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. 2020 Dec;27(1):358-366.
doi: 10.1080/10717544.2020.1730522.

Effectively suppressed angiogenesis-mediated retinoblastoma growth using celastrol nanomicelles

Zhanrong Li  1 , Zhihua Guo  1 , Dandan Chu  1 , Huayang Feng  1 , Junjie Zhang  1 , Lei Zhu  1 , Jingguo Li  1
Affiliations

Effectively suppressed angiogenesis-mediated retinoblastoma growth using celastrol nanomicelles

Zhanrong Li et al. Drug Deliv. 2020 Dec.

Abstract

Celastrol, a Chinese herbal medicine, has already shown an inhibition effect on retinoblastoma growth activity in our previous research, but its mechanism is not well understood. Angiogenesis is a main driving force in many tumors. Here, we studied whether celastrol could inhibit angiogenesis-mediated retinoblastoma growth, if so, through what mechanism. In this work, we developed celastrol-loaded polymeric nanomicelles to improve the poor water solubility of celastrol. When given an intraperitoneal injection to mice bearing human retinoblastoma xenografts, celastrol nanomicelles (CNMs, 27.2 mg/kg/2 days) significantly reduced the weight and the volume of tumors and decreased tumor angiogenesis. We found that CNMs suppressed hypoxia-induced proliferation, migration, and invasion by human umbilical vascular endothelial cells (EA.hy 926) in a dose-dependent manner. Furthermore, CNMs inhibited SO-Rb 50 cells-induced sprouting of the vessels and vascular formation in chick embryo chorioallantoic membrane assay in vitro. To understand the molecular mechanism of these activities, we assessed the signaling pathways in CoCl2 treated EA.hy 926. CNMs inhibited the hypoxia-induced HIF-1α and VEGF. In conclusion, our results reveal that CNMs target the HIF-1α/VEGF pathway, which may be an important reason for the suppression of retinoblastoma growth and angiogenesis.

Keywords: Celastrol; SO-Rb 50 cells; angiogenesis; nanomicelles; retinoblastoma.

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Figures

Figure 1.
Figure 1.
Schematic illustration of the preparation of celastrol nanomicelles for celastrol delivery, resulting in suppressing retinoblastoma growth and angiogenesis by the HIF-1α/VEGF pathway.
Figure 2.
Figure 2.
CNMs inhibit hypoxia-inducible migration and invasion of endothelial cells. (A) CNMs inhibited vascular endothelial cells migration. Representative images of CNMs inhibiting EA.hy 926 cells migration in the scratching assay (magnification: × 200). (B) The quantitative analysis of migration (*p < 0.05, **p < 0.01). (C) CNMs inhibited endothelial cells invasion. Representative images of CNMs inhibiting EA.hy 926 cells invasion. cell migration in the Transwell chamber assay (magnification: × 200). (D) The quantitative analysis of invasion (*p < 0.05).
Figure 3.
Figure 3.
Celastrol nanomicelles inhibit the growth of human umbilical vein endothelial cells EA.hy 926 treated CoCl2 (100 µmol/L) for 72 hours. (*p < 0.05).
Figure 4.
Figure 4.
CNMs suppress hypoxia-inducible VEGF-A and HIF-1α protein expression in EA.hy 926.7 cells treated with CoCl2. EA.hy 926.7 cells were incubated in the presence or absence of 27.2 µg/mL CNMs for 24 hours under normal or hypoxic (CoCl2) conditions. VEGF-A and HIF-1α protein levels were detected by western blotting. (A) shows one representative western blot of three independent experiments. (B) show the relative protein levels and the statistical analysis results (mean values ± SD). cytosolic and nuclear fractions under normal conditions without CNMs were set as 1, *p < 0.05.
Figure 5.
Figure 5.
CNMs inhibited angiogenesis in the chick chorioallantoic membrane (CAM). The neovascularization of CAM was induced by retinoblastoma SO-Rb 50 cells in vitro, treated with various concentrations of CNMs (0, 3.4, 6.8, and 13.6 µg/mL) continuously for 48 hours, then recorded by using stereomicroscope (Olympus). Representative photographs of CAM assays.
Figure 6.
Figure 6.
CNMs suppress retinoblastoma growth in a xenograft mouse model. SO-Rb 50 cells were subcutaneously injected into 6-week-old NOD SCID mice (5 × 107 per mouse). The mice were administrated CNMs or blank micelles (27.2 mg/kg/2 days) by intraperitoneal injections after solid tumors grew to 100 mm3. (A) CNMs inhibit tumor growth as measured by tumor volume. (B) As demonstrated by the change in body weight, CNMs had little toxicity in mice at the doses tested. (C) Solid tumors in mice treated with CNMs were significantly smaller than those in control mice. *p < 0.01 versus control. Error bars: 95% CI.
Figure 7.
Figure 7.
CNMs inhibited neovascularization in retinoblastoma in mice as measured by H&E staining analysis and CD31 staining.
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Grants and funding

This research was supported by the National Natural Science Foundation of China [81600775 and 21504082], National Key R&D Program of China [2016YFE0117100], Medical Science and Technology Program of Henan Province [2018020398 and SB201902026].

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