Saijo Y, Perlaky L, Wang H, Busch H
Department of Pharmacology, Baylor College of Medicine, Houston, TX 77030.
Oncol Res. 1994;6(6):243-9.
Phosphorothioate oligonucleotides have a potential as therapeutic agents. The pharmacokinetics, tissue distribution, stability, and cellular uptake by LOX ascites tumor of p120 antisense phosphorothioate oligonucleotide, ISIS 3466, were studied in vivo. The oligonucleotide, which was quickly cleared from the circulation in the normal mice after IV injection, was readily absorbed into the systemic circulation from the peritoneum. The oligonucleotide was found in most tissues 48 h after IP administration. The highest concentrations were in kidney and liver, but the brain had a very low concentration. The phosphorothioate oligonucleotide was intact even after 48 h. When the oligonucleotide was complexed with cationic lipid DOTMA, the DOTMA did not affect the oligonucleotide uptake or tissue distribution in normal mice. However, DOTMA significantly increased the oligonucleotide cellular uptake (4-10 times) in LOX ascites tumors in an IP/IP model. These results indicate that the phosphorothioate oligonucleotide is stable, has favourable kinetics for use as an therapeutic agent, and that DOTMA could be useful in local delivery of the oligonucleotide in vivo.
硫代磷酸酯寡核苷酸具有作为治疗剂的潜力。对p120反义硫代磷酸酯寡核苷酸ISIS 3466在体内的药代动力学、组织分布、稳定性以及被LOX腹水瘤细胞摄取的情况进行了研究。静脉注射后，该寡核苷酸在正常小鼠体内从循环中迅速清除，但能从腹膜很容易地吸收进入体循环。腹腔注射48小时后，在大多数组织中都发现了该寡核苷酸。浓度最高的是肾脏和肝脏，而大脑中的浓度非常低。即使在48小时后，硫代磷酸酯寡核苷酸仍保持完整。当该寡核苷酸与阳离子脂质DOTMA复合时，DOTMA在正常小鼠中不影响寡核苷酸的摄取或组织分布。然而，在腹腔内/腹腔内模型中，DOTMA显著增加了LOX腹水瘤中寡核苷酸的细胞摄取（4至10倍）。这些结果表明，硫代磷酸酯寡核苷酸是稳定的，具有作为治疗剂的良好动力学特性，并且DOTMA可用于体内寡核苷酸的局部递送。
