A Nucleolin-Targeted Multimodal Nanoparticle Imaging Probe for Tracking Cancer Cells Using an Aptamer

被引:240
作者
Hwang, Do Won [7 ,8 ,9 ]
Ko, Hae Young [6 ,7 ,8 ]
Lee, Jung Hwan [5 ]
Kang, Hyungu [5 ]
Ryu, Sung Ho [5 ]
Song, In Chan [4 ]
Lee, Dong Soo [2 ,3 ,8 ,9 ]
Kim, Soonhag [1 ]
机构
[1] CHA Univ, CHA Stem Cell Inst, Dept Appl Biosci, Lab Mol Imaging, Seoul 135081, South Korea
[2] Seoul Natl Univ, Coll Med, Dept Mol Med & Biopharmaceut Sci, Seoul, South Korea
[3] Seoul Natl Univ, Coll Med, Dept Nucl Med, Seoul, South Korea
[4] Seoul Natl Univ, Coll Med, Dept Radiol, Seoul, South Korea
[5] Pohang Univ Sci & Technol, Aptamer Unit, Postech Biotech Ctr, Pohang, Kyungbuk, South Korea
[6] Med Res Ctr, Inst Radiat Med, Seoul, South Korea
[7] Seoul Natl Univ, Coll Med, Canc Res Inst, Seoul, South Korea
[8] Seoul Natl Univ, Coll Med, Dept Nucl Med, Seoul, South Korea
[9] Seoul Natl Univ, Programs Neurosci, Seoul, South Korea
基金
新加坡国家研究基金会;
关键词
multimodal image; cancer targeting; nanoparticles; aptamer; optical and radionuclide image; DRUG-DELIVERY; QUANTUM-DOT; NANOMEDICINE; THERAPY; AGENT; MICE; PET;
D O I
10.2967/jnumed.109.069880
中图分类号
R8 [特种医学]; R445 [影像诊断学];
学科分类号
1002 ; 100207 ; 1009 ;
摘要
The recent advances in molecular imaging techniques, using cancer-targeting nanoparticle probes, provide noninvasive tracking information on cancer cells in living subjects. Here, we report a multimodal cancer-targeted imaging system capable of concurrent fluorescence imaging, radionuclide imaging, and MRI in vivo. Methods: A cobalt-ferrite nanoparticle surrounded by fluorescent rhodamine (designated MF) within a silica shell matrix was synthesized with the AS1411 aptamer (MF-AS1411) that targets nucleolin (a cellular membrane protein highly expressed in cancer) using N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDC). This purified MF-AS1411 particle was bound with 2-(p-isothio-cyanatobenzyl)-1,4,7-triazacyclonane1,4,7-triacetic acid (p-SCN-bn-NOTA) chelating agent and further labeled with Ga-67-citrate (MFR-AS1411). The shape and size distribution of MFR-AS1411 were characterized by transmission electron microscope (TEM). The cellular distribution of the nucleolin protein using the MFR-AS1411 nanoparticle was detected by fluorescence confocal microscopy. Phantom MR images were obtained as the concentration of MFR-AS1411 increased, using a 1.5-T MRI scanner. In vivo Ga-67 radionuclide imaging and MRI were performed using a gamma-camera and a 1.5-T MR imager, respectively. Results: TEM imaging revealed MF and MFR-AS1411 to be spheric and well dispersed. The purified MFR-AS1411 nanoparticle showed specific fluorescence signals in nucleolin-expressing C6 cells, compared with MFR-AS1411 mutant (MFR-AS1411mt)-treated C6 cells. The rhodamine fluorescence intensity and Ga-67 activity of MFR-AS1411 were enhanced in a dose-dependent manner as the concentration of MFR-AS1411 was increased. The Ga-67 radionuclide was detected in both thighs of the mice injected with MFR-AS1411, whereas the MFR-AS1411 mutant (MFR-AS1411mt) administration revealed rapid clearance via the bloodstream, demonstrating that MFR-AS1411 specifically targeted cancer cells. Bioluminescence images in the C6 cells, stably expressing the luciferase gene, illustrated the in vivo distribution. T2-weighted MR images of the same mice injected with MFR-AS1411 showed dark T2 signals inside the tumor region, compared with the MRI signal of the tumor region injected with MFR-AS1411mt particles. Conclusion: We developed a nanoparticle-based cancer-specific imaging probe using the AS1411 aptamer in vivo and in vitro. This multimodal targeting imaging strategy, using a cancer-specific AS1411 aptamer, can be used as a versatile imaging tool for specific cancer diagnosis.
引用
收藏
页码:98 / 105
页数:8
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