Pro-oxidant drug-loaded porphyrinic zirconium metal-organic-frameworks for cancer-specific sonodynamic therapy.

Sonodynamic therapy, which utilizes ultrasound (US) to produce cytotoxic reactive oxygen species (ROS), can overcome the critical drawbacks of photodynamic therapy, such as limited tissue penetration depth. However, the development of sonosensitizers having superior sonodynamic effects and desirable biocompatibility remains a major challenge. In this study, nanoscale zirconium-based porphyrinic metal organic frameworks (MOFs) (PCN-222) were developed as safe and effective nanosonosensitizers. Polyethylene glycol (PEG)-coated PCN-222 (PEG-PCN) was loaded with a pro-oxidant drug, piperlongumine (PL), to enable tumor-specific chemo-photodynamic combination therapy. Both PEG-PCN and PL-incorporated PEG-PCN (PL-PEG-PCN) showed high colloidal stability in biological media. In addition, nanoscale PL-PEG-PCN was efficiently internalized by breast cancer cells, leading to substantially increased ROS generation under US exposure. The effective intracellular delivery of PL by PEG-PCN further elevated the level of intracellular ROS in breast cancer cells owing to the pro-oxidative activity of PL. Therefore, PL-PEG-PCN revealed significantly higher sonotoxicity than free PL and PEG-PCN. Owing to the cancer-specific apoptosis triggered by PL, PL-PEG-PCN showed cancer-selective cell death in breast cancer cells compared with normal fibroblast cells. This study demonstrates that pro-oxidant drug-loaded porphyrinic MOFs are biocompatible and effective sonosensitizers for cancer-targeted chemo-sonodynamic combination therapy. Nanoscale zirconium-based porphyrinic metal organic frameworks (MOFs) were developed as safe and effective nanosonosensitizers. Pro-oxidant drug-loaded, PEG-coated porphyrinic MOFs under US irradiation excessively increased intracellular ROS levels in breast cancer cells, leading to efficient and cancer-targeted chemo-sonodynamic combination therapy. [Display omitted] ● Nanoscale zirconium-based porphyrinic metal organic frameworks (PEG-PCN) were developed as sonosensitizers. ● PL-loaded PEG-PCN showed higher sonotoxicity against MCF-7 breast cancer cells than normal hDFB cells. ● PL-loaded PEG-PCN excessively increased intracellular ROS in breast cancer cells under US irradiation. ● PL-loaded PEG-PCN achieved cancer-specific chemo-sonodynamic combination therapy. [ABSTRACT FROM AUTHOR]