Dual-responsive nanoparticles based on oxidized pullulan and a disulfide-containing poly(β-amino) ester for efficient delivery of genes and chemotherapeutic agents targeting hepatoma

Abstract

A dual-responsive nanoparticle system was designed based on oxidized pullulan (oxPL) and a disulfide-containing poly(β-amino) ester (ssPBAE) for the efficient delivery of genes and chemotherapeutic agents through polymer degradation responding to the tumor intracellular pH and redox state. oxPL containing abundant aldehyde groups was obtained through the periodate oxidation of pullulan. ssPBAE was modified with diethylenetriamine and then grafted onto oxPL by the Schiff's base reaction. Doxorubicin was conjugated to ssPBAE-oxPL via the acid-cleavable hydrazone bond, thus obtaining ssPBAE-oxPL-DOX in which the DOX content was about 3.6%. ssPBAE-oxPL-DOX exhibited in vitro hepatoma-targeting properties to some extent and good ability for condensing genes including plasmid DNA (pDNA) and fluorescein-labeled oligoDNA (FAM-DNA). ssPBAE-oxPL-DOX/pDNA nanoparticles had non-spherical shapes and relatively uniform sizes. The in vitro releases of DOX and pDNA from ssPBAE-oxPL-DOX/pDNA nanoparticles displayed significant pH- and redox-responsive properties. In hepatoma HepG2 cells, ssPBAE-oxPL-DOX/pDNA nanoparticles effectively inhibited cell proliferation, and induced cell apoptosis and cell cycle arrest at the S-phase. Moreover, ssPBAE-oxPL-DOX/FAM-DNA nanoparticles efficiently delivered DOX and FAM-DNA respectively into the nucleus and the cytoplasm in HepG2 cells, and also exhibited distinct hepatoma targeting properties in HepG2 tumor-bearing mice after intravenous injection. In summary, this novel dual-responsive nanoparticle system showed great potential for the combined gene therapy and chemotherapy on hepatoma.