Antitumor effect of chondroitin sulfate-coated ternary granulocyte macro phage-colony-stimulating factor plasmid complex for ovarian cancer
Antitumor effect of chondroitin sulfate-coated ternary granulocyte macro phage-colony-stimulating factor plasmid complex for ovarian cancer
复制标题
硫酸软骨素包被的三元粒细胞巨噬细胞集落刺激因子质粒复合物对卵巢癌的抗肿瘤作用
DOI：
10.1002/jgm.1647
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发表时间：
2012
影响因子：
3.5
通讯作者：
他
中科院分区：
文献类型：
--
作者：
Katsuyuki Hamada;他
背景虽然已经开发了用于治疗癌症的具有复制能力的病毒，但是由于中和抗体的产生抑制了感染，因此其细胞毒性效果不足，并且由于病毒诱导的细胞因子激增的危及生命的严重副作用，全身给药是困难的。为了克服这些关键问题，我们设计了一种质粒/聚阳离子/聚阴离子复合物，并评估了用硫酸软骨素包被的三元质粒复合物在卵巢癌基因治疗中的潜力。方法将鼠粒细胞巨噬细胞集落刺激因子（mGM-CSF）基因的质粒与聚乙烯亚胺（PEI）、透明质酸或硫酸软骨素复合，制备成复合物，并与透明质酸、硫酸软骨素复合，观察复合物对卵巢癌的抑制作用。将小鼠卵巢癌细胞接种于（C57 BL/6 × C3 H/He）F1小鼠皮下或腹腔内，制备肿瘤模型。与用更高分子量的硫酸软骨素或透明质酸包被相比，用10千道尔顿（kDa）硫酸软骨素包被的质粒绿色荧光蛋白（GFP）/PEI增加了转染效率。GFP/PEI/10-kDa硫酸软骨素在卵巢癌细胞中的转染效率是正常细胞的6倍。与透明质酸包被相比，腹膜内注射包被有10-kDa硫酸软骨素的mGM-CSF/PEI延长了存活。瘤内注射10-kDa硫酸软骨素包被的mGM-CSF/PEI可使小鼠存活率达到100%，而透明质酸则不能达到100%。版权所有© 2012约翰威利父子有限公司.
BackgroundAlthough replication‐competent viruses have been developed for treating cancers, their cytotoxic effects are insufficient as a result of infection inhibited by the generation of neutralizing antibodies, and systemic administration is difficult as a result of the life‐threatening serious side‐effects of virus‐induced cytokine surge. To overcome these critical problems, we devised a plasmid/polycation/polyanion complex and assessed the potential of ternary plasmid complexes coated with chondroitin sulfate in gene therapy for ovarian cancer. The antitumor effects of chondroitin sulfate‐coated complex as an anionic component were compared with those of hyaluronic acid on ovarian cancer.MethodsPlasmid harboring the gene of murine granulocyte macrophage‐colony‐stimulating factor (mGM‐CSF) was complexed with polyethyleneimine (PEI) and hyaluronic acid or chondroitin sulfate. Murine ovarian cancer cells were injected into (C57BL/6 × C3H/He) F1mice to prepare a subcutaneous or intraperitoneal tumor model.ResultsDNA/PEI was charged positively and DNA/PEI/chondroitin sulfate or DNA/PEI/hyaluronic acid was charged negatively. Plasmid‐green fluorescent protein (GFP)/PEI coated with 10‐kilodalton (kDa) chondroitin sulfate increased transfection efficiency compared to coating with chondroitin sulfate of higher‐molecular‐weight or hyaluronic acid. The transfection efficiency of GFP/PEI/10‐kDa chondroitin sulfate in ovarian cancer cells was six‐fold higher than that in normal cells. Intraperitoneal injection of mGM‐CSF/PEI coated with 10‐kDa chondroitin sulfate prolonged survival compared to that coated with hyaluronic acid. Intratumoral injection of mGM‐CSF/PEI coated with 10‐kDa chondroitin sulfate achieved mouse survival rates of 100%, although that with hyaluronic acid did not.ConclusionsThese findings suggest that GM‐CSF/PEI coated with 10‐kDa chondroitin sulfate has the potential for use in gene therapy of ovarian cancer. Copyright © 2012 John Wiley & Sons, Ltd.