Characterization and antitumor effect of doxorubicin-loaded Fe3O4-Au nanocomposite synthesized by electron beam evaporation for magnetic nanotheranostics.

Magnetic nanocomposites (MNC) are promising theranostic platforms with tunable physicochemical properties allowing for remote drug delivery and multimodal imaging. Here, we developed doxorubicin-loaded Fe3O4-Au MNC (DOX-MNC) using electron beam physical vapor deposition (EB-PVD) in combination with magneto-mechanochemical synthesis to assess their antitumor effect on Walker-256 carcinosarcoma under the influence of a constant magnetic (CMF) and electromagnetic field (EMF) by comparing tumor growth kinetics, magnetic resonance imaging (MRI) scans and electron spin resonance (ESR) spectra. Transmission (TEM) and scanning electron microscopy (SEM) confirmed the formation of spherical magnetite nanoparticles with a discontinuous gold coating that did not significantly affect the ferromagnetic properties of MNC, as measured by vibrating-sample magnetometry (VSM). Tumor-bearing animals were divided into the control (no treatment), conventional doxorubicin (DOX), DOX-MNC and DOX-MNC + CMF + EMF groups. DOX-MNC + CMF + EMF resulted in 14% and 16% inhibition of tumor growth kinetics as compared with DOX and DOX-MNC, respectively. MRI visualization showed more substantial tumor necrotic changes after the combined treatment. Quantitative analysis of T2-weighted (T2W) images revealed the lowest value of skewness and a significant increase in tumor intensity in response to DOX-MNC + CMF + EMF as compared with the control (1.4 times), DOX (1.6 times) and DOX-MNC (1.8 times) groups. In addition, the lowest level of nitric oxide determined by ESR was found in DOX-MNC + CMF + EMF tumors, which was close to that of the muscle tissue in the contralateral limb. We propose that the reason for the relationship between the observed changes in MRI and ESR is the hyperfine interaction of nuclear and electron spins in mitochondria, as a source of free radical production. Therefore, these results point to the use of EB-PVD and magneto-mechanochemically synthesized Fe3O4-Au MNC loaded with DOX as a potential candidate for cancer magnetic nanotheranostic applications.

Combination Treatment with Liposomal Doxorubicin and Inductive Moderate Hyperthermia for Sarcoma Saos-2 Cells.

Despite efforts in osteosarcoma (OS) research, the role of inductive moderate hyperthermia (IMH) in delivering and enhancing the antitumor effect of liposomal doxorubicin formulations (LDOX) remains unresolved. This study investigated the effect of a combination treatment with LDOX and IMH on Saos-2 human OS cells. We compared cell viability using a trypan blue assay, apoptosis and reactive oxygen species (ROS) measured by flow cytometry and pro-apoptotic Bax protein expression examined by immunocytochemistry in response to IMH (42 MHz frequency, 15 W power for 30 min), LDOX (0.4 µg/mL), and LDOX plus IMH. The lower IC50 value of LDOX at 72 h indicated increased accumulation of the drug in the OS cells. LDOX plus IMH resulted in a 61% lower cell viability compared to no treatment. Moreover, IMH potentiated the LDOX action on the Saos-2 cells by promoting ROS production at temperatures of <42 °C. There was a 12% increase in cell populations undergoing early apoptosis with a less heterogeneous distribution of Bax after combination treatment compared to those treated with LDOX (p < 0.05). Therefore, we determined that IMH could enhance LDOX delivery and its antitumor effect via altered membrane permeabilization, ROS generation, and a lower level of visualized Bax heterogeneity in the Saos-2 cells, suggesting the potential translation of these findings into in vivo studies.

Nanotherapy based on magneto-mechanochemical modulation of tumor redox state.

Magnetic nanoparticles (MNs) are typically used as contrast agents for magnetic resonance imaging or as drug carriers with a remotely controlled delivery to the tumor. However, they can also potentiate the action of anticancer drugs under the influence of applied constant magnetic (CMFs) and electromagnetic fields (EMFs). This review demonstrates the role of magneto-mechanochemical effects produced by MNs alone and loaded with anticancer agents (MNCs) in response to CMFs and EMFs for modulation of tumor redox state. The combined treatment is suggested to act by two mechanisms: spin-dependent electron transport propagates free radical chain reactions, while magnetomechanical interactions cause conformational changes in drug molecules loaded onto MNs and generate reactive oxygen species (ROS). By adjusting the parameters of CMFs and EMFs during the magneto-mechanochemical synthesis and subsequent treatment, it is possible to modulate ROS production and switch redox signaling involved in ERK1/2 and NF-κB pathways from initiation of tumor growth to inhibition. Observations of tumor volume in different animal models and treatment combinations reported a 6%-70% reduction as compared with conventional drugs. Despite these results, there is a general lack of research in magnetic nanotheranostics that link redox changes across multiple levels of organization in the tumor-bearing host. Further multidisciplinary studies with more focus on the relationship between the electron transport processes in biomolecules and their effects on the tumor-host interaction should accelerate the clinical translation of magnetic nanotheranostics. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology.

Texture Analysis of Tumor and Peritumoral Tissues Based on 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Hybrid Imaging in Patients With Rectal Cancer.

OBJECTIVE: This study aimed to determine whether texture parameters could be used in differentiation between the tumor and the peritumoral tissues based on hybrid 18F-Fluorodeoxyglucose positron emission tomography/computed tomography imaging for patients with rectal cancer. METHODS: Seven parameters, including heterogeneity, entropy, energy, skewness, kurtosis, standard deviation, and average brightness, were extracted from positron emission tomography/computed tomography scans of 22 patients (12 male and 10 female; mean age, 61 ± 2 years). RESULTS: The peritumoral tissue had a significantly lower value of the heterogeneity parameter (23%) than the tumor. Tumor size (r = -0.48, P < 0.05) and extramural venous invasion scores (r = 0.64, P < 0.05) correlated with heterogeneity in the peritumoral tissue. There were significant differences (P < 0.05) in the correlation coefficients between men and women. CONCLUSIONS: Therefore, we provided additional quantitative information to differentiate the tumor from the peritumoral tissue and indicated possible application for extramural venous invasion evaluation in rectal cancer.

Effects induced by a 50 Hz electromagnetic field and doxorubicin on Walker-256 carcinosarcoma growth and hepatic redox state in rats.

We compare the effects of an extremely low-frequency electromagnetic field (EMF) with the chemotherapeutic agent doxorubicin (DOX) on tumor growth and the hepatic redox state in Walker-256 carcinosarcoma-bearing rats. Animals were divided into five groups with one control (no tumor) and four tumor-bearing groups: no treatment, DOX, DOX combined with EMF and EMF. While DOX and DOX + EMF provided greater inhibition of tumor growth, treatment with EMF alone resulted in some level of antitumor effect (p < .05). Superoxide dismutase, catalase activity and glutathione content were significantly decreased in the liver of tumor-bearing animals as compared with the control group (p < .05). The decreases in antioxidant defenses accompanied histological findings of suspected liver damage. However, hepatic levels of thiobarbituric acid reactive substances, an indicator of lipid peroxidation, were three times lower in EMF and DOX + EMF groups than in no treatment and DOX (p < .05). EMF and DOX + EMF showed significantly lower activity of serum ALT than DOX alone (p < .05). These results indicate that EMF treatment can inhibit tumor growth, causing less pronounced oxidative stress damage to the liver. Therefore, EMF can be used as a therapeutic strategy to influence the hepatic redox state and combat cancer with reduced side-effects.

Remote control of magnetic nanocomplexes for delivery and destruction of cancer cells.

Although nanotechnology advances have been exploited for a myriad of purposes, including cancer diagnostics and treatment, still there is little discussion about the mechanisms of remote control. Our main aim here is to explain the possibility of a magnetic field control over magnetic nanocomplexes to improve their delivery, controlled release and antitumor activity. In doing so we considered the nonlinear dynamics of magnetomechanical and magnetochemical effects based on free radical mechanisms in cancer development for future pre-clinical studies.

Efficacy of Combination Neoadjuvant Chemotherapy and Regional Inductive Moderate Hyperthermia in the Treatment of Patients With Locally Advanced Breast Cancer.

PURPOSE: To evaluate the efficacy of neoadjuvant chemotherapy in combination with regional inductive moderate hyperthermia for patients with locally advanced breast cancer. PATIENTS AND METHODS: 200 patients with stage IIB-IIIA breast cancer received neoadjuvant chemotherapy (control group, n = 97) or chemotherapy combined with hyperthermia (experimental group, n = 103). Inductive hyperthermia was set at 27.12 ± 0.16 MHz and the 50 W output power. RESULTS: Thermal and color Doppler ultrasound imaging demonstrated that hyperthermia increased the surface temperature on the breasts to < 4°Ð¡ while the mean values for systolic blood flow were 3.5 times as high as those prior to treatment. Assessment of tumor size and response found a (31.24 ± 3.85)% reduction in the size of the primary tumor in patients receiving chemotherapy + hyperthermia, while chemotherapy alone showed a (22.95 ± 3.61)% decrease on average (p = 0.034). The rate of objective response increased by 15.9% in the experimental group (р = 0.034) compared with the control group. The patients in the experimental group also had axillary lymph node regression of 14.17% greater than in the control group (p = 0.011). Moreover, the combination treatment allowed to increase the proportion of women eligible for breast-conserving and reconstructive surgery by 13.63% in the experimental group. The viable tumor volume was lower in patients receiving neoadjuvant chemotherapy + hyperthermia (24.4 ± 0.2)% compared with those given chemotherapy alone (30.4 ± 0.25)%. The 10-year overall survival rates were higher (log-rank: p = 0.009) in breast cancer patients who underwent chemotherapy combined with hyperthermia than in patients receiving chemotherapy only. CONCLUSION: The combination neoadjuvant chemotherapy and the technology of regional inductive moderate hyperthermia improved the efficacy of treatment for patients with locally advanced breast cancer staged IIB-IIIA.

The comparison between superparamagnetic and ferromagnetic iron oxide nanoparticles for cancer nanotherapy in the magnetic resonance system.

The paper aims to compare zeta potentials, magnetic properties, electron spin resonance, photoluminescence (PL) spectra and antitumor effect of magneto-mechano-chemically synthesized magneto-sensitive nanocomplexes loaded with the anticancer drug doxorubicin (DOXO) during nanotherapy of Walker-256 carcinosarcoma carried out by a magnetic resonance system. Diamagnetic DOXO acquired the properties of a paramagnetic substance after synthesis. MNC comprising superparamagnetic nanoparticles (NP) and DOXO had different g-factors, zeta potentials, a lower saturation magnetic moment, area of the hysteresis loop, and a higher coercivity compared to similar MNC with ferromagnetic NP. The main PL peak of MNC spectrum was defined by DOXO at 598 nm. MNC composed of superparamagnetic NP and DOXO showed a lower standard deviation of the normal PL spectral distribution than MNC based on ferromagnetic NP in relation to conventional DOXO. MNC containing superparamagnetic NP responded to resonance conditions leading to a more pronounced antitumor effect compared to MNC with ferromagnetic NP in the course of magnetic nanotherapy for Walker-256 carcinosarcoma bearing animals (temperature inside the tumor did not exceed 40 °C). Therefore, these findings are associated with differences in chemotherapeutic effect between MNC due to a different surface charge and conformational changes in DOXO molecules during its magnetoelectric interaction with single- and multidomain NP.

Nonlinear Magnetochemical Effects in Nanotherapy of Walker-256 Carcinosarcoma.

The biological and medical aspects of magnetochemical effects in nanotherapy of tumors remain poorly studied. The present paper investigates the influence of nonlinear magnetochemical effects of anisotropic magnetic nanodots on an animal tumor model. The magnetic properties and electron spin resonance spectra of magnetic nanodots and doxorubicin were investigated after mechano-magnetochemical synthesis. The results obtained from the analysis of nonlinear kinetics and survival in Walker-256 carcinosarcoma-bearing animals found a nonlinear dependence between the value of the growth factor, braking ratio, survival rate, tumor redox state, and the treatment by the magnetic nanodot combined with a nonuniform constant magnetic field. To quantify the heterogeneity in microphotographs of Walker-256 carcinosarcoma sections, we applied the entropy parameter. The control (no treatment) group showed the greatest heterogeneity. The lowest value of tumor heterogeneity among animals given treatment was found in groups with the minimum growth factor. Similarly, the lowest entropy value was found in muscle tissue taken from inoculation areas of the tumor. The evidence from this study concluded that inhomogeneous constant magnetic fields with different strength applied to heterogeneous tumor tissues induced different magnetic anisotropy in the magnetic nanodot which had a significant influence on the nonlinear kinetics, redox state, and histological pattern of the tumor.

Efficacy of Combined Regional Inductive Moderate Hyperthermia and Chemotherapy in Patients With Multiple Liver Metastases From Breast Cancer.

PURPOSE: Regional inductive moderate hyperthermia in combination with chemotherapy can improve the therapeutic efficacy in patients with breast cancer with multiple liver metastases. METHODS: The study included 103 patients with breast cancer with multiple liver metastases: 53 patients (main group) who received a combined chemotherapy (TC drug combination) and regional inductive moderate hyperthermia treatment and 50 patients (control group) who received chemotherapy (TC drug combination) alone. Regional inductive moderate hyperthermia exploited electromagnetic fields with an operating frequency of 27.17 ± 0.16 MHz and output power of 75 W. Treatment results were assessed by computed tomography and ultrasound imaging. RESULTS: Partial regression was defined as a 30% decrease in the sum of the maximum diameters of investigated tumors. In the current study, partial regression was described in 8 (15.1%) patients assigned to the main group and 2 (4%) patients in the control ( P < .05). The process stabilization was reported in 32 (60.4%) patients receiving the combined treatment and 19 (38%) in the control ( P < .05). Equally important, tumor progression was observed in 13 (24.5%) patients representing the main group and 29 (58%) in the control. During a 30-minute treatment session, a temperature increase overlaying greater than 90% of the liver projection exposed to electromagnetic irradiation was not exceeding 40°C. CONCLUSION: The combined regional inductive moderate hyperthermia and chemotherapy treatment increased the overall therapeutic efficacy by 33.9% (χ2 = 12.182; P < .01).

Nanomagnetic Modulation of Tumor Redox State.

Modulation of reactive oxygen and nitrogen species in a tumor could be exploited for nanotherapeutic benefits. We investigate the antitumor effect in Walker-256 carcinosarcoma of magnetic nanodots composed of doxorubicin-loaded Fe3O4 nanoparticles combined with electromagnetic fields. Treatment using the magnetic nanodot with the largest hysteresis loop area (3402 erg/g) had the greatest antitumor effect with the minimum growth factor 0.49 ± 0.02 day-1 (compared to 0.58 ± 0.02 day-1 for conventional doxorubicin). Electron spin resonance spectra of Walker-256 carcinosarcoma treated with the nanodots, indicate an increase of 2.7 times of free iron (that promotes the formation of highly reactive oxygen species), using the nanodot with the largest hysteresis loop area, compared to conventional doxorubicin treatment as well as increases in ubisemiquinone, lactoferrin, NO-FeS-proteins. Hence, we provide evidence that the designed magnetic nanodots can modulate the tumor redox state. We discuss the implications of these results for cancer nanotherapy.