pH-Responsive magnetic nanocarriers for chelator-free bimodal (MRI/SPECT-CT) image-guided chemo-hyperthermia therapy in human breast carcinoma†

Although chemotherapy with magnetic nanocarriers has witnessed significant advancement in the field of cancer treatment, multimodal diagnosis and combinatorial therapy using a single nanoplatform will have much better efficacy in achieving superior results. Herein, we constructed a smart theranostic system by combining pH-sensitive tartaric acid-stabilized Fe₃O₄ magnetic nanocarriers (TMNCs) with SPECT imaging and a chemotherapeutic agent for image-guided chemo-hyperthermia therapy. The carboxyl-enriched exteriors of TMNCs provided sites for the conjugation of a chemotherapeutic drug (doxorubicin hydrochloride, DOX) and radiolabeling (¹⁴¹Ce). The usage of 145.4 keV gamma rays made this platform an ideal choice for in vivo SPECT-CT imaging, showing the retention of the nanoformulation in the tumor site even after 28 days. Further, TMNCs showed a very high transverse relaxation rate (r₂) of 171 mM⁻¹ s⁻¹, which is higher than that of clinically approved magnetic resonance imaging (MRI) contrast agents such as ferumoxtran (65 mM⁻¹ s⁻¹) and ferumoxides (120 mM⁻¹ s⁻¹). Further, the developed drug-loaded hybrid platform showed significantly higher cytotoxicity towards breast cancer cells, which was augmented by in vitro magnetic hyperthermia. Bright-field microscopy and cell cycle analysis suggested that cell death occurred through induction of G2-M arrest and subsequent apoptosis. These findings clearly suggest the potential of the developed hybrid nanoplatform for image-guided combination therapy.