Co-delivery of doxorubicin and RNA using pH-sensitive poly (β-amino ester) nanoparticles for reversal of multidrug resistance of breast cancer

An appropriate co-delivery system for chemotherapeutic agents and nucleic acid drugs will provide a more efficacious approach for the treatment of breast cancer by reversing multidrug resistance (MDR). In this work, a new amphiphilic poly (β-amino ester), poly[(1,4-butanediol)-diacrylate-β-5-polyethylenimine]-block-poly[(1,4-butanediol)-diacrylate-β-5-hydroxy amylamine] (PDP-PDHA) was synthesized, and the doxorubicin (DOX) and survivin-targeting shRNA (shSur) co-loading nanoparticle (PDNs) were prepared. The pH-sensitive poly[(1,4-butanediol) diacrylate-β-5-hydroxy amylamine] (PDHA) endowed PDNs both pH-triggered drug release characteristics and enhanced endo/lysosomal escape ability, thus improving the cytotoxicity of DOX and the transfection efficiency. PDNs also increased the DOX accumulation, down-regulated 57.7% survivin expression, induced 80.8% cell apoptosis and changed the cell cycle in MCF-7/ADR cells. In the MCF-7/ADR tumor-bearing mice models, after administrated intravenously, PDNs raised the accumulation of DOX and shSur in the tumor tissue by 10.4 and 20.2 folds, respectively, resulting in obvious inhibition of the tumor growth with tumor inhibiting rate of 95.9%. The combination of DOX and RNA interference showed synergistic effect on overcoming MDR. Therefore, PDNs could be a promising co-delivery vector for effective therapy of drug resistant breast cancer.