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Optimization of drug delivery system for antitumor agents based on the energy metabolism inhibition of tumor cells

基于肿瘤细胞能量代谢抑制的抗肿瘤药物递送系统优化

基本信息

批准号：
09557197
负责人：
HARASHIMA Hideyoshi
金额：
$ 7.87万
依托单位：
The University of Tokushima, Faculty of Pharmaceutical Sciences
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09557197/
关键词：
Drug delivery system Liposomes Tumor Gene エネルギー代謝抗がん剤アンチセンス

项目摘要

The objective of this study is to develop an optimum drug delivery system to increase antitumor effect by enhancing targeting efficiency of antitumor agents. An artificial carrier system for macromolecules to the nuclei was developed by using a pH-sensitive liposomes, which can enhance cytosolic escape of liposomally encapsulated macromolecules depending on the intra-endosomal pH decrease. The cytosolic delivery of macromolecules was confirmed by confocal laser microscopy. In addition, nuclear targeting of macromoleules was achieved by adding a nuclear localization signal (NLS) to the molecules. The FITC-labelled albumin, which can not be passively delivered to nucleus, was successfully targeted to nucleus by adding NLS.This system for intracellular control of macromolecules can be a basic strategy to manipulate intracellular trafficking of high molecular weight compounds. On the other hand, it has been shown that hexokinase type-II is specifically transcripted in tumor cells and this can be a target enzyme to be inhibited. We aimed to deliver DNA to inhibit the transcription of hexokinase-II in tumor cells. To achieve this, the quantitative assay system was required to measure DNA in intracellular organella such as nucleus. We have succeeded to develop a sound assay system to measure intra-nuclear DNA by applying PCR-method. This method provided us an interesting relationship between targeted nuclear DNA and transcription activity. By using this newly developed intracellular regulation system and quantitative assay method, we will be able to optimize rational drug carrier system to inhibit transcription in tumor cells.

本研究的目的是开发一种最佳的给药系统，通过提高抗肿瘤药物的靶向效率来提高抗肿瘤效果。利用一种pH敏感的脂质体，开发了一种大分子到细胞核的人工载体系统，该系统可以增强脂质体包裹的大分子的胞浆逃逸，依赖于内膜内pH的降低。激光共聚焦显微镜证实了大分子的胞浆转运。此外，通过在大分子上添加核定位信号(NLS)，实现了大分子的核靶向性。FITC标记的白蛋白不能被动地传递到细胞核，通过加入NLS成功地将其靶向到细胞核。这个大分子细胞内控制系统可以作为控制大分子化合物细胞内转运的基本策略。另一方面，已有研究表明己糖激酶-II在肿瘤细胞中特异性转录，这可能是一个被抑制的靶酶。我们的目标是运送DNA来抑制肿瘤细胞中己糖激酶-II的转录。为了实现这一点，需要定量分析系统来测量细胞核等细胞内细胞器中的DNA。我们成功地建立了一套完善的应用聚合酶链式反应方法检测核内DNA的检测体系。这种方法为我们提供了靶向核DNA和转录活性之间的有趣关系。利用这种新开发的细胞内调控系统和定量检测方法，我们将能够优化合理的药物载体系统来抑制肿瘤细胞的转录。