本研究為設計一具磁場響應之生物相容性藥物載體模型，利用電源供應器搭配訊號產生器產生之交替電流訊號並透過線圈驅動電路放大電流訊號後，再配合電流產生磁場之原理，使用交變磁場來誘導具磁性之奈米粒子之磁響應行為，進而控制藥物之釋放。利用共沉澱法將四氧化三鐵沉積至聚苯乙烯奈米粒子表面；再透過多巴胺溶液自發氧化聚合至四氧化三鐵-聚苯乙烯奈米粒子模板上，接著利用THF蝕刻聚苯乙烯得到聚多巴胺-四氧化三鐵中空粒子。透過無乳化劑聚合法來合成粒徑均一之聚苯乙烯奈米粒子，而調整苯乙烯單體濃度可獲得不同大小之聚苯乙烯奈米粒子。
利用親水性藥劑羅丹明B (Rhodamine B, RhB)、疏水性藥劑尼羅紅(Nile Red)與抗癌藥物DOX進行載體裝載率、包覆率，其中使用0.5mg DOX，載體可包覆約0.46mg之藥量，而最佳裝載率約為18%；利用RhB進行釋放測試，探討不同頻率與磁場下之藥物釋放，找到最佳之粒子磁響應條件，利用磁場控制可做穩定且緩慢之藥物釋放系統，五天緩慢釋約有74%之釋放量，相較於無磁場控制釋放下，總釋放量多出約30%。
將四氧化三鐵-聚多巴胺中空粒子與HCT-116大腸癌細胞共培養，藉由CCK-8證明中空粒子之無毒性以及CLSM觀察細胞攝取載體之螢光影像，再藉由施加交變磁場觀察細胞中藥物釋放的效果，以CCK-8以及細胞分選比較磁場有無之細胞活性，其中磁場控制釋放下其細胞存活率較無磁場之存活率低30%，顯示磁場控制藥物釋放之可行性。
本篇研究成功製備出具有磁場響應之藥物載體模型，能透過交變磁場誘導改變四氧化三鐵-聚多巴胺中空粒子與藥物之相對移動位置來控制藥物釋放。磁場響應藥物運送系統能夠於特定的部位和時間釋放，未來於藥物運送系統具有相當之潛力。

In this study, we designed a biocompatible drug carrier model with magnetic field response system. The alternating current signal generated by a power supply and a signal generator is further amplified through a coil drive circuit, and then by using the principle of generating a magnetic field with the current, the demand drug is released. Polydopamine hollow magnetic nanoparticles (PDA@Fe3O4 h-NPs) were synthesized by using co-precipitation method, and Fe3O4 was deposited onto polystyrene nanoparticles template (PS NPs); and the spontaneous oxidative polymerization of dopamine solution was placed onto polystyrene nanoparticles adsorbed Fe3O4 (PS@Fe3O4 NPs), followed by removal of the template. By using emulsifier-free polymerization method, we can make identical size of polystyrene nanoparticles; by adjusting the concentration of styrene monomer, we can obtain different size of polystyrene nanoparticles.
Loading content and encapsulation efficiency were carried out by using hydrophilic agent Rhodamine B (RhB), hydrophobic agent Nile Red and anti-cancer drug (DOX). Among them, 0.5mg DOX was used, and the carrier could be encapsulated about 0.46mg of drug. The best loading capacity is about 18%. Using RhB for release test, the drug was released under different frequencies and magnetic fields, and the best magnetic response conditions were found. The magnetic field control could be used as a stable and slow drug release system, which have 74% drug release for five days. Its total released amount was 30% more than that of no magnetic field control.
The PDA@Fe3O4 h-NPs were co-cultured with HCT-116 cell. We used CCK-8 assay to prove that PDA@Fe3O4 h-NPs were non-toxic polymer. We observed the cellular uptake and the effect of drug release under the electric-field from CLSM image. Also we used CCK-8 assay and cell sorter to compare cell viability with and without a magnetic field, and the cell survival rate under magnetic field control is 30% lower than that of without magnetic field, which showed the feasibility of magnetic field to control drug release.
In these results, a drug carrier model with a magnetic field response was successfully prepared, which could be controlled by the alternating magnetic field for drug releasing. The drug delivery system represents an effective method for attaining spatiotemporal control of drug release at the desired site.

1. Ghosh Chaudhuri, R. and S. Paria, Core/shell nanoparticles: classes, properties, synthesis mechanisms, characterization, and applications. Chemical reviews, 2012. 112(4): p. 2373-2433.
2. Uhrich, K.E., et al., Polymeric systems for controlled drug release. Chemical Reviews-Columbus, 1999. 99(11): p. 3181-3198.
3. Zhao, L., et al., Nanoparticle vaccines. Vaccine, 2014. 32(3): p. 327-37.
4. Chen, G., et al., Nanochemistry and Nanomedicine for Nanoparticle-based Diagnostics and Therapy. Chem Rev, 2016. 116(5): p. 2826-85.
5. Mura, S., J. Nicolas, and P. Couvreur, Stimuli-responsive nanocarriers for drug delivery. Nature materials, 2013. 12(11): p. 991-1003.
6. Sharma, R., et al., Polymer nanotechnology based approaches in mucosal vaccine delivery: challenges and opportunities. Biotechnol Adv, 2015. 33(1): p. 64-79.
7. Zhang, J. and H. Liu, A novel approach to preparing polystyrene/Fe 3 O 4 multihollow microspheres with porous walls. Colloid and Polymer Science, 2016. 294(11): p. 1755-1763.
8. Hossen, S., et al., Smart nanocarrier-based drug delivery systems for cancer therapy and toxicity studies: A review. J Adv Res, 2019. 15: p. 1-18.
9. Zhou, J., et al., Synthesis of porous magnetic hollow silica nanospheres for nanomedicine application. The Journal of Physical Chemistry C, 2007. 111(47): p. 17473-17477.
10. Liu, S., et al., Magnetically separable and recyclable Fe3O4–polydopamine hybrid hollow microsphere for highly efficient peroxidase mimetic catalysts. Journal of colloid and interface science, 2016. 469: p. 69-77.
11. Zhong, X., et al., Polydopamine as a Biocompatible Multifunctional Nanocarrier for Combined Radioisotope Therapy and Chemotherapy of Cancer. Advanced Functional Materials, 2015. 25(47): p. 7327-7336.
12. Peng, S. and S. Sun, Synthesis and characterization of monodisperse hollow Fe3O4 nanoparticles. Angewandte Chemie, 2007. 119(22): p. 4233-4236.
13. Ding, Y., et al., Polymer–monomer pairs as a reaction system for the synthesis of magnetic Fe3O4–polymer hybrid hollow nanospheres. Angewandte Chemie, 2004. 116(46): p. 6529-6532.
14. Yang, L., et al., A facile “polystyrene-dissolving” strategy to hollow periodic mesoporous organosilica with flexible structure-tailorability. Microporous and Mesoporous Materials, 2017. 239: p. 173-179.
15. Fu, X., X. He, and Y. Wang, Facile preparation of silica hollow microspheres by precipitation-phase separation method. Colloids and Surfaces A: Physicochemical and Engineering Aspects, 2011. 380(1-3): p. 241-249.
16. Wen, R., et al., Nanoparticle systems for cancer vaccine. Nanomedicine, 2019. 14(5): p. 627-648.
17. Zhao, L., et al., Nanoparticle vaccines. Vaccine, 2014. 32(3): p. 327-337.
18. Das, S.S., et al., Stimuli-responsive polymeric nanocarriers for drug delivery, imaging, and theragnosis. Polymers, 2020. 12(6): p. 1397.
19. Majumder, J. and T. Minko, Multifunctional and stimuli-responsive nanocarriers for targeted therapeutic delivery. Expert Opinion on Drug Delivery, 2021. 18(2): p. 205-227.
20. Alsehli, M., Polymeric nanocarriers as stimuli-responsive systems for targeted tumor (cancer) therapy: Recent advances in drug delivery. Saudi Pharmaceutical Journal, 2020. 28(3): p. 255-265.
21. Al-Ahmady, Z.S., et al., Lipid–Peptide Vesicle Nanoscale Hybrids for Triggered Drug Release by Mild Hyperthermia in Vitro and in Vivo. ACS Nano, 2012. 6(10): p. 9335-9346.
22. Chen, K.-J., et al., A Thermoresponsive Bubble-Generating Liposomal System for Triggering Localized Extracellular Drug Delivery. ACS Nano, 2013. 7(1): p. 438-446.
23. Yoo, J.-W., N. Doshi, and S. Mitragotri, Adaptive micro and nanoparticles: temporal control over carrier properties to facilitate drug delivery. Advanced drug delivery reviews, 2011. 63(14-15): p. 1247-1256.
24. Rizwanullah, M., et al., Phytochemical based nanomedicines against cancer: current status and future prospects. Journal of drug targeting, 2018. 26(9): p. 731-752.
25. Chen, Z., et al., Dual enzyme-like activities of iron oxide nanoparticles and their implication for diminishing cytotoxicity. Acs Nano, 2012. 6(5): p. 4001-4012.
26. Thomas, C.R., et al., Noninvasive Remote-Controlled Release of Drug Molecules in Vitro Using Magnetic Actuation of Mechanized Nanoparticles. Journal of the American Chemical Society, 2010. 132(31): p. 10623-10625.
27. Ruiz-Hernández, E., A. Baeza, and M. Vallet-Regí, Smart Drug Delivery through DNA/Magnetic Nanoparticle Gates. ACS Nano, 2011. 5(2): p. 1259-1266.
28. Li, L., W.-W. Yang, and D.-G. Xu, Stimuli-responsive nanoscale drug delivery systems for cancer therapy. Journal of drug targeting, 2019. 27(4): p. 423-433.
29. Rapoport, N.Y., et al., Controlled and targeted tumor chemotherapy by ultrasound-activated nanoemulsions/microbubbles. J Control Release, 2009. 138(3): p. 268-76.
30. Khandare, J.J., et al., Dendrimer versus linear conjugate: influence of polymeric architecture on the delivery and anticancer effect of paclitaxel. Bioconjugate chemistry, 2006. 17(6): p. 1464-1472.
31. Schroeder, A., et al., Remotely activated protein-producing nanoparticles. Nano Lett, 2012. 12(6): p. 2685-9.
32. Xiao, Z., et al., DNA self-assembly of targeted near-infrared-responsive gold nanoparticles for cancer thermo-chemotherapy. Angew Chem Int Ed Engl, 2012. 51(47): p. 11853-7.
33. Li, N., et al., A Near‐Infrared Light‐Triggered Nanocarrier with Reversible DNA Valves for Intracellular Controlled Release. Advanced Functional Materials, 2013. 23(18): p. 2255-2262.
34. Ge, J., et al., Drug Release from Electric-Field-Responsive Nanoparticles. ACS Nano, 2012. 6(1): p. 227-233.
35. Yan, Q., et al., Voltage-Responsive Vesicles Based on Orthogonal Assembly of Two Homopolymers. Journal of the American Chemical Society, 2010. 132(27): p. 9268-9270.
36. Fitch, R.M., M.B. Prenosil, and K.J. Sprick. The mechanism of particle formation in polymer hydrosols. I. kinetics of aqueous polymerization of methyl methacrylate. in Journal of Polymer Science Part C: Polymer Symposia. 1969. Wiley Online Library.
37. Harkins, W.D., A General Theory of the Mechanism of Emulsion Polymerization1. Journal of the American Chemical Society, 1947. 69(6): p. 1428-1444.
38. Li, Y., T. Kunitake, and S. Fujikawa, Efficient Fabrication of Large, Robust Films of 3D-ordered Polystyrene Latex. Colloids and Surfaces A: Physicochem. Eng. Aspects, 2006. 275: p. 209-217.
39. Fu, Y., et al., Self-assembly of Polystyrene Sphere Colloidal Crystals by in Situ Solvent Evaporation Method. Synthetic Metals, 2009. 159: p. 1744-1750.
40. Kumoda, M., Y. Takeoka, and M. Watanabe, Template Synthesis of Poly(N-isopropylacrylamide) Minigels Using Interconnecting Macroporous Polystyrene. Langmuir, 2003. 19: p. 525-528.
41. Goodwin, J.W., et al., Colloid. Polym. Sci., 1974.
42. Goodall, A.R., M.C. Wilkinson, and J. Hearn, J. Polym. Sci., Part A: Polym. Chem, 1977. 15.
43. Cox, R.A., et al., J. Polym. Sci.,Part A: Polym. Chem, 1977.
44. Qi, H., W. Hao, and H. Xu, Synthesis of Large-sized Monodisperse Polystyrene Microspheres by Dispersion Polymerization with Dropwise Monomer Feeding Procedure. Colloid. Polym. Sci., 2009. 287: p. 243-248.
45. Sun, S. and H.J.J.o.t.A.C.S. Zeng, Size-controlled synthesis of magnetite nanoparticles. 2002. 124(28): p. 8204-8205.
46. Friák, M., A. Schindlmayr, and M. Scheffler, Ab initio study of the half-metal to metal transition in strained magnetite. New journal of physics, 2007. 9(1): p. 5.
47. Cullity, B.D. and C.D. Graham, Introduction to magnetic materials. 2011: John Wiley & Sons.
48. Bychkov, Y.A. and E.I.J.J.o.p.C.S.s.p. Rashba, Oscillatory effects and the magnetic susceptibility of carriers in inversion layers. 1984. 17(33): p. 6039.
49. Meissner, W. and R. Ochsenfeld, Ein neuer effekt bei eintritt der supraleitfähigkeit. Naturwissenschaften, 1933. 21(44): p. 787-788.
50. Kittel, C., Introduction to Solid State Physics, 6th edn., 1986. Wiley.
51. Ngo, A., et al., Nanoparticles of: Synthesis and superparamagnetic properties. 1999. 9(4): p. 583-592.
52. Xuan, S., et al., Tuning the grain size and particle size of superparamagnetic Fe3O4 microparticles. 2009. 21(21): p. 5079-5087.
53. Valenzuela, R., et al., Influence of stirring velocity on the synthesis of magnetite nanoparticles (Fe3O4) by the co-precipitation method. Journal of Alloys and Compounds, 2009. 488(1): p. 227-231.
54. Rani, S. and G.D. Varma, Superparamagnetism and metamagnetic transition in Fe3O4 nanoparticles synthesized via co-precipitation method at different pH. Physica B: Condensed Matter, 2015. 472: p. 66-77.
55. Xu, H., et al., Development of High Magnetization Fe3O4/Polystyrene/Silica Nanospheres via Combined Miniemulsion/Emulsion Polymerization. Journal of the American Chemical Society, 2006. 128(49): p. 15582-15583.
56. Zhou, K., et al., Preparation and application of mediator‐free H2O2 biosensors of graphene‐Fe3O4 composites. 2011. 23(4): p. 862-869.
57. Levite, M., Dopamine and T cells: dopamine receptors and potent effects on T cells, dopamine production in T cells, and abnormalities in the dopaminergic system in T cells in autoimmune, neurological and psychiatric diseases. Acta Physiol (Oxf), 2016. 216(1): p. 42-89.
58. Cao, X. and A. Aballay, Neural Inhibition of Dopaminergic Signaling Enhances Immunity in a Cell-Non-autonomous Manner. Curr Biol, 2016. 26(17): p. 2329-34.
59. Beaulieu, J.M. and R.R. Gainetdinov, The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev, 2011. 63(1): p. 182-217.
60. Simon, J.D. and D.N. Peles, The Red and the Black. Accounts of Chemical Research, 2010. 43(11): p. 1452-1460.
61. Wang, K. and Y. Luo, Defined Surface Immobilization of Glycosaminoglycan Molecules for Probing and Modulation of Cell–Material Interactions. Biomacromolecules, 2013. 14(7): p. 2373-2382.
62. Liu, Y., K. Ai, and L. Lu, Polydopamine and its derivative materials: synthesis and promising applications in energy, environmental, and biomedical fields. Chem Rev, 2014. 114(9): p. 5057-115.
63. Zhang, X., et al., Biocompatible polydopamine fluorescent organic nanoparticles: facile preparation and cell imaging. Nanoscale, 2012. 4(18): p. 5581-4.
64. Miao, Z.H., et al., Intrinsically Mn2+-Chelated Polydopamine Nanoparticles for Simultaneous Magnetic Resonance Imaging and Photothermal Ablation of Cancer Cells. ACS Appl Mater Interfaces, 2015. 7(31): p. 16946-52.
65. Liu, Q., et al., Highly selective uptake and release of charged molecules by pH-responsive polydopamine microcapsules. Macromol Biosci, 2011. 11(9): p. 1227-34.
66. Yang, X., et al., High-Efficiency Loading and Controlled Release of Doxorubicin Hydrochloride on Graphene Oxide. The Journal of Physical Chemistry C, 2008. 112(45): p. 17554-17558.
67. Liang, Y., et al., Terminal modification of polymeric micelles with pi-conjugated moieties for efficient anticancer drug delivery. Biomaterials, 2015. 71: p. 1-10.
68. Zeng, J.-Y., et al., π-Extended Benzoporphyrin-Based Metal–Organic Framework for Inhibition of Tumor Metastasis. ACS Nano, 2018. 12(5): p. 4630-4640.
69. Fung, S.-Y., et al., Amino Acid Pairing for De Novo Design of Self-Assembling Peptides and Their Drug Delivery Potential. Advanced Functional Materials, 2011. 21(13): p. 2456-2464.
70. Li, F., et al., Engineering the Aromaticity of Cationic Helical Polypeptides toward “Self-Activated” DNA/siRNA Delivery. ACS Applied Materials & Interfaces, 2017. 9(28): p. 23586-23601.
71. Zhuang, W.-R., et al., Applications of π-π stacking interactions in the design of drug-delivery systems. Journal of Controlled Release, 2019. 294: p. 311-326.