RNA Interference and Nonviral Targeted Gene Therapy of Experimental Brain Cancer

摘要

>Summary: 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 ∼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.