Targeted co-delivery of Beclin 1 siRNA and FTY720 to hepatocellular carcinoma by calcium phosphate nanoparticles for enhanced anticancer efficacy

Abstract

PurposeFTY720, known as fingolimod, is a new immunosuppressive agent with effective anticancer properties. Although it was recently confirmed that FTY720 inhibits cancer cell proliferation, FTY720 can also induce protective autophagy and reduce cytotoxicity. Blocking autophagy with Beclin 1 siRNA after treatment with FTY720 promotes apoptosis. The objective of this study was to enhance the anticancer effect of FTY720 in hepatocellular carcinoma (HCC) by targeted co-delivery of FTY720 and Beclin 1 siRNA using calcium phosphate (CaP) nanoparticles (NPs).Materials and methodsFirst, the siRNA was encapsulated within the CaP core. To form an asymmetric lipid bilayer structure, we then used an anionic lipid for the inner leaflet and a cationic lipid for the outer leaflet; after removing chloroform by rotary evaporation, these lipids were dispersed in a saline solution with FTY720. The NPs were analyzed by transmission electron microscopy, dynamic light scattering and ultraviolet–visible spectrophotometry. Cancer cell viability and cell death were analyzed by MTT assays, fluorescence-activated cell sorting analysis and Western blotting. In addition, the in vivo effects of the NPs were investigated using an athymic nude mouse subcutaneous transplantation tumor model.ResultsWhen the CaP NPs, called LCP-II NPs, were loaded with FTY720 and siRNA, they exhibited the expected size and were internalized by cells. These NPs were stable in systemic circulation. Furthermore, co-delivery of FTY720 and Beclin 1 siRNA significantly increased cytotoxicity in vitro and in vivo compared with that caused by treatment with the free drug alone.ConclusionThe CaP NP system can be further developed for co-delivery of FTY720 and Beclin 1 siRNA to treat HCC, enhancing the anticancer efficacy of FTY720. Our findings provide a new insight into HCC treatment with co-delivered small molecules and siRNA, and these results can be readily translated into cancer clinical trials.

Therapeutic potential of Fingolimod in triple negative breast cancer preclinical models

“…2 ) which is equivalent of around 1 µg/mL. This anti-cancer effect is also observed at similar dosing in other tumor preclinical models [ 17 , 75 ]. Therefore, a higher dose of Fingolimod starting from 10 mg/day might represent an interesting clinical dosing for patients with cancer, suggesting that further clinical and safety investigations might be particularly useful.…”

Hepatitis�C virus nonstructural�5A protein inhibits the starvation‑induced apoptosis of hepatoblastoma cells by increasing Beclin�1 expression

“…Furthermore, miR-216a enhances the radiosensitivity of pancreatic cancer cells by suppressing Beclin 1-mediated autophagy (35). The combined delivery of Beclin 1 siRNA and FTY720 (a novel immunosuppressive agent with effective anticancer properties) more efficiently inhibits liver cancer cell progression by suppressing protective autophagy and increasing apoptosis (36), which is consistent with the results of the present study. The present study found that Beclin 1 inhibited p53, Bax, and cleaved caspase-3 expression in starved HepG2 cells.…”

Drug targeting strategies for liver cancer and other liver diseases

“…This review concluded that there are some new strategies available such as ligand mediated active targeting, nano carrier based RES uptake and some molecular conjugates of targeting ligands and active drugs that applicable to target effectively and killed the actively proliferating cancer cells, 68,69 and the available targeting ligands such as asialoglycoprotein, lactose and mannose, liver cancer cell specific antibodies, aptamers, avimers, bile acid conjugation, Collagen Type VI Receptor, Collagen Type VI Receptor and others ligands were successfully used for targeting liver cancer and further can be used for targeting and deliver anticancer drug or drug which are used to treatment of liver diseases. 70…”