Targeting and Photodynamic Killing of Cancer Cell by Nitrogen-Doped Titanium Dioxide Coupled with Folic Acid

doi:10.3390/nano6060113

. 2016 Jun 14;6(6):113.

doi: 10.3390/nano6060113.

Targeting and Photodynamic Killing of Cancer Cell by Nitrogen-Doped Titanium Dioxide Coupled with Folic Acid

Jin Xie¹, Xiaobo Pan², Mengyan Wang³, Longfang Yao⁴, Xinyue Liang⁵, Jiong Ma⁶, Yiyan Fei⁷, Pei-Nan Wang⁸, Lan Mi⁹

Affiliations

¹ Department of Optical Science and Engineering, Shanghai Engineering Research Center of Ultra-Precision Optical Manufacturing, Green Photoelectron Platform, Fudan University, 220 Handan Road, Shanghai 200433, China. jinxie13@fudan.edu.cn.
² Department of Optical Science and Engineering, Shanghai Engineering Research Center of Ultra-Precision Optical Manufacturing, Green Photoelectron Platform, Fudan University, 220 Handan Road, Shanghai 200433, China. xiaobopan11@fudan.edu.cn.
³ Department of Optical Science and Engineering, Shanghai Engineering Research Center of Ultra-Precision Optical Manufacturing, Green Photoelectron Platform, Fudan University, 220 Handan Road, Shanghai 200433, China. mengyanwang14@fudan.edu.cn.
⁴ Department of Optical Science and Engineering, Shanghai Engineering Research Center of Ultra-Precision Optical Manufacturing, Green Photoelectron Platform, Fudan University, 220 Handan Road, Shanghai 200433, China. yaolongfang@126.com.
⁵ Department of Optical Science and Engineering, Shanghai Engineering Research Center of Ultra-Precision Optical Manufacturing, Green Photoelectron Platform, Fudan University, 220 Handan Road, Shanghai 200433, China. liangxy14@fudan.edu.cn.
⁶ Department of Optical Science and Engineering, Shanghai Engineering Research Center of Ultra-Precision Optical Manufacturing, Green Photoelectron Platform, Fudan University, 220 Handan Road, Shanghai 200433, China. jiongma@fudan.edu.cn.
⁷ Department of Optical Science and Engineering, Shanghai Engineering Research Center of Ultra-Precision Optical Manufacturing, Green Photoelectron Platform, Fudan University, 220 Handan Road, Shanghai 200433, China. fyy@fudan.edu.cn.
⁸ Department of Optical Science and Engineering, Shanghai Engineering Research Center of Ultra-Precision Optical Manufacturing, Green Photoelectron Platform, Fudan University, 220 Handan Road, Shanghai 200433, China. pnwang@fudan.edu.cn.
⁹ Department of Optical Science and Engineering, Shanghai Engineering Research Center of Ultra-Precision Optical Manufacturing, Green Photoelectron Platform, Fudan University, 220 Handan Road, Shanghai 200433, China. lanmi@fudan.edu.cn.

PMID: 28335242
PMCID: PMC5302625
DOI: 10.3390/nano6060113

Targeting and Photodynamic Killing of Cancer Cell by Nitrogen-Doped Titanium Dioxide Coupled with Folic Acid

Jin Xie et al. Nanomaterials (Basel). 2016.

. 2016 Jun 14;6(6):113.

doi: 10.3390/nano6060113.

Authors

Jin Xie¹, Xiaobo Pan², Mengyan Wang³, Longfang Yao⁴, Xinyue Liang⁵, Jiong Ma⁶, Yiyan Fei⁷, Pei-Nan Wang⁸, Lan Mi⁹

Affiliations

¹ Department of Optical Science and Engineering, Shanghai Engineering Research Center of Ultra-Precision Optical Manufacturing, Green Photoelectron Platform, Fudan University, 220 Handan Road, Shanghai 200433, China. jinxie13@fudan.edu.cn.
² Department of Optical Science and Engineering, Shanghai Engineering Research Center of Ultra-Precision Optical Manufacturing, Green Photoelectron Platform, Fudan University, 220 Handan Road, Shanghai 200433, China. xiaobopan11@fudan.edu.cn.
³ Department of Optical Science and Engineering, Shanghai Engineering Research Center of Ultra-Precision Optical Manufacturing, Green Photoelectron Platform, Fudan University, 220 Handan Road, Shanghai 200433, China. mengyanwang14@fudan.edu.cn.
⁴ Department of Optical Science and Engineering, Shanghai Engineering Research Center of Ultra-Precision Optical Manufacturing, Green Photoelectron Platform, Fudan University, 220 Handan Road, Shanghai 200433, China. yaolongfang@126.com.
⁵ Department of Optical Science and Engineering, Shanghai Engineering Research Center of Ultra-Precision Optical Manufacturing, Green Photoelectron Platform, Fudan University, 220 Handan Road, Shanghai 200433, China. liangxy14@fudan.edu.cn.
⁶ Department of Optical Science and Engineering, Shanghai Engineering Research Center of Ultra-Precision Optical Manufacturing, Green Photoelectron Platform, Fudan University, 220 Handan Road, Shanghai 200433, China. jiongma@fudan.edu.cn.
⁷ Department of Optical Science and Engineering, Shanghai Engineering Research Center of Ultra-Precision Optical Manufacturing, Green Photoelectron Platform, Fudan University, 220 Handan Road, Shanghai 200433, China. fyy@fudan.edu.cn.
⁸ Department of Optical Science and Engineering, Shanghai Engineering Research Center of Ultra-Precision Optical Manufacturing, Green Photoelectron Platform, Fudan University, 220 Handan Road, Shanghai 200433, China. pnwang@fudan.edu.cn.
⁹ Department of Optical Science and Engineering, Shanghai Engineering Research Center of Ultra-Precision Optical Manufacturing, Green Photoelectron Platform, Fudan University, 220 Handan Road, Shanghai 200433, China. lanmi@fudan.edu.cn.

PMID: 28335242
PMCID: PMC5302625
DOI: 10.3390/nano6060113

Abstract

Titanium dioxide (TiO₂) has attracted wide attention as a potential photosensitizer (PS) in photodynamic therapy (PDT). However, bare TiO₂ can only be excited by ultraviolet illumination, and it lacks specific targeting ligands, which largely impede its application. In our study, we produced nitrogen-doped TiO₂ and linked it with an effective cancer cell targeting agent, folic acid (FA), to obtain N-TiO₂-FA nanoconjugates. Characterization of N-TiO₂-FA included Zeta potential, absorption spectra and thermogravimetric analysis. The results showed that N-TiO₂-FA was successfully produced and it possessed better dispersibility in aqueous solution than unmodified TiO₂. The N-TiO₂-FA was incubated with human nasopharyngeal carcinoma (KB) and human pulmonary adenocarcinoma (A549) cells. The KB cells that overexpress folate receptors (FR) on cell membranes were used as FR-positive cancer cells, while A549 cells were used as FR-negative cells. Laser scanning confocal microscopy results showed that KB cells had a higher uptake efficiency of N-TiO₂-FA, which was about twice that of A549 cells. Finally, N-TiO₂-FA is of no cytotoxicity, and has a better photokilling effect on KB cells under visible light irradiation. In conclusion, N-TiO₂-FA can be as high-value as a PS in cancer targeting PDT.

Keywords: cancer cell targeting; folic acid; photodynamic therapy; titanium dioxide nanoparticle.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

**Figure 1**
Synthesis procedure of N-TiO₂-folic acid (FA) nanoparticles (NPs).

**Figure 2**
(A) Comparison of the absorption spectrum of 1 μg·mL⁻¹ folic acid (FA) solution and the subtraction spectrum of N-TiO₂-FA subtracting N-TiO₂-NH₂; (B) Absorption spectra of N-TiO₂ and N-TiO₂-FA NPs; (C) Thermogravimetric analysis of the air-dried N-TiO₂, N-TiO₂-NH₂ and N-TiO₂-FA NPs.

**Figure 3**
(A) Confocal microscopic images of human nasopharyngeal carcinoma (KB) and human pulmonary adenocarcinoma (A549) cells treated with N-TiO₂-FA (red) for 40 min. Scale bar is 50 μm. (B) Reflection intensity of internalized N-TiO₂-FA in KB (black), FA-pretreated KB (red), A549 (blue) cells and FA-pretreated A549 (green) as a function of incubation time.

**Figure 4**
The dark cytotoxicity of N-TiO₂-FA with the incubation concentrations of 50–200 μg·mL⁻¹ on KB and A549 cells. The control groups of untreated cells were also shown for comparison. Data are expressed as mean ± SD (n = 4).

**Figure 5**
Photokilling effects of N-TiO₂-FA (green) and N-TiO₂-NH₂ (blue) with the concentration of 200 μg·mL⁻¹ on A549 and KB cells. The control group (black) and light irradiated group (red) were also shown for comparison. Data are expressed as mean ± SD (n = 4).

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References

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1. Dolmans D.E., Fukumura D., Jain R.K. Photodynamic therapy for cancer. Nat. Rev. Cancer. 2003;3:380–387. doi: 10.1038/nrc1071. - DOI - PubMed
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1. Lin J., Wang S.J., Huang P., Wang Z., Chen S.H., Niu G., Li W.W., He J., Cui D.X., Lu G.M. Photosensitizer-loaded gold vesicles with strong plasmonic coupling effect for imaging-guided photothermal/photodynamic therapy. ACS Nano. 2013;7:5320–5329. doi: 10.1021/nn4011686. - DOI - PMC - PubMed
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[1] Dougherty T.J., Gomer C.J., Henderson B.W., Jori G., Kessel D., Korbelik M., Moan J., Peng Q. Photodynamic therapy. J. Natl. Cancer Inst. 1998;90:889–905. doi: 10.1093/jnci/90.12.889. - DOI - PMC - PubMed

[2] Dougherty T.J., Gomer C.J., Henderson B.W., Jori G., Kessel D., Korbelik M., Moan J., Peng Q. Photodynamic therapy. J. Natl. Cancer Inst. 1998;90:889–905. doi: 10.1093/jnci/90.12.889. - DOI - PMC - PubMed

[3] Dolmans D.E., Fukumura D., Jain R.K. Photodynamic therapy for cancer. Nat. Rev. Cancer. 2003;3:380–387. doi: 10.1038/nrc1071. - DOI - PubMed

[4] Dolmans D.E., Fukumura D., Jain R.K. Photodynamic therapy for cancer. Nat. Rev. Cancer. 2003;3:380–387. doi: 10.1038/nrc1071. - DOI - PubMed

[5] Kamkaew A., Lim S.H., Lee H.B., Kiew L.V., Chung L.Y., Burgess K., Burgess K. BODIPY dyes in photodynamic therapy. Chem. Soc. Rev. 2013;42:77–88. doi: 10.1039/C2CS35216H. - DOI - PMC - PubMed

[6] Kamkaew A., Lim S.H., Lee H.B., Kiew L.V., Chung L.Y., Burgess K., Burgess K. BODIPY dyes in photodynamic therapy. Chem. Soc. Rev. 2013;42:77–88. doi: 10.1039/C2CS35216H. - DOI - PMC - PubMed

[7] Lin J., Wang S.J., Huang P., Wang Z., Chen S.H., Niu G., Li W.W., He J., Cui D.X., Lu G.M. Photosensitizer-loaded gold vesicles with strong plasmonic coupling effect for imaging-guided photothermal/photodynamic therapy. ACS Nano. 2013;7:5320–5329. doi: 10.1021/nn4011686. - DOI - PMC - PubMed

[8] Lin J., Wang S.J., Huang P., Wang Z., Chen S.H., Niu G., Li W.W., He J., Cui D.X., Lu G.M. Photosensitizer-loaded gold vesicles with strong plasmonic coupling effect for imaging-guided photothermal/photodynamic therapy. ACS Nano. 2013;7:5320–5329. doi: 10.1021/nn4011686. - DOI - PMC - PubMed

[9] Pelaez M., Nolan N.T., Pillai S.C., Seery M.K., Falaras P., Kontos A.G., Dunlop P.S.M., Hamilton J.W.J., Byrne J.A., O’shea K. A review on the visible light active titanium dioxide photocatalysts for environmental applications. Appl. Catal. B. 2012;125:331–349. doi: 10.1016/j.apcatb.2012.05.036. - DOI

[10] Pelaez M., Nolan N.T., Pillai S.C., Seery M.K., Falaras P., Kontos A.G., Dunlop P.S.M., Hamilton J.W.J., Byrne J.A., O’shea K. A review on the visible light active titanium dioxide photocatalysts for environmental applications. Appl. Catal. B. 2012;125:331–349. doi: 10.1016/j.apcatb.2012.05.036. - DOI

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Targeting and Photodynamic Killing of Cancer Cell by Nitrogen-Doped Titanium Dioxide Coupled with Folic Acid

Affiliations

Targeting and Photodynamic Killing of Cancer Cell by Nitrogen-Doped Titanium Dioxide Coupled with Folic Acid

Authors

Affiliations

Abstract

Conflict of interest statement

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