CONCEPTION OF USE OF MAGNETITE NANOPARTICLES AS CONTRASTING MEANS FOR MALIGNANT TUMORS AT MRI INVESTIGATION

CONCEPTION OF USE OF MAGNETITE NANOPARTICLES AS CONTRASTING MEANS FOR MALIGNANT TUMORS AT MRI INVESTIGATION

Andrey N. Belousov

 

Abstract. In an experiment it is shown on rats, that biocompatible standardized nanoparticles of ICNB can be effectively used at MRI. It is well-proven that nanoparticles of ICNB for certain (р<0.001) strengthen the MRI. Methodology of safe intravenous application of ICNB is excluding the use of magnetite of nanoparticles in the variant of independent contrasting means at MRI. It is set that in 24 hours after intravenous insert of ICNB the magnetite of nanoparticles for certain (p<0.001) selectively accumulate in tissue of malignant tumour and rise brightness of image. On 4th days investigation the dynamics of reduction of brightness of image in tumour and muscles was establishment for certain (р<0.001). This fact is cause by process eliminating of nanoparticles from organism of rat. On the mechanism of action the nanoparticles of ICNB cause the convertible changes which is reason to the temporal increase of mobility of protons of hydrogen in near cell liquid. It inevitably modifies the metabolic process in malignant cells that in perspective has hope in elaboration new ways the target therapy of malignant neoplasm.              

Keywords: nanoparticles; magnetic; ICNB; MRI;  malignant tumour; contrast; selectively.           

 

INTRODUCTION

 Idea of use magnetite of nanoparticles as contrasting means in MRI investigation is not new. Objectively it follows from physical properties of nanoparticles. At new in scientific literature abounds information about of the use magnetite of nanoparticles as contrasting means [1-5]. Separate actuality application magnetite of nanoparticles has in early MRI diagnostics and target therapy of malignant tumors. In spite of the fact that application magnetite of nanoparticles is look simple, it is not necessary to forget about a high danger the origins of complications as a result of their intravessel insert. At least it is necessary to take into account such indexes as a concentration, doze, rate of entered solution of nanoparticles, time of allocation nanoparticles in blood circulation after insert.  The enumerated parameters for reliable have influence on haemorreology and state of microcirculation on the whole. The high local concentration of magnetite in vessels is causes disturbances blood circulation, microcirculation and hypoxia of tissues [6, 8].  It is dangerous in main vital organs: brain, heart, lungs, liver and kidneys. Direct cross-correlation dependence between concentration of nanoparticles and level hypoxia is physiopathology obvious. Consequently, before to insert inravessel magnetite of nanoparticles, is necessary have not only reliable scientific dates about safety of recommended methodology to use of nanoparticles, but also to have standardized water solution magnetite of nanoparticles with early studied and well-proven noninvasive physical and chemical properties. 

Unfortunately, to date the advanced studies that would take into account it are absent. In the published advanced studies we met not a single reference to the use of the early studied standardized noninvasive forms magnetite of nanoperticles and methodologies of their application. Are absent information about the mechanism of influence magnetite of nanoparticles on main biological systems of living organism including respiratory, cardiovascular, secretory, immune systems, cellular exchange. Also we did not discover among the scientific publications of reliable dates about quantitative distribution magnetite of nanoparticles in organs and tissues after intravenous insert. Are absent information about a mechanism of eliminate magnetite of nanoparticles from an organism.   

On the whole, aforesaid does not allow properly estimating the scientific and practicing significance early advanced studies which were published on theme to using magnetite of nanoparticles as contrasting means for MRI. 

It was founding in the choice of theme of the present investigation. The task was set in an experiment on animals to check possibility of the use of the before worked out and studied methodology of intravenous insert of the standardized form water solution magnetite of nanoparticles (preparation of ICNB) [7-17] for contrasting of malignant tumour at MRI research.   

The main purpose – to change the indexes of relaxation of T1 and T2 in area of malignant tumour during realization MRI by means nanoparticles of ICNB.

 

MATERIALS AND METHODS

Investigations were performed on the males of rats of Vistar line, by age 26-27 months. Rats lived in individual cages with standard ration of vivarium with free access to water and food.

One rat was relatively health. Other – with the present adenocarcinoma of mammary gland. Wait of rates was identical. During investigations with animals we observed the principles of humanity, which expounded in declaration of Helsinki.

For 5 minutes prior to research intramuscular the rats get sedation. In subsequent was carrying out control of MRI.

After the performed control of MRI, singly in a tail vein of the rat, from a calculation 0.6-0.8 ml/100 mg, 0.0225% was inserted ICNB. The repeated was performed of MRI studies. Conditionally all MRI studies were divided into 4 stages:

Stage I is control (before intravenous insert of nanoparticles);

Stage II - in 5 minutes after insert magnetite of nanoparticles;

Stage III - in 24 hours after insert magnetite of nanoparticles;

Stage IV - in 96 hour after insert magnetite of nanoparticles. 

Physical and chemical properties of ICNB:

- Osmolality theoretical of colloid solution is 500 mosm/l

- Size of magnetite of nanoparticles is 6-12 nm;

- Total area of surface magnetite of nanoparticles Ss = 800-1200 m2/g;

- Magnetized of saturation Is = 2.15 кА/m;

- ζ - potential = - 19 mV.

The investigations were performed on the MR-tomagraph Magneton Concerto of   Siemens firm with power magnetic-field 0.2 T.

Got axial tomograms:

  1. T1 - the self-weighted sequences of Echo Spin of TR 50 ms, TE 17 ms the field of review a 250 mm, the thickness of cut 2 mm.
  2. T2 - the self-weighted sequences Echo Gradient of TR 500 ms, TE 17 ms the field of review a 180 mm, the thickness of cut 4 mm.

The concentration of accumulation magnetite of nanoparticles was estimated by measuring of brightness of image in a tumour and tissue of muscular of rats at MRI. The middle index brightness of image was accounts by measuring in arbitrarily taken 8 points of minimum and maximal values of the investigated tissues. Got results were statistically processed by means of computer mathematical complex "Statgraf". The method of variation statistics comparison averages was used on the t-criterion of Student.      

 

RESULTS AND DISCUSSION

 Before the beginning implementation of MRI was performed research of ICNB for the purpose visualization his contrast effect. In parallel of solution 0.9% NaCl was studied for comparison. Results MRI of research ICNB and solution of 0.9% NaCl were presented on a fig. 1.

 

Fig.1. MRI research of ICNB and solution of 0.9% NaCl

The fig. 1 demonstrates the expressed contrasting effect of ICNB by comparison to solution of 0.9% NaCl.  

Initially the protons of atom of hydrogen in preparation of ICNB are in the maximally structured state and has low index of relaxation. Therefore contrasting effect of ICNB at MRI is registered as darkening of image. This research confirmed possibility of the use of ICNB as contrasting means at MRI.

As a result of insert to the tail vein of rats preparation of ИКНБ at МРТ research an opposite effect is reliable. If fig.1 demonstrated the effect of darkening from ICNB at MRI, then after the intravenous insert of ICNB, opposite was exposed increase brightness of image in investigated tissues (fig. 3).   

Author’s methodology the intravenous of insert allows to magnetite of nanoparticles of ICNB quickly dissolving in blood and in subsequent distributed in organs and tissues. Rapid dissolution of ICNB in blood is prevent appear rheological, microcirculation disorders and consequently the phenomena of hypoxia [6, 8].

Distributed nanoparticles of ICNB in tissues against a background of MR radiation strengthen influencing of magnetic field on the protons of atom of hydrogen. The protons of atom of hydrogen alter the magnetic moment on opposite and then go back into initial position. As a result energy increases in nucleus atoms of hydrogen, time of relaxation of the excited protons grows. It registers oneself the system of tomograph.

The comparative image of contrasting effect before and after insert of ICNB in rat with the adenocarcinoma of mammary gland is presented on fig. 2, 3.

Fig 2, 3 in comparison show evidently that already on the first minutes after the intravenous insert nanoparticles of ICNB at MRI the parameters of relaxation T1 and T2 change and reliable (p<0.001) a contrasting effect increase in like brightness of image in the investigated tissues. So, after insert of ICNB in tumour of tissue the index of brightness of image increased on the average on 329±12 conventional sign and was 800±12 conventional sign (p<0,001), but in muscular – on 457±12 conventional sign and was 700±12 conventional sign (p<0,001).     

Fig. 2. Initial MRI study the brightness of image in  rat with the adenocarcinoma of mammary gland  and  tissue of muscular (471 conventional sign – tumour; 243 conventional sign – tissue of muscular).

Fig. 3. МRI study the brightness of image rat with the adenocarcinoma of mammary gland  and  tissue of muscular on the first minutes after intravenous insert of ICNB (800 conventional sign - tumour; 700 conventional sign - tissue of muscular).

It should be noted that registering the low parameters of relaxation is possible only in case of high concentration magnetite of nanoparticles in blood and tissues. However the high concentration of nanoparticles in blood stream is potentially dangerous for living organism, because it is cause the origin of hypoxia in tissues. Especially this very significant for organs: brain, heart, liver, lungs, and kidneys.    

Thus, taking into account foregoing, application magnetite of nanoparicles as contrasting means at MRI in the safe variant of methodology practically is not possible. This experiment showed that used nanoparticles of ICNB in certain methodology can not be as independent contrasting means at MRI. Worked out methodology of intravenous insert nanoparticles of ICNB on a background of MR of radiation in it safe variant only for certain (p<0.001) strengthens the brightness of image of tissues. Dynamic change of indexes brightness image in tumour and muscular tissues in a sick rat after intravenous insert of ICNB present on fig.4.  

Fig. 4. The change dynamic of indexes brightness image in tumour and muscular tissues in a sick rat after intravenous insert of ICNB on various stages at MRI investigation (M±m; n=8).

Fig.4 shows, that on stage III the investigation (in 24 hours after intravenous insert of ICNB) the index of brightness image maximally increased in tumour tissue and in average was 836±12 conventional sing. Maximum increasing of brightness image is result in selective accumulation nanoparticles of ICNB in tumour of tissue. Dynamic change of indexes brightness image at MRI investigation in muscular tissues in both rats groups after intravenous insert of ICNB on various stages is presenting on fig.5.

 

 

Fig. 5. Dynamic change of indexes brightness image at MRI investigation in muscular tissues in both rats groups after intravenous insert of ICNB on various stages (M±m; n=8).

Opposite, in health rat on stage III investigation was reliable (p<0.001) revealed maximally increasing brightness of image in muscular tissue (700±19 conventional sing). Change of brightness image on stage III investigation in muscular tissue is cause by less accumulation in muscular tissue nanoparticles of ICNB in rat with tumour than in muscular tissue in health rat. This effect is explained to the following:

  1. The surface of malignant tumour cells as compared to healthy has higher negative charge. Because nanoparticles of ICNB selectively accumulated in malignant tumour tissue.
  2. Weak contact between cells of malignant tumour is reason elevating accumulating nanoparticles of ICNB in intercellular space and rising of time of their elimination.

 

CONCLUSION 

  1. In an experiment it is shown on rats, that biocompatible standardized nanoparticles of ICNB can be effectively used at MRI. It is well-proven that nanoparticles of ICNB for certain (р<0.001) strengthen a contrasting effect at MRI.   
  2. Methodology of safe intravenous application of ICNB is excluding the use of magnetite of nanoparticles in the variant of independent contrasting means at MRI.    
  3. It is set that in 24 hours after intravenous insert of ICNB the magnetite of nanoparticles for certain (p<0.001) selectively accumulate in tissue of malignant tumour and rise brightness of image.
  4.  On 4th days investigation the dynamics of reduction of brightness of image in tumour and muscles was establishment for certain (р<0.001). This fact is cause by process eliminating of nanoparticles from organism of rat.  
  5. On the mechanism of action the nanoparticles of ICNB cause the convertible changes which is reason to the temporal increase of mobility of protons of hydrogen in near cell liquid. It inevitably modifies the metabolic process in malignant cells that in perspective has hope in elaboration new ways the target therapy of malignant neoplasm.                 

 

ACKNOWLEDGMENT

The author is thankful to the department of biological of Kharkov National University and depatment of MRI of Kharkov Region Hospital.

 

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