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

为了构建一种高效、安全的实体肿瘤体内给药系统，在局部给药后进行了一系列的药代动力学研究。采用原位单次血管灌注技术研究了第二代反义寡核素在大鼠Walker 256组织分离肿瘤制剂中的瘤内药代动力学。一些第一代寡核苷酸也被用于比较。这些寡核苷酸通过两种方式直接进入肿瘤：持续动脉输注和直接瘤内注射。结果表明，该寡核苷酸可用于实体瘤的局部直接注射。另一方面，研究了裸质粒DNA在实体瘤小鼠体内的药代动力学和基因表达。质粒DNA迅速从注射部位清除，并观察到淋巴转移。将编码荧光素酶基因的裸裸质粒DNA在瘤内注射到皮下接种的小鼠结肠肿瘤中，基因表达显著。当同时注射特定的多阴离子时，基因表达被抑制，这表明在质粒DNA的细胞摄取中参与了特定的机制。这些结果表明肿瘤组织可能是直接基因转移的一个有希望的目标。用裸质粒DNA。因此，本研究为基因药物在实体肿瘤中的基本配置特征提供了有用的信息，如反义寡核苷酸和质粒DNA。

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.