A Multifunctional, Highly Biocompatible, and Double-Triggering Caramelized Nanotheranostic System Loaded with Fe3O4 and DOX for Combined Chemo-Photothermal Therapy and Real-Time Magnetic Resonance Imaging Monitoring of Triple Negative Breast Cancer

Fangqing Wang,1,* Nianlu Li,2,* Wenbo Wang,1 Long Ma,3 Yaru Sun,4 Hong Wang,1 Jinhua Zhan,5 Dexin Yu1 1Department of Radiology, Qilu Hospital, Shandong University, Affiliated Hospital of Shandong University, Jinan, 250012, People’s Republic of China; 2Physical and Chemical Laboratory, Shandong Academy of Occupational Health and Occupational Medicine, Affiliated Hospital of Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250002, People’s Republic of China; 3The Testing Center of Shandong Bureau of China Metallurgical Geology Bureau, Shandong Normal University, Jinan, 250014, People’s Republic of China; 4Department of Nuclear Medicine, The Second Hospital of Shandong University, Affiliated Hospital of Shandong University, Jinan, 250033, People’s Republic of China; 5School of Chemistry and Chemical Engineering, Shandong University, Jinan, 250100, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jinhua Zhan, School of Chemistry and Chemical Engineering, Shandong University, Jinan, 250100, People’s Republic of China, Email jhzhan@sdu.edu.cn Dexin Yu, Department of Radiology, Qilu Hospital, Shandong University, Affiliated Hospital of Shandong University, Jinan, 250012, People’s Republic of China, Tel +86-18560081629, Fax +86-531-86927544, Email yudexin0330@sina.comPurpose: Owing to lack of specific molecular targets, the current clinical therapeutic strategy for triple negative breast cancer (TNBC) is still limited. In recent years, some nanosystems for malignancy treatment have received considerable attention. In this study, we prepared caramelized nanospheres (CNSs) loaded with doxorubicin (DOX) and Fe3O4 to achieve the synergistic effect of combined therapy and real-time magnetic resonance imaging (MRI) monitoring, so as to improve the diagnosis and therapeutic effect of TNBC.Methods: CNSs with biocompatibility and unique optical properties were prepared by hydrothermal method, DOX and Fe3O4 were loaded on it to obtain Fe3O4/DOX@CNSs nanosystem. Characteristics including morphology, hydrodynamic size, zeta potentials and magnetic properties of Fe3O4/DOX@CNSs were evaluated. The DOX release was evaluated by different pH/near-infrared (NIR) light energy. Biosafety, pharmacokinetics, MRI and therapeutic treatment of Fe3O4@CNSs, DOX and Fe3O4/DOX@CNSs were examined in vitro or in vivo.Results: Fe3O4/DOX@CNSs has an average particle size of 160 nm and a zeta potential of 27.5mV, it demonstrated that Fe3O4/DOX@CNSs is a stable and homogeneous dispersed system. The hemolysis experiment of Fe3O4/DOX@CNSs proved that it can be used in vivo. Fe3O4/DOX@CNSs displayed high photothermal conversion efficiency, extensive pH/heat-induced DOX release. 70.3% DOX release is observed under the 808 nm laser in the pH = 5 PBS solution, obviously higher than pH = 5 (50.9%) and pH = 7.4 (less than 10%). Pharmacokinetic experiments indicated the t1/2β, and AUC0–t of Fe3O4/DOX@CNSs were 1.96 and 1.31 -fold higher than those of DOX solution, respectively. Additionally, Fe3O4/DOX@CNSs with NIR had the greatest tumor suppression in vitro and in vivo. Moreover, this nanosystem demonstrated distinct contrast enhancement on T2 MRI to achieve real-time imaging monitoring during treatment.Conclusion: Fe3O4/DOX@CNSs is a highly biocompatible, double-triggering and improved DOX bioavailability nanosystem that combines chemo-PTT and real-time MRI monitoring to achieve integration of diagnosis and treatment of TNBC.Keywords: caramelized nanotheranostic system, combining chemo-photothermal therapy, magnetic resonance imaging monitoring, double-triggering, triple negative breast cancer