近50年來，5-氟尿嘧啶（5-fluorouracil, 5-FU）作為癌症病患全身化療之關鍵藥物。但5-FU藥物受限於半衰期極短（10-15分鐘）之缺點，易被代謝而失去藥效，因此臨床上皆使用靜脈連續輸注為主要治療手段。本研究設計包覆5-FU於白蛋白微氣泡對比劑 (Microbubbles, MBs)並結合超音波(Ultrasound, US) 以增加局部腫瘤內5-FU濃度之工具，並延長5-FU的半衰期。實驗中使用白蛋白溶液（132 mg / mL）和0.32 mg / mL 5-FU溶液製備5FU-MBs。從結果可發現，MBs和5FU-MBs的平均直徑分別為1.24 ± 0.85和2.00 ± 0.53 µm，5-FU於MBs中最大藥物負載效率為19.04 ± 0.24％。於體外實驗中，5FU-MBs結合超音波後可以增加16.1％的細胞毒性（p <0.001）。而動物治療實驗中發現，治療時間為期31天，5FU-MBs + US組治療效果比5-FU組更加顯著。因此可預期，包覆5-FU之MBs結合超音波可增加腫瘤中局部藥物傳遞效率且延長5-FU於動物體內的半衰期。

Over the past 50 years, 5-fluorouracil (5-FU) has played a critical role in the systemic chemotherapy of cancer patients. However, the IV continuous infusion of 5-FU was used since the limitation of 5-FU’s extremely short half-life (10–15 minutes). In this study, we created a 5FU loaded microbubbles (MBs) combined with ultrasound (US) as a tool to increase the local intratumoral 5-FU level while the half-life of 5FU was extended. In the results, the 5-FU-MBs prepared with the concentrations of albumin solution (132 mg/mL) and 0.32 mg/mL 5-FU solution. The mean diameters of MBs and 5FU-MBs were 1.24 ± 0.85 and 2.00 ± 0.53 µm respectively, and the maximum loading efficiency of 5-FU on MBs was 19.04 ± 0.24 %. In the in vitro study, 5FU-MBs can increase 16.1 % cell toxicity after US insolation (p<0.001). In small animal treatment, the treatment efficacies in 5FU-MBs+US group was more significant than in 5FU group during 31 treatment period. Instead of 5FU, it can be expected that 5FU-loaded MBs combined with US increases local drug delivery in the tumor and extends the half-life in small animals.

[1] A. Sudhakar, "History of Cancer, Ancient and Modern Treatment Methods," J Cancer Sci Ther, vol. 1, no. 2, pp. 1-4, 2009.
[2] N. C. Institute. (2015). What Is Cancer. Available: https://www.cancer.gov/about-cancer/understanding/what-is-cancer
[3] N. C. Institute. (2000). Head and Neck Cancers. Available: https://www.cancer.gov/types/head-and-neck/head-neck-fact-sheet
[4] H. J. “Hypopharyngeal Cancer.” in Medscape, (2019). Available: https://emedicine.medscape.com/article/1375268-overview
[5] G. B. F. MURA, "Surgical treatment of hypopharyngeal cancer:a review of the literature and proposal for a decisional flow chart," Acta Otorhinolaryngol Italic, vol. 33, no. 5, pp. 299-306, 2013.
[6] E. Katsoulakis, "Hypopharyngeal squamous cell carcinoma: Three-dimensional or Intensity-modulated radiotherapy: A single institution's experience," Laryngoscope, vol. 126, no. 2, pp. 620-626, 2016.
[7] 張金堅. (2013)談百年來人類癌症治療發展史. 臺灣醫界. pp. 39-44. Available: http://www.tma.tw/ltk/102560209.pdf
[8] A. S. E. H, "Introduction to Radiotherapy and Standard Teletherapy Techniques," Ophthalmic Radiation Therapy, vol. 52, pp. 1-14, 2013.
[9] U. o. F. Health. (2017). An Introduction to Radiation Therapy. Available: http://radonc.med.ufl.edu/patient-care/information-for-patients/an-introduction-to-radiation-therapy/
[10] G. Patrick, An Introduction to Medicinal Chemistry. Oxford University Press, 2017.
[11] D. S. K. Shewach, "Introduction to cancer chemotherapeutics," Chem Rev, vol. 109, no. 7, pp. 2859-2861, 2009.
[12] N. C. Institute. (2000). CANCER REGISTRATION & SURVEILLANCE MODULES. Available: https://training.seer.cancer.gov/modules_reg_surv.html
[13] A. A. Urruticoechea, "Recent advances in cancer therapy: an overview," Curr Pharm Des, vol. 16, no. 1, pp. 3-10, 2010.
[14] DANNEBERG PB, MONTAG BJ, HEIDELBERGER C. Studies on fluorinated pyrimidines. IV. Effects on nucleic acid metabolism in vivo. Cancer Res. vol. 18, no. 3, pp. 329-334, 1958 .
[15] Diasio, R. B. & Harris, B. E. Clinical pharmacology of 5-fluorouracil. Clin. Pharmacokinet, vol. 16, pp. 215-237, 1989.
[16] Kemeny N, Fata F. Arterial, portal or systemic chemotherapy for patients with hepatic metastasis of colorectal carcinoma. Journal of Hepato-Biliary-Pancreatic Surgery, vol. 6, no. 1, pp. 39-49, 1999.
[17] Kuropkat C, Griem K, Clark J, Rodriguez ER, Hutchinson J, Taylor SGT. Severe cardiotoxicity during 5-fluorouracil chemotherapy: a case and literature report. Am J Clin Oncol, vol. 22, pp. 466-470, 1999.
[18] Matsusaka S, Lenz HJ. Pharmacogenomics of fluorouracil-based chemotherapy toxicity. Expert Opin Drug Metab Toxicol, vol. 11, no. 5, pp. 811-821, 2015
[19] Fluorouracil. Wikipedia, Available: https://en.wikipedia.org/wiki/Fluorouracil
[20] 5-Fluorouracil. Sigma, Available: https://www.sigmaaldrich.com/catalog/product/sigma/f6627?lang=en®ion=TW
[21] Longley, D. B., Harkin, D. P. & Johnston, P. G. 5-fluorouracil: mechanisms of action and clinical strategies. Nature Rev. Cancer, vol. 3, pp. 330-338, 2003.
[22] Eidinoff, M. L., et al. "Effect of 5-fluorouracil on the incorporation of precursors into nucleic acid pyrimidines." Arch Biochem Biophys , vol. 71, no.1, pp. 274-275, 1957.
[23] Souglakos, J., et al. "Combination of irinotecan (CPT-11) plus oxaliplatin (L-OHP) as first-line treatment in locally advanced or metastatic gastric cancer: a multicentre phase II trial." Annals of Oncology, vol. 15, no.8, pp. 1204-1209, 2004.
[24] Houghton, J. A. and P. J. Houghton. "Elucidation of pathways of 5-fluorouracil metabolism in xenografts of human colorectal adenocarcinoma." Eur J Cancer Clin Oncol, vol.19, no.6, pp. 807-815, 1983.
[25] Hyams, J. S., et al. "Cancer chemotherapy-induced lactose malabsorption in children." Cancer , vol.49, no. 4, pp. 646-650, 1982.
[26] F. Kratz, "Albumin as a drug carrier: design of prodrugs, drug conjugates and nanoparticles," J Control Release, vol. 132, no. 3, pp. 171-83, 2008.
[27] Marković OS, Cvijetić IN, Zlatović MV, et al. Human serum albumin binding of certain antimalarials. Spectrochim Acta A Mol Biomol Spectrosc, vol. 5, no. 192, pp. 128-139, 2018.
[28] Chen, H. K., et al. "Insonation of Systemically Delivered Cisplatin-Loaded Microbubbles Significantly Attenuates Nephrotoxicity of Chemotherapy in Experimental Models of Head and Neck Cancer." Cancers (Basel), vol. 10, 2018.
[29] S. Chinnathambi, S. Karthikeyan, M. Kesherwani,D. Velmurugan, and N. Hanagata, “Underlying the mechanism of 5-fluorouracil and human serum albumin interaction:a biophysical study,” Journal of Physical Chemistry and Biophysics, vol. 6, no. 2, pp. 2161–0398, 2016.
[30] 陳思嘉, "靶向超音波於血栓溶解之研究," Master, 電機資訊學院生依電子與資訊學研究所, 國立台灣大學, 2009.
[31] B. R. T. S, "Microbubbles as ultrasound triggered drug carriers," J Pharm Sci, vol. 98, no. 6, pp. 1935-1961, 2009.
[32] Y. Z. D. Zhao, "Potential and problems in ultrasound-responsive drug delivery systems," Int J Nanomedicine, vol. 8, pp. 1621-1633, 2013.
[33] “Ultrasound”, New World Encyclopedia, Online Available: http://www.newworldencyclopedia.org/entry/Ultrasound , 2016.
[34] 陳思嘉，「靶向超音波於血栓溶解之研究」，碩士論文，國立台灣大學電機資訊學院生依電子與資訊學研究所，台北，2009。
[35] K. A. H. S, "Microbubbles in ultrasound-triggered drug and gene delivery," Adv Drug Deliv Rev, vol. 60, no. 10, pp. 1153-1166, 2008.
[36] S. R. Sirsi and M. A. Borden “Advances in Ultrasound Mediated Gene Therapy Using Microbubble Contrast Agents.”, Theranostics, vol. 2, no. 12, pp. 1208-1222, 2012.
[37] 謝依峻，「組織背景抑制於諧波對比劑偵測」，碩士論文，國立台灣科技大學電機工程系, 2008。
[38] 王鴻偉, "使用三倍頻發射相位法對比劑諧波影像," Master, 電機工程系, 國立台灣科技大學, 2008.
[39] 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," Master, 生醫工程與環境科學研究所, 國立清華大學, 2008.
[40] P. C. F. FS, "Advances in Ultrasound Biomicroscopy," Ultrasound Med. Biol, vol. 26, no. 1, pp. 1-27, 2000.
[41] M. AJ, "Scanning Acoustic Microscopy in Eletronics Research IEEE Trans," On Ultrasound, Ferroelectrics, and Frequency Control, vol. 32, no. 2, pp. 320-324, 1985.
[42] G. R. L. DH, "Turnbull DA. Christopher Foster , A 40-100 MHz B-scan Ultrasound backscatter skin imaging," Ultrasound in Med.＆Biol, vol. 21, no. 1, pp. 79-88, 1995.
[43] K. DA, "A 100-200 MHz ultrasound biomicroscope.," IEEE Trans Ultrason Ferroelectr Freq Control, vol. 47, no. 6, pp. 1540-9, 2000.
[44] C. Passmann, "Adaptive 150 MHz ultrasound imaging of the skin and the eye using an optimal combination of short pulse mode and pulse compression mode," Seattle, WA, USA, USA, 1995.
[45] C. J. Pavlin, Ultrasound Biomicroscothe Eye Springer-Verlag. Springer, New York, NY, 1995.
[46] 何祚明, "高頻超音波影像系統," Master,電機工程學研究所,國立台灣大學, 2002.
[47] I. Lentacker, S.C. De Smedt and N.N. Sanders, “Drug loaded microbubble design for ultrasound triggered delivery.”, The Royal Society of Chemistry, 5, 2161-2170, 2009.
[48] DA. Christensen, “Ultrasonic Bioinstrumentation.”, Journal of Biomedical Engineering, 11, 1988.
[49] 王鴻偉，「使用三倍頻發射相位法對比劑諧波影像」，碩士論文，國立台灣科技大學電機工程系，台北，2008。
[50] FS. Foster, CJ. Pavlin, and KA. Harasiewicz et al., “Advances in Ultrasound Biomicroscopy.”, Ultrasound in Medicine & Biology, 26, 1, 1-27, 2000.
[51] M. J. K. Blomley, J. C. Cooke, and E. C. Unger et al., “Microbubble contrast agents: a new era in ultrasound.”, British Medical Journal, 322, 2001.
[52] C. H. Su, Y. J. Wu, and H. H. Wang et al., “Nonviral gene therapy targeting cardiovascular system.”, American Journal of Physiology. Heart and Circulatory Physiology, 303, pp. 629-638, 2012.
[53] M. I. Ltd. (2015). Measuring Molecular Weight, Size and Branching of Polymers. Available: https://wiki.anton-paar.com/tw-zh/the-principles-of-dynamic-light-scattering/