt, E. Bortey, P. Delavault, R. Olivares, P.C. Warnke, I.R. Whittle, J. Jääskeläinen, and Z. Ram, “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, 2003.
[28] X. Xu, X. Chen, X. Xu, T. Lu, X. Wang, L. Yang and X. Jing, “BCNU-loaded PEG-PLLA ultrafine fibers and their in vitro antitumor activity against Glioma C6 cells,” J Control Release., vol. 114, pp. 307–316, 2006.
[29] L.H. Treat, N. McDannold, N. Vykhodtseva, Y. Zhang, K. Tam and K. Hynynen, “Targeted delivery of doxorubicin to the rat brain at therapeutic levels using MRI-guided focused ultrasound,” Int J Cancer., vol. 121, pp. 901–907, 2007.
[30] BiCNU, Bristol-Myers Squibb Company, 2007.
[31] ] G.Y. Kim, B.M. Tyler, M.M. Tupper, J.M. Karp, R.S. Langer, H. Brem and M.J. Cima, “Resorbable polymer microchips releasing BCNU inhibit tumor growth in the rat 9L flank model,” J Control Release., vol. 123, pp. 172–178, 2007.
[32] H.L. Liu, M.Y. Hua, P.Y. Chen, P.C. Chu, C.H. Pan, H.W. Yang, et al., “Blood-brain barrier disruption with focused ultrasound enhances delivery of chemotherapeutic drugs for glioblastoma treatment,” Radiology, vol. 255, pp. 415–425, 2010.
[33] K.W. Kohn, “Interstrand cross-linking of DNA by 1,3-bis(2-chloroethyl)-1-nitrosourea and other 1-(2-haloethyl)-1-nitro-soureas,” Cancer Research., vol. 37, pp. 1450–1454, 1977.
[34] Y. Li, H.L. Ho Duc, B. Tyler, T. Williams, M. Tupper, R. Langer, H. Brem and M.J. Cima, “In vivo delivery of BCNU from a MEMS device to a tumor model,” J Control Release., vol. 106, pp. 138–145, 2005.
[35] M. Deutsch, S.B. Green, T.A. Strike, P.C. Burger, J.T. Robertson, R.G. Selker et al., “Results of a randomized trial comparing BCNU plus radiotherapy, streptozotocin plus radiotherapy, BCNU plus hyperfractionated radiotherapy, and BCNU following misonidazole plus radiotherapy in the postoperative treatment of malignant glioma,” Int J Radiat Oncol Biol Phys., vol. 16, pp. 1389–1396, 1989.
[36] T.L. Loo, R.L. Dion, R.L. Dixon and D.P. Rall, “The antitumor agent, 1,3-bis(2-chloroethyl)-1-nitrosourea,” J. Pharm. Sci., vol. 55, pp. 492–497, 1966.
[37] K.T. Wheeler, V.A. Levin and D.F. Deen, “The concept of drug dose for in vitro studies with chemotherapeutic agents,” Radiat Res., vol. 76, pp. 441–581, 1978.
[38] P.L. Kornblith, M. Walker, “Chemotherapy for malignant gliomas,” J. Neurosurg. vol. 68, pp. 1–17, 1988.
[39] P. Ehrlich, “Das Sauerstoffbedu¨ rfnis des Organismus. Eine farbenanalytische Studie,” Hirschwald, Berlin, 1885.
[40] M. Lewandowsky, “Zur Lehre von der Cerebrospinalflussigkeit,” Z .Klin. Med., vol. 40, pp. 480–494, 1900.
[41] E. Goldmann, “Vitalfa¨ rbung am Zentralnervensystem,” Abhandl Konigl preuss Akad Wiss, vol. 1, pp. 1–60, 1913.
[42] H. Davson and E. Spaziani, “The blood–brain barrier and the extracellular space of brain,” J. Physiol., vol. 149, pp. 135–143, 1959.
[43] T. Reese and M. Karnovsky, “Fine structural localization of a blood–brain barrier to exogenous peroxidase,” J. Biol. Chem., vol. 34, pp. 207–217, 1967.
[44] W.M. Pardridge, “Advances in cell biology of blood–brain barrier transport,” Semin. Cell. Biol., vol. 2, pp. 419–426, 1991.
[45] W.M. Pardridge, “The blood-brain barrier: bottleneck in brain drug development,” NeuroRx., vol. 2, pp. 3–14, 2005.
[46] J.M. Staddon and L.L. Rubin, “Cell adhesion, cell junctions and the blood-brain barrier,” Curr Opin Neurobiol., vol. 6, pp. 622–627, 1996.
[47] N. J. Abbott, L. R¨onnb¨ack, and E. Hansson, “Astrocyte-endothelial interactions at the blood-brain barrier,” Nat Rev Neurosci., vol. 7, pp. 41–53, 2006.
[48] P.A. Stewart and U.I. Tuor, “Blood-eye barriers in the rat: correlation of ultrastructure with function,” J Comp Neurol., vol. 340, pp. 566–576. 1994.
[49] W.M. Pardridge, “Blood–brain barrier drug targeting: the future of brain drug development,” Mol. Interv., vol. 3, pp. 90–105, 2003.
[50] R.A. Kroll and E.A. Neuwelt, “Outwitting the blood–brain barrier for therapeutic purposes: osmotic opening and other means,” Neurosurgery., vol. 42, pp. 1083–1099, 1998.
[51] E.H. Lo, A.B. Singhal, V.P. Torchilin and N.J. Abbott, “Drug delivery to damaged brain,” Brain Res. Brain Res. Rev., vol. 38, pp. 140–148, 2001.
[52] J.R. Ewing, S.L. Brown, M. Lu, S. Panda, G. Ding, R.A. Knight, et al., “Model selection in magnetic resonance imaging measurements of vascular permeability: Gadomer in a 9L model of rat cerebral tumor,” J Cereb Blood Flow Metab., vol. 26, pp. 310–320, 2006.
[53] N.D. Doolittle, C.P. Anderson, W.A. Bleyer, J.G. Cairncross, T. Cloughesy, S.L. Eck, et al., “Importance of dose intensity in neuro-oncology clinical trials: summary report of the Sixth Annual Meeting of the Blood–Brain Barrier Disruption Consortium,” Neuro-Oncology, vol. 3, pp. 46–54, 2001.
[54] E.A. Neuwelt, P.A. Barnett, D.D. Bigner and E.P. Frenkel, “Effects of adrenal cortical steroids and osmotic blood-brain barrier opening on methotrexate delivery to gliomas in the rodent: the factor of the blood-brain barrier,” Proc Natl Acad Sci U S A., vol. 79, pp. 4420–4423, 1982.
[55] E.A. Neuwelt, E.P. Frenkel and A.N. D'Agostino, “Growth of human lung tumor in the brain of the nude rat as a model to evaluate antitumor agent delivery across the blood-brain barrier,” Cancer Res., vol. 45, pp. 2827–2833, 1985.
[56] D.R. Groothuis, J.M. Fischer, G. Lapin, D.D. Bigner, and N.A. Vick, “Permeability of different experimental brain tumor models to horseradish peroxidase,” J Neuropathol Exp Neurol., vol. 41, pp. 164–185, 1982.
[57] P.C. Burger, “The anatomy of astrocytomas,” Mayo Clin Proc., vol. 62, pp. 527–529, 1987.
[58] E.C. Halperin, P.C. Burger and D.E. Bullard, “The fallacy of the localized supratentorial malignant glioma,” Int J Radiat Oncol Biol Phys., vol. 15, pp. 505–509, 1988.
[59] W.M. Pardridge, “Brain Drug Targeting: The Future of Brain Drug Development,” (Cambridge, UK: Cambridge University Press), 2001.
[60] J. Huwyler, D. Wu and W.M. Pardridge, “Brain drug delivery of small molecules using immunoliposomes,” Proc. Natl. Acad. Sci. U S A., vol. 93, pp. 14164–14169, 1996.
[61] A.E. Gulyaev, S.E. Gelperina, I.N. Skidan, A.S. Antropov, G.Y. Kivman and J. Kreuter, “Significant transport of doxorubicin into the brain with polysorbate 80-coated nanoparticles,” Pharm. Res., vol. 16, pp. 1564–1569, 1999.
[62] M. Singh, “Transferrin as a targeting ligand for liposomes and anticancer drugs,” Curr. Pharm. Des., vol. 5, pp. 443–451, 1999.
[63] W.M. Pardridge, Y.S. Kang and J.L. Buciak, “Transport of human recombinant brain-derived neurotrophic factor (BDNF) through the rat blood–brain barrier in vivo using vector-mediated peptide drug delivery,” Pharm. Res., vol. 11, pp. 738–746, 1994.
[64] S.R. Schwarze, A. Ho, A. Vocero-Akbani and S.F. Dowdy, “In vivo protein transduction: delivery of a biologically active protein into the mouse,” Science., vol. 285, pp. 1569–1572, 1999.
[65] A.S. Lossinsky, A.W. Vorbrodt and H.M. Wisniewski, “Scanning and transmission electron microscopic studies of microvascular pathology in
the osmotically impaired blood-brain barrier,” J Neurocytol., vol. 24, pp. 795–806, 1995.
[66] G.Y. Pan, X.D. Liu and G.Q. Liu, “Intracarotid infusion of hypertonic mannitol
changes permeability of blood-brain barrier to methotrexate in rats,” Acta Pharmacol Sin., vol. 21, pp. 613–616, 2000.
[67] S.I. Rapoport, “Functional brain imaging to identify affected subjects
genetically at risk for Alzheimer’s disease,” Proc Natl Acad Sci U S A., vol. 97, pp. 5696–5698, 2000.
[68] A. Nadal, E. Fuentes, J. Pastor and P.A. McNaughton, “Plasma albumin is a potent trigger of calcium signals and DNA synthesis in astrocytes,” Proc Natl Acad Sci U S A., vol. 92, pp. 1426–1430, 1995.
[69] G.P. Dietz and M. Bahr, “Delivery of bioactive molecules into the cell: the Trojan horse approach,” Mol. Cell. Neurosci., vol. 27, pp. 85– 131, 2004.
[70] R.A. Kroll and E.A. Neuwelt, “Outwitting the blood-brain barrier for therapeutic purposes: osmotic opening and other means,” Neurosurgery., vol. 42, pp. 1083–1099, 1998.
[71] M.S. Shoichet, and S.R. Winn, “Cell delivery to the central nervous system,” Adv. Drug Deliv. Rev., vol. 42, pp. 81–102, 2000.
[72] R. Gramiak and P.M. Shah, “Echocardiography of the aortic root,” Investigative radiology., vol. 3, pp. 356–366, 1968.
[73] E. Quaia, “Microbubble ultrasound contrast agents: an update,” European Radiology., vol. 17, pp. 1995-2008, 2007.
[74] P.J. Frinking, A. Bouakaz, J. Kirkhorn, F.J. Ten Cate and N. de Jong, “Ultrasound contrast imaging: current and new potential methods,” Ultrasound Med Biol., vol. 26, pp. 965–975, 2000.
[75] P.A. Dayton and K.W. Ferrara, “Targeted imaging using ultrasound,” J Magn Reson Imaging., vol. 16, pp. 362–377, 2002.
[76] J.L. Cohen, J. Cheirif, D.S. Segar, L.D. Gillam, J.S. Gottdiener, E. Hausnerova et al., “Improved left ventricular endocardial border delineation and opacification with OPTISON (FS069), a new echocardiographic contrast agent,” J Am Coll Cardiol., vol. 32, pp. 746–52, 1998.
[77] W. Keller, S. B. Feinstein and D. Watson, “Successful left ventricular opacification following peripheral venous injection of sonicated contrast agent: An experimental evaluation,” Am Heart J., vol. 114, pp. 570–575, 1987.
[78] F. Ries, C. Honisch, M. Lambertz, and R. Schlief, “A transpulmonary contrast medium enhances the transcranial Doppler signal in humans,” Stroke., vol. 24, pp. 1903–1909, 1993.
[79] M.E. Loveless, X. Li, J. Huamani, A. Lyshchik, B. Dawant, D. Hallahan, et al., “A method for assessing the microvasculature in a murine tumor model using contrast-enhanced ultrasonography,” J Ultrasound Med., vol. 27, pp. 1699–1709, 2008.
[80] C.J. Harvey, M.J. Blomley, R.J. Eckersley, D.O. Cosgrove, N. Patel, R.A.
Heckemann, et al. “Hepatic maliganancies: improved detection with pulse inversion
US in late phase of enhancement with SHU 508A-early experience,” Radiology., vol.
216, pp. 903–908, 2000.
[81] P. Hauff, T. Fritzsch, M. Reinhardt, W. Weitschies, F. Lüders, V. Uhlendorf, et al. “Delineation of experimental liver tumors in rabbits by a new ultrasound contrast agent and stimulated acoustic emission,” Invest Radiol., vol. 32, pp. 94–99, 1997.
[82] H.X. Xu, G.J. Liu, M.D. Lu, X.Y. Xie, Z.F. Xu, Y.L. Zheng, et al., “Characterization of focal liver lesions with contrast-specific US mode and a sulfur hexafluoride-filled microbubble contrast agents: diagnostic performance and confidence: diagnostic performance analysis in 200 patients,” J Ultrasound Med., vol. 25, pp. 349–61, 2006.
[83] J. Correas, O. Helenon and J. F. Moreau, “Contrast-enhanced ultrasonography of native and transplanted kidney diseases, ” Eur. Radiol., vol. 9 Suppl 3, pp. S394-400, 1999.
[84] J. Hancock, H. Dittrich, D.E. Jewitt and M.J. Monaghan, “Evaluation of myocardial, hepatic, and renal perfusion in a variety of clinical conditions using an intravenous ultrasound contrast agent (optison) and second harmonic imaging,” Heart., vol. 81, pp. 636–641, 1999.
[85] SonoVue: EPAR-Product Information. Available: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_I
nformation/human/000303/WC500055380.pdf
[86] Optison: EPAR-Product Information. Available: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_I
nformation/human/000166/WC500059461.pdf
[87] Luminity: EPAR-Product Information. Available: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_I
nformation/human/000654/WC500045020.pdf
[88] S.T. Kang and C.K. Yeh, “Ultrasound microbubble contrast agents for diagnostic and therapeutic applications: current status and future design,” Chang Gung medical journal., vol. 35, pp. 125–139, 2012.
[89] L.J. Juffermans, D.B. Meijering, A. van Wamel, R.H. Henning, K. Kooiman, M. Emmer, et al., “Ultrasound and microbubble-targeted delivery of therapeutic compounds: ICIN Report Project 49: Drug and gene delivery through ultrasound and microbubbles.” Neth Heart J., vol. 17, pp. 82–86, 2009.
[90] J.C. Chappell, J. Song, A.L. Klibanov and R.J. Price, “Ultrasonic microbubble destruction stimulates therapeutic arteriogenesis via the CD18-dependent recruitment of bone marrow-derived cells,” Arterioscler Thromb Vasc Biol., vol. 28, pp. 1117–1122, 2008.
[91] V. Sboros, “Response of contrast agents to ultrasound,” Adv Drug Deliv Rev., vol. 60, pp. 1117–1136, 2008.
[92] G.A. Husseini, M.A. Diaz de la Rosa, E.S. Richardson, D.A. Christensen and W.G. Pitt, “The role of cavitation in acoustically activated drug delivery,” J Control Release., vol. 107, pp. 253–261, 2005.
[93] G. Basta, L. Venneri, G. Lazzerini, E. Pasanisi, M. Pianelli, N. Vesentini, et al., “In vitro modulation of intracellular oxidative stress of endothelial cells by diagnostic cardiac ultrasound,” Cardiovasc Res., vol. 58, pp. 156–161, 2003.
[94] S. Mitragotri, “Healing sound: the use of ultrasound in drug delivery and other therapeutic applications,” Nat Rev Drug Discov., vol. 4, pp. 255–260, 2005.
[95] D. Dalecki, “Mechanical bioeffects of ultrasound,” Annu Rev Biomed Eng., vol. 6, pp. 229–248, 2004.
[96] Y. Liu, S. Yi, J. Zhang, Z. Fang, F. Zhou, W. Jia, et al., “Effect of Microbubble-enhanced Ultrasound on Prostate Permeability: A Potential Therapeutic Method for Prostate Disease,” Urology., vol. 81, pp. e1–7, 2013.
[97] R. Karshafian, P.D. Bevan, R. Williams, S. Samac and P.N. Burns, “Sonoporation by ultrasound-activated microbubble contrast agents: effect of acoustic exposure parameters on cell membrane permeability and cell viability,” Ultrasound Med Biol., vol. 35, pp. 847–860, 2009.
[98] A. van Wamel, K. Kooiman, M. Emmer, F.J. ten Cate, M. Versluis, N. de Jong, “Ultrasound microbubble induced endothelial cell permeability,” J Control Release., vol. 116, pp. 100–102, 2006.
[99] R. Bekeredjian, R.D. Kroll, E. Fein, S. Tinkov, C. Coester, G. Winter, et al., “Ultrasound targeted microbubble destruction increases capillary permeability in hepatomas,” Ultrasound Med Biol., vol. 33, pp. 1592–1598, 2007.
[100] K. Tachibana, S. Tachibana, “The use of ultrasound for drug delivery,” Echocardiography., vol. 18, pp. 323–328, 2001.
[101] K. Ferrara, R. Pollard, M. Borden, “Ultrasound microbubble contrast agents: fundamentals and application to gene and drug delivery,” Annu Rev Biomed Eng., vol. 9, pp. 415–447, 2007.
[102] E.C. Unger, T. Porter, W. Culp, R. Labell, T. Matsunaga, R. Zutshi. “Therapeutic applications of lipid-coated microbubbles,” Adv Drug Deliv Rev., vol. 56, pp. 1291–1314, 2004.
[103] S. Hernot and A.L. Klibanov, “Microbubbles in ultrasound-triggered drug and gene delivery,” Adv Drug Deliv Rev., vol. 60, pp. 1153–1166, 2008.
[104] M.A. Borden, C.F. Caskey, E. Little, R.J. Gillies and K.W. Ferrara, “DNA and polylysine adsorption and multilayer construction onto cationic lipid-coated microbubbles,” Langmuir., vol. 23, pp. 9401–9408, 2007.
[105] E.C. Unger, T.P. McCreery, R.H. Sweitzer, V.E. Caldwell and Y. Wu, “Acoustically active lipospheres containing paclitaxel: a new therapeutic ultrasound contrast agent,” Invest Radiol., vol. 33, pp. 886–892, 1998.
[106] M.J. Shortencarier, P.A. Dayton, S.H. Bloch, P.A. Schumann, T.O. Matsunaga and K.W. Ferrara, “A method for radiation-force localized drug delivery using gas-filled lipospheres,” IEEE Trans Ultrason Ferroelectr Freq Control., vol. 51, pp. 822–831, 2004.
[107] A.F. Lum, M.A. Borden, P.A. Dayton, D.E. Kruse, S.I. Simon and K.W. Ferrara, “Ultrasound radiation force enables targeted deposition of model drug carriers loaded on microbubbles,” J Control Release., vol. 111, pp. 128–134, 2006.
[108] Y. Dufrene, W. Barger, J. Green and Lee, G, “Nanometerscale surface properties of mixed phospholipid monolayers and bilayers,” Langmiur, vol. 13, pp. 4779–4784, 1997.
[109] D. May, J. Allen, J. Gut and K.W. Ferrara, “Acoustic fragmentation of therapeutic contrast agents designed for localized drug delivery,” IEEE Ultras Symp Proc., 2001.
[110] K.T. Cheng, “Air-filled, cross-linked, human serum albumin microcapsules,” Molecular Imaging and Contrast Agent Database (MICAD) [Internet], pp. 2004–2013, 2006.
[111] S. Mehier-Humbert, F. Yan, P. Frinking, M. Schneider, R.H. Guy, T. Bettinger, “Ultrasound-mediated gene delivery: Influence of contrast agent on transfection,” Bioconjugate Chem., vol. 18, pp. 652–662, 2007.
[112] E.C. Unger, T.P. McCreery, R.H. Sweitzer, V.E. Caldwell and Y. Q. Wu, “Acoustically active lipospheres containing paclitaxel: a new therapeutic ultrasound contrast agent,” Invest. Radiol., vol. 33, pp. 886–892, 1998.
[113] M.J. Shortencarier, P.A. Dayton, S.H. Bloch, P.A. Schumann, T.O. Matsunaga and K.W. Ferrara, “A method for radiation-force localized drug delivery using gas-filled lipospheres,” IEEE Trans Ultrason Ferroelectr Freq Control., vol. 51, 822–831, 2004.
[114] J. Fang, C.F. Hung, M.H. Liao and C.C. Chien, “A study of the formulation design of acoustically active lipospheres as carriers for drug delivery,” Eur J Pharm Biopharm., vol. 67, pp. 67–75, 2007.
[115] C. Teupe, S. Richter, B. Fisslthaler, V. Randriamboavonjy, C. Ihling,
I. Fleming, et al., “Vascular gene transfer of phosphomimetic endothelial nitric oxide synthase (S1177D) using ultrasound-enhanced destruction of plasmid-loaded microbubbles improves vasoreactivity,” Circulation., vol. 150, pp. 1104–1109, 2002.
[116] J.P. Christiansen, B.A. French, A.L. Klibanov, S. Kaul and J.R. Lindner, “Targeted tissue transfection with ultrasound destruction of plasmid-bearing cationic microbubbles,” Ultrasound Med. Biol., vol. 29, pp. 1759–1767, 2003.
[117] M. Vannan, T. McCreery, P. Li, Z. G. Han, E. Unger, B. Kuersten, et al, “Ultrasound-mediated transfection of canine myocardium by intravenous administration of cationic microbubble-linked plasmid DNA,” J Am Soc Echocardiogr., vol. 15, pp. 214–218, 2002.
[118] Y. Z. Zhao, H. D. Liang, X. G. Mei and M. Halliwell, “Preparation, characterization and in vivo observation of phospholipid-based gas-filled microbubbles containing hirudin,” Ultrasound Med. Biol., vol. 31, pp. 1237–1243, 2005.
[119] C.M. Howard, F. Forsberg, C. Minimo, J.B. Liu, D.A. Merton, P.P. Claudio, “Ultrasound guided site specific gene delivery system using adenoviral vectors and commercial ultrasound contrast agents,” J Cell Physiol., vol. 209, pp. 413–421, 2006.
[120] S. L. Taylor, A. A. Rahim, N. L. Bush, J. C. Barnber and C. D. Porter, “Targeted retroviral gene delivery using ultrasound,”J. Gene Med., vol. 9, pp. 77–87, 2007.
[121] O. J. Muller, S. Schinkel, J. A. Kleinschmidt, H. A. Katus and R. Bekeredjian, “Augmentation of AAV-mediated cardiac gene transfer after systemic administration in adult rats,” Gene Ther., vol. 15, pp. 1558–1565, 2008.
[122] C.Y. Ting, C.H. Fan, H.L. Liu, C.Y. Huang, H.Y. Hsieh, T.C. Yen, et al, “Concurrent bloodebrain barrier opening and local drug delivery using drug-carrying microbubbles and focused ultrasound for brain glioma treatment,” Biomaterials., vol. 33, pp. 704–712, 2012.
[123] J.C. Adair, N. Baldwin, M. Kornfeld and G.A Rosenberg, “Radiation-induced blood-brain barrier damage in astrocytoma: relation to elevated gelatinase B and
urokinase,” J Neurooncol., vol. 44, pp. 283–289, 1999.
[124] K.T. Wheeler, V.A. Levin and D.F. Deen, “The concept of drug dose for in vitro studies with chemotherapeutic agents,” Radiat Res., vol. 76, pp. 441–458, 1978.
[125] S. Tinkov, G. Winter, C. Coester and R. Bekeredjian, “New doxorubicin-loaded phospholipid microbubbles for targeted tumor therapy: Part I--Formulation development and in-vitro characterization,” J Control Release., vol. 143, pp. 143–150, 2010.
[126] S. Tinkov, C. Coester, S. Serba, N.A. Geis, H.A. Katus, G. Winter and R. Bekeredjian, “New doxorubicin-loaded phospholipid microbubbles for targeted tumor therapy: in-vivo characterization,” J Control Release., vol. 148, pp. 368–372, 2010.
[127] I. Lentacker, B. Geers, J. Demeester, S.C. De Smedt and N.N. Sanders, “Design and evaluation of doxorubicin-containing microbubbles for ultrasound-triggered doxorubicin delivery: cytotoxicity and mechanisms involved,” Mol Ther., vol. 18, pp. 101–108, 2010.
[128] J. Kang, X. Wu, Z. Wang, H. Ran, C. Xu, J. Wu, Z. Wang and Y. Zhang, “Antitumor effect of docetaxel-loaded lipid microbubbles combined with ultrasound-targeted microbubble activation on VX2 rabbit liver tumors,” J Ultrasound Med., vol. 29, pp. 61–70, 2010.
[129] W. Xing, W.Z. Gang, Z. Yong, Z.Y. Yi, X.C. Shan and R.H. Tao, “Treatment of xenografted ovarian carcinoma using paclitaxel-loaded ultrasound microbubbles,” Acad Radiol., vol. 15, pp. 1574–1579, 2008.
[130] A. L. Klibanov, “Microbubble contrast agents: targeted ultrasound imaging and ultrasound-assisted drug-delivery applications,” Invest. Radiol., vol. 41, pp. 354–362, 2006.
[131] A. L. Klibanov, “Ligand-carrying gas-filled microbubbles: ultrasound contrast agents for targeted molecular imaging,” Bioconjugate Chem., vol. 16, pp. 9–17, 2005.
[132] B. A. Kaufmann, J.M. Sanders, C. Davis, A. Xie, P. Aldred, I.J. Sarembock, et al., “Molecular imaging of inflammation in atherosclerosis with targeted ultrasound detection of vascular cell adhesion molecule-1,” Circulation., vol. 116, pp. 276–284, 2007.
[133] A.L. Klibanov, M.S. Hughes, F.S. Villanueva, R.J. Jankowski, W.R. Wagner, J.K. Wojdyla, et al., “Targeting and ultrasound imaging of microbubble-based contrast agents,” MAGMA, vol. 8, pp. 177–184, 1999.
[134] A.L. Klibanov, “Targeted delivery of gas-filled microspheres, contrast agents for ultrasound imaging,” Adv Drug Deliv Rev. vol. 37, pp. 139–157, 1999.
[135] A.L. Klibanov, J.J. Rychak, W.C. Yang, S. Alikhani, B. Li, S. Acton, et al., “Targeted ultrasound contrast agent for molecular imaging of inflammation in high-shear flow.,” Contrast Media Mol Imaging., vol. 1, pp. 259–66, 2006.
[136] A.L. Klibanov, “Ultrasound molecular imaging with targeted microbubble contrast agents,” J. Nucl. Cardiol., vol. 14, pp. 876–884, 2007.
[137] J.R. Lindner, “Molecular imaging with contrast ultrasound and targeted microbubbles,” J. Nucl. Cardiol., vol. 11, pp. 215–221, 2004.
[138] J.R. Lindner, M.P. Coggins, S. Kaul, A.L. Klibanov, G.H. Brandenburger and K. Ley, “Microbubble Persistence in the Microcirculation During Ischemia/Reperfusion and Inflammation Is Caused by Integrin- and Complement-Mediated Adherence to Activated Leukocytes,” Circulation., vol. 101, pp. 668–675, 2000.
[139] J.R. Lindner, J. Song, F. Xu, A.L. Klibanov, K. Singbartl, K. Ley and S. Kaul,“Noninvasive ultrasound imaging of inflammation using microbubbles targeted to activated leukocytes,” Circulation., vol. 102, pp. 2745–2750, 2000.
[140] D.B. Ellegala, H.L. Poi, J.E. Carpenter, A.L. Klibanov, S. Kaul, M.E. Shaffrey, et al., “Imaging tumor angiogenesis with contrast ultrasound and microbubbles targeted to αvβ3,” Circulation, vol. 108, pp. 336–341, 2003.
[141] H. Leong-Poi, J. Christiansen, A. L. Klibanov, S. Kaul and J. R. Lindner, “Noninvasive assessment of angiogenesis by ultrasound and microbubbles targeted to αv-integrins,” Circulation, vol. 107, pp. 455–460, 2003.
[142] S. Ottoboni, R.E. Short, M.B. Kerby, E.G. Tickner, E. Steadman and
T.B. Ottoboni, “Characterization of the in vitro adherence behavior of ultrasound responsive double-shelled microspheres targeted to cellular adhesion molecules,” Contrast Media Mol Imaging., vol. 1, pp. 279–290, 2006.
[143] J.J. Rychak, J.R. Lindner, K. Ley and A.L. Klibanov, “Deformable gas-filled microbubbles targeted to P-selectin,” J Control. Release, vol. 114, pp. 288–299, 2006.
[144] A.M. Takalkar, A.L. Klibanov, J.J. Rychak, J.R. Lindner and K. Ley, “Binding and detachment dynamics of microbubbles targeted to P-selectin under controlled shear flow,” J. Control. Release, vol., 96, pp. 473–482, 2004.
[145] G.E.R. Weller, F.S. Villanueva, A.L. Klibanov and W.R. Wagner, “Modulating Targeted Adhesion of an Ultrasound Contrast Agent to Dysfunctional Endothelium,” Ann Biomed Eng., vol. 30, pp. 1012–1019, 2002.
[146] G.E.R. Weller, E. Lu, M.M. Csikari, A.L. Klibanov, D. Fischer, W.R. Wagner F.S. Villanueva, et al., “Ultrasound imaging of acute cardiac transplant rejection with microbubbles targeted to intercellular adhesion molecule-1,” Circulation, vol. 108, pp. 218–224, 2003.
[147] G.E.R. Weller, F.S. Villanueva, E.M. Tom and W.R. Wagner, “Targeted ultrasound contrast agents: In vitro assessment of endothelial dysfunction and multi‐targeting to ICAM‐1 and sialyl Lewisx,” Biotechnol Bioeng., vol. 92, pp. 780–788, 2005.
[148] G.E.R. Weller, M.K.K. Wong, R.A. Modzelewski, E.X. Lu, A.L. Klibanov and W.R. Wagner, “Ultrasonic imaging of tumor angiogenesis using contrast microbubbles targeted via the tumor-binding peptide arginine-arginine-leucine,” Cancer Res., vol. 65, pp. 533–539, 2005.
[149] J.K. Willmann, R. Paulmurugan, K. Chen, O. Gheysens, M. Rodriguez-Porcel, A. M. Lutz, et al., “US Imaging of Tumor Angiogenesis with Microbubbles Targeted to Vascular Endothelial Growth Factor Receptor Type 2 in Mice,” Radiology, vol. 246, pp. 508–518, 2008.
[150] A. Alonso, A. Della Martina, M. Stroick, M. Fatar, M. Griebe, S. Pochon, et al., “Molecular imaging of human thrombus with novel abciximab immunobubbles and ultrasound,” Stroke, vol. 38, pp. 1508–1514, 2007.
[151] F. Cavalieri, A. El Hamassi, E. Chiessi, G. Paradossi, R. Villa and N. Zaffaroni, “Tethering Functional Ligands onto Shell of Ultrasound Active Polymeric Microbubbles,”Biomacromolecules, vol. 7, pp. 604–611, 2006.
[152] M.A. Wheatley, J.D. Lathia and K.L. Oum, “Polymeric ultrasound contrast agents targeted to integrins: importance of process methods and surface density of ligands,” Biomacromolecules, vol. 8, pp. 516–522, 2007.
[153] M.A. Borden, M. R. Sarantos, S.M. Stieger, S.I. Simon, K.W. Ferrara and P.A. Dayton, “Ultrasound radiation force modulates ligand availability on targeted contrast agents,” Mol. Imaging Biol., vol. 5, pp. 139–147, 2006.
[154] M.A. Borden, H. Zhang, R.J. Gillies, P.A. Dayton and K.W. Ferrara, “A stimulus-responsive contrast agent for ultrasound molecular imaging,” Biomaterials., vol. 29, pp. 597–606, 2008.
[155] V.R. Stewart and P.S. Sidhu, “New directions in ultrasound: microbubble contrast,” Br J Radiol., vol. 79, pp. 188–194, 2006.
[156] J.J. Chen, C.S. Chiang, J.H. Hong and C.K. Yeh, “Assessment of tumor vasculature for diagnostic and therapeutic applications in a mouse model in vivo using 25-MHz power Doppler imaging,” Ultrasonics, vol. 51, pp. 925–931, 2011.
[157] I.K. Jang, B.E. Bouma, D.H. Kang, S.J. Park, S.W. Park, K. B. Seung, et al., “Visualization of coronary atherosclerotic plaques in patients using optical coherence tomography: comparison with intravascular ultrasound,” J. Am. Coll. Cardiol., vol. 39, pp. 604–609, 2002.
[158] C.R. Jr. Joyner and J.M. Reid, “Applications of ultrasound in cardiology and cardiovascular physiology,” Prog. Cardiovasc. Dis., vol. 5, pp. 482–497, 1963.
[159] Y.Y. Liao, P.H. Tsui, C.H. Li, K.J. Chang, W.H. Kuo, C.C. Chang, et al., “Classification of scattering media within benign and malignant breast tumors based on ultrasound texture-feature-based and Nakagami-parameter images,” Med. Phys., vol. 38, pp. 2198–2207, 2011.
[160] C.K. Yeh, J.J. Chen, M.L. Li and J.J. Luh, “In vivo imaging of blood flow in the mouse Achilles tendon using high-frequency ultrasound,” Ultrasonics., vol. 49, pp. 226–230, 2009.
[161] T. Browder, C.E. Butterfield, B.M. Kraling, B. Shi, B. Marshall, M.S. O'Reilly et al., “Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer,” Cancer Res., vol. 60, pp. 1878–1886, 2000.
[162] J. Folkman, “New perspectives in clinical oncology from angiogenesis research,” Eur. J. Cancer., vol. 32A, pp. 2534–2539, 1996.
[163] R. S. Kerbel, “Tumor angiogenesis: past, present and the near future,” Carcinogenesis., vol. 21, pp. 505–515, 2000.
[164] A.M. Schor and S.L. Schor, “Tumour angiogenesis,” J. Pathol., vol. 141, pp. 385–413, 1983.
[165] S.H. Bloch, P.A. Dayton and K.W. Ferrara, “Targeted imaging using ultrasound contrast agents. Progress and opportunities for clinical and research applications,” IEEE Eng Med Biol Mag., vol. 23, pp. 18–29, 2004.
[166] H. Liu, Y.X. Jiang, J.B. Liu, Q.L. Zhu, Q. Sun and X.Y. Chang, “Contrast-enhanced breast ultrasonography: imaging features with histopathologic correlation,” J Ultrasound Med., vol. 28, pp. 911–920, 2009.
[167] F. Aigner, L. Pallwein, M. Mitterberger, G.M. Pinggera, G. Mikuz, W. Horninger, et al., “Contrast-enhanced ultrasonography using cadence-contrast pulse sequencing technology for targeted biopsy of the prostate,” BJU Int., vol. 103, pp. 458–463, 2009.
[168] F. Moriyasu and K. Itoh, “Efficacy of perflubutane microbubble-enhanced ultrasound in the characterization and detection of focal liver lesions: phase 3 multicenter clinical trial,” AJR Am J Roentgenol., vol. 193, pp. 86–95, 2009.
[168] F. Piscaglia and L. Bolondi, “The safety of SonoVue in abdominal applications: retrospective analysis of 23,188 investigations,” Ultrasound Med Biol., vol. 32, pp. 1369–1375, 2006.
[169] J.R. Lindner, “Microbubbles in medical imaging: current applications and future directions,” Nat Rev Drug Discov., vol. 3, pp. 527–532, 2004.
[170] A. B. Harris, L. Erickson, J. H. Kendig, S. Mingrino and S. Goldring, “Observations on selective brain heating in dogs,” J Neurosurg., vol. 19, pp. 514–521, 1962.
[171] F. J. Burger and F. A. Fuhrman, “Evidence of Injury by Heat in Mammalian Tissues,” Am J Physiol., vol. 206, pp. 1057–1061, 1964.
[172] K. Hynynen, “Biophysics and technology of ultrasound hyperthermia,” Methods of External Hyperthermic Heating, Springer-Verlag. pp. 61–115, 1990.
[173] C.J. Diederich and K. Hynynen, “Ultrasound technology for hyperthermia,” Ultrasound Med. Biol., vol. 25, pp. 871–887, 1999.
[174] J.W. Hunt, “Principles of ultrasound used for generating localized hyperthermia, in: S.B. Field, J.W. Hand (Eds.), Principle Aspects of Clinical Hyperthermia, Taylor and Francis, London, pp. 371–422, 1990.
[175] P.P. Lele, “Induction of deep, local hyperthermia by ultrasound and electromagnetic fields: problems and choices,” Radiat Environ Biophys., vol. 17, pp. 205–217, 1980.
[176] J. M. Larkin, “A clinical investigation of total-body hyperthermia as cancer therapy,” Cancer Res., vol. 39, pp. 2252–2254, 1979.
[177] K. Hynynen, G. Clement, N. McDannold, R. King, P.J. White, F. Jolesz, et al. , “Pre-clinical testing of a phased array ultrasound system for MRI-guided noninvasive surgery of the brain,” Eur J Radiol., vol. 59, pp. 149–56, 2006.
[178] A.H. Chan, V.Y. Fujimoto, D.E. Moore, R.W. Martin and S. Vaezy, “An image-guided high intensity focused ultrasound device for uterine ﬁbroids treatment,” Med. Phys., vol. 29, pp. 2611–2620, 2002.
[179] J.Y. Chapelon, M. Ribault, F. Vernier, R. Souchon and A. Gelet, “Treatment of localised prostate cancer with transrectal high intensity focused ultrasound,” Eur. J. Ultrasound., vol. 9, pp. 31–38, 1999.
[180] W. Chen, Z. Wang, F. Wu, H. Zhu, J. Zou, J. Bai, et al. , “High intensity focused ultrasound in the treatment of primary malignant bone tumor,” Zhonghua Zhong Liu Za Zhi., vol. 24, pp. 612–615, 2002.
[181] A. Gelet, J.Y. Chapelon, L. Poissonnier, R. Bouvier, O. Rouviere, L. Curiel, et al., “Local recurrence of prostate cancer after external beam radiotherapy: early experience of salvage therapy using high-intensity focused ultrasonography,” Urology., vol. 63, pp. 625–629, 2004.
[182] F. Wu, Z.B. Wang, Y.D. Cao, W.Z. Chen, J. Bai, J.Z. Zou, et al., “A randomised clinical trial of high-intensity focused ultrasound ablation for the treatment of patients with localised breast cancer,” Br. J. Cancer., vol. 89, pp. 2227–2233, 2003.
[183] D. Gianfelice, A. Khiat, M. Amara, A. Belblidia and Y. Boulanger, “MR imaging-guided focused ultrasound surgery of breast cancer: correlation of dynamic contrast-enhanced MRI with histopathologic ﬁndings,” Breast Cancer Res. Treat., vol. 82, pp. 93–101, 2003.
[184] K.U. Kohrmann, M.S. Michel, J. Gaa, E. Marlinghaus and P. Alken, “High intensity focused ultrasound as noninvasive therapy for multilocal renal cell carcinoma: case study and review of the literature,” J. Urol., vol. 167, pp. 2397–2403, 2002.
[185] C.M. Tempany, E.A. Stewart, N. McDannold, B.J. Quade, F.A. Jolesz and K. Hynynen, “MR imaging-guided focused ultrasound surgery of uterine leiomyomas: a feasibility study,” Radiology., vol. 226, pp. 897–905, 2003.
[186] G.R. ter Haar, “High intensity focused ultrasound for the treatment of tumors,” Echocardiography., vol. 18, pp. 317–322, 2001.
[187] F. Wu, Z.B. Wang, W.Z. Chen, H. Zhu, J. Bai, J.Z. Zou, et al., “Extracorporeal high intensity focused ultrasound ablation in the treatment of patients with large hepatocellular carcinoma,” Ann. Surg. Oncol., vol. 11, pp. 1061–1069, 2004.
[188] S. Vaezy, M.L. Noble, A. Keshavarzi, M. Paun, A.F. Prokop, C. Cornejo, et al., “Liver hemostasis with high-intensity ultrasound: repair and healing,” J. Ultrasound Med., vol. 23, pp. 217–225, 2004 .
[189] J.H. Hwang, S. Vaezy, R.W. Martin, M.Y. Cho, M.L. Noble, L.A. Crum, et al., “High-intensity focused US: a potential new treatment for GI bleeding,” Gastrointest. Endosc., vol. 58, pp. 111–115, 2003.
[190] M.L. Noble, S. Vaezy, A. Keshavarzi, M. Paun, A.F. Prokop, E.Y. Chi, et al., “Spleen hemostasis using high-intensity ultrasound: survival and healing,” J. Trauma., vol. 53, pp. 1115–1120, 2002.
[191] S. Vaezy, R. Martin and L. Crum, “High intensity focused ultrasound: a method of hemostasis,” Echocardiography., vol. 18, pp. 309–315, 2001.
[192] K. Hynynen, V. Colucci, A. Chung and F. Jolesz, “Noninvasive arterial occlusion using MRI-guided focused ultrasound,” Ultrasound Med. Biol., vol. 22, pp. 1071–1077, 1996.
[193] I.H. Rivens, I.J. Rowland, M. Denbow, N.M. Fisk, G.R. ter Haar and M.O. Leach, “Vascular occlusion using focused ultrasound surgery for use in fetal medicine,” Eur. J. Ultrasound., vol. 9, pp. 89–97, 1999.
[194] C.W. Connor and K. Hynynen, “Patterns of thermal deposition in the skull during transcranial focused ultrasound surgery,” IEEE Trans Biomed Eng. vol. 51, pp. 1693–1706, 2004.
[195] A. Pulkkinen, Y. Huang, J. Song, and K. Hynynen, “Simulations and measurements of transcranial low-frequency ultrasound therapy: skull-base heating and effective area of treatment,” Phys Med Biol., vol. 56, pp. 4661–4683, 2011.
[196] K. Hynynen and F.A. Jolesz, “Demonstration of potential noninvasive ultrasound brain therapy through an intact skull,” Ultrasound Med. Biol., vol. 24, pp. 275–283, 1998.
[197] J. Sun and K. Hynynen, “The potential of transskull ultrasound therapy and surgery using the maximum available skull surface area,” J. Acoust. Soc. Am., vol. 105, pp. 2519–2527, 1999.
[198] G.T. Clement and K. Hynynen, “A non-invasive method for focusing ultrasound through the human skull,” Phys. Med. Biol., vol. 47, pp. 1219–1236, 2002.
[199] J. Sun and K. Hynynen, “Focusing of therapeutic ultrasound through a human skull: a numerical study,” J. Acoust. Soc. Am., vol. 104, pp. 1705–1715, 1998.
[200] J.F. Aubry, M. Tanter, M. Pernot, J.L. Thomas and M. Fink, “Experimental demonstration of noninvasive transskull adaptive focusing based
on prior computed tomography scans,” J. Acoust. Soc. Am., vol. 113, pp. 84–93, 2003.
[201] M. Pernot, J.F. Aubry, M. Tanter, J.L. Thomas and M. Fink, “High power transcranial beam steering for ultrasonic brain therapy,” Phys. Med. Biol., vol. 48, pp. 2577–2589, 2003.
[202] X. Yin and K. Hynynen, “A numerical study of transcranial focused ultrasound beam propagation at low frequency,” Phys. Med. Biol., vol. 50, pp. 1821–1836, 2005.
[203] R. G. Holt and R. A. Roy, “Measurements of bubble-enhanced heating from focused, MHz-frequency ultrasound in a tissue-mimicking material,” Ultrasound Med Biol., vol. 27, pp. 1399–1412, 2001.
[204] K. Hynynen, “The threshold for thermally signiﬁcant cavitation in dog’s thigh muscle in vivo,” Ultrasound Med Biol., vol. 17, pp. 157–169, 1991.
[205] S. D. Sokka, R. King and K. Hynynen, “MRI-guided gas bubble enhanced ultrasound heating in in vivo rabbit thigh,” Phys Med Biol., vol. 48, pp. 223–241, 2003.
[206] W. T. Shi and F. Forsberg, “Ultrasonic characterization of the nonlinear properties of contrast microbubbles,” Ultrasound Med Biol., vol. 26, pp. 93–104, 2000.
[207] W.T. Shi, F. Forsberg, J.S. Raichlen, L. Needleman and B.B. Goldberg, “Pressure dependence of subharmonic signals from contrast microbubbles,” Ultrasound Med Biol., vol. 25, pp. 275–283, 1999.
[208] I. Lentacker, S.C.D. Smedta and N.N. Sanders, “Drug loaded microbubble design for ultrasound triggered delivery,” Soft Matter., vol. 5, pp. 2161–2170, 2009.
[209] J. Wu, J. P. Ross and J. F. Chiu, “Reparable sonoporation generated by microstreaming,” J Acoust Soc Am., vol. 111, pp. 1460–1464, 2002.
[210] P.P. Lele, “Effects of ultrasound on “solid” mammalian tissues and tumors in vivo,” Ultrasound., pp. 275–306, 1987.
[211] C. K. Holland and R. E. Apfel, “An improved theory for the prediction of microcavitation thresholds,” IEEE Trans Ultrason Ferroelectr Freq Control., vol. 36, pp. 204–208, 1989.
[212] K. Hynynen, N. McDannold, N. Vykhodtseva and F.A. Jolesz, “Noninvasive MR imaging–guided focal opening of the blood-brain barrier in rabbits,” Radiology., vol. 154, pp. 640–646, 2001.
[213] K. Hynynen, N. McDannold, N.A. Sheikov, F.A. Jolesz, and N. Vykhodtseva, “Local and reversible blood–brain barrier disruption by noninvasive focused ultrasound at frequencies suitable for trans-skull sonications,” Neuroimage., vol. 24, 12–20, 2005.
[214] H.L. Liu, Y.Y. Wai, W.S. Chen, J.C. Chen, P.H. Hsu, X.Y. Wu, et al., “Hemorrhage detection during focused-ultrasound induced blood–brain-barrier opening by using susceptibility-weighted magnetic resonance imaging,” Ultrasound Med Biol., vol., 34, pp. 598–606, 2008.
[215] F.Y. Yang, Y.S. Lin, K.H. Kang, and T.K. Chao, “Reversible blood-brain barrier disruption by repeated transcranial focused ultrasound allows enhanced extravasation,” J Control Release., vol. 150, pp. 111–116, 2011.
[216] Xie F, Boska MD, Lof J, Uberti MG, Tsutsui JM, Porter TR., “Effects of transcranial ultrasound and intravenous microbubbles on blood brain barrier permeability in a large animal model,” Ultrasound Med Biol., vol. 34, pp. 2028–2034, 2008.
[217] H.L. Liu, P.Y. Chen, H.W. Yang, J.S. Wu, I.C. Tseng, Y.J. Ma, et al., “In vivo MR quantiﬁcation of superparamagnetic iron oxide nanoparticle leakage during
low-frequency-ultrasound-induced blood-brain barrier opening in swine,” J Magn Reson Imaging., vol. 34, pp. 1313–1324, 2011.
[218] N. McDannold, C.D. Arvanitis, N. Vykhodtseva and M.S. Livingstone, “Temporary disruption of the blood-brain barrier by use of ultrasound and microbubbles: safety and efficacy evaluation in rhesus macaques,” Cancer Res., vol. 72, pp. 3652–3663, 2012.
[219] F. Marquet, Y.S. Tung, T. Teichert, V. P. Ferrera and E. E. Konofagou, “Noninvasive, transient and selective Blood-Brain barrier opening in Non-Human primates in vivo,” PLoS One., vol.6, pp. e22598, 2011.
[220] Y.S. Tung, F. Marquet, T. Teichert, V. Ferrera and E. Konofagou, “Feasibility of noninvasive cavitation-guided blood-brain barrier opening using focused ultrasound and microbubbles in nonhuman primates,” Appl Phys Lett., vol. 98, pp. 163704, 2011.
[221] K. Hynynen, N. McDannold, H. Martin, F.A. Jolesz and N. Vykhodtseva, “The threshold for brain damage in rabbits induced by bursts of ultrasound in the presence of an ultrasound contrast agent (Optison),” Ultrasound Med Biol., vol. 29, pp. 473–481, 2003.
[222] C.H. Fan, H.L. Liu, C.Y. Huang, Y.J. Ma, T.C. Yen and C.K. Yeh, “Detection of intracerebral hemorrhage and transient blood-supply shortage in focused-ultrasound-induced blood-brain barrier disruption by ultrasound imaging,” Ultrasound Med Biol., vol. 38, pp.1372–1382, 2012.
[223] R. Chopra, N. Vykhodtseva and K. Hynynen, “Inﬂuence of exposure time and pressure amplitude on blood-brain-barrier opening using transcranial ultrasound exposures,” ACS Chem. Neurosci., vol. 1, pp. 391–398, 2010.
[224] J.J. Choi, K. Selert, Z. Gao, G. Samiotaki, B. Baseri, and E.E. Konofagou, “Noninvasive and localized blood-brain barrier disruption using focused ultrasound can be achieved at short pulse lengths and low pulse repetition frequencies,” J Cereb Blood Flow Metab., vol. 31, pp. 725–737, 2011.
[225] N. McDannold, N. Vykhodtseva, and K. Hynynen, “Effects of Acoustic Parameters and Ultrasound Contrast Agent Dose on Focused-Ultrasound Induced Blood-Brain Barrier Disruption,” Ultrasound Med Biol., vol. 34, pp. 930–937, 2008
[226] D.E. Goertz, C. Wright and K. Hynynen, “Contrast agent kinetics in the rabbit brain during exposure to therapeutic ultrasound,” Ultrasound Med Biol., vol. 36, pp. 916–924, 2010.
[227] K.F. Bing, G.P. Howles, Y. Qi, M.L. Palmeri and K.R. Nightingale, “Blood-Brain Barrier (BBB) Disruption Using a Diagnostic Ultrasound Scanner and Deﬁnity R n Mice,” Ultrasound Med Biol., vol. 35, pp. 1298–1308, 2009.
[228] M.A. O’Reilly, A.C. Waspe, M. Ganguly and K. Hynynen, “Focused-Ultrasound Disruption of the Blood-Brain Barrier Using Closely-Timed Short Pulses Inﬂuence of Sonication Parameters and Injection Rate,” Ultrasound Med Biol., vol. 37, pp. 587–594, 2011.
[229] M.A. O’Reilly and K. Hynynen, “A PVDF receiver for ultrasound monitoring of transcranial focused ultrasound therapy,” IEEE Trans Biomed Eng., vol. 57, pp. 2286–2294, 2010.
[230] N. McDannold, N. Vykhodtseva and K. Hynynen, “Blood-brain barrier disruption induced by focused ultrasound and circulating preformed microbubbles appears to be characterized by the mechanical index,” Ultrasound Med Biol., vol. 34, pp. 834–840, 2008.
[231] H.L. Liu, C.H. Pan, C.Y. Ting and M.J. Hsiao, “Opening of the Blood-Brain Barrier by Low-Frequency (28-kHz) Ultrasound A Novel Pinhole-Assisted Mechanical Scanning Device,” Ultrasound Med Biol., vol. 36, pp. 325–335, 2010.
[232] K. Hynynen, N. McDannold, N. Vykhodtseva, S. Raymond, R. Weissleder, F. Jolesz et al., “Focal disruption of the blood-brain barrier due to 260-kHz ultrasound bursts A method for molecular imaging and targeted drug delivery,” J. Neurosurg., vol. 105, pp. 445–454, 2006.
[233] N. McDannold, N. Vykhodtseva and K. Hynynen, “Use of ultrasound pulses combined with Definity for targeted blood-brain barrier disruption: a feasibility study,” Ultrasound Med Biol., vol. 33, 584–590, 2007.
[234] J.C. Weng, S.K. Wu, W.L. Lin and W.Y. Tseng, “Detecting blood-brain barrier disruption within minimal hemorrhage following transcranial focused ultrasound a correlation study with contrast-enhanced MRI,” Magn Reson Med., vol. 65, pp. 802–811, 2011.
[235] J.C. Weng, S.K. Wu, F.Y. Yang, W.L. Lin and W.-Y. Tseng, “Pulse sequence and timing of contrast-enhanced MRI for assessing blood-brain barrier disruption after transcranial focused ultrasound in the presence of hemorrhage,” J Magn Reson Imaging., vol. 31, pp. 1323–1330, 2010.
[236] F.Y. Yang, W.M. Fu, W.S. Chen, W.L. Yeh and W.L. Lin, “Quantitative evaluation of the use of microbubbles with transcranial focused ultrasound on blood-brain-barrier disruption,” Ultrason Sonochem., vol. 15, pp. 636–643, 2008.
[237] 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. 1421–1427, 2007.
[238] J.J. Choi, J.A. Feshitan, B. Baseri, S. Wang, Y.S. Tung, M.A. Borden, et al., “Microbubble-size dependence of focused ultrasound-induced blood-brain barrier opening in mice in vivo,” IEEE Trans Biomed Eng., vol. 57, pp. 145–154, 2010.
[239] G. Samiotaki, F. Vlachos, Y.S. Tung and E.E. Konofagou, “A quantitative pressure and microbubble-size dependence study of focused ultrasound-induced blood-brain barrier opening reversibility in vivo using MRI,” Magn Reson Med., vol. 67, pp. 769–777, 2012.
[240] F. Vlachos, Y.S. Tung and E. Konofagou, “Permeability dependence study of the focused ultrasound-induced blood-brain barrier opening at distinct pressures and microbubble diameters using DCE-MRI,” Magn Reson Med., vol. 66, pp. 821–830, 2011.
[241] N. Sheikov, N. McDannold, N. Vykhodtseva, F. Jolesz and K. Hynynen, “Cellular mechanisms of the blood-brain barrier opening induced by ultrasound in presence of microbubbles,” Ultrasound Med Biol., vol. 30, pp. 979–989, 2004.
[242] K. Hynynen, N. McDannold, N. Sheikov, F. Jolesz and N. Vykhodtseva, “Local and reversible blood-brain barrier disruption by noninvasive focused ultrasound at frequencies suitable for trans-skull sonications,” NeuroImage., vol. 24, pp. 12–20, 2005.
[243] J. Deng, Q. Huang, F. Wang, Y. Liu, Z. Wang, Z. Wang, et al., “The role of caveolin-1 in blood-brain barrier disruption induced by focused ultrasound combined with microbubbles.,” J Mol Neurosci. Vol. 46, pp. 677–687, 2012.
[244] N. Sheikov, N. McDannold, F. Jolesz, Y.Z. Zhang, K. Tam and K. Hynynen, “Brain arterioles show more active vesicular transport of blood-borne tracer molecules than capillaries and venules after focused ultrasound-evoked opening of the blood-brain barrier,” Ultrasound Med Biol., vol. 32, pp. 1399–1409, 2006.
[245] N. Sheikov, N. McDannold, S. Sharma and K. Hynynen, “Effect of Focused Ultrasound Applied With an Ultrasound Contrast Agent on the Tight Junctional Integrity of the Brain Microvascular Endothelium,” Ultrasound Med Biol., vol. 34, pp. 1093–1104, 2008.
[246] C.Y. Xia, Z. Zhang, Y.X. Xue, P. Wang and Y.H. Liu, “Mechanisms of the increase in the permeability of the blood - tumor barrier obtained by combining low-frequency ultrasound irradiation with small-dose bradykinin,” J Neurooncol., vol. 94, pp. 41–50, 2009.
[247] A.H. Mesiwala, L. Farrell, H.J. Wenzel, D. L. Silbergeld, L. A. Crum, H. R. Winn, et al., “High-intensity focused ultrasound selectively disrupts the blood-brain barrier in vivo,” Ultrasound Med. Biol., vol. 28, pp. 389–400, 2002.
[248] J.E. Wang, Y.H. Liu, L.B. Liu, C.Y. Xia, Z. Zhang, and Y.X. Xue, “Effects of combining low frequency ultrasound irradiation with papaverine on the permeability of the blood-tumor barrier,” J Neurooncol., vol.102, pp. 213–224, 2011.
[249] S. Jalali, Y. Huang, D. J. Dumont and K. Hynynen, “Focused ultrasound-mediated bbb disruption is associated with an increase in activation of AKT: Experimental study in rats,” BMC Neurol., vol. 10, pp. 114, 2010.
[250] X. Shang, P. Wang, Y. Liu, Z. Zhang and Y. Xue, “Mechanism of low-frequency ultrasound in opening blood-tumor barrier by tight junction,” J Mol Neurosci., vol. 43, pp. 364–369, 2011.
[251] Z. Zhang, C. Xia, Y. Xue and Y. Liu, “Synergistic effect of low-frequency ultrasound and low-dose bradykinin on increasing permeability of the blood-tumor barrier by opening tight junction,” J Neurosci Res., vol. 87, pp. 2282–2289, 2009.
[252] Z. Zhang, Y. Xue, Y. Liu and X. Shang, “Additive effect of low-frequency ultrasound and endothelial monocyte-activating polypeptide II on blood-tumor barrier in rats with brain glioma,” Neurosci Lett., vol. 481, pp. 21–25, 2010.
[253] J. Park, Z. Fan, R.E. Kumon, M.E.H. El-Sayed and C.X. Deng, “Modulation of intracellular ca2+ concentration in brain microvascular endothelial cells in vitro by acoustic cavitation,” Ultrasound Med Biol., vol. 36, pp. 1176–1187, 2010.
[254] A. Alonso, E. Reinz, J. Jenne, M. Fatar, H. Schmidt-Glenewinkel, M. G. Hennerici, et al., “Reorganization of gap junctions after focused ultrasound blood-brain barrier opening in the rat brain,” J Cereb Blood Flow Metab., vol. 30, pp. 1394–1402, 2010.
[255] E.E. Cho, J. Drazic, M. Ganguly, B. Stefanovic, and K. Hynynen, Two-photon ﬂuorescence microscopy study of cerebrovascular dynamics in ultrasound-induced blood-brain barrier opening,” J Cereb Blood Flow Metab., vol. 31, pp. 1852–1862, 2011.
[256] S.B. Raymond, J. Skoch, B.J. Bacskai and K. Hynynen, “Modular design for in vivo optical imaging and ultrasound treatment in the murine brain,” I IEEE Trans Ultrason Ferroelectr Freq Control., vol. 54, pp. 431–434, 2007.
[257] S.B. Raymond, J. Skoch, K. Hynynen and B.J. Bacskai, “Multi-photon imaging of ultrasound/Optison mediated cerebrovascular effects in vivo,” J Cereb. Blood Flow Metab., vol. 27, pp. 393–403, 2007.
[258] B. Baseri, J.J. Choi, Y. S. Tung, and E.E. Konofagou, “Multi-modality safety assessment of blood-brain barrier opening using focused ultrasound and deﬁnity microbubbles A short-term study,” Ultrasound Med. Biol., vol. 36, pp. 1445–1459, 2010.
[259] L.L. Berland, C.R. Bryan, B.C. Sekar and C.N. Moss, “Sonographic examination of the adult brain,” J Clin Ultrasound., vol. 16, pp. 337–345, 1988.
[260] R. Chopra, L. Curiel, R. Staruch, L. Morrison and K. Hynynen, “An MRI-compatible system for focused ultrasound experiments in small animal models,” Med. Phys., vol. 36, pp. 1867–1874, 2009.
[261] N. McDannold, N. Vykhodtseva and K. Hynynen, “Targeted disruption of the blood-brain barrier with focused ultrasound: Association with cavitation activity,” Phys. Med. Biol., vol. 51, pp. 793–807, 2006.
[262] Y. S. Tung, F. Vlachos, J.J. Choi, T. Defﬁeux, K. Selert and E.E. Konofagou, “In vivo transcranial cavitation threshold detection during ultrasound-induced blood-brain barrier opening in mice,” Phys Med Biol., vol. 55, pp. 6141–6155, 2010.
[263] M.A. O'Reilly, K. Hynynen. “Blood-brain barrier: real-time feedback-controlled focused ultrasound disruption by using an acoustic emissions-based controller,” Radiology., vol. 263, pp. 96–106, 2012.
[264] C.D. Arvanitis, M.S. Livingstone, N. Vykhodtseva and N. McDannold, “Controlled ultrasound-induced blood-brain barrier disruption using passive acoustic emissions monitoring,” PLoS One., vol. 7, pp. e45783, 2012.
[265] H.L. Liu, Y.Y. Wai, P.H. Hsu, L.A. Lyu, J.S. Wu, C.R. Shen, et al., “In vivo assessment of macrophage CNS infiltration during disruption of the blood-brain barrier with focused ultrasound: a magnetic resonance imaging study,” J Cereb Blood Flow Metab., vol. 30, pp. 177–186, 2010.
[266] G. Xi, R.F. Keep and J.T. Hoff, “Mechanisms of brain injury after intracerebral haemorrhage,” Lancet Neurol., vol. 5, pp. 53–63, 2006.
[267] A.I. Qureshi, G.S. Ling, J. Khan, M.F. Suri, L. Miskolczi, L.R. Guterman, et al., “Quantitative analysis of injured, necrotic, and apoptotic cells in a new experimental model of intracerebral hemorrhage,” Crit Care Med., vol. 29, pp. 152–157, 2001.
[268] A.H. Ropper, “Lateral displacement of the brain and level of consciousness in patients with an acute hemispheral mass,” N Engl J Med., vol. 314, pp. 953–958, 1986.
[269] S.A. Mayer, A. Lignelli, M.E. Fink, D.B. Kessler, C.E. Thomas, R. Swarup, et al., “Perilesional blood flow and edema formation in acute intracerebral hemorrhage: a SPECT study,” Stroke., vol. 29, pp. 1791–1798, 1998.
[270] A. Nishino, M. Suzuki, H. Ohtani, O. Motohashi, K. Umezawa, H. Nagura, et al., “Thrombin may contribute to the pathophysiology of central nervous system injury,” J Neurotrauma vol. 10, pp. 167–179, 1993.
[271] G. Xi, R.F. Keep and J.T. Hoff, “Erythrocytes and delayed brain edema formation following intracerebral hemorrhage in rats,” J Neurosurg., vol. 89, pp. 991–996, 1998.
[272] Y. Hua, G. Xi, R.F. Keep and J.T. Hoff, “Complement activation in the brain after experimental intracerebral hemorrhage,” J Neurosurg., vol. 92, pp. 1016–1022, 2000.
[273] T. Nakamura, R. Keep, Y. Hua, T. Schallert, J. Hoff and G. Xi, “Deferoxamine-induced attenuation of brain edema and neurological deficits in a rat model of intracerebral hemorrhage,” J Neurosurg., vol. 100, pp. 672–678, 2004.
[274] T. Nakamura, G. Xi, J.W. Park, Y. Hua, J.T. Hoff and R.F. Keep, “Holotransferrin and thrombin can interact to cause brain damage,” Stroke., vol. 36, pp. 348–352, 2005.
[275] Kinoshita M., McDannold N., Jolesz F.A. and Hynynen K., “Targeted delivery of antibodies through the blood-brain barrier by MRI-guided focused ultrasound,” Biochem Biophys Res Commun., vol. 340, pp. 1085–1090, 2006.
[276] F.Y. Yang, G.L. Lin, S.C. Horng, T.K. Chang, S.Y. Wu, T.T. Wong, et al., “Pulsed high-intensity focused ultrasound enhances the relative permeability of the blood-tumor barrier in a glioma-bearing rat model,” IEEE Trans Ultrason Ferroelectr Freq Control., vol. 58, pp. 964–970, 2011.
[277] F.Y. Yang, S.C. Horng, Y.S. Lin and Y.H. Kao, “Association between contrast-enhanced MR images and blood-brain barrier disruption following transcranial focused ultrasound,” J Magn Reson Imaging., vol. 32, pp. 593–599, 2010.
[278] F. Vlachos, Y.S. Tung and E.E. Konofagou, “Permeability dependence study of the focused ultrasound-induced blood-brain barrier opening at distinct pressures and microbubble diameters using DCE-MRI,” Magn Reson Med., vol. 66, pp. 821–830, 2011.
[279] J.J. Choi, K. Selert, F. Vlachos, A. Wong and E.E. Konofagou, “Noninvasive and localized neuronal delivery using short ultrasonic pulses and microbubbles,” Proc Natl Acad Sci U S A., vol. 108, pp. 16539–16544, 2011.
[280] J.J. Choi, S. Wang, Y.S. Tung, B. Morrison III and E.E. Konofagou, “Molecules of Various Pharmacologically-Relevant Sizes Can Cross the Ultrasound-Induced Blood-Brain Barrier Opening in vivo,” Ultrasound Med. Biol., vol. 36, pp. 58–67, 2010.
[281] K.J. Lin, H.L. Liu, P.H. Hsu, Y.H. Chung, W.C. Huang, J.C. Chen, et al., “Quantitative micro-SPECT/CT for detecting focused ultrasound-induced blood-brain barrier opening in the rat,” Nucl Med Biol., vol. 36, pp. 853–861, 2009.
[282] F.Y. Yang, H.E. Wang, G.L. Lin, M.C. Teng, H.H. Lin, T.T. Wong, et al., “Micro-SPECT/CT-based pharmacokinetic analysis of 99mTc- diethylenetriaminepentaacetic acid in rats with blood-brain barrier disruption induced by focused ultrasound,” J Nucl Med., vol. 52, pp. 478–484, 2011.
[283] H.L. Liu, P.H. Hsu, P.N. Chu, Y.Y. Wai, J.C. Chen, C.R. Shen, et al., “Magnetic resonance imaging enhanced by superparamagnetic iron oxide particles: Usefulness for distinguishing between focused ultrasound-induced blood-brain barrier disruption and brain hemorrhage,” J Magn Reson Imaging., vol. 29, pp. 31–38, 2009.
[284] G.P. Howles, K.F. Bing, Y. Qi, S.J. Rosenzweig, K.R. Nightingale and G. A. Johnson, “Contrast-enhanced in vivo magnetic resonance microscopy of the mouse brain enabled by noninvasive opening of the blood-brain barrier with ultrasound,” Magn Reson Med., vol. 64, pp. 995–1004, 2010.
[285] P.H. Wang, H.L. Liu, P.H. Hsu, C.Y. Lin, C.R. Wang, P.Y. Chen, et al., “Gold-nanorod contrast-enhanced photoacoustic micro-imaging of focused-ultrasound induced blood-brain-barrier opening in a rat model,” J Biomed Opt., vol. 17, pp. 061222, 2012.
[286] M. Kinoshita, N. McDannold, F.A. Jolesz and K. Hynynen, “Noninvasive localized delivery of Herceptin to the mouse brain by MRI-guided focused ultrasound-induced blood-brain barrier disruption,” Proc Natl Acad Sci U S A., vol. 103, pp. 11719–11723, 2006.
[287] J. Mei, Y. Cheng, Y. Song, Y. Yang, F. Wang, Y. Liu, et al., “Experimental study on targeted methotrexate delivery to the rabbit brain via magnetic resonance imaging-guided focused ultrasound,” J Ultrasound Med., vol. 28, pp. 871–880, 2009.
[288] L. Treat, Y. Zhang, N. McDannold and K. Hynynen, “MRI-guided focused ultrasound-enhanced chemotherapy of 9 l rat gliosarcoma: Survival study,” Proc. Intl. Soc. Mag. Reson. Med., vol.16, 2008.
[289] H.L. Liu, M.Y. Hua, H.W. Yang, C.Y. Huang, P.N. Chu, J.S. et al., “Magnetic resonance monitoring of focused ultrasound magnetic nanoparticle targeting delivery of therapeutic agents to the brain,” Proc Natl Acad Sci U S A., vol. 107, pp. 15205–15210, 2010.
[290] K.C., Wei, P.C. Chu, H.Y. Wang, C.Y. Huang, P.Y. Chen, H.C. Tsai et al., “Focused ultrasound-induced blood-brain barrier opening to enhance temozolomide delivery for glioblastoma treatment: a preclinical study,” PLoS One., vol. 8, pp. e58995, 2013.
[291] F.Y. Yang, Y.W. Chen, F.I. Chou, S.H. Yen, Y.L. Lin and T.T. Wong, “Boron neutron capture therapy for glioblastoma multiforme: enhanced drug delivery and antitumor effect following blood-brain barrier disruption induced by focused ultrasound,” Future Oncol., vol. 8, pp. 1361–1369, 2012.
[292] R.D. Alkins, P.M. Brodersen, R.N. Sodhi and K.Hynynen, “Enhancing drug delivery for boron neutron capture therapy of brain tumors with focused ultrasound,” Neuro Oncol., 2013.
[293] J.F. Jord˜ao, C.A. Ayala-Grosso, K. Markham, Y. Huang, R. Chopra,
J. McLaurin, et al, “Antibodies targeted to the brain with image-guided focused ultrasound reduces amyloid-beta plaque load in the TgCRND8 mouse model of Alzheimer’s disease,” PLoS One., vol 5, pp. e10549, 2010.
[294] S.B. Raymond, L.H. Treat, J.D. Dewey, N.J. McDannold, K. Hynynen and B.J. Bacskai, “Ultrasound enhanced delivery of molecular imaging and therapeutic agents in Alzheimer’s disease mouse models,” PLoS One., vol. 3, pp. e2175, 2008.
[295] A. Burgess, C.A. Ayala-Grosso, M. Ganguly, J.F. Jordão, I. Aubert and K. Hynynen, “Targeted Delivery of Neural Stem Cells to the Brain Using MRI-Guided Focused Ultrasound to Disrupt the Blood-Brain Barrier,” PLoS One., vol. 6, pp. e27877, 2011.
[296] R. Alkins, A. Burgess, M. Ganguly, G. Francia, R. Kerbel, W.S. Wels, et al., “Focused ultrasound delivers targeted immune cells to metastatic brain tumors,” Cancer Res., vol. 15, pp. 1892–1899, 2013.
[297] A. Burgess, Y. Huang, W. Querbes, D.W. Sah and K. Hynynen, “Focused ultrasound for targeted delivery of siRNA and efficient knockdown of Htt expression,” J Control Release., vol. 163, pp. 125–129, 2012.
[298] A. Burgess, Y. Huang, W. Querbes, D.W. Sah and K. Hynynen, “Non-invasive delivery of small interfering ribonucleic acid for reduction of Huntingtin expression in the brain is achieved using focused ultrasound to disrupt the blood-brain barrier,” J Acoust Soc Am., vol. 133, pp. 3408, 2013.
[299] Q. Huang, J. Deng, F. Wang, S. Chen, Y. Liu, Z. Wang, et al., “Targeted gene delivery to the mouse brain by MRI-guided focused ultrasound-induced blood-brain barrier disruption,” Exp Neurol., vol. 233, pp. 350–356, 2012.
[300] P.H. Hsu, K.C. Wei, C.Y. Huang, C.J. Wen, T.C. Yen, C.L. Liu, et al., “Noninvasive and Targeted Gene Delivery into the Brain Using Microbubble-Facilitated Focused Ultrasound,” PLoS One., vol. 8, pp. e57682, 2013.
[301] N. McDannold, N. Vykhodtseva, S. Raymond, F.A. Jolesz and K. Hynynen, “MRI-guided targeted blood-brain barrier disruption with focused ultrasound: Histological ﬁndings in rabbits,” Ultrasound Med Biol. vol. 31, pp. 1527–1537, 2005.
[302] N. Vykhodtseva, N. McDannold and K. Hynynen, “Induction of apoptosis in vivo in the rabbit brain with focused ultrasound and Optison,” Ultrasound Med Biol., vol. 32, pp. 1923–1929, 2006.
[303] M. Ichihara, K. Sasaki, S.I. Umemura, M. Kushima and T. Okai, “Blood ﬂow occlusion via ultrasound image-guided high intensity focused ultrasound and its effect on tissue perfusion,” Ultrasound Med Biol., vol. 33, pp. 452–459, 2007.
[304] S.B. Raymond, J. Skoch, K. Hynynen, B.J. Bacskai, “Multiphoton imaging of ultrasound/Optison mediated cerebrovascular effects in vivo,” J Cereb Blood Flow Metab., vol. 27, 393–403, 2007.
[305] P. Nicotera, “Caspase requirement for neuronal apoptosis and neurodegeneration,” IUBMB Life., vol. 49, pp. 421–425, 2000.
[306] I. Unal-Cevik, M. Kilinc, A. Can, Y. Gursoy-Ozdemir and T. Dalkara, “Apoptotic and necrotic death mechanisms are concomitantly activated in the same cell after cerebral ischemia,” Stroke., vol. 35, pp. 2189–2194, 2004.
[307] L.P. Howard, “Molecular imaging using contrast-enhanced ultrasound:
Evaluation of angiogenesis and cell therapy,” Cardiovasc Res., vol. 84, pp. 190–200, 2009.
[308] J.R. Lindner, “Contrast ultrasound molecular imaging of inﬂammation in cardiovascular disease,” Cardiovasc Res., vol. 84, pp. 182–189, 2009.
[309] K. Hynynen, V. Colucci, A. Chung and F. Jolesz, “Noninvasive arterial occlusion using MRI-guided focused ultrasound,” Ultrasound Med Biol., vol. 22, pp. 1071–1077, 1996.
[310] S.R. Wilson, H.J. Jang, T.K. Kim and P.N. Burns, “Diagnosis of focal liver masses on ultrasonography: Comparison of unenhanced and contrast-enhanced scans,” J Ultrasound Med., vol. 26, pp. 775–787, 2007.
[311] C.K. Yeh, S.Y. Lu and Y.S. Chen, “Microcirculation volumetric ﬂow assessment using high-resolution, contrast-assisted images,” IEEE Trans Ultrason Ferroelectr Freq Control., vol. 55, pp. 74–83, 2008.
[312] S.T. Kang and C.K. Yeh, “A maleimide-based in vitro model for ultrasound tar-
geted imaging,” Ultrason Sonochem., vol. 18, pp. 327–333, 2010.
[313] C.K. Yeh and S.Y. Su, “Effects of acoustic insonation parameters on ultrasound
contrast agent destruction,” Ultrasound Med Biol., vol. 34, pp. 1281–1291, 2008.
[314] C.K. Yeh, S.W. Wang and P.C. Li, “Feasibility study on the time-intensity based
blood ﬂow measurements using deconvolution,” Ultrason Imaging., vol. 23, pp. 90–105, 2001.
[315] L. Claassen, G. Seidel and C. Algermissen, “Quantiﬁcation of ﬂow rates using harmonic grey-scale imaging and an ultrasound contrast agent: An in vitro and in vivo study,” Ultrasound Med Biol., vol. 27, pp. 83–88, 2001.
[316] I.V. Victorov, K. Prass and U. Dirnagl, “Improved selective, simple, and contrast staining of acidophilic neurons with vanadium acid fuchsin,” Brain Res Brain Res Protoc., vol. 5, pp. 135–139, 2000.
[317] Y.S. Tung, J.J. Choi, B. Baseri, E.E. Konofagou, “Identifying the inertial cavitation threshold and skull effects in a vessel phantom using focused ultrasound and microbubbles,” Ultrasound Med Biol., vol. 36, pp. 840–852, 2010.
[318] M.E. Loveless, X. Li, J. Huamani, A. Lyshchik, B. Dawant, D. Hallahan, et al., “A method for assessing the microvasculature in a murine tumor model using contrast-enhanced ultrasonography,” J Ultrasound Med., vol. 27, pp. 1699–1709, 2008.
[319] D.L. Miller, “A review of the ultrasonic bioeffects of microsonation, gas-body activation, and related cavitation-like phenomena,” Ultrasound Med. Biol., vol. 13, pp. 443–470, 1987.
[320] Y. Sun, D.E. Kruse, P.A. Dayton and K.W. Ferrara, “High-Frequency Dynamics of ultrasound contrast agents,” IEEE Trans Ultrason Ferroelectr Freq Control., vol. 52, pp. 1981–1991, 2005.
[321] D.E. Goertz, A. Needles, P.N. Burns and F.S. Foster, “High-frequency, nonlinear flow imaging of microbubble contrast agents,” IEEE Trans. IEEE Trans Ultrason Ferroelectr Freq Control., vol. 52, pp. 495–502, 2005.
[322] W.S. Chen, A.A. Brayman, T.J. Matula, L.A. Crum and M.W. Miller, “The pulse length-dependence of inertial cavitation dose and hemolysis,” Ultrasound Med Biol., vol. 29, pp. 739–748, 2003.
[323] C.H. Farny, R.G. Holt and R.A. Roy, “Temporal and spatial detection of HIFU induced inertial and hot-vapor cavitation with a diagnostic ultrasound system,” Ultrasound Med Biol., vol. 35, pp. 603–615, 2009.
[324] Y. Gavrieli, Y. Sherman and S.A. Ben-Sasson, “Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation,” J Cell Biol., vol. 119, pp. 493–501, 1992.
[325] I. Lentacker, S.C. De Smedta and N.N. Sanders, “Drug loaded microbubble design for ultrasound triggered delivery,” Soft Matter., vol. 5, pp. 2161–2170, 2009.
[326] J. O’Brien, I. Wilson, T. Orton and F. Pognan, “Investigation of the Alamar Blue (resazurin) ﬂuorescent dye for the assessment of mammalian cell cytotoxicity,” Eur J Biochem., vol. 367, pp. 5421–5426, 2000.
[327] J. Mikus and D. Steverding, “A simple colorimetric method to screen drug cyto-
toxicity against Leishmania using the dye Alamar Blue,” Parasitol Int., vol. 48, pp. 265–269, 2000.
[328] C. Andersen, J.F. Taagehøj, A. Mühler and M. Rehling, “Approximation of arterial input curve data in MRI estimation of cerebral blood-tumor-barrier leakage: comparison between Gd-DTPA and 99mTc-DTPA input curves,” Magn Reson Imaging., vol. 14, pp. 235–241, 1996.
[329] B. Orakcioglu, K. Becker, O.W. Sakowitz, A. Unterberg and P.D. Schellinger, “Serial diffusion and perfusion MRI analysis of the perihemorrhagic zone in a rat ICH model,” Acta Neurochir Suppl., vol. 103, pp. 15–18, 2008.
[330] G.Y. Yang, A.L. Betz, T.L. Chenevert, J.A. Brunberg and Hoff J.T., “Experimental intracerebral hemorrhage: relationship between brain edema, blood flow, and blood-brain barrier permeability in rats,” J Neurosurg., vol. 81, pp. 93–102, 1994.
[331] W. Lewelt, L.W. Jenkins and J.D. Miller, “Autoregulation of cerebral blood flow after experimental fluid percussion injury of the brain,” J Neurosurg., vol. 53, pp. 500–511, 1980.
[332] P. Dayton, J.S. Allen and K.W. Ferrara, “The magnitude of radiation force on ultrasound contrast agents,” J Acoust Soc Am., vol. 112, pp. 2183–2192, 2002.
[333] J.H. Hwang, A.A. Braymen, M.A. Reidy, T.J. Matula, M.B. Kimmey and L.A. Crum, “Vascular effects induced by combined 1-MHz ultrasound and microbubble contrast agent treatments in vivo,” Ultrasound Med Biol., vol. 31, pp. 553–564, 2005.
[334] J.S. Allen, D.J. May and K.W. Ferrara, “Dynamics of therapeutic ultrasound contrast agents,” Ultrasound Med Biol., vol. 28, pp. 805–816, 2002.
[335] P. Dayton, A. Klibanov, G. Brandenburger and K. Ferrara, “Acoustic radiation force in vivo: a mechanism to assist targeting of microbubbles,” Ultrasound Med Biol., vol. 25, pp. 1195–1201, 1999.
[336] C. Ayata, H.K. Shin, S. Salomone, Y. Ozdemir-Gursoy, D.A. Boas, A.K. Dunn, et al., “Pronounced hypoperfusion during spreading depression in mouse cortex,” J Cereb Blood Flow Metab., vol. 24, pp. 1172–1182, 2004.
[337] V.I. Koroleva, N.I. Vykhodtseva and V.A. Elagin, “Spreading depression in the cortex and subcortical structures of the brain of the rat induced by exposure to focused ultrasound,” Neirofiziologiia., vol. 18, pp. 55–61, 1986.
[338] N.I. Vykhodtseva and V.I. Koroleva, “Changes in the steady potential in various structures of the rat brain induced by focused ultrasound,” Dokl Akad Nauk SSSR., vol. 287, pp. 248–251, 1986.
[339] C.Y. Lai, C.H. Wu, C.C. Chen and P.C. Li, “Quantitative relations of acoustic inertial cavitation with sonoporation and cell viability,” Ultrasound Med Biol., vol. 32, pp. 1931–1941, 2006.
[340] D.L. Miller and C. Dou, “Membrane damage thresholds for 1- to 10-MHz pulsed ultrasound exposure of phagocytic cells loaded with contrast agent gas bodies in vitro,” Ultrasound Med Biol. vol. 30, pp. 973–977, 2004.
[341] S. Fukuda, T. Kato, H. Kakita, Y. Yamada, M.H. Hussein, I. Kato, et al. “Hemodynamics of the cerebral arteries of infants with periventricular leukomalacia,” Pediatrics., vol. 117, pp. 1–8, 2006.
[342] T. Inder, N.J. Anderson, C. Spencer, S. Wells and J.J. Volpe, “White matter injury in the premature infant: a comparison between serial cranial sonographic and MR findings at term,” AJNR. Am. J. Neuroradiol., vol. 24, pp. 805–809, 2003.
[343] L.S. De Vries, I.L. Van Haastert, K.J. Rademaker, C. Koopman, and F. Groenendaal, “Ultrasound abnormalities preceding cerebral palsy in high-risk preterm infants,” J. Pediatr., vol. 144, pp. 815–820, 2004.
[344] G. Klement, S. Baruchel, J. Rak, S. Man, K. Clark, D.J. Hicklin, et al. , “Continuous low-dose therapy with vinblastine and VEGF receptor-2 antibody induces sustained tumor regression without overt toxicity,” J Clin Invest., vol. 105, pp. 15–24, 2000.
[345] D. Hanahan and R.A. Weinberg, “The hallmarks of cancer,” Cell., vol. 100, pp. 57–70, 2000.
[346] R.K. Jain, E. di Tomaso, D.G. Duda, J.S. Loefﬂer, A.G. Sorensen and T.T. Batchelor, “Angiogenesis in brain tumours,” Nat Rev Neurosci., vol. 8, pp. 610–622, 2007.
[347] O.O. Kanu, A. Mehta, C. Di, N. Lin, K. Bortoff, D.D. Bigner, et al. , “Glioblastoma multiforme: a review of therapeutic targets,” Expert Opin Ther Targets., vol. 13, pp.701–718, 2009.
[348] F.R. Lima, S.A. Kahn, R.C. Soletti, D. Biasoli, T. Alves, A.C. da Fonseca, et al., “ Glioblastoma: therapeutic challenges, what lies ahead,” Biochim Biophys Acta., vol. 1826, pp. 338–349, 2012.
[349] M. Najaﬁ, H. Soltanian-Zadeh, K. Jafari-Khouzani, L. Scarpace and T. Mikkelsen, “Prediction of glioblastoma multiform response to bevacizumab treatment using multi-parametric MRI,” PLoS One., vol.7, pp. e29945, 2012.
[350] M. Kioi, H. Vogel, G. Schultz, R.M. Hoffman, G.R. Harsh and J.M. Brown, “Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice,” J Clin Invest., vol. 120, pp. 694–705, 2010.
[351] S.A. Suslov, A. Ooi and R. Manasseh, “Nonlinear dynamic behavior of microscopic bubbles near a rigid wall,” Phys Rev E Stat Nonlin Soft Matter Phys., vol. 85, pp. 066309, 2012.
[352] A.A. Doinikov, L. Aired and A. Bouakaz, “Dynamics of a contrast agent microbubble attached to an elastic wall,” IEEE Trans Med Imaging., vol. 31, pp. 654–62, 2012.
[353] M. Lankford, C.Z. Behm, J. Yeh, A.L. Klibanov, P. Robinson and J.R. Lindner, “Effect of microbubble ligation to cells on ultrasound signal enhancement: implications for targeted imaging,” Invest Radiol., vol. 41, pp. 721–728, 2006.
[354] M. Ward, J. Wu and J.F. Chiu, “Experimental study of the effects of Optison concentration on sonoporation in vitro,” Ultrasound Med Biol., vol. 26, pp. 1169–1175 2000.
[355] K. Kooiman, M. Foppen-Harteveld, A.F. van der Steen and N. de Jong, “Sonoporation of endothelial cells by vibrating targeted microbubbles,” J Control Release., vol. 154, pp. 35–41, 2011.
[356] A. van Wamel, K. Kooiman, M. Harteveld, M. Emmer, F.J. ten Cate, M. Versluis, et al., “Vibrating microbubbles poking individual cells: drug transfer into cells via sonoporation,” J Control Release.. vol. 112, pp. 149–155, 2006.
[357] B.D. Meijering, L.J. Juffermans, A. van Wamel, R.H. Henning, I.S. Zuhorn, M. Emmer, et al., “Ultrasound and microbubble-targeted delivery of macromolecules is regulated by induction of endocytosis and pore formation,” Circ Res., vol. 104, pp. 679–87, 2009.
[358] R. Stupp, W.P. Mason, M.J. van den Bent, M. Weller, B. Fisher, M. J.B. Taphoorn, et al., “Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma,” N Engl J Med., vol. 352, pp. 987–996, 2005.
[359] M. Chahal, Y. Xu, D. Lesniak, K. Graham, K. Famulski, J.G. Christensen, et al., “MGMT modulates glioblastoma angiogenesis and response to the tyrosine kinase inhibitor sunitinib,” Neuro Oncol., vol. 12, pp. 822–833, 2010.
[360] A.R. Hsu, W. Cai, A. Veeravagu, K.A. Mohamedali, K. Chen, S. Kim, et al., “Multimodality molecular imaging of glioblastoma growth inhibition with vasculature-targeting fusion toxin VEGF121/rGel,” J Nucl Med., vol. 48, pp. 445–454, 2007.
[361] T.K. Nayak, K. Garmestani, K.E. Baidoo, D.E. Milenic and M.W. Brechbiel., “PET imaging of tumor angiogenesis in mice with VEGF-A-targeted (86)Y-CHX-A”-DTPA-bevacizumab,” Int J Cancer., vol. 128, pp. 960–966, 2011.
[362] W. Cai and X. Chen, “Multimodality molecular imaging of tumor angiogenesis,” J Nucl Med., vol. 49, pp. 113–128, 2008.
[363] G. Gambarota, W. Leenders, C. Maass, P. Wesseling, B. van der Kogel, O. van Tellingen, et al., “Characterisation of tumour vasculature in mouse brain by USPIO contrast-enhanced MRI,” Br J Cancer., vol. 98, pp. 1784–1789, 2008.
[364] N. Ferrara, “Vascular endothelial growth factor: basic science and clinical progress,” Endocr Rev., vol. 25, pp. 581–611, 2004.
[365] M.R. Horsman, A.B. Bohn and M. Busk, “Vascular targeting therapy: potential benefit depends on tumor and host related effects,” Exp Oncol., vol. 32, pp. 143–148, 2010.

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