Abstract

Bioresponsive nanoparticles (NPs) are of interest for anticancer nanomedicines, owing to the possibility to 'design in' selective modulation of drug release at target sites. Here we describe the double emulsion formulation of redox-responsive NPs based on modified polyethylene glycol (PEG)-co-poly(lactic-co-glycolic acid) (PLGA) block copolymers and oligo (β-aminoesters) (OBAE), both of which contained disulfide linkages, for the co-delivery of a cytotoxic small molecule drug and a nucleic acid. In particular, we focused our attention on docetaxel (DTX) and a siRNA against TUBB3, a gene that encodes for βIII-tubulin, in order to have a synergistic effect in the treatment of lung cancer. Spherical NPs of around 150 nm with negative zeta potential and high loading efficiencies of both drugs were obtained. Stability and release studies showed "on demand" drug release under reducing conditions. Unloaded NPs containing PEG-disulfide-PLGA and OBAE were well-tolerated by lung cancer cells, thus masking the intrinsic cytotoxicity of OBAE, while for intracellular siRNA delivery, redox responsive NPs demonstrated a higher cell internalization with a preferential cytoplasmic accumulation of siRNA, with a subsequent fast gene-silencing efficiency. The viability of cells treated with combined DTX/TUBB3-siRNA NPs significantly decreased as compared to NPs loaded only with DTX, thus showing an efficient combined anticancer effect, due to a substantial reduction of β-tubulin expression. Finally, in an in vivo feasibility study employing an orthotopic lung cancer model, NPs formulated with an anti-luciferase siRNA distributed throughout the lungs following oro-tracheal administration, and demonstrated effective gene knockdown and no apparent cytotoxicity. Taken together, these results show that the double emulsion formulated redox responsive PEG-PLGA and OBAE systems represent a promising new therapeutic approach for the local combined chemo- and gene-therapy of lung cancer.

Highlights

  • Lung cancer (LC) is one of the most common cancers worldwide and non-small cell lung cancer (NSCLC) accounts for approximately 85% of all LC cases.[1]

  • In order to develop effective inhalable NPs for pulmonary delivery, we have focused on redox responsive NPs based on a biodegradable and amphiphilic diblock copolymer containing a reducible disulfide bridge between poly(lactic-co-glycolic acid) (PLGA) and polyethylene glycol (PEG) blocks intended for the treatment of LC

  • We have decided to combine PLGA-block copolymers with OBAEs in the same nanoplatform to: (i) ensure the tolerability of the formulation due to the well-known safety of PLGA and PEG polymers; (ii) exploit the mucus penetrating properties of PEG, critical for a pulmonary administration; (iii) load with high efficiency a short-interfering RNA (siRNA) for the presence of the cationic OBAE in NP core, able to induce a proton sponge effect at cell level; (iv) load a second drug in the polymeric matrix of NPs, in order to have a combined effect with siRNA

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Summary

Introduction

Lung cancer (LC) is one of the most common cancers worldwide and non-small cell lung cancer (NSCLC) accounts for approximately 85% of all LC cases.[1]. Fig. S2† evidenced a partial release of siRNA from PLGA-SS-PEG NPs after incubation in GSH.

Results
Conclusion
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