Codelivery of VEGF siRNA and Gemcitabine Monophosphate in a Single Nanoparticle Formulation for Effective Treatment of NSCLC

Abstract

There is an urgent need for new therapeutics for the treatment of aggressive and metastatic refractory human non-small-cell lung cancer (NSCLC). Antiangiogenesis therapy and chemotherapy are the two major treatment options. Unfortunately, both types of therapies when used individually have their disadvantages. Integrating antiangiogenesis therapy with chemotherapy is expected to target the tumor's vascular endothelial cells and the tumor cells simultaneously. In this study, we coformulated Vascular endothelial growth factor (VEGF) siRNA targeting VEGFs and gemcitabine monophosphate (GMP) into a single cell-specific, targeted lipid/calcium/phosphate (LCP) nanoparticle formulation. Antitumor effect of the combination therapy using LCP loaded with both VEGF siRNA and GMP was evaluated in both subcutaneous and orthotopic xenograft models of NSCLC with systemic administration. The improved therapeutic response, as compared with either VEGF siRNA or GMP therapy alone, was supported by the observation of 30-40% induction of tumor cell apoptosis, eightfold reduction of tumor cell proliferation and significant decrease of tumor microvessel density (MVD). The combination therapy led to dramatic inhibition of tumor growth, with little in vivo toxicity. In addition, the current studies demonstrated the possibility of incorporating multiple nucleic acid molecules and phosphorylated small-molecule drugs, targeting to different pathways, into a single nanoparticle formulation for profound therapeutic effect.

Nanocarriers for Delivery of siRNA and Co-Delivery of siRNA and Other Therapeutic Agents

“…The co-delivery formulation achieved complete inhibition of tumor growth in 8 days [112] Gemcitabine and C-MYC…”

“…To facilitate co-delivery, CaP-polymer or CaP-liposome hybrid delivery systems have been developed. Zhang et al loaded both VEGF siRNA and gemcitabine monophosphate in the CaP core of the targeted CaP-liposome (i.e., CaP core liposome shell nanoparticle, LCP) hybrid nanoparticle for the combination of chemotherapy and antiangiogenesis therapy (Figure 7) [112]. The co-delivery formulation achieved complete inhibition of tumor growth in 8 days.…”

Nanocomplexes for gene therapy of respiratory diseases: Targeting and overcoming the mucus barrier

“…Thus, Gemcitabine monophosphate (GMP) and vascular endothelial growth factor (VEGF) siRNA were entrapped into NPs composed of a calcium phosphate core coated with a single lipid bilayer (LCP) [139]. The antitumor effect of such LCP formulation was evaluated against H460 human non small-cell lung cancer (NSCLC) cells.…”

“…The antitumor effect of such LCP formulation was evaluated against H460 human non small-cell lung cancer (NSCLC) cells. It was found that the antiangiogenesis treatment with VEGF siRNA combined with the chemotherapy by GMP resulted in an additive antitumor effect better than with VEGF siRNA or GMP alone [139]. Finally, among the gene-silencing technique, miRNA recently gained a great deal of interest, also in lung diseases [116].…”

“Evolving nanoparticle gene delivery vectors for the liver: What has been learned in 30 years”

“…Small (30 nm) DNA calcium phosphate nanoparticles are not only endocytosed and trafficked through cells [103,104], but have been adapted for in vivo after encapsulation by cationic lipids. Calcium phosphate nanoparticles were modified with PEG and targeting ligand, and shown to produce efficient gene transfer of DNA, siRNA and mRNA in vivo [56,105,106]. Galactose targeted calcium phosphate nanoparticles resulted in the most efficient gene delivery system for liver hepatocytes reported to date [56] achieving a level of 1% transfection efficiency relative to dose matched hydrodynamic delivery.…”