Co-delivery of VEGF siRNA and Etoposide for Enhanced Anti-angiogenesis and Anti-proliferation Effect via Multi-functional Nanoparticles for Orthotopic Non-Small Cell Lung Cancer Treatment.
Li F+, Wang Y+, Chen WL+, Wang DD, Zhou YJ, You BG, Liu Y, Qu CX, Yang SD, Chen MT, Zhang XN*.
Theranostics 2019; 9(20): 5886-5898. doi: 10.7150/thno.32416 IF 8.063 一区
Targeting tumor angiogenesis pathway via VEGF siRNA (siVEGF) has shown great potential in treatinghighly malignant and metastatic non-small cell lung cancer (NSCLC). However, anti-angiogenicmonotherapy lacked sufficient antitumor efficacy which suffered from malignant tumor proliferation.Therefore, the combined application of siVEGF and chemotherapeutic agents for simultaneous targetingof tumor proliferation and angiogenesis has been a research hotspot to explore a promising NSCLCtherapy regimen.
Methods: We designed, for the first time, a rational therapy strategy via intelligently co-deliveringsiVEGF and chemotherapeutics etoposide (ETO) by multi-functional nanoparticles (NPs) directed againstthe orthotopic NSCLC. These NPs consisted of cationic liposomes loaded with siVEGF and ETO andthen coated with versatile polymer PEGylated histidine-grafted chitosan-lipoic acid (PHCL). We thencomprehensively evaluated the anti-angiogenic and anti-proliferation efficiency in the in vitro tumor cellmodel and in bioluminescent orthotopic lung tumor bearing mice model.
Results: The NPs co-delivering siVEGF and ETO exhibited tailor-made surface charge reversal featuresin mimicking tumor extracellular environment with improved internal tumor penetration capacity andhigher cellular internalization. Furthermore, these NPs with flexible particles size triggered byintracellular acidic environment and redox environment showed pinpointed and sharp intracellular cargorelease guaranteeing adequate active drug concentration in tumor cells. Enhanced VEGF gene expressionsilencing efficacy and improved tumor cell anti-proliferation effect were demonstrated in vitro. In addition,the PHCL layer improved the stability of these NPs in neutral environment allowing enhanced orthotopiclung tumor targeting efficiency in vivo. The combined therapy by siVEGF and ETO co-delivered NPs fororthotopic NSCLC simultaneously inhibited tumor proliferation and tumor angiogenesis resulting inmore significant suppression of tumor growth and metastasis than monotherapy.
Conclusion: Combined application of siVEGF and ETO by the multi-functional NPs with excellent andon-demand properties exhibited the desired antitumor effect on the orthotopic lung tumor. Our workhas significant potential in promoting combined anti-angiogenesis therapy and chemotherapy regimen forclinical NSCLC treatment.
 Doxorubicin and siRNA-PD-L1 co-delivery with T7 modified ROS-sensitive nanoparticles for tumor chemoimmunotherapy.
Wan WJ+, Qu CX+, Zhou YJ+, Zhang L, Chen MT, Liu Y, You BG, Li F, Wang DD, Zhang XN*.
Int J Pharm,2019,566:731-744.DOI:10.1016/j.ijpharm. 2019.06.030，IF 4.213二区
Tumor cells avoid immunosurveillance during the tumorigenesis, metastasis and recurrence periods thanks to the overexpressed immunosuppressive molecules on their surface. For instance, the programmed cell death 1 ligand (PD-L1) binds with the T-cells’ programmed cell death receptor 1 (PD-1) impairing the anti-tumor activity of the host T cells. In this study, a new reactive oxygen species (ROS) responsive nanoparticle (NP), modified with the HAIYPRH (T7) peptide, was developed for the co-delivery of siRNA-PD-L1 and doxorubicin (Dox).These NPs can block the inhibitory signal responding to T cells and enhance cytotoxicity of Dox against tumor cells. The T7 modification binds to the overexpressed transferrin receptor on tumor cells facilitating its cellular uptake. Dox rapid release is then triggered by the high tumor cells cytoplasmic concentration of ROS, leading to cell apoptosis. Our results demonstrated these NPs exhibited a T7-mediated cellular uptake and an intracellular ROS-triggered payloads release in vitro. They also suggested an improved in vivo 4T1 tumor targeting efficiency and chemoimmunotherapy. Most notably, the co-delivery system exhibited a significantly enhanced antitumor effect over Dox-only loaded NPs following prompting the proliferation of T cells by siRNA-PD-L1. In conclusion,these ROS-responsive NPs provided a promising strategy to combine siRNA-PD-L1 immunotherapy and Dox chemotherapy.