Enhancing SDT Efficacy of Doxorubicin-Loaded Sonosensitizer Micelles to Overcome Resistance of Cancer Therapy by Optimizing Acoustic Parameters

Abstract

Tumor drug resistance has been reported to be associated with drug efflux in tumor cells. Recently, a noninvasive and safe mechanism, sonodynamic therapy (SDT), has been proposed to be an oxidative stress strategy to potentially overcome drug efflux, but with efficacy limitation. Herein, we propose a systematic strategy for optimizing SDT, especially revealing the key role of acoustics parameters acting in SDT efficiency. A doxorubicin (DOX)-loaded sonosensitive micelle (DPM) mediated “sono-force” combination (chemotherapy and sonodynamic) therapy strategy, named DPCSTs, which was designed for amplifying SDT to augment oxidative stress to overcome drug efflux and induce robust long-term inhibition of tumor development by optimized acoustic parameters. The sub-10 nm size DPM enhanced tumor targeting and renal clearance. Meanwhile, another important component, doxorubicin, significantly suppressed residual tumors (78.6%) due to “sono-force” augmented oxidative stress reversing drug efflux, finally leading to long-term tumor development limitation in vivo. It is the first time to propose a systematic strategy for optimizing SDT regimens to overcome resistance, which can synergize with chemotherapy to exert long-term tumor development inhibition. We believe that this work will advance SDT-related research to a new level, and improve our understanding of overcoming resistance of targeted cancer therapy.