在本篇研究中，我們設計新的負電型奈米載體結構：藉著將雙股去氧核醣核酸(Deoxyribonucleic acid，DNA)修飾在金奈米棒表面作為攜帶雙重抗癌藥物鉑的前驅藥物(Pt(IV)-prodrug)和艾黴素(Doxorubicin，Dox)的載體，其中Pt(IV)-prodrug經由化學共價鍵接在雙股DNA的尾端，而Dox則是利用非共價鍵嵌入於雙股DNA的鹼基對間。由於此奈米載體與細胞膜表面皆帶負電，因此在靜電排斥力的作用之下，攜帶藥物的奈米載體並不會被正常細胞攝入，因而不會對正常細胞造成傷害，然而當以近紅外光雷射照射時，具高效率光熱轉換性質的金奈米棒便可以使表面對熱敏感的的雙股DNA受熱使兩股序列解旋，釋放出來Pt(IV)-prodrug與Dox分子在被癌細胞攝入後即可達到治療的效果。此一同時攜帶雙重抗癌藥物的奈米載體，經由釋放出來的Pt(IV)-prodrug和Dox分子間的協同作用(synergism)之下能夠大幅的提升對於癌細胞的毒殺效果。這些結果顯示雙股DNA修飾之金奈米棒能夠利用材料不會被細胞攝入的性質並搭配近紅外光雷射對於藥物的控制釋放，以減少化療藥物對於正常細胞產生的副作用而達到具選擇性的治療效果，並且在雙重抗癌藥物的作用之下能夠顯著的提升癌細胞的治療效率。

In the present study, we conjugated the thermosensitive double helices DNA on gold nanorods to demonstrate codelivery of drug and prodrug. The antineoplastic drugs Pt(IV)-prodrug and doxorubicin (Dox) were loaded to the double-stranded DNA by covalent bonding and non-covalent intercalation respectively. Since both the nanoplatform and the surface of the cell are negatively charged, the nanoplatform will not be uptaken by cells. Whereas upon the irradiation of near-infrared laser at the target site, such as malignant cells, the double-stranded DNA dehybridize to release Pt(IV)-prodrug and doxorubicin due to the photothermal conversion of gold nanorods. This codelivery of Pt(IV)-prodrug and doxorubicin with single nanocarriers promise both the drugs available at cell level. Hence, the cytotoxicity to A549 and MCF-7 cancer cell lines increase dramatically. These results indicate that the Pt(IV)/Dox-dsDNA-Au NRs nanoplatform can release the drug at target site to evade the damages to normal cells and offer high therapeutic efficiency via synergism.

1. Alivisatos, A. P., Semiconductor clusters, nanocrystals, and quantum dots. Science 1996,
271 (5251), 933-937.
2. Stewart, M. E.; Anderton, C. R.; Thompson, L. B.; Maria, J.; Gray, S. K.; Rogers, J. A.;
Nuzzo, R. G., Nanostructured plasmonic sensors. Chem. Rew. 2008, 108 (2),
494-521.
3. Lin, Y. S.; Wu, S. H.; Hung, Y.; Chou, Y. H.; Chang, C.; Lin, M. L.; Tsai, C. P.; Mou, C.
Y., Multifunctional composite nanoparticles: Magnetic, luminescent, and mesoporous.
Chem. Mat. 2006, 18 (22), 5170-5172.
4. Wang, Z. L.; Petroski, J. M.; Green, T. C.; El-Sayed, M. A., Shape transformation and
surface melting of cubic and tetrahedral platinum nanocrystals. J. Phys. Chem. B 1998,
102 (32), 6145-6151.
5. 王崇人, 神奇的奈米科學. 科學發展月刊 2002, 354, 48.
6. 張立德, 奈米材料. 2002.
7. Memming, R., Semiconductor Electrochemistry. 2001, 264.
8. Huang, X. H.; Neretina, S.; El-Sayed, M. A., Gold Nanorods: From Synthesis and
Properties to Biological and Biomedical Applications. Adv. Mater. 2009, 21 (48),
4880-4910.
9. Jain, P. K.; El-Sayed, M. A., Noble metal nanoparticle pairs: effect of medium for
enhanced nanosensing. Nano lett. 2008, 8 (12), 4347-52.
10. Weissleder, R., A clearer vision for in vivo imaging. Nat. Biotechnol. 2001, 19 (4),
316-7.
11. Wijaya, A.; Schaffer, S. B.; Pallares, I. G.; Hamad-Schifferli, K., Selective release of
multiple DNA oligonucleotides from gold nanorods. ACS Nano 2009, 3 (1), 80-6.
12. Chen, C. C.; Lin, Y. P.; Wang, C. W.; Tzeng, H. C.; Wu, C. H.; Chen, Y. C.; Chen, C. P.;
Chen, L. C.; Wu, Y. C., DNA-gold nanorod conjugates for remote control of localized
gene expression by near infrared irradiation. J. Am. Chem. Soc.2006, 128 (11),
3709-3715.
13. Lee, S. E.; Liu, G. L.; Kim, F.; Lee, L. P., Remote optical switch for localized and
selective control of gene interference. Nano lett. 2009, 9 (2), 562-70.
14. Martin, C. R., Nanomaterials - a Membrane-Based Synthetic Approach. Science 1994,
266 (5193), 1961-1966.
15. Martin, C. R., Membrane-based synthesis of nanomaterials. Chem. Mat. 1996, 8 (8),
1739-1746.
16. Billot, L.; de la Chapelle, M. L.; Grimault, A. S.; Vial, A.; Barchiesi, D.; Bijeon, J. L.;
Adam, P. M.; Royer, P., Surface enhanced Raman scattering on gold nanowire arrays:
Evidence of strong multipolar surface plasmon resonance enhancement. Chem. Phys.
Lett. 2006, 422 (4-6), 303-307.
17. Cubukcu, E.; Kort, E. A.; Crozier, K. B.; Capasso, F., Plasmonic laser antenna. Appl.
Phys. Lett. 2006, 89 (9).
18. Smythe, E. J.; Cubukcu, E.; Capasso, F., Optical properties of surface plasmon
resonances of coupled metallic nanorods. Opt. express 2007, 15 (12), 7439-7447.
19. Taub, N.; Krichevski, O.; Markovich, G., Growth of gold nanorods on surfaces. J. Phys.Chem. B 2003, 107 (42), 11579-11582.
20. Reetz, M. T.; Helbig, W., Size-Selective Synthesis of Nanostructured Transition-Metal
Clusters. J. Am. Chem. Soc. 1994, 116 (16), 7401-7402.
21. Yu, Y. Y.; Chang, S. S.; Lee, C. L.; Wang, C. R. C., Gold nanorods: Electrochemical
synthesis and optical properties. J. Phys. Chem. B 1997, 101 (34), 6661-6664.
22. Chang, S. S.; Shih, C. W.; Chen, C. D.; Lai, W. C.; Wang, C. R. C., The shape
transition of gold nanorods. Langmuir 1999, 15 (3), 701-709.
23. Jana, N. R., Gram-scale synthesis of soluble, near-monodisperse gold nanorods and
other anisotropic nanoparticles. Small 2005, 1 (8-9), 875-882.
24. Zijlstra, P.; Bullen, C.; Chon, J. W. M.; Gu, M., High-temperature seedless synthesis of
gold nanorods. J. Phys. Chem. B 2006, 110 (39), 19315-19318.
25. Jana, N. R.; Gearheart, L.; Murphy, C. J., Evidence for seed-mediated nucleation in the
chemical reduction of gold salts to gold nanoparticles. Chem. Mat. 2001, 13 (7),
2313-2322.
26. Jana, N. R.; Gearheart, L.; Murphy, C. J., Seeding growth for size control of 5-40 nm
diameter gold nanoparticles. Langmuir 2001, 17 (22), 6782-6786.
27. Nikoobakht, B.; El-Sayed, M. A., Preparation and growth mechanism of gold nanorods
(NRs) using seed-mediated growth method. Chem. Mat. 2003, 15 (10), 1957-1962.
28. Murphy, C. J.; San, T. K.; Gole, A. M.; Orendorff, C. J.; Gao, J. X.; Gou, L.; Hunyadi,
S. E.; Li, T., Anisotropic metal nanoparticles: Synthesis, assembly, and optical
applications. J. Phys. Chem. B 2005, 109 (29), 13857-13870.
29. Johnson, C. J.; Dujardin, E.; Davis, S. A.; Murphy, C. J.; Mann, S., Growth and form of
gold nanorods prepared by seed-mediated, surfactant-directed synthesis. J. Mater.
Chem.2002, 12 (6), 1765-1770.
30. Perez-Juste, J.; Liz-Marzan, L. M.; Carnie, S.; Chan, D. Y. C.; Mulvaney, P.,
Electric-field-directed growth of gold nanorods in aqueous surfactant solutions. Adv.
Funct. Mater. 2004, 14 (6), 571-579.
31. Jana, N. R.; Gearheart, L.; Murphy, C. J., Seed-mediated growth approach for
shape-controlled synthesis of spheroidal and rod-like gold nanoparticles using a
surfactant template. Adv. Mater. 2001, 13 (18), 1389-1393.
32. Alkilany, A. M.; Thompson, L. B.; Boulos, S. P.; Sisco, P. N.; Murphy, C. J., Gold
nanorods: Their potential for photothermal therapeutics and drug delivery, tempered by
the complexity of their biological interactions. Adv. Drug. Deliv. Rev. 2012, 64 (2),
190-199.
33. von Maltzahn, G.; Park, J. H.; Agrawal, A.; Bandaru, N. K.; Das, S. K.; Sailor, M. J.;
Bhatia, S. N., Computationally Guided Photothermal Tumor Therapy Using
Long-Circulating Gold Nanorod Antennas. Cancer res. 2009, 69 (9), 3892-3900.
34. Connor, E. E.; Mwamuka, J.; Gole, A.; Murphy, C. J.; Wyatt, M. D., Gold nanoparticles
are taken up by human cells but do not cause acute cytotoxicity. Small 2005, 1 (3),
325-327.
35. Niidome, T.; Yamagata, M.; Okamoto, Y.; Akiyama, Y.; Takahashi, H.; Kawano, T.;
Katayama, Y.; Niidome, Y., PEG-modified gold nanorods with a stealth character for in
vivo applications. J. Control. Release 2006, 114 (3), 343-347.
36. Dujardin, E.; Hsin, L. B.; Wang, C. R. C.; Mann, S., DNA-driven self-assembly of gold
nanorods. Chem. Commun. 2001, (14), 1264-1265.
37. Huff, T. B.; Tong, L.; Zhao, Y.; Hansen, M. N.; Cheng, J. X.; Wei, A., Hyperthermic
effects of gold nanorods on tumor cells. Nanomedicine 2007, 2 (1), 125-132.
38. Yu, C. X.; Varghese, L.; Irudayaraj, J., Surface modification of
cetyltrimethylammonium bromide-capped gold nanorods to make molecular probes.
Langmuir 2007, 23 (17), 9114-9119.
39. Pissuwan, D.; Valenzuela, S. M.; Killingsworth, M. C.; Xu, X. D.; Cortie, M. B.,
Targeted destruction of murine macrophage cells with bioconjugated gold nanorods. J.
Nanopart. Res. 2007, 9 (6), 1109-1124.
40. Hauck, T. S.; Ghazani, A. A.; Chan, W. C. W., Assessing the effect of surface chemistry
on gold nanorod uptake, toxicity, and gene expression in mammalian cells. Small 2008,
4 (1), 153-159.
41. Gole, A.; Murphy, C. J., Polyelectrolyte-coated gold nanorods: Synthesis,
characterization and immobilization. Chem Mat. 2005, 17 (6), 1325-1330.
42. Grabinski, C.; Schaeublin, N.; Wijaya, A.; D'Couto, H.; Baxamusa, S. H.;
Hamad-Schifferli, K.; Hussain, S. M., Effect of Gold Nanorod Surface Chemistry on
Cellular Response. ACS Nano 2011, 5 (4), 2870-2879.
43. Sendroiu, I. E.; Warner, M. E.; Corn, R. M., Fabrication of Silica-Coated Gold
Nanorods Functionalized with DNA for Enhanced Surface Plasmon Resonance
Imaging Biosensing Applications. Langmuir 2009, 25 (19), 11282-11284.
44. Zhang, Z. J.; Wang, L. M.; Wang, J.; Jiang, X. M.; Li, X. H.; Hu, Z. J.; Ji, Y. H.; Wu, X.
C.; Chen, C. Y., Mesoporous Silica-Coated Gold Nanorods as a Light-Mediated
Multifunctional Theranostic Platform for Cancer Treatment. Adv. Mater. 2012, 24 (11),
1418-1423.
45. Huang, X. H.; El-Sayed, I. H.; Qian, W.; El-Sayed, M. A., Cancer cell imaging and
photothermal therapy in the near-infrared region by using gold nanorods. J.
Am. Chem. Soc. 2006, 128 (6), 2115-2120.
46. Orendorff, C. J.; Baxter, S. C.; Goldsmith, E. C.; Murphy, C. J., Light scattering from
gold nanorods: tracking material deformation. Nanotechnology 2005, 16 (11),
2601-2605.
47. Zhu, J.; Huang, L. Q.; Zhao, J. W.; Wang, Y. C.; Zhao, Y. R.; Hao, L. M.; Lu, Y. M.,
Shape dependent resonance light scattering properties of gold nanorods. Mat Sci Eng
B-Solid 2005, 121 (3), 199-203.
48. Bao, P.; Frutos, A. G.; Greef, C.; Lahiri, J.; Muller, U.; Peterson, T. C.; Warden, L.;Xie,
X. Y., High-sensitivity detection of DNA hybridization on microarrays using resonance
light scattering. Anal. chem. 2002, 74 (8), 1792-1797.
49. Dvorak, H. F.; Nagy, J. A.; Dvorak, J. T.; Dvorak, A. M., Identification and
Characterization of the Blood-Vessels of Solid Tumors That Are Leaky to Circulating
Macromolecules. Am J Pathol 1988, 133 (1), 95-109.
50. Peer, D.; Karp, J. M.; Hong, S.; FaroKHzad, O. C.; Margalit, R.; Langer, R.,
Nanocarriers as an emerging platform for cancer therapy. Nat. nanotechnol. 2007,
2 (12), 751-760.
51. Hu, K. W.; Hsu, K. C.; Yeh, C. S., pH-Dependent biodegradable silica nanotubes
derived from Gd(OH)(3) nanorods and their potential for oral drug delivery and MR
imaging. Biomaterials 2010, 31 (26), 6843-6848.
52. Liu, T. Y.; Liu, K. H.; Liu, D. M.; Chen, S. Y.; Chen, I. W., Temperature-Sensitive
Nanocapsules for Controlled Drug Release Caused by Magnetically Triggered
Structural Disruption. Adv. Funct. Mater. 2009, 19 (4), 616-623.
53. Choi, S. K.; Thomas, T.; Li, M. H.; Kotlyar, A.; Desai, A.; Baker, J. R.,
Light-controlled release of caged doxorubicin from folate receptor-targeting PAMAM
dendrimer nanoconjugate. Chem. Commun. 2010, 46 (15), 2632-2634.
54. Jain, P. K.; Lee, K. S.; El-Sayed, I. H.; El-Sayed, M. A., Calculated absorption and
scattering properties of gold nanoparticles of different size, shape, and composition:
Applications in biological imaging and biomedicine. J. Phys. Chem. B 2006, 110 (14),
7238-7248.
55. Wijaya, A.; Schaffer, S. B.; Pallares, I. G.; Hamad-Schifferli, K., Selective Release of
Multiple DNA Oligonucleotides from Gold Nanorods. ACS Nano 2009, 3 (1), 80-86.
56. Wei, Q. S.; Ji, J.; Shen, J. C., Synthesis of near-infrared responsive gold
nanorod/PNIPAAm core/shell nanohybrids via surface initiated ATRP for smart drug
delivery. Macromol. Rapid Comm. 2008, 29 (8), 645-650.
57. Agarwal, A.; Mackey, M. A.; El-Sayed, M. A.; Bellamkonda, R. V., Remote Triggered
Release of Doxorubicin in Tumors by Synergistic Application of Thermosensitive
Liposomes and Gold Nanorods. ACS Nano 2011, 5 (6), 4919-4926.
58. Lee, S. E.; Liu, G. L.; Kim, F.; Lee, L. P., Remote Optical Switch for Localized and
Selective Control of Gene Interference. Nano lett. 2009, 9 (2), 562-570.
59. Kuo, W. S.; Chang, C. N.; Chang, Y. T.; Yang, M. H.; Chien, Y. H.; Chen, S. J.; Yeh, C.
S., Gold Nanorods in Photodynamic Therapy, as Hyperthermia Agents, and in
Near-Infrared Optical Imaging. Angew. Chem. Int. Edit. 2010, 49 (15), 2711-2715.
60. Kuo, W. S.; Chang, C. N.; Chang, Y. T.; Yeh, C. S., Antimicrobial gold nanorods with
dual-modality photodynamic inactivation and hyperthermia. Chem. Commun. 2009,
(32), 4853-4855.
61. Jang, B.; Park, J. Y.; Tung, C. H.; Kim, I. H.; Choi, Y., Gold Nanorod-Photosensitizer
Complex for Near-Infrared Fluorescence Imaging and Photodynamic/Photothermal
Therapy In Vivo. ACS Nano 2011, 5 (2), 1086-1094.
62. Xiao, W.; Chen, W. H.; Xu, X. D.; Li, C.; Zhang, L.; Zhuo, R. X.; Zhang, X. Z., Design
of a Cellular-Uptake-Shielding "Plug and Play" Template for Photo Controllable Drug
Release. Adv. Mater. 2011, 23 (31), 3526-+.
63. Martoni, A. B., A.; Canova, N.; Pannuti, F., Four-Year Analysis of Platinum and
Anthracycline Combination for Ovarian Cancer. Oncology 1989, 46 (2), 109-116.
64. Nielsen, D.; Dombernowsky, P.; Larsen, S. K.; Hansen, O. P.; Skovsgaard, T.,
Epirubicin or epirubicin and cisplatin as first-line therapy in advanced breast cancer. A
phase III study. Cancer Chemoth. Pharm. 2000, 46 (6), 459-466.
65. Thigpen, J. T.; Brady, M. F.; Homesley, H. D.; Malfetano, J.; DuBeshter, B.; Burger, R.
A.; Liao, S., Phase III trial of doxorubicin with or without cisplatin in advanced
endometrial carcinoma: A gynecologic oncology group study. Journal of Clinical
Oncology 2004, 22 (19), 3902-3908.
66. Lee, S. M.; O'Halloran, T. V.; Nguyen, S. T., Polymer-Caged Nanobins for Synergistic
Cisplatin-Doxorubicin Combination Chemotherapy. J. Am. Chem. Soc. 2010, 132 (48),
17130-17138.
67. Hurst, S. J.; Lytton-Jean, A. K. R.; Mirkin, C. A., Maximizing DNA loading on a range
of gold nanoparticle sizes. Anal. chem. 2006, 78 (24), 8313-8318.
68. Johnsson, B.; Lofas, S.; Lindquist, G., Immobilization of Proteins to a
Carboxymethyldextran-Modified Gold Surface for Biospecific Interaction Analysis in
Surface-Plasmon Resonance Sensors. Anal. biochem. 1991, 198 (2), 268-277.
69. Demers, L. M.; Mirkin, C. A.; Mucic, R. C.; Reynolds, R. A.; Letsinger, R. L.;
Elghanian, R.; Viswanadham, G., A fluorescence-based method for determining the
surface coverage and hybridization efficiency of thiol-capped oligonucleotides bound
to gold thin films and nanoparticles. Anal. chem. 2000, 72 (22), 5535-5541.
70. Storhoff, J. J.; Elghanian, R.; Mucic, R. C.; Mirkin, C. A.; Letsinger, R. L., One-pot
colorimetric differentiation of polynucleotides with single base imperfections using
gold nanoparticle probes. J. Am. Chem. Soc. 1998, 120 (9), 1959-1964.
71. Zhao, W. T.; Lee, T. M. H.; Leung, S. S. Y.; Hsing, I. M., Tunable stabilization of gold
nanoparticles in aqueous solutions by mononucleotides. Langmuir 2007, 23 (13), 7143-7147.
72. Ihmels, H.; Otto, D., Intercalation of organic dye molecules into double-stranded DNA
general principles and recent developments. Top. Curr. Chem. 2005, 258, 161-204.
73. Cashman, D. J.; Scarsdale, J. N.; Kellogg, G. E., Hydropathic analysis of the free
energy differences in anthracycline antibiotic binding to DNA. Nucleic acids res.
2003, 31 (15), 4410-4416.
74. Bailly, C.; Suh, D.; Waring, M. J.; Chaires, J. B., Binding of daunomycin to
diaminopurine- and/or inosine-substituted DNA. Biochemistry 1998, 37 (4),1033-1045.
75. Alexander, C. M.; Maye, M. M.; Dabrowiak, J. C., DNA-capped nanoparticles
designed for doxorubicin drug delivery. Chem. Commun. 2011, 47 (12), 3418-3420.
76. Bagalkot, V.; Farokhzad, O. C.; Langer, R.; Jon, S., An aptamer-doxorubicin physical
conjugate as a novel targeted drug-delivery platform. Angew. Chem. Int. Edit. 2006, 45
(48), 8149-8152.
77. Kim, D.; Jeong, Y. Y.; Jon, S., A Drug-Loaded Aptamer-Gold Nanoparticle
Bioconjugate for Combined CT Imaging and Therapy of Prostate Cancer. ACS Nano
2010, 4 (7), 3689-3696.
78. Yang, J.; Lee, J.; Kang, J.; Oh, S. J.; Ko, H. J.; Son, J. H.; Lee, K.; Suh, J. S.; Huh, Y.
M.; Haam, S., Smart Drug-Loaded Polymer Gold Nanoshells for Systemic and
Localized Therapy of Human Epithelial Cancer. Adv. Mater. 2009, 21 (43), 4339-4342.
79. Schneider, Y. J.; Baurain, R.; Zenebergh, A.; Trouet, A., DNA-Binding Parameters of
Daunorubicin and Doxorubicin in the Conditions Used for Studying the Interaction of
Anthracycline-DNA Complexes with Cells Invitro. Cancer Chemoth. Pharm. 1979, 2
(1),7-10.
80. Goldberg, S. N.; Gazelle, G. S.; Mueller, P. R., Thermal ablation therapy for focal
malignancy: A unified approach to underlying principles, techniques, and diagnostic
imaging guidance. Am. J. Roentgenol. 2000, 174 (2), 323-331.
81. Min, Y. Z.; Mao, C. Q.; Xu, D. C.; Wang, J.; Liu, Y. Z., Gold nanorods for platinum
based prodrug delivery. Chem. Commun. 2010, 46 (44), 8424-8426.
82. Hall, M. D.; Amjadi, S.; Zhang, M.; Beale, P. J.; Hambley, T. W., The mechanism of
action of platinum(IV) complexes in ovarian cancer cell lines. J. Inorg.
biochem. 2004, 98 (10), 1614-1624.
83. Meschini, S.; Marra, M.; Calcabrini, A.; Monti, E.; Gariboldi, M.; Dolfini, E.; Arancia,
G., Role of the lung resistance-related protein (LRP) in the drug sensitivity of cultured
tumor cells. Toxicol. Vitro 2002, 16 (4), 389-398.