PH-Sensitive pullulan-DOX conjugate nanoparticles for co-loading PDTC to suppress growth and chemoresistance of hepatocellular carcinoma.

Abstract

Chemoresistance is one of the primary causes of cancer treatment failure. Pyrrolidinedithiocarbamate (PDTC), a nuclear-factor-kappa B (NF-κB) inhibitor, was demonstrated to be able to overcome chemoresistance and enhance doxorubicin (DOX) efficacy as a chemotherapeutic sensitizer. Combination of a chemotherapeutic drug and a sensitizer has emerged as a promising strategy for cancer chemotherapy. To ensure that the drug and the sensitizer could be accurately delivered to the target region for further exerting their synergy, a safe and effective delivery system is highly desirable. In this work, we fabricated a pullulan-adipodihydrazide-doxorubicin conjugate as a carrier to co-load PDTC for achieving enhanced anti-tumor efficiency and suppressing chemoresistance through targeted delivery with a pH-responsive drug release pattern. The self-assembled Pu-DOX-PDTC nanoparticles with a diameter of 128.1-179.7 nm exhibited excellent size stability in a neutral physiological environment and rapid drug release under acidic conditions. In comparison with treatment by single loaded Pu-DOX nanoparticles, the combination chemotherapy using Pu-DOX-PDTC nanoparticles synergistically induced the apoptosis of DOX-sensitive HepG2 and DOX-resistant HepG2/ADR cells, and suppressed HepG2 and HepG2/ADR tumor growth in vivo. Hence, the Pu-DOX-PDTC nanoparticles exhibited great potential in overcoming chemoresistance in hepatoma cells and markedly improved overall treatment efficiency against hepatocellular carcinoma.