Complex experimental and theoretical approaches in the evaluation of magnetic hyperthermia application.

Project Director: Dr. Gabriel SCHINTEIE

Beneficiary: Unitatea Executiva pentru Finantarea Invatamantului Superior, a Cercetarii, Dezvoltarii si Inovarii (UEFISCDI)
Proiect Code: PN-III-P1-1.1-TE-2021-1300
Contract no.: TE 91/16.05.2022
Project title: Complex experimental and theoretical approaches in the evaluation of magnetic hyperthermia applications.
Funding period: 13/05.2022- 12/05/2024
The contracted amount: 450.000 lei
Project director: Gabriel Schinteie

The project scope is to develop new experimental approaches for the evaluation of the most important parameters which influence the magnetic hyperthermia(MH), to provide original procedures/methodologies for the evaluation of the Specific Absorption Rate (SAR). New magnetic single-domain iron oxide-based nanoparticles for biomedical applications will be designed and in vitro MH assays will be approached. By using specific preparation procedures, suitable and functionalization of mono-dispersed spherical, cubic or acicular shaped nanoparticles, for tailoring their effective anisotropy constant will be synthesized. It is envisaged: (i) the systematic evaluation of the most important parameters of interest in hyperthermia, (ii) the evaluation of the relationships between the magnetic and morpho-structural parameters with impact on SAR and the determination of SAR in correlation to realistic volume fraction of nanoparticles dispersed in a media compatible with the human tissue, (iii) the development of original SAR evaluation procedures by accounting for the heat loses , (iv) the consideration the spatial distribution of the magnetic field and nanoparticle concentration as input data for the discrete estimation of the dissipated power and further inputs in the bio-heat transfer equation, (v) the optimization of the RF magnetic field exposures on the NP systems, in correlation to morpho-structural characteristics and volume fractions specific to MH applications.

Project objective:

The actual proposal promotes a complex study of systems of magnetic iron oxides nanoparticles, with various morphologies and covered by different surfactants which control the MNPs interactions. The main purpose of this project is to embed efficiently the results that will be obtained into a safer and reproductible method for better treatments against tumors. It is worth mention that in present the most commonly used treatments for tumors implies non-targeting methods that are highly toxic for both tumor cells and healthy cells. Thus, it is of paramount importance to achieve a low cost way for treatment of tumors in a localized manner to maintain the as much as possible the integrity of healthy cells. The novelty of the project resides in the extraction and the unitar evaluation of every morphology and of every magnetic parameter that infleunces the SAR in relation to system behavior versus the particle density. The aim is a detailed understanding of the methods to control the phenomena associated to each parameter involved in the hyperthermia processes as well as of the advancing protocols, offering support,consistency and trust in the future approaches in the domain.

Estimated results:

Synthesis of at least 5 sets of samples for hyperthermia; Design and implementation of an adiabatically isolated device for compounds storage during exposure to RF fields for minimaize the heat loss; Original methods in the assessment of SAR distributions; In vitro testing of the hyperthermia efficency; All the results will be disseminated in high impact factor journals( minimum 4 publicationes) and communications at international/national conferences. A web-page with the most important results and the latest news in the field of project will be elaborated.



All the objectives provided in the implementation plan related to Stage 1 ("(“Processing and morpho-structural characterization of Fe based magnetic nanoparticles and their optimization in relation to different applications”) consisting of: i) Synthesis, morpho-structural and magnetic characterization of at least 5 systems of magnetic nanoparticles (objectives O1 and O2), ii) scientific research report, iii) 1 scientific article sent for publication in ISI listed journals, iv) creation of a website for project and v) participation in a national/international conference) were fulfilled integral.

Following the studies from specific literature, the preparation methods and precursors for obtaining magnetic monodomain particles, with specific morphologies, controlled size and a relatively narrow particle size distribution, were established.

Preliminary preparations of oxo-hydroxides and iron oxides (magnetite) were carried out by: i) co-precipitation, ii) treatment of acicular oxy-hydroxide precursors, iii) hydrothermal decomposition and iv) thermal decomposition of organo-metallic compounds in solvents with high boiling point.

The influence of the preparation conditions (molar ratio of surfactant mixture, time and temperature of thermal treatment) on the morphology and size of magnetite nanoparticles obtained by the thermal decomposition of organo-metallic compounds was studied. The correlation between the magnetite morphology and the mixture of surfactants was established.

Various systems of hydrophobic magnetite, magnetic monodomain, with spherical, hexagonal, cubic or polyhedral morphologies were prepared.

Starting from the hydrophobic particles synthesized by the thermal decomposition of organo-metallic compounds in solvents with a high boiling point, hydrophilic particles functionalized with azelaic acid were obtained .

Through morpho-structural measurements the crystalline phases, shape and size of the constituent nanoparticles were identified (iron oxide nanoparticles with diameters between 20-50 nm were processed).

Mössbauer spectroscopy measurements and magnetic measurements confirmed the formation of magnetic monodomain nanoparticles, that do not reach the superparamagnetic regime, but which have saturation magnetizations and coercive appropriate for magnetic hyperthermia applications.

The results obtained were disseminated through a participation in a national conference, 2 articles published in ISI rated journals and an article sent for publication to Materials magazine.

Stage II: Comparative studies on specific mechanisms revealed by SAR measurements. Final characteristics of new mechanisms for optimizing compounds for hyperthermia applications.


  • Through the thermal decomposition of organo-metallic compounds in solvents with a high boiling point, hydrophobic magnetic nanoparticle systems with controlled shape and size were obtained. In order to be able to use them in bio-medical applications, the following procedures were approached to functionalize the surface of hydrophobic magnetic nanoparticles: i) the transformation of hydrophobic magnetite into hydrophilic magnetite through oxidative reactions; ii) using a Shaker with Eppendorf blocks, with mixing and heating functions, in the attempt to replace the organic surfactant on the NPs surface with citric acid or ascorbic acid; iii) functionalization of hydrophobic Fe3O4 with Silica; iv) removal of the surfactant/organic ligand from the hydrophobic MNPs surface by dissolving it in DMSO or DMF;

  • To improve the stability of magnetic nanoparticle systems in aqueous solutions, new processing methods were approached consisting of: i) Synthesis of magnetite MNPs by direct functionalization with citric acid right during the preparation procedure; ii) Synthesis by coprecipitation of magnetite MNPs and surface functionalization by coating with compounds that induce electrostatic repulsive forces;

  •  In order to reduce/eliminate as much as possible the heat losses in the magnetic hyperthermia experiments, a device with quasi-adiabatic isolation (patent pending) was designed and made to increase the precision of the specific absorption rate (SAR) measurements of a suspension of magnetic nanoparticles. Only non-magnetic materials (Duramid, Plexiglas, plastic) were used in order not to interact with the electromagnetic field of the induction coil;

  • For a more accurate assessment of the specific absorption rate (SAR) in magnetic hyperthermia experiments, an original methodology was proposed for the compensation of heat losses over a wide range of temperature, along with a series of experimental precautions to minimize the heat losses, maintaining the inductor's cooling liquid at a constant temperature (as close as possible to room temperature), as well as gravitational sedimentation of the MNPs under investigation;

  • The morpho-structural and magnetic measurements confirm the formation of superparamagnetic particles or the formation of magnetic monodomain nanoparticles (which do not reach the superparamagnetic regime), but which show saturation magnetizations and coercive fields that recommend them for magnetic hyperthermia applications;

  • Recommendations for average concentrations of nanoparticles intended for biomedical applications and the optimization of heat transfer in relation to the frequencies and biological RF field intensities accepted.

Name Stage III: Evaluation of the cytotoxic effects of hyperthermia induced by magnetic nanoparticles on cancer cell line


  • The processing  conditions and methods of magnetic nanoparticle assemblies (MNPs) of  magnetite with specific morphologies (spherical and cubic) and narrow  size distribution were optimized, which were used on two cell lines:  L929 line - fibroblasts from adipose tissue subcutaneous and HT29 –  human colon adenocarcinoma cell line. Starting from the thermal  decomposition of organo-metallic compounds in solvents with a high  boiling point, 3 optimized procedures were proposed for:
    • i) Synthesis of magnetite MNPs coated with oleic acid: Fe3O4@OA;
    • ii) Synthesis of magnetite MNPs coated with citric acid: Fe3O4@CA;
    • iii) Synthesis of magnetite MNPs functionalized with folic acid: Fe3O4@FA.
  • A  first protocol (P1) was implemented for testing the biocompatibility in  vitro of Fe3O4@OA, Fe3O4@CA and Fe3O4@FA nanoparticles on L929 and HT29  cell lines through specific colorimetric tests: MTS (the metabolic  activity of viable cells is evaluated) and/or LDH (cytotoxicity tests).
  • The Ambrell EasyHeat magnetic hyperthermia device has been adapted and optimized for experiments with cell culture lines.
  • A  second protocol (P2) was implemented to study the viability and  cytotoxicity of nanoparticles systems incubated with cells, following  magnetic hyperthermia experiments.
  • Preliminary fluorescence  microscopy studies were performed on the system of magnetic  nanoparticles functionalized with folic acid.
  • The  biocompatibility tests, applied on the two cell lines L929 and HT-29 and  compared to the control samples, showed a decrease in viability by  approximately 20% for L929 in the presence of Fe3O4@AO and  Fe3O4@AC and by approximately 30% for the system Fe3O4@AF. The results  obtained for the HT-29 line showed a more pronounced decrease in  viability, the values being between 30-35%. Cytotoxicity tests showed  values comparable to those of viability.




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