In vivo imaging of oligonucleotides with positron emission tomography
In vivo imaging of oligonucleotides with positron emission tomography
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DOI：
10.1038/nm0498-467
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发表时间：
1998-04-01
期刊：
影响因子：
82.9
通讯作者：
Di Giamberardino, L
中科院分区：
文献类型：
--
作者：
Tavitian, B;Terrazzino, S;Di Giamberardino, L
本研究报告的数据表明：(1)所提出的放射性标记方法不改变反义寡核苷酸与其目标互补序列杂交的能力；(2)静脉注射[18F]寡核苷酸后，有可能通过PET定量地评估[18F]在任何选定组织或器官中的放射性动力学；(3)这些动力学与寡核苷酸骨架的性质高度可变；以及(4)在PET测量期间有可能降低[18F]标记的代谢物在血浆中的浓度，从而为定量评估[18F]寡核苷酸的组织浓度开辟了道路。因此，本文报道的组合技术构成了直接在体内评估反义寡核苷酸的药代动力学的基础，包括它们在血浆中的代谢性降解，几乎适用于任何序列和一些最常见的糖-磷酸盐骨架修饰。尽管有希望，但寡核苷酸的临床应用仍有待等待，因为许多困难限制了它们在体内的使用。要实现的改进包括对血浆和组织核酸酶的抵抗，更好的细胞膜穿透性(由于靶RNA是细胞内的，这是必要的)，以及减少毒性和副作用。绕过这些困难的研究遵循两个方向：对磷脂二酯-脱氧核糖骨架的修饰和通过将反义寡核苷酸与各种试剂如脂质体、阳离子脂类、纳米颗粒、病毒载体等相结合来将其矢量化。然而，寡核苷酸化学性质的修饰和矢量化影响了寡核苷酸的药代动力学行为。因此，为了筛选新一代的治疗目标反义寡核苷酸，有必要容易和快速地获得它们在体内的药代动力学行为的知识。这里提出的方法与这个问题相关，并且毫无疑问地证明了它对于[18F]标记的核苷酸和PET是可行的。此外，反义寡核苷酸与其生物靶标结合的特异性使其成为体内成像编码特定蛋白21、22的RNA的候选对象。进一步的研究将告诉我们，目前的方法将有助于评估更有效地将反义寡核苷酸输送到靶组织的策略，ALOS是否代表着用PET进行核酸成像的第一步。
The data reported in this study show (1) that the proposed radiolabelling methods does not modify the capcity of the antisense oligonucleotide to hybridize to its target complemetary sequence;(2) that after iv injection of the [18 F] oligonucleotide it is possible to evaluate quantitatively byt PET the kinetics of [18 F] adioactivity in any selected tissue or organ;(3) that these kinetics are highly variable with the nature of the oligonucleotide backbone; and (4) that it is possible to emasure the concentration of [18 F]-labeled metabolites in the plasma during the PET measurements, opening the way to the quantitative evaluation of the tissular concentration of [18 F] oligonucleotide. Hence, the combined techniques reported here constitute the basis to assess directly in vivo the pharmacokinetics of the antisense oligonucleotides, including their metaboloc degradation in the plasma, applicable to virtually any sequence and to some of the most common sugar-phospate backbone modifications. In spite of their promises, clinical applications of oligonucleotides are still to be awaited because a number of difficulties limit their use in vivo. Improvements to be achieved include resistance to plasma and tissular nucleases, better cell membrane penetration (a necessary requisite as the target RNA is intracellular), and reduced toxicity and side effects. Research to circumbent these difficulties follows two directions: Modifications in the phospodiester-deoxyribose backbone and vectorization of antisense oligonucleotides by combining them with various agents, such as liposomes, cationic lipids, nanoparticles, viral vectors, etc. In return however, modification of the chemical nature of the oligonucleotides and vectorization influence the pharmacokinetics behavior of the oligonucleotides. Thus, in order to screen new generations of antisense oligonucleotides proposed for therapeutic goals, it is necessary to acquire easily and rapidly he knowledge of their pharmacokinetics behavior in vivo. The methodology presentes here is relevant to this issue and undoubtedlu demonstrate that it is feasible with [18 F]-labeled ligonucleotides and PET. In addition, the specificity of binding of antisense oligonucleotides to their biological targets could make them food candidates for in vivo imaging of RNAs coding for specifi proteins 21, 22. Further investigations will tell us if the present methodology, which will help to evaluate stratehies for more effective delivery of antisense oligonucleotides to target tissues, alos represents the first step towards nuclei acid imaging with PET.