双乙基去甲精脒脂质聚胺作为联合药物/基因抗癌治疗的潜在递药载体。

Bisethylnorspermine lipopolyamine as potential delivery vector for combination drug/gene anticancer therapies.

机构信息

Department of Pharmaceutical Sciences, Wayne State University, Detroit, Michigan 48202, USA.

出版信息

Pharm Res. 2010 Sep;27(9):1927-38. doi: 10.1007/s11095-010-0197-4. Epub 2010 Jun 25.

PURPOSE

To design novel synthetic gene delivery system in which the carrier molecule functions dually as a carrier and a cytotoxic agent targeting dysregulated polyamine metabolism in cancer.

METHODS

Bisethylnorspermine (BENSpm) lipopolyamine was synthesized and its toxicity evaluated by MTS assay in MCF-7 and MCF-10A cells. Transfection activity was determined using luciferase plasmid DNA.

RESULTS

Asymmetrical lipid analogue of polyamine anticancer drug BENSpm was synthesized using nucleophilic ring opening of azetidinium ion. The synthesized LipoBENSpm showed cytotoxicity comparable to that of parent BENSpm in human breast cancer cell line MCF-7 but mediated 3-4 orders magnitude higher transfection activity. Importantly, cytostatic activity of BENSpm, typically in a low muM range, falls within a relevant and typical concentration range required for efficient gene delivery.

CONCLUSIONS

These findings make gene delivery vectors based on BENSpm promising candidates for combination drug/gene approaches to the treatment of cancer.

目的

设计新型的合成基因传递系统，其中载体分子具有双重功能，既可以作为载体，又可以作为靶向癌症中失调的多胺代谢的细胞毒性剂。

方法

合成了双乙基去甲精脒（BENSpm）脂多胺，并通过 MTS 测定法在 MCF-7 和 MCF-10A 细胞中评估其毒性。通过荧光素酶质粒 DNA 测定转染活性。

结果

使用亲核开环氮杂环丁烷离子合成了多胺抗癌药物 BENSpm 的不对称脂质类似物。合成的 LipoBENSpm 在人乳腺癌细胞系 MCF-7 中表现出与亲本 BENSpm 相当的细胞毒性，但介导了 3-4 个数量级更高的转染活性。重要的是，BENSpm 的细胞生长抑制活性通常在低 μM 范围内，处于有效基因传递所需的相关和典型浓度范围内。