68Ga-labeled oligonucleotides for in vivo imaging with PET.
68Ga-labeled oligonucleotides for in vivo imaging with PET.
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2004-02
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通讯作者：
A. Roivainen;T. Tolvanen;Satu Salomäki;G. Lendvai;I. Velikyan;P. Numminen;Maria Välilä;H. Sipilä;M. Bergström;P. Härkönen;H. Lönnberg;B. Långström
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作者：
A. Roivainen;T. Tolvanen;Satu Salomäki;G. Lendvai;I. Velikyan;P. Numminen;Maria Välilä;H. Sipilä;M. Bergström;P. Härkönen;H. Lönnberg;B. Långström
本文报道了（68）Ga标记寡核苷酸作为PET显像剂在活体大鼠中的生物学评价。方法以正电子放射性核素68 Ga（半衰期68 min）沿着大环螯合剂1，4，7，10-四氮杂环十二烷-N，N '，N”，N“'-四乙酸（DOTA）标记人K-ras癌基因反义寡核苷酸。首先研究了3种不同形式的磷脂酰肌醇的生物学性质，即2 '-脱氧磷酸二酯（PO）、2'-脱氧硫代磷酸酯（PS）和2 '-O-甲基磷酸二酯（OMe）。在无胸腺大鼠体内评价了生物分布和生物活性，每只大鼠均携带A549细胞肿瘤（在密码子12中含有K-ras点突变）和BxPC-3细胞肿瘤（含有野生型K-ras）。在静脉注射（68）Ga-寡核苷酸后立即进行持续长达2 h的动态PET成像。使用单独的（68）GaCl（3）或（68）Ga-DOTA而不使用寡核苷酸进行空白研究。还将肿瘤中的（68）Ga-反义寡核苷酸摄取与（18）F-FDG和（68）Ga-正义寡核苷酸摄取进行比较。此外，通过超滤检查了寡核苷酸与人血浆蛋白和人白蛋白的结合。结果该寡核苷酸能被（68）Ga和DOTA螯合物稳定标记。脑内注射的（68）Ga-寡核苷酸的17聚体长度显示高质量的PET图像，允许量化的主要器官和肿瘤中的生物活性物质。静脉注射给药的（68）Ga-寡核苷酸的生物分布和生物活性随寡核苷酸骨架的性质而变化。结论（68）Ga标记寡核苷酸是一种简便的PET活体成像和定量寡核苷酸生物活性的方法。
UNLABELLED The biologic evaluation in living rats of (68)Ga-labeled oligonucleotides as imaging agents for PET is reported. METHODS (68)Ga, a positron-emitting radionuclide (half-life, 68 min), along with a macrocyclic chelating agent, 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid (DOTA), was used for labeling of antisense oligonucleotides targeting activated human K-ras oncogene. The biologic properties of 3 different forms of the oligonucleotides-that is, 2'-deoxyphosphodiester (PO), 2'-deoxyphosphorothioate (PS), and 2'-O-methyl phosphodiester (OMe)-were studied first. The biodistribution and biokinetics were evaluated in vivo in athymic rats, each bearing a tumor of A549 cells, containing K-ras point mutation in codon 12, and a tumor of BxPC-3 cells, containing wild-type K-ras. Dynamic PET imaging lasting up to 2 h was performed immediately after intravenous injection of (68)Ga-oligonucleotide. Blank studies were performed using (68)GaCl(3) or (68)Ga-DOTA alone without oligonucleotide. The (68)Ga-antisense oligonucleotide uptake in tumors was also compared with the (18)F-FDG and (68)Ga-sense oligonucleotide uptakes. In addition, oligonucleotide binding to human plasma proteins and to human albumin was examined by means of ultrafiltration. RESULTS The oligonucleotides can be stably labeled with (68)Ga and DOTA chelate. Intravenously injected (68)Ga-oligonucleotides of 17-mer length revealed high-quality PET images, allowing quantification of the biokinetics in major organs and in tumors. The biodistribution and biokinetics of intravenously administered (68)Ga-oligonucleotide varied considerably with the nature of the oligonucleotide backbone. CONCLUSION We conclude that (68)Ga labeling of oligonucleotides is a convenient approach for in vivo imaging and quantification of oligonucleotide biokinetics in living animals with PET.