Optimized Sonodynamic Therapy for Inhibiting Tumor Resistance and Development

Tumor drug resistance is often linked to drug efflux in tumor cells. Drug efflux in tumor cells is the process by which cancer cells actively pump out chemotherapy drugs, reducing their effectiveness and contributing to drug resistance. Recently, sonodynamic therapy (SDT), a noninvasive and safe oxidative stress-based approach, has been proposed as a potential strategy to overcome drug efflux. However, its efficacy remains limited, partly due to the poor therapeutic performance of traditional sonosensitizers. Acoustic parameters play a crucial role in SDT by influencing interactions between ultrasound, sonosensitizers, and target cells, yet this aspect has received little research attention.

Zhifei Dai, Peking University, Beijing, China, Yingjuan Zheng, The First Affiliated Hospital of Zhengzhou University, China, and colleagues have developed an optimized sonosensitizer by combining protoporphyrin molecules with hydrophilic polyethylene glycol (PEG), froming micelles with small particle size, excellent hydrophilicity, and enhanced accumulation in tumor tissues.

The researchers systematically evaluated the impact of various acoustic parameters on SDT efficacy and safety, examining acoustic intensity, pressure, duty cycle, and pulse repetition frequency, all under the mechanical and thermal effects induced by focused ultrasound. Through this, the researchers identified optimal parameters and demonstrated that SDT effectively eliminated tumors while ensuring safety.

The team further investgated whether the optimized SDT system could overcome tumor chemoresistance, a major challenge to chemotherapy. By encapsulating doxorubicin (DOX) within protoporphyrin micelles, the researchers created doxorubicin-loaded protoporphyrin micelles (DPM) and combined them with the optimized acoustic parameters to develop a synergistic “SDT + chemotherapy” system called DPCSTs. The researcher found that DPCSTs could effectively overcome chemoresistance, allowing DOX to exert its therapeutic effects. In a bilateral mouse model, the team confirmed that DPCSTs treatment significantly eliminated tumors at the treatment site while activating an anti-tumor immune response that inhibited distant tumors.