Efficient VEGF targeting delivery of DOX using Bevacizumab conjugated SiO@LDH for anti-neuroblastoma therapy.

Unlabelled: Vascular endothelial growth factor (VEGF) plays an important role in angiogenesis and is highly expressed in carcinoma, which make it an important target for tumor targeting therapy. Neuroblastoma is the main cause for cancer-related death in children. Like most solid tumors, it is also accompanied with the overexpression of VEGF. Doxorubicin Hydrochloride (DOX), a typical chemotherapeutic agent, exhibits efficient anticancer activities for various cancers. However, DOX, without targeting ability, usually causes severe damage to normal tissues. To overcome the shortages, we designed a novel nano-composite, which is Bevacizumab (Bev) modified SiO@LDH nanoparticles (SiO@LDH-Bev), loading with DOX to achieve targeting ability and curative efficiency. SiO@LDH-DOX and SiO@LDH-Bev-DOX nanoparticles were synthesized and the physicochemical properties were characterized by TEM detection, Zeta potential analysis, FTIR, Raman and XPS analysis. Then in vitro and in vivo anti-neuroblastoma efficiency, targeting ability and mechanisms of anti-carcinoma and anti-angiogenesis of SiO@LDH-Bev-DOX were explored. Our results indicated that we obtained the core-shell structure SiO@LDH-Bev with an average diameter of 253±10nm and the amount of conjugated Bev was 4.59±0.38μg/mg SiO@LDH-Bev. SiO@LDH-Bev-DOX could improve the cellular uptake and the targeting effect of DOX to brain and tumor, enhance the anti-neuroblastoma and anti-angiogenesis efficiency both in vitro and in vivo, and alleviate side effects of DOX sharply, especially hepatic injury. In addition, we also demonstrated that angiogenesis inhibitory effect was mediated by DOX and VEGF triggered signal pathways, including PI3K/Akt, Raf/MEK/ERK, and adhesion related pathways. In summary, SiO@LDH-Bev could be a potential VEGF targeting nanocarrier applied in VEGF positive cancer therapy.

Statement Of Significance: This paper explored that a novel core-shell structure nanomaterial SiO@LDH and modified SiO@LDH with Bevacizumab (Bev) to form a new tumor vasculature targeting nanocarrier SiO@LDH-Bev as vector of DOX, which was not reported before. The results indicated that SiO@LDH-Bev could improve the VEGF targeting ability, anti-neuroblastoma and anti-angiogenesis efficiency of DOX. At the same time, SiO@LDH-Bev-DOX could erase the cardiac toxicity and hepatic injury coming from DOX. Tube formation showed SiO@LDH-Bev-DOX had the strongest effect on inhibiting angiogenesis among all the four formulations. SiO@LDH-Bev-DOX could downregulate expression of p-VEGFR and inhibit activation of the Raf/MEK/ERK, p38MAPK, PI3K/Akt and FAK signaling pathways to achieve the goal of anti-angiogenesis. This work provides a novel system for the safe and efficient use of Bev and DOX on Neuroblastoma and explores the mechanism of the function of nano carrier in cancer therapy both in vitro and in vivo.