Preparation and Characterization of F[e.sub.3][O.sub.4]@MTX Magnetic Nanoparticles for Thermochemotherapy of Primary Central Nervous System Lymphoma in vitro and in vivo

Background: Primary central nervous system lymphomas (PCNSL) are extranodal malignant non-Hodgkin lymphomas (NHL) that arise exclusively in central nervous system (CNS). Diffuse large B-cell lymphoma (DLBCL) is the most common histological subtype. Purpose: To evaluate whether nano drug-loading system-mediated magnetic-targeted thermo-chemotherapy could produce a better therapeutic effect than single chemotherapy while reducing the use of chemotherapeutic drugs. Methods: Six groups (control, F[e.sub.3][O.sub.4], MTX, F[e.sub.3][O.sub.4]@MTX, F[e.sub.3][O.sub.4] with hyperthermia and F[e.sub.3][O.sub.4]@MTX with hyperthermia) were set. Tumor cell apoptosis in each treatment group was detected by flow cytometry. Apoptosis-related gene expressions Caspase-3, Bax and Bcl-2 were detected by qPCR and Western blot; intracranial tumor model of PCNSL was established by intracranial injection of OCI-LY18 tumor cells into BALB/c-Nude mice. Magnetic resonance imaging (MRI) was used to monitor tumor progression and H&E staining was used to observe pathological changes of the tumor tissue. Results: In vitro, compared with chemotherapy alone, apoptosis rate of F[e.sub.3][O.sub.4]@MTX mediated thermochemotherapy group was significantly increased, and expression of apoptosis-inducing gene Caspase-3 and Bax were significantly upregulated in OCI-LY18 cells, while expression of apoptosis-inhibiting Bcl-2 gene was significantly downregulated. In vivo, MRI showed successful generation of intracranial tumor, and tumor volume was significantly smaller in combined thermo-chemotherapy group than in single chemotherapy group. H&E staining result of tumor tissues in each group was consistent with MRI; tumor cells were significantly reduced in thermochemotherapy group. Expression of apoptosis-related gene Caspase-3 and Bax were significantly upregulated in tumor tissues, while expression of Bcl-2 gene was significantly downregulated. Conclusion: These results demonstrated in vivo and in vitro that the combined thermo-chemotherapy of F[e.sub.3][O.sub.4]@MTX MNPs was superior to the single MTX chemotherapy with less dosage, which may promote apoptosis of DLBCL cells through the mitochondrial apoptotic pathway and provided a new way for the treatment of PCNSL. Keywords: primary central nervous lymphoma, PCNSL, F[e.sub.3][O.sub.4]@MTX magnetic nanoparticles, MNPs, hyperthermia, OCI-LY18 cells