Development of local drug disposition analysis and delivery methods in human solid tumors

人类实体瘤局部药物分布分析和递送方法的开发

基本信息

批准号：
12557212
负责人：
TAKAKURA Yoshinobu
金额：
$ 6.46万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

项目摘要

To construct a strategy for developing efficient and safe in vivo drug delivery systems to solid tumors, a series of pharmacokinetic studies following local administration were carried out. The intratumoral pharmacokinetics of a second-generation antisense oligonucleotid were studied in rat Walker 256 tissue-isolated tumor preparations using an in situ single-pass vascular perfusion technique. Some first-generation oligonucleotides were also used for comparison. These oligonucleotides were administrated directly into the tumor in two ways : constant arterial infusion and direct intratumoral injection. The results suggested that the oligonucleotide may be useful for direct local injection into solid tumors. On the other hand, the intratumoral pharmacokinetics of naked plasmid DNA and gene expression were examined in mice bearing solid tumors. Plasmid DNA was rapidly eliminated from the injection site and lymphatic transfer was observed. Intratumoral injection of naked naked plasmid DNA encoding the luciferase gene into subcutaneously inoculated mouse colon tumor resulted in significant gene expression. The gene expression was inhibited when defined polyanions were injected simultaneously, implying the involvement of a specific mechanism in cellular uptake of plasmid DNA These results demonstrated that tumor tissue might be a promising target for direct gene transfer.with naked plasmid DNA. Thus, the present study provides useful information about the basic disposition characteristics of gene drugs, such as antisense oligonucleotides and plasmid DNA in solid tumors.

为了构建开发有效且安全的实体瘤体内药物递送系统的策略，进行了一系列局部给药后的药代动力学研究。使用原位单通道血管灌注技术在大鼠 Walker 256 组织分离肿瘤制剂中研究了第二代反义寡核苷酸的瘤内药代动力学。一些第一代寡核苷酸也用于比较。这些寡核苷酸以两种方式直接施用到肿瘤中：持续动脉输注和直接瘤内注射。结果表明，寡核苷酸可用于直接局部注射到实体瘤中。另一方面，在携带实体瘤的小鼠中检查了裸质粒 DNA 和基因表达的瘤内药代动力学。质粒DNA从注射部位迅速消除，并观察到淋巴转移。将编码荧光素酶基因的裸露质粒DNA瘤内注射到皮下接种的小鼠结肠肿瘤中，导致显着的基因表达。当同时注射特定的聚阴离子时，基因表达受到抑制，这意味着细胞摄取质粒 DNA 涉及特定机制。这些结果表明，肿瘤组织可能是裸露质粒 DNA 直接基因转移的有希望的靶标。因此，本研究提供了有关实体瘤中反义寡核苷酸和质粒DNA等基因药物基本处置特征的有用信息。