Zhiyu Zheng,1 Gareth R Williams,2 Honghua Guo,3 Yilu Zheng,1 Mengting Xiu,1 Yanyan Zhang,1 Huan Zhang,4 Kai Wang,5 Jindong Xia,3 Yu Wang,4,5 Li-Min Zhu1 

1College of Biological Science and Medical Engineering, Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, Donghua University, Shanghai, People’s Republic of China; 2UCL School of Pharmacy, University College London, London, UK; 3Department of Radiology, Songjiang Hospital Affiliated to Shanghai Jiaotong University of Medicine, Shanghai, People’s Republic of China; 4International Union Laboratory on Acupuncture Based Target Discovery, International Joint Laboratory on Acupuncture Neuro-Immunology, Shanghai Research Institute of Acupuncture and Meridian, Yue Yang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 5Experiment Center for Science and Technology, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China

Correspondence: Yu Wang, Email wyshcn@shutcm.edu.cn Li-Min Zhu, Email lzhu@dhu.edu.cn

Purpose: Owing to the limitations of single-mode cancer treatments, combination therapies have attracted much attention. However, constructing a platform for combination therapies in a simple and effective way and improving the overall treatment effect remains a challenge. Our aim was to combine sonodynamic therapy, radiotherapy and chemotherapy together and improve therapeutic outcomes within one nanoplatform.
Methods: In this work, we sought to exploit the properties of nanoscale heterojunctions to this end. A multifunctional Bi2O3-TiO2@polydopamine-doxorubicin (BTPD) nanoparticle platform was constructed as an anti-cancer theranostic. Under ultrasound irradiation, the Bi2O3-TiO2 core can generate singlet oxygen to damage tumor cells. Meanwhile, the high-Z Bi2O3 can attenuate the energy of X-rays and scatter secondary electrons to enhance radiation damage in the tumor. A thin coating of polydopamine (PDA) increases the biocompatibility but also gives the particles the ability for photoacoustic imaging. Doxorubicin, a DNA repair inhibitor which can hinder tumor recovery from radiation damage, was loaded onto the PDA.
Results: A comprehensive series of in vitro and in vivo assays demonstrated that the nanoparticles were effectively taken up into cancer cells, where they could induce ROS production and cause cell death. In vivo, this led to a marked reduction in tumor volume in a murine 4T1 cancer model.
Conclusion: The formulations developed here have significant potential for future investigation and exploration in the treatment of cancer.

Keywords: sonodynamic therapy, radiosensitization, DNA repair inhibition, combination therapy