AMPLIFYING TC99M IN TUMOR USING PNA POLYMERS

放射性治疗肿瘤靶向的现有方法 诊断和治疗，虽然成功的一般，是需要的， 改进. 提供了非常显著的改进潜力 通过放大策略。 我们试图在肿瘤部位构建一个 可能会吸引极高水平的 在正常组织中具有最低水平的放射性。过去 几年来，我们开发了一种将MAG 3与胺结合的方法， 用于用99 mTc标记的衍生化寡聚物。 我们确定， 单链磷酸二酯和硫代磷酸DNA可能是 然而，我们确定PNA适合于此， 体内应用等。 最后，我们确定了一个平台（PA）， 可以构建哪些多价PNA聚合物，并且似乎 具有用于扩增的合适的药代动力学性质。使用 99 mTc-PNA和PNA-PA聚合物在初步研究中， 用扩增因子获得了阳性体外结果 超过50（一个阶段）和2,000（两个阶段）。 到目前为止，在体内 仅在小鼠珠模型中进行了研究，但使用了 一个阶段的放大系数约为50，证明了 原则 有了资金，我们将改进PA作为平台， 测量杂交的亲和力和空间位阻， 重新研究小鼠的药代动力学。 此后，研究将 集中于携带肿瘤的小鼠模型中的扩增。 我们相信我们的 初步结果很有希望，值得作出重大努力 在这个时候发展放大。 观察到的放大 50- 2，000的体外因子，尤其是扩增因子 50在体内，满足许多明显的关注，这种方法， 证明它应该起作用。

Current approaches towards tumor targeting of radioactivity for diagnosis and therapy, while successful in general, are in need of improvement. The potential for very significant improvement is offered by amplification strategies. We seek to construct at the tumor site an complex of PNAs which could attract extremely high levels of radioactivity with minimal levels in normal tissues. Over the past several years, we developed a method to conjugate MAG3 to amine- derivatized oligomers for labeling with 99mTc. We determined that both single-chain phosphodiester and phosphorothioate DNA were probably unsuitable, however, we established that PNAs are suitable for this in vivo applications such. Finally, we identified a platform (PA) upon which polyvalent PNA polymers may be constructed and which appears to possess suitable pharmacokinetic properties for amplification. Using 99mTc-PNA and PNA-PA polymers in preliminary studies, remarkably positive in vitro results have been obtained with amplification factors of more than 50 (one stage) and 2,000 (two stages). Thus far, in vivo studies have only been performed in a mouse bead model but with an amplification factor of about 50 for one stage, demonstrating proof-in- principle. With funding, we will improve upon PA as the platform, measure the affinities and steric hindrances of hybridization and reinvestigate the pharmacokinetics in mice. Thereafter, the study will focus on amplification in a tumor bearing mouse model. We believe our preliminary results are sufficiently promising to justify a major effort at this time to develop amplification. The observed amplification factors of 50-2,000 in vitro and, especially, the amplification factor of 50 in vivo, satisfy many of the obvious concerns of this approach and demonstrate that it should work.