順鉑（Cisplatin）是最常用的抗腫瘤劑之一。它被施打在靜脈內通常與其它化療藥劑組合使用。腎毒性是其主要的副作用，也限制了cisplatin使用的劑量。其他觀察到可能會導致減少劑量的毒性有外周神經病變、耳毒性、骨髓抑制和超敏反應甚至還有噁心和嘔吐。因此在過去的研究目的是新的鉑化合物發展以減少全身副作用。在本研究中，cisplatin裝載在超音波微氣泡對比劑(MBs)並施打超音波(US)，增加局部cisplatin釋放，降低使用總劑量和副作用的產生。
實驗組別隨機分為7組：(1)控制組(control) (2)單獨使用MBs(MBs) (3) cisplatin裝載在MBs(C-MBs) (4) MBs混合cisplatin (MBs+C) (5) MBs結合超音波 (MBs+US) (6) cisplatin裝載在MBs結合超音波 (C-MBs+US) (7) MBs混合cisplatin結合超音波 (MBs+C+US)。
結果中顯示，以MBs裝載cisplatin最大的包覆率(albumin：cisplatin=1：5)為25.61%(N=5)。在電子顯微鏡圖像中，C-MBs與MBs相比，外圍明顯的複合物鍵結。Cisplatin在各個處理組中都有顯著的細胞毒性，細胞毒性實驗中，細胞存活率C-MBs (62±0.046%)結合超音波比MBs+C (82±0.02%)結合超音波治療大腸癌細胞更有顯著差異(P<0.05)。動物實驗結果中，包覆cisplatin的治療組別體重較沒有下降趨勢。在控制組、C-MBs、cisplatin、MBs+C+US和C-MBs+US治療小鼠，腫瘤生長比例分別為61.89±2.10、28.33±3.35、15.89±1.43、11.24±2.04和12.91±1.94％。最後在組織切片結果中，MBs+C結合超音波和cisplatin對肝和腎有較嚴重的損傷。MBs+C結合超音波和cisplatin對腫瘤的治療分佈較不均勻，C-MBs結合超音波對腫瘤的治療較為均勻，因此C-MBs結合超音波對腫瘤有更好的治療效率。總體而言，研究cisplatin裝載在MBs結合超音波是對治療癌症有希望的方法。

Cisplatin (cis-diaminedichloroplatinum) is one of the most frequently used antineoplastic agents. It is usually administered i.v., in combination with other antineoplastic agents. Nephrotoxicity is the major side effect that limits the dose of cisplatin that can be safely administered. Other commonly observed toxicities that may lead to dose reduction are peripheral neuropathy, ototoxicity, myelosuppression, and hypersensitivity reactions or even nausea and vomiting. For this reason, research in the past was aimed at the development of new platinum compounds with less systemic side effects. In this study, ultrasound (US) mediated release of cisplatin loaded microbubbles (MBs), increased local concentrations, reduced the dose and side effects was investigated.
The experimental parameters were randomly divided into seven groups : (1) control (2) MBs alone (MBs) (3) cisplatin loaded MBs (C-MBs) (4) MBs mixed with cisplatin (MBs+C) (5) US combined with MBs (MBs+US) (6) US combined with cisplatin loaded MBs (C-MBs+US) (7) US combined with MBs mixed with cisplatin (MBs+C+US) .
In the experimental aspect, the maximum loading efficiency of cisplatin in MBs (with albumin：cisplatin=1:5) was 25.61% (n=5). Scanning electron microscopy images of the MBs and C-MBs with various compositions, respectively. In cytotoxicity experiments, the cell survival in US combined with C-MBs group (62±0.046%) is more significant lower than MBs+C (82±0.02%) (P <0.05). In animal experiments, the tumor growth rates in the control group, C-MBs, cisplatin, MBs +C+US C-MBs+US were 61.89±2.10、28.33±3.35、15.89±1.43、11.24±2.04和12.91±1.94%. In histopathological results, liver and kidney injury was observed in MBs+C combination of US and cisplatin alone groups. The treatment area in tumor tissue is not uniform in MBs+C combination of US and cisplatin alone group and is uniform in C-MBs combined with US. Overall, the combination of cisplatin loaded MBs and US is a promising approach for treating colon cancer.

[1]K. C. Ong, G. Giaever, C. Nislow. DNA-damaging agents in cancer chemotherapy : serendipity and chemical biology. Chem Biol (2013) Vol. 20, No. 5：648-659.
[2]劉義聰、許清玫。綠茶多酚減緩大鼠以Cisplatin引發之急性腎衰竭。碩士論文(2010)，國立中山大學，高雄。
[3]A. Melet , K. Song , O.Bucur. et al. Apoptotic pathways in tumor progression and therapy. Adv Exp Med Biol (2008) Vol. 615：47-79.
[4]V. Frenkel. Ultrasound mediated delivery of drugs and genes to solid tumors. Adv Drug Deliv Rev (2008) Vol. 60, No.10：1193–1208.
[5]A. Sorace. Ultrasound and microbubbles: a role in cancer. The university of alabama at Birmingham(2013) Birmingham, Alabama.
[6] C. –Y. Cheng, Y.-H. Lin, C.-C. Su. Anti-tumor activity of Sann-Joong-Kuey-Jian-Tang alone and in combination with 5-fluorouracil in a human colon cancer colo 205 cell xenograft model. Molecular Medicine RE POR TS (2010) Vol.3：227-231.
[7]A. Gulbake, A. Jain, A. Jain et al. Insight to drug delivery aspects for colorectal cancer. World J Gastroenterol (2016) Vol. 22, No.2：582-599.
[8] IARC.Colorectal cancer incidence and mortality worldwide in 2012.Globocan Cancer Fact Sheet (2013), Globocan
[9]W. Chou, C. Chen, H. Hsieh et al. G2/M arrest and apoptosis of human colorectal cancer cells induced by water extract from residues of jelly fig achene. Technol Health Care (2015) Vol. 24：147–153.
[10]蘇進成。在動物體內研究丹參酮ⅡA與5-FU對大腸癌的協同作用與分子機制。中醫藥年報 (2011) 第 29 期，第 6 冊：391-430。
[11]W. W. Huang, S. W. Ko, H. Y. Tsai et al. Cantharidin induces G2/M phase arrest and apoptosis in human colorectal cancer colo 205 cells through inhibition of CDK1 activity and caspase-dependent signaling pathways. Int J Oncol (2011) Vol.38, No.4：1067-1073.
[12]C. Liu, B. M. Tadayoni, L. A.Bourret et al. Eradication of large colon tumor xenografts by targeted delivery of maytansinoids. Proc Natl Acad Sci U S A (1996) Vol. 93, No.16：8618-8623.
[13]Y. Tan, X. Sun, M. Xu et al. Efficacy of recombinant methioninase in combination with cisplatin on human colon tumors in nude mice. Clin Cancer Res (1999) Vol.5, No.8：2157–2163.
[14]S. Arora, S. Tandon. Achyranthes aspera root extracts induce human colon cancer cell (colo-205) death by triggering the mitochondrial apoptosis pathway and s phase cell cycle arrest. Scientific World Journal (2014) Vol. 2014：1-15.
[15]F. Yang, Y. Zhang, H. Liang. Interactive Association of drugs binding to human serum albumin. Int J Mol Sci (2014) Vol. 15, No.3：3580-3595.
[16]M. C. Cochran, J. R. Eisenbrey, M. C. Soulen et al. Disposition of ultrasound sensitive polymeric drug carrier in a rat hepatocellular carcinoma model. Acad Radiol (2011) Vol. 18, No. 11：1341–1348.
[17]Y. F. Zhou. High intensity focused ultrasound in clinical tumor ablation. World J Clin Oncol (2011) Vol. 2, No. 1：8-27.
[18]B. J. Reedijk. Metal-ligand exchange kinetics in platinum and ruthenium complexes. Platinum Metals Rev (2008) Vol. 52, No. 1：2–11.
[19]M. A. Perazella. Onco-nephrology: renal toxicities of chemotherapeutic agents. Clin J Am Soc Nephrol (2012) Vol. 7, No.10：1713-1721.
[20]A. M. Florea, Dietrich Büsselberg. Cisplatin as an anti-tumor drug: cellular mechanisms of activity, drug resistance and induced side effects. Cancers (2011) Vol. 3, No. 1：1351-1371.
[21] J. Blasiak, J. Kowalik. Protective action of vitamin C against DNA damage induced by selenium-cisplatin conjugate. Quarterly (2001) Vol. 48 No. 1：233–240.
[22]Q. L. Zhou, Z. Y. Chen, Y. X. Wang et al. Ultrasound-mediated local drug and gene delivery using nanocarriers. Biomed Res Int (2014) Vol. 2014：1-13.
[23]R. P. Perez, T. C. Hamilton, R. F. Ozols et al. Mechanisms and modulation of resistance to chemotherapy in ovarian cancer. Cancer (1993) Vol. 71, No. 4：1571-1580.
[24]B. D. Humphreys, R. J. Soiffer, C. C. Magee. Renal failure associated with cancer and its treatment: an update. J Am Soc Nephrol (2005) Vol.16, No.1: 151–161.
[25]J. Levallois, M. Leblanc. Acute renal failure in cancer patients. Ann Med (2005) Vol.37, No.1：13-25.
[26]S. K. Ku, Y. J. Lee, S. D. Lee et al. Nephroprotective effect of polycan on acute renal failure induced by cisplatin in rats. ISRN Vet Sci (2012) Vol. 2012：1-6.
[27]M. Darmon, M. Ciroldi, G. Thiery et al. Clinical review: Specific aspects of acute renal failure in cancer patients. Crit Care (2006) Vol 10, No 2：1-7.
[28]G. Ramesh, W. B. Reeves. Inflammatory cytokines in acute renal failure. Kidney International (2004) Vol. 66：56–61.
[29]Y. P. Ho, S. C. Au-Yeung, K. K. To. Platinum-Based Anticancer Agents: Innovative Design Strategies and Biological Perspectives. Med Res Rev (2003) Vol. 23, No. 5：633-655.
[30]T. C. Johnstone, G. Y. Park, S. J. Lippard. Understanding and improving platinum anticancer drugs –phenanthriplatin. Anticancer Res (2014) Vol. 34, No. 1： 471–476.
[31]D. Esteban-Fernandez, E. Moreno-Gordaliza, B. Canas et al. Analytical methodologies for metallomics studies of antitumor Pt-containing drugs. Metallomics (2010) Vol. 2, No.1：19-38.
[32]N.Kunworarath, P. Muangnil, A. Itharat et al. Acute and Subchronic Treatment of hibiscus sabdariffa linn. extract on renal function and lipid peroxidation in cisplatin-induced acute renal failure rats. J Physiol Biomed Sci (2014) Vol.27, No.1：5-12.
[33]B. Rosenberg, L. V. Camp, T. Krigas. Inhibition of cell division in Escherichia coli by electrolysis products from a platinum electrode. Nature (1965) Vol. 205:698–699.
[34]A. Basu, S. Krishnamurthy. Cellular responses to cisplatin-induced DNA damage. J Nucleic Acids (2010) Vol.2010：1-16.
[35]B. Rosenberg, L. VanCamp. Platinum compounds: a new class of potent antitumour agents. Nature (1969) Vol. 222, No.5191：385–386.
[36]O’neil W. Guthrie. Gene expression kinetics and protein distribution of nucleotide excision repair factors in the inner ear as a function of cis-diamminedichloroplatinum-ii dna damage. University of Pittsburgh (2006)：1-149.
[37]j. A. Mello, E. E. Trimmer, M. Kartalou et al. Conflicting roles of mismatch and nucleotide excision repair in cellular susceptibility to anticancer drugs. Nucleic Acids and Molecular Biology (1998) Vol. 12：249-274.
[38] S. Tu, R. W.-Y. Sun, M. C. M. Lin et al. Gold (iii) porphyrin complexes induce apoptosis and cell cycle arrest and inhibit tumor growth in colon cancer. Cancer (2009) Vol. 115：4459–4469.
[39]A. I. Ivanov, John Christodoulou, John A et al. Cisplatin binding sites on human albumin. J Biol Chem (1998) Vol. 273, No. 24,：14721–14730.
[40]Marie H. Hanigan, Prasad Devarajan. Cisplatin nephrotoxicity: molecular mechanisms. HHS Author Manuscripts (2003) Vol. 1：47–61.
[41]Thomas Ludwig, Christoph Riethmü Ller, Michael Gekle et al. Nephrotoxicity of platinum complexes is related to basolateral organic cation transport. Kidney Int (2004) Vol. 66, No.1：196–202.
[42] S. S. Shrikhande, D. S. Jain, R. B. Athawale. Evaluation of anti-metastatic potential of cisplatin polymeric nanocarriers on B16F10 melanoma cells. Saudi Pharmaceutical Journal (2015)Vol. 8：1-11.
[43]M.W. Helmy, M.M. Helmy, D.M. Abd Allah et al. Role of nitrergic and endothelin pathways modulations in cisplatin-induced nephrotoxicity in male rats. J Physiol Pharmacol (2014) Vol. 65,No. 3：393–399.
[44]S. Ishida, J. Lee, D. J. Thiele et al. Uptake of the anticancer drug cisplatin mediated by the copper transporter Ctr1 in yeast and mammals. Proc Natl Acad Sci U S A (2002) Vol. 99, No. 22：14298–14302.
[45]A. Amin, M. A. Buratovich. New platinum and ruthenium complexes - the latest class of potential chemotherapeutic drugs - a review of recent developments in the field. Mini Rev Med Chem (2009) Vol. 9, No.13：1489-1503.
[46]A. Ozkok, C. L. Edelstein. Pathophysiology of cisplatin-induced acute kidney injury. Biomed Res Int (2014) Vol.2014：1-18.
[47]R. P. Miller, R. K. Tadagavadi, G. Ramesh et al. Mechanisms of Cisplatin Nephrotoxicity. Toxins (2010) Vol. 2：2490-2518.
[48]V. Mavichak, N. L. M. Wong, G. A. Quamme et al. Diiucs. Studies on the pathogenesis of cisplatin-induced hypomagnesemia in rats. Kidney Int (1985) Vol. 28, No.6：914—921.
[49] A. Pines, C. D. Kelstrup, M. G. Vrouwe. Global phosphoproteome profiling reveals unanticipated networks responsive to cisplatin treatment of embryonic stem cells. Molecular and cellular biology (2011) Vol. 31, No. 24：4964–4977.
[50]S. D. Schaefer, J. D. Post, L. G. Close et al. Ototoxicity of low- and moderate-dose cisplatin. Cancer (1985) Vol. 56, No.8：1934-1939.
[51]林祐賢、林勝豐、蕭惠樺等。順鉑造成急性腎損傷之最新進展。內科學誌(2011) Vol. 22：416-422.
[52]M. Yoshidaa, A. Fukudaa, M. Harab et al. Melatonin prevents the increase in hydroxyl radical-spin trap adduct formation caused by the addition of cisplatin in vitro. Life Sci (2003) Vol. 72, No.15：1773–1780.
[53]M. Kartalou, J. M. Essigmann. Mechanisms of resistance to cisplatin. Mutat Res (2001) Vol. 478：23–43.
[54]L Galluzzi, L Senovilla, I. Vitale et al. Molecular mechanisms of cisplatin resistance. Oncogene (2012) Vol.31, No.15：1869-1883.
[55]J. Zlatanova, J. Yaneva, S. H. Leuba. Proteins that specifically recognize cisplatin-damaged DNA: a clue to anticancer activity of cisplatin. Faseb J (1998) Vol. 12, No. 10：791-799.
[56]C. A. Rabik, M. E. Dolan. Molecular mechanisms of resistance and toxicity associated with platinating agents. Cancer Treat Rev (2007) Vol. 33, No. 1：9–23.
[57]J. C., E Quoix. Platinum drugs in the treatment of non-small-cell lung cancer. British Journal of Cancer (2002) Vol.87：825 – 833.
[58]E. R. Jamieson, S. J. Lippard. Structure, Recognition, and Processing of Cisplatin-DNA Adducts. Chem Rev (1999) Vol. 99, No. 9：2467-2498.
[59]R. C. Todd, S. J. Lippard. Inhibition of transcription by platinum antitumor compounds. Metallomics (2009) Vol. 1, No. 4：280–291.
[60]D. W. Shen, L. M. Pouliot, M. D. Hall et al. Cisplatin resistance: a cellular self-defense mechanism resulting from multiple epigenetic and genetic changes. Pharmacol Rev (2012) Vol. 64, No.3：706–721.
[61]J. Reedijk. Platinum anticancer coordination compounds: study of dna binding inspires new drug design. Eur. J. Inorg. Chem (2009)：1303–1312.
[62]J. J. Roberts , J. M. Pascoe. Cross-linking of complementary strands of DNA in mammalian cells by antitumour platinum compounds. Nature (1972) Vol. 235, No.5336：282–284.
[63]R. C. Todd, S. J. Lippard. Inhibition of transcription by platinum antitumor compounds. Metallomics (2009) Vol. 1, No. 4：280–291.
[64]S. Zhu, N. Pabla, C. Tang, Liyu He, Zheng Dong. DNA damage response in cisplatin‑induced nephrotoxicity. Arch Toxicol (2015) Vol. 89, No.12：2197–2205.
[65]T. G. Oliver, K. L. Mercer, L. C. Sayles et al. Chronic cisplatin treatment promotes enhanced damage repair and tumor progression in a mouse model of lung cancer. Genes Dev (2010) Vol. 24, No.8：837–852.
[66]G. Samimi, K. Katano, A. K. Holzer et al. Modulation of the cellular pharmacology of cisplatin and its analogs by the copper exporters ATP7A and ATP7B. Mol Pharmacol (2004) Vol. 66, No.1：25–32.
[67]D. Fink, S. B. Howell. How does cisplatin kill cells. Humana (2000)：149-161.
[68]Z. Huang, Y. Huang. The change of intracellular ph is involved in the cisplatin-resistance of human lung adenocarcinoma A549/DDP cells. Cancer Invest (2005) Vol. 23, No. 1：26-32.
[69]J. Reedijk. New clues for platinum antitumor chemistry: Kinetically controlled metal binding to DNA. Proc Natl Acad Sci U S A (2003) Vol. 100, No. 7：3611–3616.
[70]A. Weidemann, W. M. Bernhardt, B. Klanke et al. HIF activation protects from acute kidney injury. J Am Soc Nephrol (2008) Vol. 19, No.3：486–494.
[71]B. I. Arany, R. L. Safirstein. Cisplatin Nephrotoxicity. Semin Nephrol (2003) Vol. 23, No. 5：460-464.
[72]X. Yao, K. Panichpisal, N. Kurtzman et al. Cisplatin nephrotoxicity: a review. Am J Med Sci (2007) Vol. 334, No.2：115–124.
[73]M.Satoh, N. Kashihara, S. Fujimoto et al. A novel free radical scavenger, edarabone, protects against cisplatin-induced acute renal damage in vitro and in vivo. J Pharmacol Exp Ther (2003) Vol. 305, No. 3：1183–1190.
[74]M. A. Al-Kahtani, A. M. Abdel-Moneim, O. M. Elmenshawy, Mohamed A. El-Kersh. Hemin attenuates cisplatin-induced acute renal injury in male rats. Oxid Med Cell Longev (2014) Vol.2014：1-9.
[75]J. Megyesi, R. L. Safirstein, P. M. Price. Induction of p21waf1/cip1/sdi1 in kidney tubule cells affects the course of cisplatin-induced acute renal failure. J. Clin. Invest. (1988) Vol.101, No.4：777–782.
[76]R. Safirstein, P. Miller, J. B. Guttenplan. Uptake and metabolism of cisplatin by rat kidney. Kidney Int (1984) Vol. 25, No.5：753-758.
[77]A. C. Shirali, M. A. Perazella. Tubulointerstitial injury associated with chemotherapeutic agents. Adv Chronic Kidney Dis (2014) Vol 21, No. 1：56-63.
[78]L. M. Aleksunes, L. M. Augustine, G. L. Scheffer et al. Renal xenobiotic transporters are differentially expressed in mice following cisplatin treatment. Toxicology (2008) Vol. 250：82–88.
[79]K. P. Kang, D. H. Kim, Y. J. Jung et al. Alpha-lipoic acid attenuates cisplatin-induced acute kidney injury in mice by suppressing renal inflammation. Nephrol Dial Transplant (2009) Vol.24, No.10：3012-3020.
[80]M. Liu, C. C. Chien, M. B. Taney et al. A pathophysiologic role for t lymphocytes in murine acute cisplatin nephrotoxicity. J Am Soc Nephrol (2006) Vol. 17, No.3: 765–774.
[81]K. Fujiwara, M. Shin, H. Matsunaga et al. Light-microscopic immunocytochemistry for gentamicin and its use for studying uptake of the drug in kidney. Antimicrob Agents Chemother (2009) Vol. 53, No. 8：3302–3307.
[82]M. A. Hyppolito, J. A. Oliveira, R. M. Lessa et al. Amifostine otoprotection to cisplatin ototoxicity: a guinea pig study using optoacoustic emission distortion products (DPOEA) and scanning electron microscopy. Braz J Otorhinolaryngol (2005) Vol.71, No.3：268-273.
[83]P. T. Ilumens, Jan H. Brakkee, E. Cavalietti et al. Reduced glutathione protects against cisplatin-induced neurotoxicity in rats. Cancer Res (1993) Vol. 53, No.3：544-549.
[84]L. E Ta, P. A. Low, A. J. Windebank. Mice with cisplatin and oxaliplatin-induced painful neuropathy develop distinct early responses to thermal stimuli. Mol Pain (2009) Vol. 5, No.9：1-11.
[85]R. L. Safirstein. Acute renal failure: From renal physiology to the renal transcriptome. Kidney Int Suppl (2004) Vol. 91：62-66.
[86]S.Y. Loh, P. Mistry, L.R. Kelland et al. Reduced drug accumulation as a major mechanism of acquired resistance to cisplatin in a human ovarian carcinoma cell line: circumvention studies using novel platinum (II) and (IV) ammine/amine complexes. Br J Cancer (1992) Vol. 66, No.6：1109-1115.
[87]P. Ravindra, D. Bhiwgade, S. Kulkarni et al. Cisplatin induced histological changes in renal tissue of rat. Journal of Cell and Animal Biology (2010) Vol. 4, No.7：108-111.
[88]G. P. Kaushal, V. Kaushal, C. Herzog et al. Autophagy delays apoptosis in renal tubular epithelial cells in cisplatin cytotoxicity. Autophagy (2008) Vol. 4, No.5：710-712.
[89]W. D. O’Brien. Ultrasound–biophysics mechanisms. Prog Biophys Mol Biol (2007) Vol. 93：212-255.
[90]Y. Liu, H. Miyoshi, M. Nakamura. Encapsulated ultrasound microbubbles: Therapeutic application in drug/gene delivery. J Control Release (2006) Vol. 114, No.1：89-99.
[91]A. L.Klibanov. Ultrasound contrast agents: development of the field and current status. Springer-Verlag Berlin Heidelberg (2002)：73-102.
[92]S. Hernot, A. L. Klibanov. Microbubbles in ultrasound-triggered drug and gene delivery. Adv Drug Deliv Rev (2008) Vol. 60, No.10：1153-1166.
[93]K. Sugimoto, F. Moriyasu, Y.Negishi et al. Quantification in molecular ultrasound imaging: a comparative study in mice between healthy liver and a human hepatocellular carcinoma xenograft. J Ultrasound Med (2012) Vol.31, No.12：1909–1916.
[94]S. Tinkov, R. Bekeredjian, G. Winter et al. Microbubbles as ultrasound triggered drug carriers. J Pharm Sci (2009) Vol. 98, No. 6：1935-1961.
[95]A. Schneider, L. Johnson, M. Goodwin et al. Bench-to-bedside review: contrast enhanced ultrasonography - a promising technique to assess renal perfusion in the ICU. Crit Care (2011) Vol. 15, No.3：157-165.
[96]F. Gao, C. Xiong , Y. Xiong. Constrained oscillation of a bubble subjected to shock wave in microvessel. Progress in Natural Science (2009) Vol. 19：1109-1117.
[97]A. L. Klibanov. Ligand-carrying gas-filled microbubbles: ultrasound contrast agents for targeted molecular imaging. Bioconjugate Chem (2005) Vol. 16, No.1：9-17.
[98]A. Gedanken. Preparation and properties of proteinaceous mirospheres made sonochemically. Chemistry (2008) Vol. 14, No.13：3841-3853.
[99]J. YE, H. HE , J. GONG et al. Ultrasound-mediated targeted microbubbles: a new vehicle for cancer therapy. J Control Release (2012) Vol. 162, No.2：349-354.
[100]盧聖介。包覆空氣微脂體於高頻超音波影像與聲學非線性性質研究與應用。碩士論文 (2008)，國立清華大學，新竹。
[101]D. M. Hallow. Measurement and correlation of acoustic cavitation with cellular and tissue bioeffects. Ultrasound Med Biol (2006)：1111-1122.
[102]S. Mitragotri. Healing sound: the use of ultrasound in drug delivery and other therapeutic applications. Nat Rev Drug Discov (2005) Vol. 4, No.3：255-260.
[103]H. L. Liu, C. H. Fan, C. Y. Ting et al. Combining microbubbles and ultrasound for drug delivery to brain tumors: current progress and overview. Theranostics (2014) Vol. 4, No. 4：432-444.
[104]S. R. Sirsi, M. A. Borden. Advances in ultrasound mediated gene therapy using microbubble contrast agents. Theranostics (2012) Vol. 2, No. 12：1208-1222.
[105]W. G. Pitt, G.A. Husseini, B. J. Staples. Ultrasonic drug delivery – A general review. Expert Opin Drug Deliv (2004) Vol. 1, No. 1：37–56.
[106]J. E. Chomas, P. A. Dayton, D. May et al. Optical observation of contrast agent destruction. Applied Physics Letters (2000) Vol. 77, No. 7：1056-1058.
[107]X. Zhu, J. Guo, C. He et al. Ultrasound triggered image-guided drug delivery to inhibit vascular reconstruction via paclitaxel-loaded microbubbles. Sci Rep (2016) Vol. 6：1–12.
[108] M. J. Borrelli, W. D. O’Brien, Laura J. Bernock et al. Production of uniformly sized serum albumin and dextrose microbubbles. Ultrasonics Sonochemistry (2012) Vol. 19：198-208.
[109]S. WT, F. F.Destruction of contrast microbubbles and the association with inertial cavitation.Ultrasound Med Biol (2000) Vol. 26, No. 6：1009–1019.
[110]S. Tinkov, G.Winter, C. Coester et al. New doxorubicin-loaded phospholipid microbubbles for targeted tumor therapy: Part I — Formulation development and in-vitro characterization. J Control Release (2010) Vol. 143, No.1：143–150.
[111]W. S. Chen, T. J. Matula, L. A. Crum. The disappearance of ultrasound contrast bubbles: observations of bubble dissolution and cavitation nucleation. Ultrasound Med Biol (2002) Vol. 28, No. 6,：793–803.
[112]D. Park, H. Park, J. Seo et al. Sonophoresis in transdermal drug deliverys. Ultrasonics (2014) Vol. 54, No. 1：56–65.
[113]M. W. Grinstaff, K. S. Suslick. Air-filled proteinaceous microbubbles: synthesis of an echo-contrast agent. Proc Natl Acad Sci U S A (1991) Vol. 88, No.17：7708-7710.
[114]E. Quaia. Classification and safety of microbubble-based contrast agents. Springer (2005)：3-14.
[115]M. S. Dolan, S. S. Gala, S. Dodla et al. Safety and efficacy of commercially available ultrasound contrast agents for rest and stress echocardiography a multicenter experience. J Am Coll Cardiol (2009) Vol. 53, No. 1：32-38.
[116]S. Unnikrishnan,A. L. Klibanov. Microbubbles as ultrasound contrast agents for molecular imaging: preparation and application. AJR Am J Roentgenol (2012) Vol. 199, No.2：292–299.
[117] J. Tang, J.-J. Zhao, Z.-H. Li. Ethanol extract of Artemisia sieversiana exhibits anticancer effects and induces apoptosis through a mitochondrial pathway involving DNA damage in COLO-205 colon carcinoma cells. Bangladesh J Pharmacol (2015) vol. 10：518-523.
[118]Y. Watanabe, A.Aoi, S. Horie. Low-intensity ultrasound and microbubbles enhance
the antitumor effect of cisplatin. Cancer Sci(2008) vol. 99, no. 12：2525–2531.
[119]C. P. Shih, H. C. Chen, H. K. Chen et al. Ultrasound-aided microbubbles facilitate the delivery of drugs to the inner ear via the round window membrane. J Control Release (2013) Vol. 167, No.2：167-174.
[120]Y. K. Li, W. J. Lee, M. F. Wu et al. Estimate the delivery efficiency in cancer cells of drug-loaded microbubbles with US and IVIS. IEEE International Ultrasonics Symposium (2011) Vol. 2011：1470-1473.
[121]Y. Watanabe, A. Aoi. Blackwell publishing asia low-intensity ultrasound and microbubbles enhance the antitumor effect of cisplatin. Cancer Sci (2008) Vol. 99, No.12：2525–2531.
[122]P.A. Dijkmans, L.J.M. Juffermans, R.J.P. Musters et al. Microbubbles and ultrasound: from diagnosis to therapy. Eur J Echocardiogr (2004) Vol. 5, No.4：245-256.
[123]H. Chen, J. H. Hwang. Ultrasound-targeted microbubble destruction for chemotherapeutic drug delivery to solid tumors. J Ther Ultrasound (2013) Vol. 1, No. 10：2-8.
[124] N. Sasaki, N. Kudo, K. Nakamura et al. Activation of microbubbles by short-pulsed ultrasound enhances the cytotoxic effect of cis-diamminedichloroplatinum (ii) in a canine thyroid adenocarcinoma cell line in vitro. Ultrasound in Med. & Biol(2012) Vol. 38, No. 1：109–118.
[125]E. C. Unger, E. Hersh, M. Vannan et al. Local drug and gene delivery through microbubbles. Prog Cardiovasc Dis (2001) Vol. 44, No. 1: 45-54.
[126]Y. Z. Hu, J. A. Zhu, Y. G. Jiang et al. Ultrasound microbubble contrast agents: Application to therapy for peripheral vascular disease. Adv Ther (2009) Vol. 26, No. 4：425-434.
[127]T. J. Segers. Monodisperse bubbles and droplets for medical applications. University of Twente (1987), Netherlands.
[128]C. Møller, H. S. Tastesen, B. Gammelgaard et al. Stability, accumulation and cytotoxicity of an albumin-cisplatin adduct. Metallomics (2010) Vol.2, No.12：811–818.
[129]J.F. Neault, H.A. Tajmir-Riahi. Interaction of cisplatin with human serum albumin：Drug binding mode and protein secondary structure. Biochim Biophys Acta (1998) Vol. 1384, No.1：153-159.
[130]A. M. Krause-Heuer, W. S. Price, J. R. Aldrich-Wright. Spectroscopic investigations on the interactions of potent platinum(II) anticancer agents with bovine serum albumin. J Chem Biol (2012) Vol. 5, No.3：105–113.
[131]B. P. Espósitoa, E. Oliveiraa, Szulim . Zyngierb et al. Effects of human serun albumin in some biological properties of rhodium(ii) complexes. J. Braz. Chem. Soc (2000) Vol. 11, No. 5：447-452.
[132]G. Ferraro, L. Massai, L. Messori et al. Cisplatin binding to human serum albumin: a structural study. Chem Commun (2015) Vol. 51, No.46：9436–9439.