RNA interference and nonviral targeted gene therapy of experimental brain cancer.
RNA interference and nonviral targeted gene therapy of experimental brain cancer.
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DOI：
10.1007/bf03206650
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发表时间：
2005-01-01
期刊：
影响因子：
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通讯作者：
Boado, Ruben J
中科院分区：
文献类型：
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作者：
Boado, Ruben J
人表皮生长因子受体（EGFR）在实体癌（包括脑原发性和转移性癌症）中起致癌作用。经血管非病毒基因治疗结合EGFR-RNA干扰（RNAi）代表了一种新的治疗方法，沉默致癌基因在实体癌。这是通过携带短发夹RNA表达质粒的聚乙二醇化免疫脂质体（PIL）实现的，短发夹RNA表达质粒由U6 RNA聚合酶启动子驱动，并通过RNAi定向靶向EGFR表达。PIL由含有聚乙二醇（PEG）的已知脂质的混合物组成，其在体内循环中稳定PIL结构。PIL的组织靶向特异性通过将约1%的PEG残基与结合特异性内源性受体（即，胰岛素和转铁蛋白受体）分别位于形成血脑屏障（BBB）的脑血管内皮和脑细胞膜中。已知这些mAb诱导1）受体介导的PIL复合物通过BBB的转胞吞作用和2）转运至脑细胞核区室。每周静脉内RNAi基因治疗可以治疗scid小鼠中的实验性人脑肿瘤模型，导致EGFR的肿瘤表达减少，这些患有晚期颅内脑癌的小鼠的生存时间增加88%。额外RNAi肿瘤靶点的可用性可能会提高这种新型抗癌药物的治疗效果。针对人BBB和脑细胞特异性受体的嵌合和/或人源化mAb的可及性可以加速该技术在治疗人肿瘤中的应用。
The human epidermal growth factor receptor (EGFR) plays an oncogenic role in solid cancer, including brain primary and metastatic cancers. Transvascular nonviral gene therapy in combination with EGFR-RNA interference (RNAi) represents a new therapeutic approach to silencing oncogenic genes in solid cancers. This is achieved with pegylated immunoliposomes (PIL) carrying short hairpin RNA expression plasmids driven by the U6 RNA polymerase promoter and directed to target EGFR expression by RNAi. The PIL is comprised of a mixture of known lipids containing polyethyleneglycol (PEG), which stabilizes the PIL structure in vivo in circulation. The tissue target specificity of PILs is given by conjugation of approximately 1% of the PEG residues to monoclonal antibodies (mAbs) that bind to specific endogenous receptors (i.e., insulin and transferrin receptors) located in the brain vascular endothelium, which forms the blood brain barrier (BBB), and brain cellular membranes, respectively. These mAbs are known to induce 1) receptor-mediated transcytosis of the PIL complex through the BBB and 2) transport to the brain cell nuclear compartment. Treatment of an experimental human brain tumor model in scid mice is possible with weekly intravenous RNAi gene therapy causing reduced tumor expression of EGFR and 88% increase in survival time of these mice with advanced intracranial brain cancer. The availability of additional RNAi tumor targets may improve the therapeutic efficacy of this new anticancer drug. The accessibility to chimeric and/or humanized mAbs directed to human BBB and brain cell specific-receptors may accelerate the application of this technology to the treatment of human tumors.