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Cycloamylose-nanogel drug delivery system-mediated intratumor silencing of the vascular endothelial growth factor regulates neovascularization in tumor microenvironment.

Fujii H, Shin-Ya M, Takeda S, Hashimoto Y, Mukai SA, Sawada S, Adachi T, Akiyoshi K, Miki T, Mazda O - Cancer Sci. (2014)

Bottom Line: The siVEGF/nanogel complex was engulfed by renal cell carcinoma (RCC) cells through the endocytotic pathway, resulting in efficient knockdown of VEGF.Intra-tumor injections of the complex significantly suppressed neovascularization and growth of RCC in mice.The treatment also inhibited induction of myeloid-derived suppressor cells, while it decreased interleukin-17A production.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Kyoto Prefectural University of Medicine, Kyoto, Kyoto Prefectural University of Medicine, Kyoto, Japan; Department of Urology, Kyoto Prefectural University of Medicine, Kyoto, Japan.

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Vascular endothelial growth factor (VEGF)-specific short interfering RNA (siVEGF) CH-CA-Spe nanogel complex suppressed growth ofRenca tumors in vivo. Tumor-bearing mice (n = 6) were given intratumor injections with 50 μL of nanogel alone or the indicated siRNA/nanogel complex on days 0, 4, 8, 12 and 16. A group of mice were left untransfected (UT). (a) Growth curves of the tumors are shown. (b–g) Mice were killed on day 20. Representative macroscopic images (b) and weight (n = 6) (c) of the tumors are shown. VEGF mRNA levels in the tumors (n = at least 4/group) (d) and VEGF levels in the sera (n = 5) (e) were measured by real-time RT-PCR and ELISA, respectively. Cryosections of tumors were immunostained with CD31 antibody (f) and microvessel density was calculated (n = 4) (g). Data represent the means ± SD. *P < 0.05 versus control non-silencing siRNA (siCont); **P < 0.01 versus siCont; +P < 0.001 versus siCont. Original magnification in (f) was ×200.
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fig05: Vascular endothelial growth factor (VEGF)-specific short interfering RNA (siVEGF) CH-CA-Spe nanogel complex suppressed growth ofRenca tumors in vivo. Tumor-bearing mice (n = 6) were given intratumor injections with 50 μL of nanogel alone or the indicated siRNA/nanogel complex on days 0, 4, 8, 12 and 16. A group of mice were left untransfected (UT). (a) Growth curves of the tumors are shown. (b–g) Mice were killed on day 20. Representative macroscopic images (b) and weight (n = 6) (c) of the tumors are shown. VEGF mRNA levels in the tumors (n = at least 4/group) (d) and VEGF levels in the sera (n = 5) (e) were measured by real-time RT-PCR and ELISA, respectively. Cryosections of tumors were immunostained with CD31 antibody (f) and microvessel density was calculated (n = 4) (g). Data represent the means ± SD. *P < 0.05 versus control non-silencing siRNA (siCont); **P < 0.01 versus siCont; +P < 0.001 versus siCont. Original magnification in (f) was ×200.

Mentions: To assess whether siVEGF/nanogel suppresses tumor growth in vivo, mice that had been transplanted with Renca cells were given repetitive administrations of the complex, and tumor growth was monitored. As shown in Figure 5a, the siVEGF/nanogel complex significantly suppressed tumor growth, while tumors treated with control complex or nanogel alone showed comparable growth rates as non-treated tumors. These observations were confirmed by macroscopic (Fig. 5b) and gravimetrical quantification (Fig. 5c). Real-time RT-PCR revealed that VEGF mRNA was significantly reduced in the tumors treated with siVEGF/nanogel (Fig. 5d). Serum levels of VEGF were also measured by ELISA, demonstrating a significant decrease in VEGF concentration in the sera of the siVEGF/nanogel-treated animals (Fig. 5e).


Cycloamylose-nanogel drug delivery system-mediated intratumor silencing of the vascular endothelial growth factor regulates neovascularization in tumor microenvironment.

Fujii H, Shin-Ya M, Takeda S, Hashimoto Y, Mukai SA, Sawada S, Adachi T, Akiyoshi K, Miki T, Mazda O - Cancer Sci. (2014)

Vascular endothelial growth factor (VEGF)-specific short interfering RNA (siVEGF) CH-CA-Spe nanogel complex suppressed growth ofRenca tumors in vivo. Tumor-bearing mice (n = 6) were given intratumor injections with 50 μL of nanogel alone or the indicated siRNA/nanogel complex on days 0, 4, 8, 12 and 16. A group of mice were left untransfected (UT). (a) Growth curves of the tumors are shown. (b–g) Mice were killed on day 20. Representative macroscopic images (b) and weight (n = 6) (c) of the tumors are shown. VEGF mRNA levels in the tumors (n = at least 4/group) (d) and VEGF levels in the sera (n = 5) (e) were measured by real-time RT-PCR and ELISA, respectively. Cryosections of tumors were immunostained with CD31 antibody (f) and microvessel density was calculated (n = 4) (g). Data represent the means ± SD. *P < 0.05 versus control non-silencing siRNA (siCont); **P < 0.01 versus siCont; +P < 0.001 versus siCont. Original magnification in (f) was ×200.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4317968&req=5

fig05: Vascular endothelial growth factor (VEGF)-specific short interfering RNA (siVEGF) CH-CA-Spe nanogel complex suppressed growth ofRenca tumors in vivo. Tumor-bearing mice (n = 6) were given intratumor injections with 50 μL of nanogel alone or the indicated siRNA/nanogel complex on days 0, 4, 8, 12 and 16. A group of mice were left untransfected (UT). (a) Growth curves of the tumors are shown. (b–g) Mice were killed on day 20. Representative macroscopic images (b) and weight (n = 6) (c) of the tumors are shown. VEGF mRNA levels in the tumors (n = at least 4/group) (d) and VEGF levels in the sera (n = 5) (e) were measured by real-time RT-PCR and ELISA, respectively. Cryosections of tumors were immunostained with CD31 antibody (f) and microvessel density was calculated (n = 4) (g). Data represent the means ± SD. *P < 0.05 versus control non-silencing siRNA (siCont); **P < 0.01 versus siCont; +P < 0.001 versus siCont. Original magnification in (f) was ×200.
Mentions: To assess whether siVEGF/nanogel suppresses tumor growth in vivo, mice that had been transplanted with Renca cells were given repetitive administrations of the complex, and tumor growth was monitored. As shown in Figure 5a, the siVEGF/nanogel complex significantly suppressed tumor growth, while tumors treated with control complex or nanogel alone showed comparable growth rates as non-treated tumors. These observations were confirmed by macroscopic (Fig. 5b) and gravimetrical quantification (Fig. 5c). Real-time RT-PCR revealed that VEGF mRNA was significantly reduced in the tumors treated with siVEGF/nanogel (Fig. 5d). Serum levels of VEGF were also measured by ELISA, demonstrating a significant decrease in VEGF concentration in the sera of the siVEGF/nanogel-treated animals (Fig. 5e).

Bottom Line: The siVEGF/nanogel complex was engulfed by renal cell carcinoma (RCC) cells through the endocytotic pathway, resulting in efficient knockdown of VEGF.Intra-tumor injections of the complex significantly suppressed neovascularization and growth of RCC in mice.The treatment also inhibited induction of myeloid-derived suppressor cells, while it decreased interleukin-17A production.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Kyoto Prefectural University of Medicine, Kyoto, Kyoto Prefectural University of Medicine, Kyoto, Japan; Department of Urology, Kyoto Prefectural University of Medicine, Kyoto, Japan.

Show MeSH
Related in: MedlinePlus