奈米醫學所開發出的診療一體技術已朝向臨床實用逐漸發展成熟。奈米金棒粒子能表現出光聲成像(Photoacoustic Imaging)、光熱治療(Photothermal Therapy)等特性，而達到同時進行診斷與治療的效果。本研究以金奈米棒為發展平台，其表面電漿共振特性提供近紅外光照射下的光熱治療與同步藥物釋放來增強化療對腫瘤細胞的殺傷力，透過控制紅外光照射的區段集中於腫瘤患部，可顯著的減少正常組織受到的傷害。
我們在金奈米棒上以自組單層膜的組裝原理修飾上聚腺苷酸(poly-A)作為攜帶抗癌藥物的媒介，另外修飾上聚乙二醇(PEG)增加金奈米棒的生物相容性並與適體(aptamer)鍵結，使金奈米棒不僅作為光熱治療的材料，也是攜帶藥物的載體並且具有在特定部位專一性釋放藥物的能力，形成「金奈米棒-抗癌藥物-適體」的智慧型金奈米棒複合物。
目前合成的金奈米棒其特徵光學吸收波長在800 nm，透過檢測未鍵結的聚腺苷酸(poly-A)與適體(aptamer)：ap9r計算出平均一個金奈米棒帶有87.3支聚腺苷酸(poly-A)與7.4支ap9r，此外抗癌藥物的攜帶率也高達74 .4%，並使用螢光染色法去篩選與ap9r有專一性標靶的口腔癌細胞株-SAS，以及檢視修飾在金棒上的適體是否依然保有特性，並且測試出在與細胞作用4小時後會有專一性的標靶。組裝完成的金棒複合物與口腔癌細胞作細胞毒殺性的測試，在12小時內對細胞並無毒殺性的表現，而24小時卻有明顯的細胞死亡，也間接證明藥物的緩慢釋放，接著測試近紅外光的照射是否加成癌細胞的殺傷力，有組裝aptamer的組別確實因為光熱而殺死癌細胞，而攜帶5FU的組別更因為藥物釋放後，對癌細胞株的毒殺力更甚，其次組裝隨機DNA序列(適體控制組)的金棒組別，則因不會與癌細胞黏附而對細胞的存活率毫無影響，證明整個實驗設計都有確實達到預期效果。
利用金奈米棒作為載體的智慧型標靶細胞選擇性藥物釋放的策略，透過適體的標靶減緩了過去因為化療而產生的副作用，利用近紅外光的局部照射而直接激發腫瘤部位，期許能夠做為癌症治療的新平台。

The rapid development of nanomedicine based theranostics has evolved toward practical clinical solutions. The gold nanorod conjugates provide adequate contrast for photoacoustic imaging and enabled photothermal therapy (PTT) to augment anti-cancer chemotherapy would achieve simultaneous diagnostics and therapeutics in one. In this study, we would like to develop an advanced theranostic platform based on gold nanorods modification. The photothemal effect can induce simultaneous drug and heat release to kill tumor cells in synergistic way.
The as synthesized gold nanorods present surface plasma resonance absorption at 800 nm. We then modified poly adenine nucleotides (poly-A) on rods surface for carrier anti-cancer drugs, 5-fluorouracil (5FU), and targeting moiety by self-assembly. In addition, an aptamer originally designed to target lung cancer cell was evaluated for oral cancer cell lines targeting and used in this platform. Successful conjugation of poly-A and the aptamer was revealed by spectrophotometric quantification of unbound nucleotides, which averaged 87.3 poly-As molecules and 7.4 aptamers per rod. The loading capacity of the nanorods for anti-cancer drug 5FU was found to be upwards of 74.4 %. The aptamer conjugated gold nanorods still significantly improved oral cancer cell targeting as evidenced by observation with fluorescence microscopy. In order to reduce cytotoxicity, we add polyethylene glycol (PEG) to replace remaining cetyltrimethylammonium bromide (CTAB). Without 5FU conjugation, the carrier rods alone showed favorable biocompatibility while targeting conjugation slightly promoted target cell toxicity. Cytotoxicity at 12 and 24 hours, revealing significantly improved toxicity to cancer cells with 5FU loaded after 24 hours but not in 12 hours, demonstrating the slow release of 5FU and augmentation of overall efficacy under such design.
The therapeutic effect with addition of NIR exposure showed that PTT significantly decrease cancer cell survival in the targeting group AuNR-ap9r with simultaneous chemotherapy (50% viability) then PTT alone (75% ). AuNR without NIR exposure did not cause cell damage at all. These results provide evidence for the synergistic effect of synchronized PTT and chemotherapy with NIR radiation as a trigger.
The strategy of nanorod theranostics provides an opportunity to integrate targeted photothermal and chemotherapy in one platform with prior molecular imaging validation of targeting efficiency and lesion localization. Such technology is anticipated to inspire advancement of oral cancer clinical disease management.

1. Collins, A., Nanotechnology cookbook: practical, reliable and jargon-free experimental procedures. 2012: Elsevier.
2. Drexler, K.E., Drexler and Smalley make the case for and against'molecular assemblers'. Chemical & Engineering News, 2003. 81(48): p. 1.
3. Saini, R., S. Saini, and S. Sharma, Nanotechnology: The future medicine. Journal of cutaneous and aesthetic surgery, 2010. 3(1): p. 32.
4. Buzea, C., I.I. Pacheco, and K. Robbie, Nanomaterials and nanoparticles: sources and toxicity. Biointerphases, 2007. 2(4): p. MR17-MR71.
5. Chauhan, V.P., et al., Delivery of molecular and nanoscale medicine to tumors: transport barriers and strategies. Annual review of chemical and biomolecular engineering, 2011. 2: p. 281-298.
6. Nagar, K., Nanotechnology: changes and challenges for world.
7. Peer, D., et al., Nanocarriers as an emerging platform for cancer therapy. Nature nanotechnology, 2007. 2(12): p. 751-760.
8. Alexis, F., et al., Nanoparticle technologies for cancer therapy, in Drug Delivery. 2010, Springer. p. 55-86.
9. Valencia, P.M., et al., Single-Step Assembly of Homogenous Lipid− Polymeric and Lipid− Quantum Dot Nanoparticles Enabled by Microfluidic Rapid Mixing. ACS nano, 2010. 4(3): p. 1671-1679.
10. Wagner, V., et al., The emerging nanomedicine landscape. Nature biotechnology, 2006. 24(10): p. 1211-1218.
11. Torchilin, V., Tumor delivery of macromolecular drugs based on the EPR effect. Advanced drug delivery reviews, 2011. 63(3): p. 131-135.
12. Byrne, J.D., T. Betancourt, and L. Brannon-Peppas, Active targeting schemes for nanoparticle systems in cancer therapeutics. Advanced drug delivery reviews, 2008. 60(15): p. 1615-1626.
13. Zhang, Z., J. Wang, and C. Chen, Gold nanorods based platforms for light-mediated theranostics. Theranostics, 2013. 3(3): p. 223.
14. Bonoiu, A.C., et al., Nanotechnology approach for drug addiction therapy: gene silencing using delivery of gold nanorod-siRNA nanoplex in dopaminergic neurons. Proceedings of the National Academy of Sciences, 2009. 106(14): p. 5546-5550.
15. Zarogoulidis, P., et al., Inhaled chemotherapy in lung cancer: future concept of nanomedicine. International journal of nanomedicine, 2012. 7: p. 1551.
16. DeBrosse, M.C., et al., High aspect ratio gold nanorods displayed augmented cellular internalization and surface chemistry mediated cytotoxicity. Mater Sci Eng C Mater Biol Appl, 2013. 33(7): p. 4094-100.
17. Murphy, C.J., et al., Anisotropic metal nanoparticles: synthesis, assembly, and optical applications. The Journal of Physical Chemistry B, 2005. 109(29): p. 13857-13870.
18. Kim, J.H., E.W. Hahn, and S.A. Ahmed, Combination hyperthermia and radiation therapy for malignant melanoma. Cancer, 1982. 50(3): p. 478-482.
19. Xu, Y.H., J. Bai, and J.-P. Wang, High-magnetic-moment multifunctional nanoparticles for nanomedicine applications. Journal of Magnetism and Magnetic Materials, 2007. 311(1): p. 131-134.
20. Rakha, E.A., et al., Prognostic markers in triple‐negative breast cancer. Cancer, 2007. 109(1): p. 25-32.
21. Dickerson, E.B., et al., Gold nanorod assisted near-infrared plasmonic photothermal therapy (PPTT) of squamous cell carcinoma in mice. Cancer letters, 2008. 269(1): p. 57-66.
22. Cox, B.T., et al., Two-dimensional quantitative photoacoustic image reconstruction of absorption distributions in scattering media by use of a simple iterative method. Applied optics, 2006. 45(8): p. 1866-1875.
23. Werning, J.W., Oral cancer: diagnosis, management, and rehabilitation. 2007: Thieme.
24. Lozano, R., et al., Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. The Lancet, 2013. 380(9859): p. 2095-2128.
25. Vermorken, J.B., et al., Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. New England Journal of Medicine, 2007. 357(17): p. 1695-1704.
26. Yao, C.-J., et al., Honokiol Eliminates human oral cancer stem-like cells accompanied with suppression of Wnt/β-Catenin signaling and apoptosis induction. Evidence-Based Complementary and Alternative Medicine, 2013. 2013.
27. Beder, L.B., et al., Genome-wide analyses on loss of heterozygosity in head and neck squamous cell carcinomas. Laboratory investigation, 2003. 83(1): p. 99-105.
28. Möckelmann, N., et al., Circulating tumor cells in head and neck cancer: clinical impact in diagnosis and follow-up. European Archives of Oto-Rhino-Laryngology, 2014. 271(1): p. 15-21.
29. Chummun, S., et al., Adenoid cystic carcinoma of the head and neck. British journal of plastic surgery, 2001. 54(6): p. 476-480.
30. Rowe, D.E., R.J. Carroll, and C.L. Day Jr, Prognostic factors for local recurrence, metastasis, and survival rates in squamous cell carcinoma of the skin, ear, and lip: implications for treatment modality selection. Journal of the American Academy of Dermatology, 1992. 26(6): p. 976-990.
31. Grégoire, V., et al., Squamous cell carcinoma of the head and neck: EHNS–ESMO–ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of oncology, 2010. 21(suppl 5): p. v184-v186.
32. Kawecki, A. and R. Krajewski, Follow-up in patients treated for head and neck cancer. memo-Magazine of European Medical Oncology, 2014: p. 1-5.
33. Manikantan, K., et al., Current concepts of surveillance and its significance in head and neck cancer. Annals of the Royal College of Surgeons of England, 2011. 93(8): p. 576.
34. Langendijk, J.A., et al., Impact of late treatment-related toxicity on quality of life among patients with head and neck cancer treated with radiotherapy. Journal of clinical oncology, 2008. 26(22): p. 3770-3776.
35. McGuirt, W.F., Panendoscopy as a screening examination for simultaneous primary tumors in head and neck cancer: a prospective sequential study and review of the literature. The Laryngoscope, 1982. 92(5): p. 569-576.
36. Blanco, F.J., C. Bernabéu, and T. Nagata, Alternative splicing in endothelial senescence. Role of the TGF-β coreceptor endoglin. InTech). Available from: http://www. intechopen. com/articles/show/title/alternative-splicing-in-endothelial-senescence-role-of-the-tgf-beta-co-receptor-endoglin, 2012.
37. Mitchell, D.H., G. Swift, and G.L. Gilbert, Surgical wound infection surveillance: the importance of infections that develop after hospital discharge. Australian and New Zealand journal of surgery, 1999. 69(2): p. 117-120.
38. Rock, C.L., et al., Nutrition and physical activity guidelines for cancer survivors. CA: a cancer journal for clinicians, 2012. 62(4): p. 242-274.
39. Siegel, R., et al., Cancer treatment and survivorship statistics, 2012. CA: a cancer journal for clinicians, 2012. 62(4): p. 220-241.
40. White, R.R., B.A. Sullenger, and C.P. Rusconi, Developing aptamers into therapeutics. Journal of Clinical Investigation, 2000. 106(8): p. 929-934.
41. Gopinath, S.C.B., Methods developed for SELEX. Analytical and bioanalytical chemistry, 2007. 387(1): p. 171-182.
42. Sefah, K., et al., Development of DNA aptamers using Cell-SELEX. Nature protocols, 2010. 5(6): p. 1169-1185.
43. Stoltenburg, R., C. Reinemann, and B. Strehlitz, SELEX—a (r) evolutionary method to generate high-affinity nucleic acid ligands. Biomolecular engineering, 2007. 24(4): p. 381-403.
44. Tombelli, S., M. Minunni, and M. Mascini, Analytical applications of aptamers. Biosensors and Bioelectronics, 2005. 20(12): p. 2424-2434.
45. Willner, I. and M. Zayats, Electronic Aptamer‐Based Sensors. Angewandte Chemie International Edition, 2007. 46(34): p. 6408-6418.
46. Ren, F., et al., Gold nanorods carrying paclitaxel for photothermal-chemotherapy of cancer. Bioconjug Chem, 2013. 24(3): p. 376-86.
47. Orendorff, C.J., et al., Aspect ratio dependence on surface enhanced Raman scattering using silver and gold nanorod substrates. Physical Chemistry Chemical Physics, 2006. 8(1): p. 165-170.
48. Choi, W.I., et al., Tumor regression in vivo by photothermal therapy based on gold-nanorod-loaded, functional nanocarriers. ACS nano, 2011. 5(3): p. 1995-2003.
49. Huang, X., et al., Gold nanoparticles: interesting optical properties and recent applications in cancer diagnostics and therapy. 2007.
50. Letsinger, R., et al., Use of a steroid cyclic disulfide anchor in constructing gold nanoparticle-oligonucleotide conjugates. Bioconjugate chemistry, 2000. 11(2): p. 289-291.
51. Li, Z., et al., Multiple thiol-anchor capped DNA–gold nanoparticle conjugates. Nucleic acids research, 2002. 30(7): p. 1558-1562.
52. Bhatt, N., et al., Dissociation and degradation of thiol-modified DNA on gold nanoparticles in aqueous and organic solvents. Langmuir, 2011. 27(10): p. 6132-6137.
53. Vigderman, L., B.P. Khanal, and E.R. Zubarev, Functional Gold Nanorods: Synthesis, Self‐Assembly, and Sensing Applications. Advanced Materials, 2012. 24(36): p. 4811-4841.
54. Nehl, C.L., H. Liao, and J.H. Hafner, Optical properties of star-shaped gold nanoparticles. Nano Letters, 2006. 6(4): p. 683-688.
55. Li, T.J., et al., In vivo anti-cancer efficacy of magnetite nanocrystal--based system using locoregional hyperthermia combined with 5-fluorouracil chemotherapy. Biomaterials, 2013. 34(32): p. 7873-83.
56. Wu, C.M., et al., Synthesis of Polynucleotide Modified Gold Nanoparticles as a High Potent Anti‐Cancer Drug Carrier. Journal of the Chinese Chemical Society, 2009. 56(4): p. 703-708.
57. Farokhzad, O.C., et al., Targeted nanoparticle-aptamer bioconjugates for cancer chemotherapy in vivo. Proceedings of the National Academy of Sciences, 2006. 103(16): p. 6315-6320.
58. Savla, R., et al., Tumor targeted quantum dot-mucin 1 aptamer-doxorubicin conjugate for imaging and treatment of cancer. Journal of Controlled Release, 2011. 153(1): p. 16-22.
59. Liu, Y., H. Miyoshi, and M. Nakamura, Nanomedicine for drug delivery and imaging: a promising avenue for cancer therapy and diagnosis using targeted functional nanoparticles. International Journal of Cancer, 2007. 120(12): p. 2527-2537.
60. Jayasena, S.D., Aptamers: an emerging class of molecules that rival antibodies in diagnostics. Clinical chemistry, 1999. 45(9): p. 1628-1650.
61. Hansen, J.A., et al., Quantum-dot/aptamer-based ultrasensitive multi-analyte electrochemical biosensor. Journal of the American Chemical Society, 2006. 128(7): p. 2228-2229.
62. Kim, Y., Z. Cao, and W. Tan, Molecular assembly for high-performance bivalent nucleic acid inhibitor. Proceedings of the National Academy of Sciences, 2008. 105(15): p. 5664-5669.
63. Takahashi, H., et al., Surface modification of gold nanorods using layer-by-layer technique for cellular uptake. Journal of Nanoparticle Research, 2008. 10(1): p. 221-228.
64. Kumar, A., B.M. Boruah, and X.-J. Liang, Gold nanoparticles: promising nanomaterials for the diagnosis of cancer and HIV/AIDS. Journal of Nanomaterials, 2011. 2011: p. 22.
65. Koren, A., H. Motaln, and T. Cufer, Lung cancer stem cells: a biological and clinical perspective. Cellular Oncology, 2013. 36(4): p. 265-275.
66. Wu, Y., Engineering Multifunctional Nucleic Acid Probes/nanomaterials for Cancer Studies, 2009, University of Florida.
67. Luo, S., et al., GRP78/BiP is required for cell proliferation and protecting the inner cell mass from apoptosis during early mouse embryonic development. Molecular and cellular biology, 2006. 26(15): p. 5688-5697.
68. Lemieux, J., Reducing chemotherapy-induced alopecia with scalp cooling. Clinical advances in hematology & oncology: H&O, 2012. 10(10): p. 681-682.
69. Müller, F., et al., Gender-specific elimination of continuous-infusional 5-fluorouracil in patients with gastrointestinal malignancies: results from a prospective population pharmacokinetic study. Cancer chemotherapy and pharmacology, 2013. 71(2): p. 361-370.
70. Cho, Y.W., J.-R. Lee, and S.-C. Song, Novel thermosensitive 5-fluorouracil-cyclotriphosphazene conjugates: Synthesis, thermosensitivity, degradability, and in vitro antitumor activity. Bioconjugate chemistry, 2005. 16(6): p. 1529-1535.
71. Zhu, G., et al., Self-assembled, aptamer-tethered DNA nanotrains for targeted transport of molecular drugs in cancer theranostics. Proceedings of the National Academy of Sciences, 2013. 110(20): p. 7998-8003.
72. Matcher, S.J., et al. Absolute quantification methods in tissue near-infrared spectroscopy. in Photonics West'95. 1995. International Society for Optics and Photonics.
73. Shadgan, B., et al., Wireless near-infrared spectroscopy of skeletal muscle oxygenation and hemodynamics during exercise and ischemia. Journal of Spectroscopy, 2009. 23(5-6): p. 233-241.
74. Myerson, R., et al., Simultaneous superficial hyperthermia and external radiotherapy: report of thermal dosimetry and tolerance to treatment. International journal of hyperthermia, 1999. 15(4): p. 251-266.
75. Choi, J., et al., Aptamer-conjugated gold nanorod for photothermal ablation of epidermal growth factor receptor-overexpressed epithelial cancer. Journal of biomedical optics, 2014. 19(5): p. 051203-051203.
76. Loo, C., et al., Immunotargeted nanoshells for integrated cancer imaging and therapy. Nano letters, 2005. 5(4): p. 709-711.
77. Chen, J., et al., Immuno gold nanocages with tailored optical properties for targeted photothermal destruction of cancer cells. Nano Letters, 2007. 7(5): p. 1318-1322.
78. Huang, X., et al., Cancer cell imaging and photothermal therapy in the near-infrared region by using gold nanorods. Journal of the American Chemical Society, 2006. 128(6): p. 2115-2120.
79. Huff, T.B., et al., Hyperthermic effects of gold nanorods on tumor cells. 2007.
80. Khlebtsov, B., et al., Optical amplification of photothermal therapy with gold nanoparticles and nanoclusters. Nanotechnology, 2006. 17(20): p. 5167.
81. Li, P.-C., et al., In vivo photoacoustic molecular imaging with simultaneous multiple selective targeting using antibody-conjugated gold nanorods. Optics Express, 2008. 16(23): p. 18605-18615.
82. Wust, P., et al., Hyperthermia in combined treatment of cancer. The lancet oncology, 2002. 3(8): p. 487-497.
83. Iwahashi, M., et al., Clinical evaluation of hepatic arterial infusion of low dose-CDDP and 5-FU with hyperthermotherapy: a preliminary study for liver metastases from esophageal and gastric cancer. Hepato-gastroenterology, 1998. 46(28): p. 2504-2510.