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Development of Delivery Systems for the Control of Pharmacokinetics and Intracellular Trafficking of Antisense Drugs

开发用于控制反义药物的药代动力学和细胞内运输的递送系统

基本信息

批准号：
07672351
负责人：
TAKAKURA Yoshinobu
金额：
$ 1.41万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

项目摘要

Antisense oligonucleotides have been expected as a novel class of chemotherapeutic agents for the treatment of cancer, viral infections and genetic disorders because of their potentials to inhibit gene expression in a sequence-specific manner. To achieve therapeutic effect in vivo, it is necessary to control the in vivo disposition characteristics as well as intracellular pharmacokinetics of oligonucleotides. The purpose of this project was to develop delivery systems which can control in vivo pharmacokinetics and subsequent intracellular trafficking of antisense oligonucleotides. We used 20 mer phosphodiester (PO) and its phosphorothioate (PS) derivative, complimentary to the human c-myc mRNA,as model antisense molecules. The basic pharmacokinetics of the model oligonucleotides were studied at whole body, organ, cellular and subcellular levels. The in vivo studies and organ perfusion experiments have demonstrated that the oligonucleotides underwent rapid elimination by the liver and kidney as well as degradation by nucleases after systemic administration. In vitro experiments using a variety of cultured cells in combination with confocal laser microscopy have clarified the intracellular fate of oligonucleotides. On a basis of these findings, we assessed the feasibility of macromolecular carriers, galactosylated and mannosylated poly (L-lysine), which can control both in vivo disposition and intracellular pharmacokinetics of oligonucleotides.

反义寡核苷酸具有序列特异性抑制基因表达的潜力，有望成为治疗癌症、病毒感染和遗传性疾病的新型化疗药物。为了在体内达到治疗效果，有必要控制寡核苷酸的体内处置特性以及细胞内药代动力学。本项目的目的是开发可以控制反义寡核苷酸的体内药代动力学和随后的细胞内运输的递送系统。我们使用20聚体磷酸二酯（PO）及其硫代磷酸酯（PS）衍生物，互补的人c-myc mRNA，作为模型反义分子。在全身、器官、细胞和亚细胞水平上研究了模型寡核苷酸的基本药代动力学。体内研究和器官灌注实验表明，寡核苷酸在全身给药后经历肝脏和肾脏的快速消除以及核酸酶的降解。在体外实验中，使用各种培养的细胞与共聚焦激光显微镜相结合，澄清了寡核苷酸的细胞内命运。在这些研究结果的基础上，我们评估了大分子载体的可行性，半乳糖基化和甘露糖基化聚（L-赖氨酸），它可以控制在体内的处置和细胞内的寡核苷酸的药代动力学。