Boado Ruben J
ArmaGen Technologies, Inc., Santa Monica, California 90401, USA.
NeuroRx. 2005 Jan;2(1):139-50. doi: 10.1602/neurorx.2.1.139.
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.
人表皮生长因子受体（EGFR）在实体癌（包括原发性脑癌和转移性脑癌）中发挥致癌作用。经血管非病毒基因治疗与EGFR-RNA干扰（RNAi）相结合，代表了一种在实体癌中沉默致癌基因的新治疗方法。这是通过携带由U6 RNA聚合酶启动子驱动的短发夹RNA表达质粒的聚乙二醇化免疫脂质体（PIL）实现的，该质粒通过RNAi靶向EGFR表达。PIL由含有聚乙二醇（PEG）的已知脂质混合物组成，PEG可在体内循环中稳定PIL结构。PIL的组织靶向特异性是通过将约1%的PEG残基与单克隆抗体（mAb）偶联来实现的，这些单克隆抗体分别与位于形成血脑屏障（BBB）的脑血管内皮和脑细胞膜上的特定内源性受体（即胰岛素和转铁蛋白受体）结合。已知这些单克隆抗体可诱导1）PIL复合物通过血脑屏障的受体介导的转胞吞作用，以及2）向脑细胞核区室的转运。对严重联合免疫缺陷（scid）小鼠的实验性人脑肿瘤模型进行每周一次的静脉RNAi基因治疗是可行的，这会导致肿瘤中EGFR表达降低，患有晚期颅内脑癌的小鼠存活时间延长88%。其他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。针对人血脑屏障和脑细胞特异性受体的嵌合和/或人源化单克隆抗体的可及性可能会加速该技术在人类肿瘤治疗中的应用。
