Preparation and Characterization of Fe3O4@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 thermochemotherapy could produce a better therapeutic effect than single chemotherapy while reducing the use of chemotherapeutic drugs. METHODS: Six groups (control, Fe3O4, MTX, Fe3O4@MTX, Fe3O4 with hyperthermia and Fe3O4@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 Fe3O4@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 thermochemotherapy 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 thermochemotherapy of Fe3O4@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.

Fe3O4@Au composite magnetic nanoparticles modified with cetuximab for targeted magneto-photothermal therapy of glioma cells.

BACKGROUND: Thermoresponsive nanoparticles have become an attractive candidate for designing combined multimodal therapy strategies because of the onset of hyperthermia and their advantages in synergistic cancer treatment. In this paper, novel cetuximab (C225)-encapsulated core-shell Fe3O4@Au magnetic nanoparticles (Fe3O4@Au-C225 composite-targeted MNPs) were created and applied as a therapeutic nanocarrier to conduct targeted magneto-photothermal therapy against glioma cells. METHODS: The core-shell Fe3O4@Au magnetic nanoparticles (MNPs) were prepared, and then C225 was further absorbed to synthesize Fe3O4@Au-C225 composite-targeted MNPs. Their morphology, mean particle size, zeta potential, optical property, magnetic property and thermal dynamic profiles were characterized. After that, the glioma-destructive effect of magnetic fluid hyperthermia (MFH) combined with near-infrared (NIR) hyperthermia mediated by Fe3O4@Au-C225 composite-targeted MNPs was evaluated through in vitro and in vivo experiments. RESULTS: The inhibitory and apoptotic rates of Fe3O4@Au-C225 composite-targeted MNPs-mediated combined hyperthermia (MFH+NIR) group were significantly higher than other groups in vitro and the marked upregulation of caspase-3, caspase-8, and caspase-9 expression indicated excellent antitumor effect by inducing intrinsic apoptosis. Furthermore, Fe3O4@Au-C225 composite-targeted MNPs-mediated combined hyperthermia (MFH+NIR) group exhibited significant tumor growth suppression compared with other groups in vivo. CONCLUSION: Our studies illustrated that Fe3O4@Au-C225 composite-targeted MNPs have great potential as a promising nanoplatform for human glioma therapy and could be of great value in medical use in the future.

Protective and restorative effects of the traditional Chinese medicine Jitai tablet against methamphetamine-induced dopaminergic neurotoxicity.

BACKGROUND: Methamphetamine (METH) is a psychostimulant with high abuse liability that affects the monoamine neurotransmitter systems, particularly the dopamine system. Currently there are no effective medications for the treatment of METH abuse to restore METH-induced dopaminergic dysfunction. The Jitai tablet (JTT), a commercial traditional Chinese medicinal preparation, has been shown to modulate the dopaminergic function both in heroin addicts and in morphine-dependent rats. The purpose of this study was to investigate, in a rodent model, whether JTT can protect against METH-induced neurotoxicity, and/or restore METH-damaged dopaminergic function. METHODS: Immunohistochemical staining and/or autoradiography staining were used to detect tyrosine hydroxylase (TH) expression in the substantia nigra, and to examine the levels of dopamine transporter (DAT), dopamine D2 receptor (D2R) and TH levels in the striatum. Using a stereotyped behavior rating scale, we evaluated the inhibitory effect of JTT on METH-induced behavioral sensitization. RESULTS: Repeated METH administration induced obvious stereotyped behavior and neurotoxicity on the dopaminergic system. Pre-treatment with JTT significantly attenuated METH-induced stereotyped responses, and interdicted METH-induced changes in the levels of DAT, D2R and TH expression. Treatment with JTT after METH administration restored DAT, D2R and TH expression to normal levels. CONCLUSIONS: Our results indicated that JTT protects against METH-induced neurotoxicity and restores the dopaminergic function, and thus might be a potential treatment for the dopaminergic deficits associated with METH abuse.

Longitudinal changes of dopamine transporters in heroin users during abstinence.

RATIONALE: Chronic exposure to heroin results in decreased dopamine transporter levels. Jitai tablets, a traditional Chinese medicine, have been effective at increasing striatal dopamine transporter availability after 6 months of treatment. However, it remains unknown how long the heroin-induced impairment persists and whether dopamine transporter can be normalized following long-term abstinence or treatment. OBJECTIVES: This study was to evaluate the time course of dopamine transporter changes in heroin users undergoing long-term abstinence and treatment with Jitai tablets for 1 year. METHODS: Single-photon emission computed tomography using [(99m)Tc]TRODAT-1 was performed on 64 heroin users and 20 healthy subjects to assess striatal dopamine transporter availability at baseline, 3, 6, and 12 months. Heroin users were randomly assigned to treatment with either placebo or Jitai tablets. Depression and anxiety scores were measured before each imaging session. RESULTS: Compared with healthy controls, significant reduction in dopamine transporter availability was found in heroin users at baseline in both the right (by ∼ 31.6%) and left striatum (by ∼ 33.2%). At 6 months, dopamine transporter availability was significantly higher in Jitai tablet-treated group than placebo group in the bilateral striatum (p < 0.01). At 12 months, dopamine transporter levels in both groups were upregulated substantially from baseline but still not recovered to normal levels in the left striatum (p < 0.05). Depression and anxiety scores significantly decreased at 3, 6, and 12 months (p < 0.05). CONCLUSIONS: Our results confirmed that heroin abuse induces pronounced, long-term reduction in dopamine transporter. Treatment with Jitai tablets appears to stimulate recovery.

Silver nanocrystals mediated combination therapy of radiation with magnetic hyperthermia on glioma cells.

Based on the study of apoptosis-induced and anti-proliferation behavior of silver nanoparticles (AgNPs) on cancer cells, the attractively therapeutic effect and potential application of AgNPs in anti-cancer field was gradually revealed. Here we investigated the effect of 10 nm silver nanoparticles (AgNPs) on human glioma U251 cells upon the combination treatment of ionizing radiation (IR) treatment with magnetic hyperthermia (MHT). AgNPs showed both radio and thermo sensitivity on U251 cells from the surviving fraction curve. Besides, we found both X-rays and heat could enhance the content of cells uptake of AgNPs. As the amount of intracellular AgNPs accumulated, the apoptosis rate of U251 cells enhanced. Furthermore, we established a simplified model for calculating cell survival rate and demonstrated that after RT, MHT and RT combined with MHT, AgNPs could significantly inhibited cancer cell proliferation. Our results revealed that AgNPs could have a potential application in enhancing effect of RT with MHT combination therapy induced killing of cancer cells.

Silver nanocrystals sensitize magnetic-nanoparticle-mediated thermo-induced killing of cancer cells.

Magnetic nanoparticles (MNPs) can heat up tumor tissues and induce killing of cancer cells under external AC magnetic field. However, magnetic nanoparticles hyperthermia (MNPH) requires high concentration of MNPs that are injected into the tumor in order to obtain clinically needed thermal dose because of the complicated heat transfer in vivo and the limited heat quality of MNPs. To cut down the dose of MNPs and enhance the effect of this Nanotherapy, we prepared silver nanoparticles (AgNPs) with different sizes and investigated the effects of these AgNPs on cancer cells in MNPH treatment. It was found that AgNPs could enhance thermo-sensitivity of glioma cells and this effect was size dependent. AgNPs could induce cell cycles arrested in G(2)/M phase and enhanced the apoptosis rate of cancer cells after hyperthermia. In glioma bearing rats model, MNPH combined with AgNPs could enhance Bax expression in cancer cells. Our results suggested that AgNPs could be a potential thermo-sensitizer and could be further developed for the design of Ag nanostructure-based thermal seeds for MNPH therapy.

Thermal analysis in the rat glioma model during directly multipoint injection hyperthermia incorporating magnetic nanoparticles.

Hyperthermia incorporating magnetic nanoparticles (MNPs) is a hopeful therapy to cancers and steps into clinical tests at present. However, the clinical plan of MNPs deposition in tumors, especially applied for directly multipoint injection hyperthermia (DMIH), and the information of temperature rise in tumors by DMIH is lack of studied. In this paper, we mainly discussed thermal distributions induced by MNPs in the rat brain tumors during DMIH. Due to limited experimental measurement for detecting thermal dose of tumors, and in order to acquire optimized results of temperature distributions clinically needed, we designed the thermal model in which three types of MNPs injection for hyperthermia treatments were simulated. The simulated results showed that MNPs injection plan played an important role in determining thermal distribution, as well as the overall dose of MNPs injected. We found that as injected points enhanced, the difference of temperature in the whole tumor volume decreased. Moreover, from temperature detecting data by Fiber Optic Temperature Sensors (FOTSs) in glioma bearing rats during MNPs hyperthermia, we found the temperature errors by FOTSs reduced as the number of points injected enhanced. Finally, the results showed that the simulations are preferable and the optimized plans of the numbers and spatial positions of MNPs points injected are essential during direct injection hyperthermia.