本研究結合了奈米合成技術與生物醫學應用，以微波輔助加熱之水熱法合成低毒性之藍色及紅色螢光碳量子點，並搭配異原子摻雜分別提升碳量子點之螢光強度以及賦予碳量子點新穎特性。
第一部分: 錳摻雜之藍色螢光碳量子點(Mn@CDs)
本研究選用錳(Mangnese, Mn)摻雜至碳量子點結構，藉由微波輔助水熱法僅需10 min反應時間即可合成出錳摻雜之藍色螢光碳量子點(Mn@CDs)並賦予磁振顯影功能。接著以玻尿酸(Hyaluronic acid，HA)作為功能性分子與Mn@CDs結合，搭配細胞之體外毒性測試證實Mn@CDs-HA具有低生物毒性，並透過特定癌細胞表面玻尿酸受體之作用，使Mn@CDs-HA可經由B16F1癌細胞表面玻尿酸受體介導之胞飲作用而達到特異性螢光標靶顯影之功能。最後，成功藉由Mn@CDs-HA與抗癌藥物Doxorubicin (Dox)間之-作用力將Dox附載於碳量子點上(Mn@CDs-HA/Dox)，並藉由癌細胞內pH值變化驅動Dox達72%之藥物釋放率，使其能夠作為藥物載體並達到藥物治療之效果。
第二部分:磷、錳共摻雜之紅色螢光碳量子點(PMn@Cdots)
到目前為止，大多數的螢光碳量子點多呈現藍色及綠色螢光，由於其多使用紫外光或藍光作為激發波段，容易產生生物基質的自體螢光干擾並對細胞以及生物體造成損傷，限制碳量子點在生物領域上的應用。本研究利用對苯二胺為碳前驅物，選用磷(phosphorus，P)、錳(Mangnese，Mn)原子作為摻雜來源至碳量子點結構，搭配微波輔助水熱法僅需10 min反應時間即可製備出磷、錳共摻雜之紅色螢光碳量子點(PMn@Cdots)。接著以玻尿酸(Hyaluronic acid，HA)作為功能性分子與PMn@Cdots結合，搭配B16F1、HeLa癌細胞與HEL正常細胞之體外毒性測試以及斑馬魚胚胎測試，證實PMn@Cdots-HA並不影響細胞及胚胎發育，為低生物毒性奈米材料。此外，將PMn@Cdots-HA投入於B16F1與HeLa癌細胞進行測試比較，證實經由HA功能化後之PMn@Cdots-HA可具有特異性螢光標靶與癌細胞磁振顯影，達到更準確之顯影診斷資訊。

Herein, we combined with nano-synthesis technology and biomedical applications. We synthesized blue and red fluorescent carbon dots (Cdots) by using a one-pot microwave synthesis method. Furthermore, we doped heteroatom elements into Cdots to modulate the fluorescent properties and improve the functionality.
Part Ⅰ: Manganese element doped blue magnetofluorescent carbon dots (Mn@CDs)
We synthesized Manganese (Mn) element doped blue magnetofluorescent carbon dots (Mn@CDs) within 10 min by using a one-pot microwave synthesis method. Our results showed that these magnetofluorescent Mn@CDs have excellent fluorescent and magnetic properties. These blue magnetofluorescent Mn@CDs were conjugated with hyaluronic acid (HA) forming Mn@CDs-HA for targeted fluorescence imaging. In vitro studies confirmed that low cytotoxicity of Mn@CDs-HA. The targeting capabilities of Mn@CDs-HA were confirmed in B16F1 and HeLa cells using in vitro fluorescence imaging. Additionally, an anticancer drug, doxorubicin (Dox), was incorporated into Mn@CDs-HA forming Mn@CDs-HA-Dox, which enables targeted drug delivery. Importantly, the prepared Mn@CDs-HA -Dox showed a high quantity of doxorubicin loading capacity (about 72%) and pH-sensitive drug release.
Part Ⅱ: Phosphorous and Manganese element co-doped red magnetofluorescent carbon dots
So far, most of research papers show intense emission only from blue- to green-light regions under excitation with ultraviolet or blue-light. Because of the well-known blue auto fluorescence of biological matrix and severe photodamage of ultraviolet excitation light, causing restrict their further biological applications. We synthesized phosphorous (P) and Manganese (Mn) element co-doped red magnetofluorescent carbon quantum dots (PMn@Cdots) within 10 min by using a one-pot microwave synthesis method. Our results showed that these magnetofluorescent PMn@Cdots have excellent fluorescent and magnetic properties. Further, these red magnetofluorescent PMn@Cdots were conjugated with HA forming PMn@Cdots-HA. The in vitro studies on B16F1, HeLa, HEL cells and in vivo studies on zebrafish embryo confirmed the high biocompatibility and low toxicity of PMn@Cdots-HA. The targeting capabilities of PMn@Cdots-HA were confirmed in B16F1 and HeLa cells using in vitro fluorescence imaging and MR imaging to achieve more accurate diagnostic information.

[1] Z. Luo, Y. Lu, L. A. Somers and A. T. C. Johnson, J. Am. Chem. Soc., 2009, 131, 898–899.
[2] S. Zhu, Y. Song, X. Zhao, J. Shao, J. Zhang and B. Yang, Nano Res., 2015, 8, 355–381.
[3] Y. Park, J. Yoo, B. Lim, W. Kwon and S.-W. Rhee, J. Mater. Chem. A, 2016, 4, 11582-11603
[4] J. Kea, X. Lia, Q. Zhaoa, B. Liua, S. Liuc, S. Wangc, Journal of Colloid and Interface Science, 2017, 496, 425-433.
[5] Z. C. Yang, M. Wang, A. M. Yong, S. Y. Wong, X. H. Zhang, H. Tan, A. Y. Chang, X. Li and J. Wang, Chem. Commun., 2011, 47, 11615.
[6] H. Li, X. He, Z. Kang, H. Huang, Y. Liu, J. Liu, S. Lian, C. H. A. Tsang, X. Yang and S.-T. Lee, Angew. Chem. Int. Ed., 2010, 49, 4430.
[7] Y. Wang, L. Dong, R. Xiong and A. Hu, J. Mater. Chem. C, 2013, 1, 7731.
[8] Y. Yang, J. Cui, M. Zheng, C. Hu, S. Tan, Y. Xiao, Q. Yang and Y. Liu, Chem. Commun., 2012, 48, 380.
[9] R. Liu, D. Wu, S. Liu, K. Koynov, W. Knoll and Q. Li, Angew. Chem., Int. Ed., 2009, 48, 4598.
[10] J. H. Shen, Y. H. Zhu, C. Chen, X. L. Yang and C. Z. Li, Chem. Commun., 2011, 47, 2580.
[11] S. J. Zhu, J. H. Zhang, X. Liu, B. Li, X. F. Wang, S. J. Tang, Q. N. Meng, Y. F. Li, C. Shi, R. Hu and B. Yang, RSC Adv., 2012, 2, 2717.
[12] C. F. Wang, X. Wu, X. P. Li, W. T. Wang, L. Z. Wang, M. Gu and Q. Li, J. Mater. Chem., 2012, 22, 15522.
[13] Z. L. Wu, P. Zhang, M. X. Gao, C. F. Liu, W. W., F. Leng and C. Z. Huang, J. Mater. Chem. B, 2013, 1, 2868-2873
[14] X. Jia, J. Lia and E. Wang, Nanoscale, 2012, 4, 5572
[15] Y.-P. Sun, B. Zhou, Y. Lin, W. Wang, K. A. S. Fernando, P. Pathak, M. J. Meziani, B. A. Harruff, X. Wang, H. F. Wang, P. G. Luo, H. Yang, M. E. Kose, B. L. Chen, L. M. Veca and S.-Y. Xie, J. Am. Chem. Soc., 2006, 128, 7756.
[16] X. Li, S. Zhang, S. A. Kulinich, Y. Liu and H. Zeng, Scientific reports, 2014, 4, 4976.
[17] L. Bao, Z.-L. Zhang, Z.-Q. Tian, L. Zhang, C. Liu, Y. Lin, B. Qi and D.-W. Pang, Adv. Mater., 2011, 23, 5801.
[18] H. Ding, S.-B. Yu, J.-S. Wei and H.-M. Xiong, ACS Nano, 2016, 10, 484-491.
[19] M. J. Krysmann, A. Kelarakis, P. Dallas and E. P. Giannelis, J. Am. Chem. Soc., 2012, 134, 747.
[20] S. Zhu, Q. Meng, L. Wang, J. Zhang, Y. Song, H. Jin, K. Zhang, H. Sun, H. Wang and B. Yang, Angew. Chem. Int. Ed., 2013, 52, 3953.
[21] S. J. Yu, M. W. Kang, H. C. Chang, K. M. Chen and Y. C. Yu, J. Am. Chem. Soc., 2005, 127, 17604.
[22] J. G. Zhou, C. Booker, R. Y. Li, X. T. Zhou, T.-K. Sham, X. L. Sun and Z. F. Ding, J. Am. Chem. Soc., 2007, 129, 744.
[23] Y. Q. Dong, N. N. Zhou, X. M. Lin, J. P. Lin, Y. W. Chi and G. N. Chen, Chem. Mater., 2010, 22, 5895.
[24] Q. L. Wang, H. Z. Zheng, Y. J. Long, L. Y. Zhang, M. Gao and W. J. Bai, Carbon, 2011, 49, 3134.
[25] Q. Xu, T. Kuang, Y. Liu, L. Cai, X. Peng, T. S. Sreeprasad, P. Zhao, Z. Yue and N. Lif, J. Mater. Chem. B, 2016, 4, 7204-7219.
[26] X. Y. Xu, R. Ray, Y. L. Gu, H. J. Ploehn, L. Gearheart, K. Raker and W. A. Scrivens, J. Am. Chem. Soc., 2004, 126, 12736.
[27] S.-L. Hu, K.-Y. Niu, J. Sun, J. Yang, N.-Q. Zhao and X.-W. Du, J. Mater. Chem., 2009, 19, 484
[28] J. Lu, J.-x. Yang, J. Wang, A. Lim, S. Wang and K. P. Loh, ACS Nano, 2009, 3, 2367.
[29] Z. Ma, Y.-L. Zhang, L. Wang, H. Ming, H. Li, X. Zhang, F. Wang, Y. Liu, Z. Kang and S.-T. Lee, ACS Appl. Mater. Interfaces, 2013, 5, 5080.
[30] D. Tang, H. Zhang, H. Huang, R. Liu, Y. Han, Y. Liu, C. Tong and Z. Kang, Dalton Trans., 2013, 42, 6285.
[31] M. Liu, Y. Xu, F. Niu, J. J. Gooding and J. Liu, Analyst, 2016, 141, 2657.
[32] J. Deng, Q. Lu, N. Mi, H. Li, M. Liu, M. Xu, L. Tan, Q. Xie, Y. Zhang and S. Yao, Chem. Eur. J., 2014, 20, 4993.
[33] H. Liu, T. Ye and C. Mao, Angew. Chem. Int. Ed., 2007, 46, 6473.
[34] J. Zong, Y. Zhu, X. Yang, J. Shen and C. Li, Chem. Commun., 2011, 47, 764.
[35] V. N. Mehtaa, S. Jhab, S. K. Kailasaa, Mater. S. Eng. C, 2014, 38, 20-27.
[36] C. Wang, Z. Xu, H. Cheng, H. Lin, M. G. Humphrey and C. Zhang, Carbon, 2015, 82, 87-95.
[37] W.-J. Niu, Y. Li, R.-H. Zhu, D. Shan, Y.-R. Fan, X.-J. Zhang, S. Actu. B Chem., 2015, 218, 229-236.
[38] X. Cui, Y. Wang, J. Liu, Q. Yang, B. Z., Y. Gao, Y. Wang, G. Lu, S. Actu. B Chem., 2016, 242, 1272-1280.
[39] A. de la Hoz, A. Díaz-Ortiz and A. Moreno, Chem. Soc. Rev., 2005, 34, 164.
[40] H. Li, F.-Q. Shao, S.-Y. Zou1, Q.-J. Yang, H. Huang, J.-J. Feng, A.-J. Wang, Microchimica Acta, 2016, 2, 821-826.
[41] P. Ayala, R. Arenal, A. Loiseau, A. Rubio and T. Pichler, Rev. Mod. Phys., 2010, 82, 1843–1885.
[42] Y. Wang and A. Hu, J. Mater. Chem. C, 2014, 2, 6921–6939.
[43] Y.-Q. Zhang, D.-K. Ma, Y. Zhuang, X. Zhang, W. Chen, L.-L. Hong, Q.-X. Yan, K. Yu and S.-M. Huang, J. Mater. Chem., 2012, 22, 16714–16718.
[44] S. Chandra, D. Laha, A. Pramanik, A. R. Chowdhuri, P. Karmakar and S. K. Sahu, Luminescence, 2016, 31, 81–87.
[45] J. Shen, Q. Li, Y. Zhang, X.-j. She, C.-F. Wanga and S. Chen, RSC Adv., 2016, 64, 59702-59707.
[46] Y. Sun, C. Shen, J. Wang and Y. Lu, RSC Adv., 2015, 5, 16368–16375.
[47] S. Chandra, P. Patra, S. H. Pathan, S. Roy, S. Mitra, A. Layek, R. Bhar, P. Pramanik and A. Goswami, J. Mater. Chem. B, 2013, 1, 2375–2382.
[48] J. Zhou, X. Shan, J. Ma, Y. Gu, Z. Qian, J. Chen and H. Feng, RSC Adv., 2014, 4, 5465–5468.
[49] J. Cheng, C.-F. Wang, Y. Zhang, S. Yang and S. Chen, RSC Adv., 2016, 6, 37189.
[50] H.Ohno, science, 1998, 281, 951.
[51] C. Yu, T. Xuana, Y. Chen, Z. Zhao, X. Liu, G. Lian, H. Li, J. Alloys Com.,2016, 688, 611-619.
[52] S. Sun, L. Zhang, K. Jiang, A. Wu, and H. Lin, Chem. Mater., 2016, 28, 8659-8668.
[53] Y. Liu, W. Duan, W. Song, J. Liu, C. Ren, J. Wu, D. Liu and H. Chen, ACS Appl. Mater. Interfaces, 2017, 14, 12663-12672.
[54] N. Parvin and T. K. Mandal, Microchimica Acta, 2017, 4, 1117-1125.
[55] Y. Choi, S. Kim, M.-H. Choi, S.-R. Ryoo, J. Park, D.-H. Min, B.-S. Kim, Advanced Functional Materials, 2014, 24, 5781-5789.
[56] M. Vedamalai, A. P. Periasamy, C.-W. Wang, Y.-T. Tseng, L.-C. Ho, C.-C. Shih and H.-T. Chang, Nanoscale, 2014, 6, 13119-13125.
[57] Y. Xu, M. Wu, Y. Liu, X. Z. Feng, X. B. Yin, X. W. He, Y. K. Zhang, Chem. Eur. J., 2013, 19, 2276–2283.
[58] S. Zhao, M. Lan, X. Zhu, H Xue, T.-W. Ng, X. Meng, C.-S. Lee, P. Wang and W. Zhang, ACS Appl. Mater. Interfaces, 2015, 31, 17054-17060.
[59] S.-T. Yang, L. Cao, P. G. Luo, F. Lu, X. Wang, H. Wang, M. J. Meziani, Y. Liu, G. Qi and Y.-P. Sun, J. Am. Chem. Soc., 2009, 32, 11308-11309.
[60] S.-T. Yang, X. Wang, H. Wang, F. Lu, P. G. Luo, L. Cao, M. J. Meziani, J.-H. Liu, Y. Liu, M. Chen, Y. Huang and Y.-P. Sun, J. Phys. Chem. C, 2009, 42, 18110-18114.
[61] S. C. Ray, A. Saha, N. R. Jana and R. Sarkar, J. Phys. Chem. C, 2009, 113, 18546.
[62] Q.-L. Zhao, Z.-L. Zhang, B.-H. Huang, J. Peng, M. Zhang and D.-W. Pang, Chem. Commun., 2008, 44, 5116.
[63] E. J. Goh, K. S. Kim, Y. R. Kim, H. S. Jung, S. Beack, W. H. Kong, G. Scarcelli, S. H. Yun and S. K. Hahn, Biomacromoleculs, 2012, 13, 2554.
[64] S. Md. Sharker, S. M. Kim, J. E. Lee, J. H. Jeong, I. In, K. D. Lee, H. Lee and S. Y. Park, Nanoscale, 2015, 7, 5468.
[65] H. Zhang, Y. Chen, M. Liang, L. Xu, S. Qi, H. Chen and X. Chen, Anal. Chem., 2014, 86, 9846-9852.
[66] M. Zheng, S. Ruan, S. Liu, T. Sun, D. Qu, H. Zhao, Z. Xie, H. Gao, X. Jing and Z. Sun, ACS Nano, 2015, 9, 11455-11461.
[67] J. Feng, W.-J. Wang, X. Hai, Y.-L.Yu and J.-H. Wang, J. Mater. Chem. B, 2016, 4, 387-393
[68] Y.-F. Huang, X. Zhou, R. Zhou, H. Zhang,K.-B. Kang,M. Zhao,Y. Peng,Q. Wang,H.-L. Zhang, Chemistry-A European Journal, 2014, 20, 5640-5648.
[69] Y.-F. Kang, Y.-H. Li, Y.-W. Fang, Y. Xu, X.-M. Wei and X.-B. Yin, Scientific Reports, 2015, 5, 11835.
[70] N. Lee and T. Hyeon, Chem. Soc. Rev., 2012, 41, 2575-2589.
[71] J. Cheno, and J. Lee, Acc. Chem. Res., 2008, 41, 1630.
[72] Y. Xu, X.-H. Jia, X.-B. Yin, X.-W. He and Y.-K. Zhang, Anal. Chem., 2014, 86, 12122-12129.
[73] J. P. Zheng, Q.L. Liu, M. M. Zhen, F. Jiang, C.Y. Shu, C. Jin, Y. Yang, H.A. Alhadlaq, C.R. Wang, Nanoscale, 2012, 4, 3669-3672.
[74] Y. Liu, K. Ai, Q. Yuan, L. Lu, Biomaterials, 2011, 32, 1185-1192.
[75] N. Gong, H. Wang, S. Li, Y. Deng, X. Chen, L. Ye and W. Gu, Langmuir, 2014, 30, 10933-10939.
[76] S.-H. Chiu, G. Gedda, W. M. Girm, J.-K. Chen, Y.-C. Ling, A. V. Ghule, K.-L. Oue, J.-Y. Changa, A. Biomater., 2016, 45, 151-164.
[77] Y. Dong, H. Pang, H. B. Yang, C. Guo, J. Shao, Y. Chi, C. M. Li and T. Yu, Angew. Chem. Int. Ed., 2013, 52, 7800.
[78] K. Jiang, S. Sun, L. Zhang, Y. Lu, A. Wu, C. Cai and H. Lin, Angew. Chem. Int. Ed., 2015, 54, 5360.
[79] J. Wang, P. Zhang, C. Huang, G. Liu, K. C. Leung and Y. X. Wáng, Langmuir, 2015, 31, 8063.
[80] D. Qu, M. Zheng, P. Du, Y. Zhou, L. Zhang, D. Li, H. Tan, Z. Zhao, Z. Xie and Z. Sun, Nanoscale, 2013, 5, 12272.
[81] V. N. Mehta, S. Jha, R. K. Singhal and S. K. Kailasa, New J. Chem., 2014, 38, 6152.
[82] Q. Liu, B. Guo, Z. Rao, B. Zhang and J. R. Gong, Nano Lett., 2013, 13, 2436.
[83] J. Peng, W. Gao, B. K. Gupta, Z. Liu, R. Romero-Aburto, L. Ge, L. Song, L. B. Alemany, X. Zhan, G. Gao, S. A. Vithayathil, B. A. Kaipparettu, A. A. Marti, T. Hayashi, J.-J. Zhu and P. M. Ajayan, Nano Lett., 2012, 12, 844.
[84] A. Ananthanarayanan, Y. Wang, P. Routh, M. A. Sk, A. Than, M. Lin, J. Zhang, J. Chen, H. Sun and P. Chen, Nanoscale, 2015, 7, 8159.
[85] J.-M. Li, Y.-Y. Wang, M.-X. Zhao, C.-P. Tan, Y.-Q. Li, X.-Y. Le, L.-N. Ji and Z.-W. Mao, Biomaterials, 2012, 33, 2780.
[86] C.-L. Huang, C.-C. Huang, F.-D. Mai, C.-L. Yen, S.-H. Tzing, H.-T. Hsieh, Y.-C. Ling and J.-Y. Chang, J. Mater. Chem. B, 2015, 3, 651.
[87] M. Z. Fahmi, J.-K. Chen, C.-C. Huang, Y.-C. Ling and J.-Y. Chang, J. Mater. Chem. B, 2015, 3, 5532.
[88] L. Tang, R. Ji, X. Li, K. S. Teng and S. P. Lau, Part. Part. Syst. Charact., 2013, 30, 523.
[89] L. Tang, R. Ji, X. Li, G. Bai, C. P. Liu, J. Hao, J. Lin, H. Jiang, K. S. Teng, Z. Yang and S. P. Lau, ACS Nano, 2014, 8, 6312.
[90] Y. Xu, X.-H. Jia, X.-B. Yin, X.-W. He and Y.-K. Zhang, Anal. Chem., 2014, 86, 12122.
[91] N. Lee and T. Hyeon, Chem. Soc. Rev., 2012, 41, 2575-2589
[92] M. Z. Fahmi, J.-K. Chen, C.-C. Huang, Y.-C. Ling and J.-Y. Chang, J. Mater. Chem. B, 2015, 3, 5532.
[93] M. Dadsetan, K. E. Taylor, C. Yong, Ž. Bajzer, L. Lu and M. J. Yaszemski, Acta Biomaterialia, 2013, 9, 5438.