Large-scale synthesis of monodisperse Prussian blue nanoparticles for cancer theranostics via an “in situ modification” strategy

Yanjun Xu,1,* Yang Zhang,2,* Xiaojun Cai,1,2 Wei Gao,1,2 Xiuzhen Tang,3 Yini Chen,1,2 Jie Chen,1,2 Li Chen,1,2 Qiwei Tian,4 Shiping Yang,4 Yuanyi Zheng,1,3 Bing Hu2 1Department of Ultrasound in Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China; 2Department of Ultrasound in Medicine, Shanghai Institute of Ultrasound in Medicine, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai 200233, China; 3Department of Ultrasound in Medicine, Institute of Ultrasound Imaging, Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, China; 4Department of Chemistry, Shanghai Normal University, Shanghai 200234, China *These authors contributed equally to this work Background: The intrinsic properties of Prussian blue (PB) nanoparticles make them an attractive tool in nanomedicine, including magnetic resonance imaging (MRI), photoacoustic imaging (PAI), and photothermal therapy (PTT) properties. However, there still remains the challenge of their poor dispersible stability in the physiological environment. In this study, we developed an efficient hydrothermal method to address the poor dispersible stability of PB nanoparticles in the physiological environment. Materials and methods: The concentration of H+, the mass of polyvinylpyrrolidone (PVP), and iron sources (K3[Fe(CN)6]) are very vital in the preparation of PB nanoparticles. Through exploring the preparation process, optimized PB nanoparticles (OPBs) with excellent physiological stability were prepared. Hydrodynamic diameter and UV-vis absorption properties were measured to verify the stability of the prepared OPBs. Properties of dual-mode imaging, including MRI/PAI, and PTT of OPBs were investigated both in vitro and in vivo. In addition, the in vivo biosafety of OPBs was systematically assessed. Results: OPBs were stable in different environments including various media, pH, and temperatures for at least 90 days, indicating that they are suitable for biomedical application via intravenous administration and easily stored in a robust environment. Compared with other research into the synthesis of PB nanoparticles, the “in situ modification” synthesis of PB nanoparticles had advantages, including a simple process, low cost, and easy mass preparation. OPBs showed no significant signs of toxicity for 90 days. As a proof of concept, the OPBs served as dual-mode image contrast agents and photothermal conversion agents for cancer diagnosis and therapy both in vitro and in vivo. Conclusion: Our findings suggest a facile but efficient strategy with low cost to address the poor dispersible stability of PB nanoparticles in physiological environments. This will promote the development of further clinical transformations of PB nanoparticles, especially in cancer theranostics. Keywords: nanomedicine, magnetic resonance imaging, photoacoustic imaging, photothermal therapy, stability