T. N. Brusentsova

Evaluation of ferromagnetic fluids and suspensions for the site-specific radiofrequency-induced hyperthermia of MX11 sarcoma cells in vitro

Seventeen different ferromagnetic fluids and suspensions were prepared and evaluated for application in radiofrequency-induced hyperthermia. Specific power absorption rates were measured at 0.88 MHz to range from 0 to 240 W per gram of iron for different preparations. Survival of MX11 cells mixed with ferrofluids and subjected to radiofrequency was much lower than with RF without ferrofluid or ferrofluid alone.

Ferrimagnetic fluids and ferro- and ferrimagnetic suspensions for the RF-induction hyperthermia of tumors

Ferroand ferrimagnetic induction heating (hyperthermia) of tumors under the action of a radio-frequency (RF) electromagnetic field in the frequency ( f ) range from 0.1 to 1 MHz is used in experimental and clinical hyperthermic oncology [ 1 ]. The RF field comprises a sum of the electric and magnetic field components. The electric component induces electric charges on the surface of materials surrounding experimental animals and the operator [1, 2]. The electric charges may generate electric spark discharges known to be a factor of high toxicity. Protection against the undesired effects of the electric field is provided by the Faraday shield [3]. We have developed a series of ferrimagnetic fluids (FFs), based on dextran ferrite (DF) [ 4 10] and carboxymethyldextran ferrite (CMDF) [9], and ferrimagnetic suspensions (FSs) based on DF, CMDF, and reduced iron powder [ 7 17]. Exposed to an RF electromagnetic field, these media exhibit pyromagnetic properties in accordance with the principle of chemical, structural, and phase complexity [8, 10]. The ferroand ferrimagnetic nuclei in FFs and FSs convert the RF field energy into heat by various energy loss mechanisms, which results in heating of a zone where these nuclei are localized. The rate of heating, or the specific energy absorbed by the nuclei, depends on their size and structure [18]. Coincidence of the FF demagnetization curves measured at 77 and 293 K upon switch-off of the magnetic field indicates that the FF magnetization relaxation is related primarily to rotation of the internal magnetic moments in the particles [19, 20]. The specific absorbed energy and the total

Magnetic-Fluid Induction Regional Hyperthermia of Sarcoma

Development of magnetic-fluid systems for the hyperthermia of tumors is necessary for increasing the efficiency of multicomponent therapy programs and decreasing the number of inoperable tumors not amenable to treatment because of technical limitations. Recent achievements in the induction hyperthermia therapy of oncologic patients, based on the thermal treatment of tumor tissues at 43 – 45°C, have stimulated further progress in this direction [1]. We have developed a method for the synthesis of magnetic nanoparticles of dextran ferrite (DF) No. 363, which were successfully tested in magnetic-fluid induction regional hyperthermia experiments in vitro [2]. The DF particles in our magnetic fluids, characterized by a low toxicity both in mice (LD50 = 5 g kg at pH 7.4) and in other experimental animals [3], can be considered as the ideal magnetic media for the given purpose [4]. The DF particles dissipate the alternating magnetic field energy via various loss channels and produce hyperthermia in the region of their location [1, 2, 4 – 7]. In the experiments in vitro, the survival of sarcoma MX11 cells as a function of the time of exposure at 44°C for heating provided by magnetic fluids based on DF No. 363 under RF induction treatment at a frequency of 0.88 MHz and a magnetic induction of 7.2 kA m was equivalent to the same exposure on a water bath [2]. A still unsolved technical problem encountered in RF induction hyperthermia in vivo is the difficulty of providing for uniform heating of only the tumor tissue, without any damage to surrounding normal tissues. The purpose of this study was to assess applicability of magnetic fluids (MFs) based on DF No. 363 for RF induction hyperthermia of sarcoma MX11 in vivo at a frequency of 0.88 MHz, a magnetic induction of 9.3 kA m, and a power of 0.15 kW.

MRI‐Adaptive Magneto‐Thermo‐Chemotherapy for Improved Cancer Treatment

Dextran‐ferrite (DF) has been synthesized and tested as magnetic resonance imaging (MRI) negative contrast agent for tumors, invasions and metastases. MRI‐adaptive Magneto‐thermo‐chemotherapy (MTCT) by cisplatin (CP), melphalan (MP) and DF led to improved cancer treatment. MTCT by using AC magnetic field (0.88 MHz, 7.3 kA/m and 0.15 kW) was performed at early stages of oncogenesis at +46° C for 30 min using DF at a dose of 60 mg Fe/kg containing CP or MP. MTCT led to regression of adenocarcinoma Ca‐755 tumor ∼45 mm3 before metastases in female mice up to 40% and increasing of life span up to 280%. As for tumor ∼300 mm3 the use of MTCT with slime aspiration and the invasions of cyclophosphamide into metastases led to 200% increased life span.Dextran‐ferrite (DF) has been synthesized and tested as magnetic resonance imaging (MRI) negative contrast agent for tumors, invasions and metastases. MRI‐adaptive Magneto‐thermo‐chemotherapy (MTCT) by cisplatin (CP), melphalan (MP) and DF led to improved cancer treatment. MTCT by using AC magnetic field (0.88 MHz, 7.3 kA/m and 0.15 kW) was performed at early stages of oncogenesis at +46° C for 30 min using DF at a dose of 60 mg Fe/kg containing CP or MP. MTCT led to regression of adenocarcinoma Ca‐755 tumor ∼45 mm3 before metastases in female mice up to 40% and increasing of life span up to 280%. As for tumor ∼300 mm3 the use of MTCT with slime aspiration and the invasions of cyclophosphamide into metastases led to 200% increased life span.

Cytotoxicity of Photoheme-Containing Ferrimagnetic Fluid in Alternating Magnetic Field

Ferrimagnetic fluids suitable for magnetothermosensitization (MTS) of tumor cells in ac magnetic field were obtained by mixing photoheme (PH) and dextran ferrite (DF) sols. The mechanisms of the PH + DF-induced MTS most likely involves free-radical processes.

Increase in Photohem Cytotoxicity in a High-Frequency Magnetic Field

The decrease in survivability of cells containing photosensitive substances depends on the degree of excitation [1 – 12]. By the same token, the survival of cells containing magnetically sensitive agents and or substances excited by heating in the dark is determined by the degree of magnetic-field-induced excitation [5, 6] and or the thermal excitation [6, 7]. Hematoporphyrin (HP), its derivatives such as photohem (PH) [1 – 4], and other compounds which, being irradiated by light with a wavelength of 600 – 1000 nm, exhibit electron excitation with the formation of superoxide anions capable of producing singlet oxygen and thus increasing cytotoxicity belong to the class of photosensitizers. Previously, we have developed the PH analog photohem [1 – 4] and used this derivative in the process of photohem-induced magnetothermosensitization (MTS) of cells in the dark. Photohem is capable, by analogy with HP (Fig. 1) [9], of forming superoxide radical anions generating singlet oxygen, an agent destroying tumor cells. In the course of the MTS process, as well as during photosensitization, intercalated photohem particles may increase their ability to generate free radicals. As is known, histidine is capable of trapping singlet oxygen [5, 9]. The increase in the HP-induced damage during tumor cell hyperthermia was inhibited by -carotene (another well-known agent trapping singlet oxygen) or superoxide radical anion (O2 ), but not by mannitol (this agent traps only hydroxyl radicals). Hematoporphyrin and its derivatives also increase the radiosensitizing action of 2-deoxy-D-glucose on tumor cells, probably by reducing the energy spent for the reversible inhibition of DNA repair and increasing cytogenetic damage and tumor cell loss [9 – 11]. An analysis of the literature devoted to photohem (Russia) and its analog photofrin (USA and Canada) showed that

Biological Preparations for Diagnostics and Therapy of Oncologic Patients: Biocompatible Magnetic Carriers, Immunomagnetic Sorbents, Principles and Methods of Immunomagnetic Antigen Separation (A Review)

There are many papers devoted to the development and laboratory testing of magnetic-field-controlled preparations, magnetic systems for their delivery to tumors, devices for the induction heating of tumors, immunomagnetic sorbents, and magnetic separators [1 – 68]. Since only thoroughly tested magnetic preparations provided with exhaustive specification may be implemented into clinical practice, it was suggested to characterize magnetic fluids by the saturation magnetization Ms (State Standard GOST 492-73), density mf (GOST 18995.1-73), rheological parameters (GOST 26581-85), and toxicity values [1, 2, 31]. More than a decade has passed since the first proposals were published for the standardization of magnetic fluids developed for use in biology and medicine. An analysis of the data published in 1990 – 2000 on magnetic fluids and magnetic-field-controlled preparations for biomedical applications showed no positive response to the proposals. This situation led to an increasing number of uncompleted investigations (Table 1). In order to study magnetic-field-controlled systems and the corresponding application methods that are promising for introduction into clinical practice, we review scientific publications devoted to such magnetic preparations, immunomagnetic sorbents, and immunomagnetic antigen separators. Among the biocompatible highly dispersed ferroand ferrimagnets, the closest to the stage of preclinical testing are dextran ferrite (DF) [2 – 31, 40 – 52] and dextran magnetite [32, 33, 65]. The former compound is developed in many research centers of the Russian Academy of Sciences and Russian Academy of Medical Sciences, while the latter system is mostly studied in the USA and Germany (Tables 1 and 2). From the results of long-term test involving five batches of DF stored for eight years, it was concluded that a DF sol located in the arterial bed of tumors can be reliably controlled with the aid of an inhomogeneous constant magnetic field (ICMF) and effectively induction-heated at a frequency of f = 0.88 MHz, an RF field strength of H = 7.2 kA m, and a generator power of 0.15 kW, provided that the ferrite nuclei in DF are 9 – 12 nm in size (micelle diameter is usually 15 – 20 times greater) [26, 30, 31, 40 – 52]. Particles of this size are less subject to heteroand homocoagulation when DF solutions are stored both in vitro and in vivo (in the blood vessel endothelium of animals). This markedly reduces the danger of thrombosis, eliminates infarction development in vital organs [40 – 52], and allows a 30% DF sol with a specific saturation magnetization of 21 (A · m) kg to be stable in ICMFs with an induction of up to 4 T and an induction gradient, up to 0.3 T cm [5, 8, 14, 25, 26, 30, 49]. The specific energy absorption of commercial DF preparations, reaching 180 – 210 W (g Fe) at f = 0.88 MHz and H = 7.2 kA m, allows a 3 ml volume of the 30% DF sol to be induction-heated in an RF setup with a power of up to 1 kW at a rate of up to 5 K min [52, 66]. The maximum storage time of lyophilized DF preparations at –5°C is up to 8 years [49]. Prior to infusion into an artery supplying a tumor with blood, a DF sol has to be sterilized for 1 h at 100°C [14, 49]. The acute toxicity of DF tested on mice is characterized by LD50 = 5 g kg. DF exhibited neither pyrogenicity nor local irritation manifestations when introduced into the otic vein of rabbit at a dose of up to 1.5 g kg [51]. DF has passed successful laboratory tests as x-ray [29] and NMR [8] contrast agent.

Combined Photodynamic Thermochemotherapy of Glial Tumors Controlled by MRI and Electronic Sensor

As a result of consecutive intravenous injections of combination from 0.05 up to 1.0 ml 1.0-10 % sol Dextran-ferrite (DF), and 0.001-0.02 ml Magnevist contrast-enhansend (CE) MRI, have reduced to 4 days time of early visualization CE MRI of proliferation centres of glial tumor. Electron-touch mapping DF in a tumor and a liver have defined size of a ratio of contents DF in a tumor to contents DF in a liver ≥ 100 at which combined photodynamic magneto-thermochemotherapy, was preferable and have increased life span of rats with glioma C6 (GC6) up to 166% and at glioblastoma 101/8 (GB 101/8) up to 74%.