Multifunctional Nanosnowflakes for TI-T2 Double-Contrast Enhanced MRI and PAI Guided Oxygen Self-Supplementing Effective Anti-Tumor Therapy

Introduction: Accurate tumor diagnosis is essential to achieve the ideal therapeutic effect. However, it is difficult to accurately diagnose cancer using a single imaging method because of the technical limitations. Multimodal imaging plays an increasingly important role in tumor treatment. Photodynamic therapy (PDT) has received widespread attention in tumor treatment due to its high specificity and controllable photocytotoxicity. Nevertheless, PDT is susceptible to tumor microenvironment (TME) hypoxia, which greatly reduces the therapeutic effect of tumor treatment. Methods: In this study, a novel multifunctional nano-snowflake probe (USPIO@Mn[O.sub.2]@Ce6, UMC) for oxygen-enhanced photodynamic therapy was developed. We have fabricated the honeycomb-like Mn[O.sub.2] to co-load chlorin e6 (Ce6, a photosensitizer) and ultrasmall superparamagnetic iron oxide (USPIO, T1-T2 double contrast agent). Under the high [H.sub.2][O.sub.2] level of tumor cells, UMC efficiently degraded and triggered the exposure of photosensitizers to the generated oxygen, accelerating the production of reactive oxygen species (ROS) during PDT. Moreover, the resulting USPIO and [Mn.sup.2+] allow for MR T1-T2 imaging and transformable PAI for multimodal imaging-guided tumor therapy. Results: TEM and UV-vis spectroscopy results showed that nano-snowflake probe (UMC) was successfully synthesized, and the degradation of UMC was due to the pH/ [H.sub.2][O.sub.2] responsive properties. In vitro results indicated good uptake of UMC in 4T-1 cells, with maximal accumulation at 4 h. In vitro and in vivo experimental results showed their imaging capability for both T1-T2 MR and PA imaging, providing the potential for multimodal imaging-guided tumor therapy. Compared to the free Ce6, UMC exhibited enhanced treatment efficiency due to the production of [O.sub.2] with the assistance of 660 nm laser irradiation. In vivo experiments confirmed that UMC achieved oxygenated PDT under MR/PA imaging guidance in tumor-bearing mice and significantly inhibited tumor growth in tumor-bearing mice, exhibiting good biocompatibility and minimal side effects. Conclusion: The multimodal imaging contrast agent (UMC) not only can be used for MR and PA imaging but also has oxygen-enhanced PDT capabilities. These results suggest that UMC may have a good potential for further clinical application in the future. Keywords: photodynamic therapy, oxygen generation, magnetic resonance imaging, photoacoustic imaging, theranos