Tumor angiogenesis involves multiple signaling pathways that provide potential therapeutic targets to inhibit
tumor growth and
metastasis. Regarding the significant role of
vascular endothelial growth factor (
VEGF) in angiogenesis and
tumor progression,
VEGF sequence-specific
small interfering RNA (
siRNA) for anti-angiogenic
tumor therapy are under development. In the present study, dual-modified
liposomes (At-Lp) was designed by attaching two receptorspecific
peptides, Angiopep and tLyP-1, which specifically targeting
low-density lipoprotein receptor (LRP) for
brain tumor targeting and
neuropilin-1 receptor (NRP-1) for
tumor penetration, respectively. Gene transfection and silencing, and antitumor effect of the At-Lp loaded with
VEGF siRNA were evaluated in vitro and in orthotopic xenograft models of U87 MG
tumor. The At-Lp significantly enhanced cellular uptake (2-fold) and down-regulated expression of
VEGF in U87 MG
glioblastoma cells compared with non-modified and single-modified
liposomes. The internalization of the At-Lp into
tumor cells was taken via the enhanced permeability and retention effect and receptor-mediated endocytosis, followed by an effective endosomal escape of loaded
siRNA into the cytoplasm. The At-Lp showed great superiority in inhibition of
tumor growth, anti-angiogenesis, expression of
VEGF and apoptosis effect after in vivo application against nude mice bearing U87 MG
glioblastoma without activation of system-associated toxicity and the innate immune response. These results demonstrated that the combination of two receptor-specific
peptides-mediated
liposomes presented a promising platform for effective targeting delivery of
siRNA for
cancer anti-angiogenic
therapy.