Magnetic mesoporous silica nanoparticles co-delivering doxorubicin and VEGF siRNA for cervical cancer targeting therapy and MR imaging

RNA interference (RNAi) has been widely applied in biology and medicine because it can down-regulate the expression of specifically targeted genes. However, considerable barriers need to be overcome for delivery naked siRNA to appropriate site including rapid degradation by serum nucleases, hepatic clearance, low transfection efficiency, off-target effect, and inefficient release from endosomes. Therefore, developing effective delivery carrier holds the key to successful in clinical application of therapeutic siRNA. Inhibition of the vascular endothelial growth factor (VEGF) expression has been proven to effectively inhibit tumor growth and metastasis. The use of single chemotherapeutic drug has shown some limitations in anti-tumor treatment. Combining chemotherapy and gene therapy may be a promising approach for cancer treatment.In this study, a multifunctional co-delivery nanocarrier based on magnetic mesoporous silica nanoparticles(M-MSNs) was designed to simultaneously deliver VEGF shRNA and doxorubicin (Dox) in vitro and in vivo. The abundant pores on the surfaces of M-MSNs improved drug loading capacity. The targeting ligand folic acid (FA) conjugated polyethyleneimine (PEI-FA) was coated on the M-MSN surfaces through electrostatic interactions. PEI-FA modification increases VEGFshRNA binging capability because of electrostatic interactions between amino groups of PEI-FA and VEGF shRNA. The nanocomplexes were characterized by scanning electron microscopy, transmission electron microscopy, Brunauer–Emmett–Teller (BET) and zeta potential assy. The M-MSN(Dox)/PEI-FA nanocomplexes had average particle size of 217 ± 1 nm and drug-loading amount of 15%. They were stable and well-dispersed in 10% fetal bovine serum and had ability to protect VEGF shRNA degradation. Confocal microscopy confirmed that the FA receptor-mediated endocytosis of the M-MSN(Dox)/PEI-FA/VEGF shRNA composite was greater than that of the M-MSN(Dox)/PEI in folate receptor-overexpressed HeLa cells. The M-MSN(Dox)/PEI-FA/VEGF shRNA nanocomplexes also demonstrated excellent gene silencing efficiency in vitro and reduced the expression of VEGF expression. The in vitro magnetic resonance (MR) imaging indicated that M-MSN(DOX)/PEI-FA could be also used as an excellent MR contrast agent. Our results suggested that the M-MSN(Dox)/PEI-FA/VEGF shRNA nanocomplexes are a safe and efficient integration platform for MR imaging and co-delivering Dox and VEGF shRNA