Cerenkov Radiation-Induced Photodynamic Therapy Amplified by Magnetic Nanotheranostics

661 Objectives: Photodynamic therapy (PDT) has been widely used in fundamental research and clinical practice, but still suffered from tissue penetration limitation, light dependence, and low tumor uptake of photosensitizers. The interaction between radionuclides and nanomaterials could generate Cherenkov radiation (CR) and has provoked an emerging field that utilized such interaction for CR-induced PDT, which could overcome the disadvantages of traditional PDT. However, such CR interaction is not strong enough, leaving clinicians uncertain of the benefit of this novel PDT method. Our goal is to develop an amplified strategy to improve the therapeutic effects of CR-induced PDT. Methods: Herein, the magnetic vectors were used to greatly enhance the effects of CR-induced PDT under the presence of an external magnetic field, which provides a major step forward in photodynamic therapy. The magnetic nanoparticles (MNPs), namely, (Zn0.4Mn0.6)Fe2O4 nanoparticles, with 89Zr radiolabeling and porphyrin molecules (TCPP) conjugation (89Zr-MNPs/TCPP) were developed for CR-induced PDT with magnetic targeting tumor delivery. The labeled 89Zr on the surface of MNPs could be used for PET imaging to monitor the behavior of MNPs in vivo and intrinsically excited TCPP for singlet oxygen-mediated destruction of tumor cells without any requirement of external excitation. The magnetic-targeted CR-induced PDT was investigated on bilateral 4T1 tumor-bearing mice with a magnet being applied on the right tumor side for 3 h after intravenous injection of 89Zr-MNP/TCPP. Results: These MNPs showed high saturation magnetization with no hysteresis, which were highly sensitive to the external applied magnetic field. After PEGlyation, the radionuclide 89Zr was chelator-free labeled with MNP-PEG and relatively high labeling yields were achieved after incubation at 75 °C (about 60%). PET images of normal mice showed the 89Zr-MNP-PEG with a long circulation half-life of 2.46 h, and mainly accumulated in the liver and spleen within two weeks after injection. Importantly, the magnetic field (MF)-targeted tumors exhibited a higher accumulation of 89Zr-MNP-PEG (15.2 ± 4.8%ID/g at 3 h p.i.), which was 5 fold higher than that of nontargeted tumors. After conjugating TCPP on the surface of MNP-PEG (i.e., 89Zr-MNP/TCPP), the lasting generation of singlet oxygen (1O2) was found within one day, leading to decreased relative viabilities of the 4T1 cells at higher radioactivity levels. For in vivo studies, tumor growth of mice that received 89Zr-MNP/TCPP treatment with magnetic targeting was significantly inhibited, whereas rapid tumor growth was found for the MNP/TCPP-treated group. The whole process was further verified by fluorescence, Cherenkov luminescence, and Cherenkov resonance energy transfer imaging of tumors. CONCLUSION: Our findings revealed that 89Zr-MNP/TCPP nanostructures with efficient singlet oxygen generation could overcome the depth and light dependence of traditional PDT. The magnetism-targeted and enhanced CR-induced PDT has been demonstrated on bilateral 4T1 tumor-bearing mice, with rapid and significant inhibition of tumor growth in vivo under the presence of an external magnetic field. These magnetic nanostructures also displayed excellent magnetic targeting fluorescence, Cherenkov luminescence, and Cherenkov resonance energy transfer imaging to monitor the therapeutic effects of tumors. Overall, the strategy described herein is versatile and has great promise as an advanced phototherapy tool for treating a variety of lesions in clinics.