Dual pH- and Glutathione-Responsive CO₂-Generating Nanodrug Delivery System for Contrast-Enhanced Ultrasonography and Therapy of Prostate Cancer

Abstract

Ultrasonography (US) contrast imaging using US contrast agents has been widely applied for the diagnosis and differential diagnosis of tumors. Commercial US contrast agents have limited applications because of their large size and shorter imaging time. At the same time, the desired therapeutic purpose cannot be achieved by applying only conventional US contrast agents. The development of nanoscale US agents with US imaging and therapeutic functions has attracted increasing attention. In this study, we successfully developed DOX-loaded poly-1,6-hexanedithiol-sodium bicarbonate nanoparticles (DOX@HADT-SS-NaHCO₃ NPs) with pH-responsive NaHCO₃ and GSH-responsive disulfide linkages. DOX@HADT-SS-NaHCO₃ NPs underwent acid-triggered decomposition of NaHCO₃ to generate CO₂ bubbles and a reduction of disulfide linkages to further promote the release of CO₂ and DOX. The potential of DOX@HADT-SS-NaHCO₃ NPs for contrast-enhanced US imaging and therapy of prostate cancer was thoroughly evaluated using in vitro agarose gel phantoms and a C4-2 tumor-bearing nude mice model. These polymeric NPs displayed significantly enhanced US contrast at acidic pH and antitumor efficacy. Therefore, the NaHCO₃ and DOX-encapsulated polymeric NPs hold tremendous potential for effective US imaging and therapy of prostate cancer.