Background Sonodynamic therapy (SDT) and its synergistic cancer therapy derivatives, such as combined chemotherapy-SDT (chemo-SDT), are promising approaches for tumor treatment. However, the main drawbacks restricting their applications are hypoxia in tumors and the reducing microenvironment or high glutathione (GSH) levels. Methods In this study, a hybrid metal MnO 2 was deposited onto nanoparticles fabricated using poly(lactic-co-glycolic acid) (PLGA), carrying docetaxel (DTX) and the sonosensitizer hematoporphyrin monomethyl ether (HMME) (PHD@MnO 2 ) via a one-step flash nanoprecipitation (FNP) method. Characterization and in vitro and in vivo experiments were conducted to explore the chemo-SDT effect of PHD@MnO 2 and evaluate the synergetic antitumor treatment of this nanosystem. Results When low-power ultrasound is applied, the acquired PHD@MnO 2 , whether in solution or in MCF-7 cells, generated ROS more efficiently than other groups without MnO 2 or those treated via monotherapy. Specifically, GSH-depletion was observed when MnO 2 was introduced into the system. PHD@MnO 2 presented good biocompatibility and biosafety in vitro and in vivo. These results indicated that the PHD@MnO 2 nanoparticles overcame hypoxia in tumor tissue and suppressed the expression of hypoxia-inducible factor 1 alpha (HIF-1α), achieving enhanced chemo-SDT. Conclusion This study provides a paradigm that rationally engineered multifunctional metal-hybrid nanoparticles can serve as an effective platform for augmenting the antitumor therapeutic efficiency of chemo-SDT.

Combined chemotherapy and sonodynamic therapy (chemo-SDT) based on the nanoplatform/nanocarrier is a potential antitumor strategy that has shown higher therapeutic efficacy than any monotherapy. Therefore, a safe and effective multifunctional system with a concise design and simple preparation process is urgently needed. In this work, by using a one-step cross-linking method, a multifunctional nanosystem, which employs phycocyanin nanoparticles (PCNPs) as a nanocarrier to deliver the chemotherapy drug docetaxel (DTX) and a nanosonosensitizer to generate reactive oxygen species (ROS), was prepared and evaluated (PCNP-DTX). Under low-intensity ultrasound irradiation, PCNP-DTX retained the ROS generation ability of phycocyanin and caused the destruction of mitochondrial potential. PCNP was also revealed to be an acidic and ultrasound-sensitive carrier with good biocompatibility. In addition to its cumulation behavior in tumors, PCNP can achieve tumor-targeted delivery and release of DTX. PCNP-DTX has also been proven to have a significant chemo-SDT synergy effect when low-intensity ultrasound was applied, showing enhanced antitumor activity both in vitro and in vivo. This study provides a concise yet promising nanoplatform based on the natural protein phycocyanin for achieving an effective, targeted, and synergetic chemo-SDT for antitumor therapy.

The development of novel sonosensitizers with safety and efficiency is a key problem in anti-tumor sonodynamic therapy. Phycocyanin (PC) has been proved to have the singlet oxygen radicals (ROS) generation ability, and the potential of PC as a novel sonosensitizer has been investigated. To overcome the disadvantages of PC in vivo, such as poor stability and low half-life, PC nanoparticles (PCNP) were prepared by the cross-linking method. According to the results, PCNP has been found with good morphology, good particle size distribution and good stability. Human breast cancer cell line MCF-7 was used to investigate PCNP cell uptake ability. ROS generation and cytotoxicity under ultrasonic irradiation (sonotoxicity) were also studied on this cell. Under the condition of 0.75 w/cm2 ultrasound, PCNP has a good ROS productivity and is equivalent to the sonotoxicity of the known sonosensitizer hematoporphyrin monomethyl Ether (HMME). In conclusion, PCNP is expected to be developed as an effective sonosensitizer for the sonodynamic therapy of tumors.