Glioblastoma is the most common and aggressive
primary brain tumor, whose
malignancy is closely correlated with elevated proto-oncogene c-myc.
Intranasal administration emerges as a potential approach to deliver gene into the brain and interfere c-Myc expression. However, powerful permeability in nasal mucosa, selective delivery to
glioma and avoidance of premature release during remote transport are imperative to ensure the therapeutic effectiveness. To address the above concerns, herein we constructed a lipoplex based on pre-compression of c-Myc-targeting
siRNA (sic-Myc) by
octaarginine and subsequent encapsulation by
liposome modified with a selected
peptide derived from
penetratin, named 89WP. It was found that the lipoplex exhibited a stable core-shell structure and could be preferentially internalized along with cell debris by
glioma cells via active macropinocytosis. Through this cellular uptake pathway, the lipoplex avoided being entrapped by lysosome and released
siRNA in cytoplasm within 4 h, inducing substantial downregulation of c-Myc
mRNA and
protein expression of
glioma cells. Furthermore, due to significantly enhanced permeability in
tumor spheroids and nasal mucosa, the lipoplex was competent to deliver more
siRNA to orthotopic
glioma after
intranasal administration, and therefore prolonged the survival time of
glioma-bearing mice by inducing apoptosis. STATEMENT OF SIGNIFICANCE: In the present work, a lipoplex was designed to address the unmet demands on intranasal
siRNA delivery to the brain for treatment of
glioma. First, a powerful
peptide was selected to enable the lipoplex to penetrate nasal mucosa. Second, we found the lipoplex could be selectively internalized along with cell debris by
glioma cells via active macropinocytosis, and recorded the entire process. This cellular uptake pathway not only prevented the lipoplex being entrapped by lysosome, but also increased distribution of the lipoplex in orthotopic
glioma. Third, this lipoplex provided additional protection for
siRNA to avoid premature release during transport from nasal to brain. Overall, this lipoplex improved the gene delivery efficiency of
intranasal administration and was promising in the perspective of selectively silencing disease-related genes in intracranial
tumor.