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Prijic S.,Nanotesla Institute | Scancar J.,Jozef Stefan Institute | Romih R.,University of Ljubljana | Cemazar M.,Institute of Oncology Ljubljana | And 3 more authors.
Journal of Membrane Biology | Year: 2010

Superparamagnetic iron oxide nanoparticles (SPIONs) are used as delivery systems for different therapeutics including nucleic acids for magnetofection-mediated gene therapy. The aim of our study was to evaluate physicochemical properties, biocompatibility, cellular uptake and trafficking pathways of the custom-synthesized SPIONs for their potential use in magnetofection. Custom-synthesized SPIONs were tested for size, shape, crystalline composition and magnetic behavior using a transmission electron microscope, X-ray diffractometer and magnetometer. SPIONs were dispersed in different aqueous media to obtain ferrofluids, which were tested for pH and stability using a pH meter and zetameter. Cytotoxicity was determined using the MTS and clonogenic assays. Cellular uptake and trafficking pathways were qualitatively evaluated by transmission electron microscopy and quantitatively by inductively coupled plasma atomic emission spectrometry. SPIONs were composed of an iron oxide core with a diameter of 8-9 nm, coated with a 2-nm-thick layer of silica. SPIONs, dispersed in 0.9% NaCl solution, resulted in a stable ferrofluid at physiological pH for several months. SPIONs were not cytotoxic in a broad range of concentrations and were readily internalized into different cells by endocytosis. Exposure to neodymium-iron-boron magnets significantly increased the cellular uptake of SPIONs, predominantly into malignant cells. The prepared SPIONs displayed adequate physicochemical and biomedical properties for potential use in magnetofection. Their cellular uptake was dependent on the cell type, and their accumulation within the cells was dependent on the duration of exposure to an external magnetic field. © 2010 The Author(s).


Bregar V.B.,Nanotesla Institute | Pavlin M.,Nanotesla Institute | Pavlin M.,University of Ljubljana | Znidarsic A.,Nanotesla Institute
AIP Conference Proceedings | Year: 2010

We examined magnetization states of agglomerates for two types of nanoparticle agglomerate systems, where primary crystallites have either blocked magnetization or are superparamagnetic at room temperature. We determined the magnetization state of the agglomerates with measuring magnetic permeability as a function of frequency and measuring magnetization as a function of temperature for zero-field cooled and field-cooled samples. Then we examined specifically the magnetization state of agglomerates made from blocked crystallites and we used magnetic flux measurements at different magnetic conditions. Our results show that in the case of superparamagnetic behavior of individual crystallites also the agglomerate can retain superparamagnetic behavior, whereas for crystallites with blocked magnetization nonuniform magnetization state of the agglomerate is possible. © 2010 American Institute of Physics.


Music B.,Helios Domzale D.d. | Venturini P.,Helios Domzale D.d. | Znidarsic A.,Nanotesla Institute
Ceramics International | Year: 2012

We have investigated an organic resin solution designed for EM wave absorption based on a magnetic filler, composed of phases within the Mn 0.66Zn0.27Fe2.07O4 system, embedded in an absorber composite with concentration ratios of 50:50, 75:25 and 90:10 by weight. The formation of the manganese zinc ferrite particles, as the principal magnetic phases, was achieved via the conventional ceramic method. The electromagnetic parameters of the composites were measured with a vector network analyser at 100 MHz to 10 GHz. The subject of the paper was a study of the electromagnetic absorber properties and the rheological properties of the resin composite based on ferrite particles with respect to using the materials in architectural coatings. © 2011 Elsevier Ltd and Techna Group S.r.l.


Prijic S.,Nanotesla Institute | Prosen L.,Nanotesla Institute | Cemazar M.,Institute of Oncology Ljubljana | Cemazar M.,University of Primorska | And 8 more authors.
Biomaterials | Year: 2012

Cancer immuno-gene therapy is an introduction of nucleic acids encoding immunostimulatory proteins, such as cytokine interleukin 12 (IL-12), into somatic cells to stimulate an immune response against a tumor. Various methods can be used for the introduction of nucleic acids into cells; magnetofection involves binding of nucleic acids to magnetic nanoparticles with subsequent exposure to an external magnetic field. Here we show that surface modified superparamagnetic iron oxide nanoparticles (SPIONs) with a combination of polyacrylic acid (PAA) and polyethylenimine (PEI) (SPIONs-PAA-PEI) proved to be safe and effective for magnetofection of cells and tumors in mice. Magnetofection of cells with plasmid DNA encoding reporter gene using SPIONs-PAA-PEI was superior in transfection efficiency to commercially available SPIONs. Magnetofection of murine mammary adenocarcinoma with plasmid DNA encoding IL-12 using SPIONs-PAA-PEI resulted in significant antitumor effect and could be further refined for cancer immuno-gene therapy. © 2012 Elsevier Ltd.


Bosnjak M.,Institute of Oncology Ljubljana | Prosen L.,Nanotesla Institute | Dolinsek T.,Institute of Oncology Ljubljana | Blagus T.,Institute of Oncology Ljubljana | And 5 more authors.
Journal of Membrane Biology | Year: 2013

The data on the biological responsiveness of melanoma and endothelial cells that are targeted by Antiangiogenic MEtargidin Peptide (AMEP) are limited; therefore, the antiproliferative, antimetastatic and antiangiogenic effects of AMEP were investigated in murine melanoma and human endothelial cells after plasmid AMEP gene electrotransfer into the cells in vitro. Plasmid AMEP, a plasmid coding for the disintegrin domain of metargidin targeting specific integrins, had cytotoxic and antiproliferative effects on murine melanoma and human endothelial cells. Among the metastatic properties of cells, migration, invasion and adhesion were investigated. Plasmid AMEP strongly affected the migration of murine melanoma and human endothelial cell lines and also affected the invasion of highly metastatic murine melanoma B16F10 and human endothelial cell lines. There was no effect on cell adhesion on MatrigelTM or fibronectin in all cell lines. The antiangiogenic effect was shown with tube formation assay, where human microvascular endothelial cell line (HMEC-1) proved to be more sensitive to plasmid AMEP gene electrotransfer than the human umbilical vein endothelial cell line (HUVEC). The study indicates that antiproliferative and antimetastatic biological responses to gene electrotransfer of plasmid AMEP in murine melanoma cells were dependent on the integrin quantity on melanoma cells and not on the expression level of AMEP. The strong antiangiogenic effect expressed in human endothelial cell lines was only partly dependent on the quantity of integrins and seemed to be plasmid AMEP dose dependent. © 2013 Springer Science+Business Media New York.


Prijic S.,Nanotesla Institute | Sersa G.,Institute of Oncology Ljubljana
Radiology and Oncology | Year: 2011

Background. Many different types of nanoparticles, magnetic nanoparticles being just a category among them, offer exciting opportunities for technologies at the interfaces between chemistry, physics and biology. Some magnetic nanoparticles have already been utilized in clinical practice as contrast enhancing agents for magnetic resonance imaging (MRI). However, their physicochemical properties are constantly being improved upon also for other biological applications, such as magnetically-guided delivery systems for different therapeutics. By exposure of magnetic nanoparticles with attached therapeutics to an external magnetic field with appropriate characteristics, they are concentrated and retained at the preferred site which enables the targeted delivery of therapeutics to the desired spot. Conclusions. The idea of binding chemotherapeutics to magnetic nanoparticles has been around for 30 years, however, no magnetic nanoparticles as delivery systems have yet been approved for clinical practice. Recently, binding of nucleic acids to magnetic nanoparticles has been demonstrated as a successful non-viral transfection method of different cell lines in vitro. With the optimization of this method called magnetofection, it will hopefully become another form of gene delivery for the treatment of cancer.


Sedlar A.,Institute of Oncology Ljubljana | Dolinsek T.,Institute of Oncology Ljubljana | Markelc B.,Institute of Oncology Ljubljana | Prosen L.,Nanotesla Institute | And 6 more authors.
Radiology and Oncology | Year: 2012

Background. Electrochemotherapy provides good local tumor control but requires adjuvant treatment for increased local response and action on distant metastasis. In relation to this, intramuscular interleukin-12 (IL-12) gene electrotransfer, which provides systemic shedding of IL-12, was combined with local electrochemotherapy with cisplatin. Furthermore, the dependence on tumor immunogenicity and immunocompetence of the host on combined treatment response was evaluated. Materials and methods. Sensitivity of SA-1 sarcoma and TS/A carcinoma cells to electrochemotherapy with cisplatin was tested in vitro. In vivo, intratumoral electrochemotherapy with cisplatin (day 1) was combined with a single (day 0) or multiple (days 0, 2, 4) intramuscular murine IL-12 (mIL-12) gene electrotransfer. The antitumor effectiveness of combined treatment was evaluated on immunogenic murine SA-1 sarcoma in A/J mice and moderately immunogenic murine TS/A carcinoma, in immunocompetent BALB/c and immunodeficient SCID mice. Results. Electrochemotherapy in vitro resulted in a similar IC 50 values for both sarcoma and carcinoma cell lines. However, in vivo electrochemotherapy was more effective in the treatment of sarcoma, the more immunogenic of the tumors, resulting in a higher log cell kill, longer specific tumor growth delay, and also 17% tumor cures compared to carcinoma where no tumor cures were observed. Adjuvant intramuscular mIL-12 gene electrotransfer increased the log cell kill in both tumor models, potentiating the specific tumor growth delay by a factor of 1.8-2 and increasing tumor cure rate by approximately 20%. In sarcoma tumors, the potentiation of the response by intramuscular mIL- 12 gene electrotransfer was dose-dependent and also resulted in a faster onset of tumor cures. Comparison of the carcinoma response to the combined treatment modality in immunocompetent and immunodeficient mice demonstrated that the immune system is needed both for increased cell kill and for attaining tumor cures. Conclusions. Based on the comparison of the antitumor effectiveness of electrochemotherapy to intratumoral cisplatin administration, we can conclude that the fraction of cells killed and the tumor cure rate are higher in immunogenic sarcoma tumor compared to moderately immunogenic carcinoma tumor. The tumor cell kill and cure rate depend on the immune response elicited by the destroyed tumor cells, which might depend on the tumor immunogenicity. The effect of adjuvant intramuscular mIL-12 gene electrotransfer is dependent on the amount of IL-12 in the system and the immune competence of the host, as demonstrated by the dose-dependent increase in the cure rate of SA-1 tumors after multiple intramuscular mIL-12 gene electrotransfer and in the differential cure rate of TS/A tumors growing in immunocompetent and immunodeficient mice.


Godnjavec J.,Helios Domzale D.d | Znoj B.,Helios Domzale D.d | Venturini P.,Helios Domzale D.d | Znidarsic A.,Nanotesla Institute
Informacije MIDEM | Year: 2010

Nano - crystalline titanium dioxide (TiO 2) in rutile crystal form, generally used to indicate particles less than 100 nm in diameter, is mainly applied as pigment, adsorbent and UV absorber. The incorporation of a nano-sized titanium dioxide powder into a liquid media is made by dispersion process, that the final product consists of fine particles distribution throught the medium. So it is regarded as necessary for us to investigate in detail the factors which may have important effect upon the homogenious distribution of TiO 2 nanoparticles in clearcoat as liquid media. In this work, titanium dioxide nano-powders were prepared by the co-precipitation method. Using various techniques, including transmission electron microscopy (TEM) and X-ray diffraction (XRD), obtained powders were studied in order to find the possible elements of affecting the microstructures and grain size. The aim of this study is to determine the photostabilisation efficiency of TiO 2 in a clear coat as UV absorber considering the preparation of stable dispersions by using different surfactants and percentage of TiO 2. titanium dioxide, rutile, co-precipitation method, UV absorber, surfactant Helios Domžale, d.d., Količevo 2, p.p. 127, 1230 Domžale, Slovenia.


Drmota A.,Nanotesla Institute | Znidarsic A.,Nanotesla Institute | Koask A.,Nanotesla Institute
Journal of Physics: Conference Series | Year: 2010

Strontium hexaferrite (SrFe12O19) nanoparticles have been prepared with co-precipitation in aqueous solutions and precipitation in microemulsion system water/SDS/n-butanol/cyclohexane, using iron and strontium nitrates in different molar rations as a starting materials. The mixed Sr 2+, Fe3+ hydroxide precursors obtained during the reaction between corresponding metal nitrates and tetramethylammonium hydroxide (TMAH), which served as a precipitating reagent, were calcined in a wide temperature range, from 350 °C to 1000 °C in a static air atmosphere. The influence of the Sr2+/Fe3+ molar ratio and the calcination temperature to the chemistry of the product formation, its crystallite size, morphology and magnetic properties were investigated. It was found that the formation of single phase SrFe12O19 with relatively high specific magnetization (54 Am2/kg) was achieved at the Sr 2+/Fe3+ molar ration of 6.4 and calcination at 800 °C for 3h with heating/cooling rate 5 °C/min. The prepared powders were characterized using X-ray diffractometry (XRD) and specific surface area measurements (BET). The specific magnetization (DSM-10, magneto-susceptometer) of the prepared samples was measured. © 2010 IOP Publishing Ltd.


PubMed | Nanotesla Institute
Type: Journal Article | Journal: Biomaterials | Year: 2012

Cancer immuno-gene therapy is an introduction of nucleic acids encoding immunostimulatory proteins, such as cytokine interleukin 12 (IL-12), into somatic cells to stimulate an immune response against a tumor. Various methods can be used for the introduction of nucleic acids into cells; magnetofection involves binding of nucleic acids to magnetic nanoparticles with subsequent exposure to an external magnetic field. Here we show that surface modified superparamagnetic iron oxide nanoparticles (SPIONs) with a combination of polyacrylic acid (PAA) and polyethylenimine (PEI) (SPIONs-PAA-PEI) proved to be safe and effective for magnetofection of cells and tumors in mice. Magnetofection of cells with plasmid DNA encoding reporter gene using SPIONs-PAA-PEI was superior in transfection efficiency to commercially available SPIONs. Magnetofection of murine mammary adenocarcinoma with plasmid DNA encoding IL-12 using SPIONs-PAA-PEI resulted in significant antitumor effect and could be further refined for cancer immuno-gene therapy.

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