Tumor blood vessels play important roles in
tumor progression and
metastasis. Targeting
tumor endothelial cells (TECs) is one of the strategies for
cancer therapy. We previously reported that
biglycan, a
small leucine-rich proteoglycan, is highly expressed in TECs. TECs utilize
biglycan in an autocrine manner for migration and angiogenesis. Furthermore, TEC-derived
biglycan stimulates
tumor cell migration in a paracrine manner leading to
tumor cell intravasation and
metastasis. In this study, we explored the
therapeutic effect of
biglycan inhibition in the TECs of
renal cell carcinoma using an in vivo
siRNA delivery system known as a multifunctional envelope-type nanodevice (MEND), which contains a unique pH-sensitive cationic
lipid. To specifically deliver MEND into TECs, we incorporated
cyclo(Arg-Gly-Asp-D-Phe-Lys) (cRGD) into MEND because αV β3
integrin, a receptor for cRGD, is selective and highly expressed in TECs. We developed RGD-MEND-encapsulating
siRNA against
biglycan. First, we confirmed that MEND was delivered into OS-RC-2
tumor-derived TECs and induced in vitro RNAi-mediated gene silencing. MEND was then injected intravenously into OS-RC-2
tumor-bearing mice. Flow cytometry analysis demonstrated that MEND was specifically delivered into TECs. Quantitative RT-PCR indicated that
biglycan was knocked down by
biglycan siRNA-containing MEND. Finally, we analyzed the
therapeutic effect of
biglycan silencing by MEND in TECs.
Tumor growth was inhibited by
biglycan siRNA-containing MEND.
Tumor microenvironmental factors such as
fibrosis were also normalized using
biglycan inhibition in TECs.
Biglycan in TECs can be a novel target for
cancer treatment.