Gadolinium Vizualization in Vivo for Dosimetry in Neutron Capture Therapy

International Journal of Nuclear Energy Science and Engineering Volume 4 Issue 2, June 2014 www.ijnese.org doi: 10.14355/ijnese.2014.0402.01

Gadolinium Vizualization in Vivo for Dosimetry in Neutron Capture Therapy A.A. Kim1, G.A. Kulabdullaev1, Yu.N. Коblik1, G.A. Abdullaeva1, G.T Juraeva1, U.S. Salikhbaev1, Sh.N. Saytjanov1, , I.R. Mavlyanov2, O.A. Agzamov3, J.M. Alimov3, N.Kh. Khodjaeva3, S.N. Navruzov3

1Institute of Nuclear Physics Uzbekistan Аcademy of Science, Tashkent, Uzbekistan 2Tashkent Medical Academy, Uzbekistan 3Republican Oncologic Scientific Center, Ministry of Health, Uzbekistan [email protected] Received 6 November, 2013; Revised 2 March, 2014; Accepted 1 April, 2014; Published 23 June, 2014 © 2014 Science and Engineering Publishing Company Abstract

Gd-NCT dosimetry requires exact analysis of the gadolinium amount in the irradiated target. For this purpose fast and convenient method for radiographic visualization of gadolinium-containing preparation (Magnevist) was developed. By using this metod, the Magnevist pharmacokinetics was carried out after intratumoral injection in mice and intramuscular injection in rats. Obtained data allowed the semiquantitative estimation of gadolinium amount in injection site. The values of gadolinium amount in irradiated region depending on time was used for correcting definition of absorbed dose.

Keywords

NCT, Gd; Dose; Kerma; Magnevist; Biological Tissue; Pharmacokinetics

Introduction

One of directions of neutron capture therapy (NCT) is GdNCT. For this direction , gadolinium containing chelate preparations was used. Proposed as contrast agent for nuclear magnetic resonance diagnostics, Gadolinium compounds were able to accumulate with heavy gradient in tumours. NCT of some types of cancer required preparations with higher gradient of accumulation in cancers compared to healthy tissues and gadolinium, having high cross section of neutron capture. The gadolinium-containing preparation Magnevist was widely applied for NCT in spite of newly developed pharmacological preparations. Advantage of Magnevist consists in, that it was well-known pharmacological preparation was registered and approved for treatment in clinical medicine in many countries. It allowed using Magnevist without

additional authorization of regulatory organizations. This preparation was used in NCT experiments on animals in resent years. Such researches continued with another gadolinium-containing preparation - Dipentast.

Generation of desired therapeutic radiation dose in a certain region of biological object, with minimal damage to healthy tissues, is one of the major problems of today's researches on GdNCT. Accurate measurement of the absorbed dose is a difficult experimental problem, as sensitivity of almost all dosimeters shows complex dependence from energy of bombarding neutrons. Therefore, for estimation of the absorbed dose it is more conve , nient to use the units of kerma. Kerma (K) - analogue of the absorbed dose, which at equilibrium of secondary charged particles is equal to the absorbed dose. In order to determine kerma it is required to know:

the energy spectrum of photons and neutrons in the target organ ;

the energy dependence of specific partial kerma of neutrons and photons for all elements of biological tissue and for elements of used NCT drugs.

For exact definition of the absorbed dose in GdNCT, the information about time dependence of Gd content in biological tissues is also required.

The preparation Magnevist was designed as a nuclear magnetic resonance-contrast agent for intravenous injection and its pharmacokinetics at such introduction was well known. Pharmacokinetics of Magnevist was poorly investigated at other injection modes, in

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particular, at intratumoral and intramuscular injections, which were applied in NCT experiments on animals. Pharmacokinetics of various Gd-containing preparations and compounds for NCT was studied by different authors. For definition of the absorbed dose depending on gadolinium concentration decrease from an irradiated target the pharmacokinetics of Мagnevist at intratumoral injection on mice and intramuscular injection on rats was studied . For this purpose the fast and convenient method of Magnevist visualisation was developed, allowing a semiquantitative estimation of preparation content in injection place.

Materials and Methods

For experiment white male mice were used. S180 sarcoma strain was inoculated to mice’s hip of right rear leg. Experiment was realized on the matured tumours with sizes from 1.5×1.0 cm to 5.0×4.0 cm. Characteristics of experimental mice are presented in table 1. Before the injection mice have been fixed a gaste downwards. Preparation Magnevist (undiluted) was injected directly into the tumour’s centre within 1 min. Various doses of Magnevist - 0.1, 0.2, 0.3, 0.4 and 0.5 ml were injected into mice.

TABLE 1 CHARACTERISTICS OF EXPERIMENTAL MICE

To study pharmacokinetics of Magnevist at intramuscular injection normal healthy white rats with weight of approximately 250g were used. The 0.4 ml of Magnevist was injected into the right muscle of rats’s hip. Roentgenoscopy of rats and mice was produced on Sirescop “Siemens” x-ray equipment. Roentgenograms of mice were skiagraphed before injection (control) and in 1, 2.5, 5 min after injection and further every 5 min until 65 min inclusive after inection. Roentgenograms was processed by means of Image J2x2.1.4.7ud2 software (Wayne Rasband, National Institute of Health, USA). The x-ray contrasting properties of gadolinium-containing preparations [Information leaflet of Optimark preparation of Malinkrodt Inc. company, USA] were used for definition of Magnevist pharmacokinetics.

Results and Discussions

Dynamics of Gd distribution at intratumoral injection of Magnevist for doses of 200 and 400 μl are presented in fig. 1 and fig. 2. Unfortunately, these results do not allow estimation of an exact value of Magnevist concentration in tumours after injection. It is caused by a number of reasons : the x-ray beam is non-uniform with pronounced focal spot; all roentgenograms are skiagraphed only in one focal plane; shielding of the image by tissues does not allow one to observe dynamics of Мagnevist decreasing to zero. For a quantitative estimation we made roentgenograms of solutions with different Magnevist concentration. In fig. 3 roentgenograms of Magnevist aliquot (200 μl) are shown in a physiological solution, where the most dark cloud corresponds to undiluted preparation Magnevist (100 %) and the most light cloud corresponds to a physiological solution (0 % Magnevist). The coefficients of image density of these roentgenograms markers expressed in percents were calculated by using the Image J2x 2.1.4.7ud2 Wayne Rasband software.

FIG. 3 ROENTGENOGRAMS OF MAGNEVIST ALIQUOTS WITH

DECREASING CONCENTRATION FROM 100 % TO 0 %.

TABLE 2 TIME OF MAGNEVIST DETECTION DEPENDING ON DOSE.

Magnevist dose, μl Time of Magnevist detection, min

100 20 200 35 300 40 400 50 500 65

The calculated coefficients of image density were applied to roentgenograms of mice and estimations of Magnevist cocentrations in a tumour were received. Thus, we can quite precisely estimate the time at which darkening of some region of roentgenogram caused by Magnevist at 50 % content in a tumour. Time of Magnevist detection depending on a dose is presented in table 2.

Magnevist dose, μl Mice weight, g Tumor size, cm

100 34 1.5×2.0 200 28 1.5×1.0 300 25 1.5×1.5 400 35 1.5×1.5 500 40 5.0×4.0

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FIG. 1 DYNAMICS OF GADOLINIUM DISTRIBUTION AT INTRATUMORAL INJECTION OF MAGNEVIST FOR DOSE OF 200 µL.

FIG. 2 DYNAMICS OF GADOLINIUM DISTRIBUTION AT INTRATUMORAL INJECTION OF MAGNEVIST FOR DOSE OF 400 µL.

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Based on received data, the dependence of Magnevist’s concentration decrease in a tumour from the injected dose is ploted (fig. 4).

0 5 10 15 20 25 30 35 40 45 50 55 60 65

90

80

70

60Conc

entra

tion

of g

adol

iniu

m, %

Time, min

0,1 ml 0,2 ml 0,3 ml 0,4 ml 0,5 ml

50

100

FIG. 4 THE TIME DEPENDENCE OF GADOLINIUM

CONCENTRATION AT INTRATUMORAL INJECTION OF MAGNEVIST

Thus, at intratumoral Magnevist injection the optimal concentration of the preparation (80 %) remains for 15 - 25 minutes depending on the injected dose. Our data are in good agreement with results obtained for Dipentast, where half-elimination at intratumoral injection to В16 melanome in mice was 23±5 minutes. Then Magnevist eliminates out of tumour sufficiently fast. In roentgenograms, one can clearly see , that on 25-th min a darkening of the left kidney appears. This can indicate that the significant amount of gadolinium accumulates in left kidney. Darkening of the right kidney is not observed. It is possible to explain this as a background darkening of tumour or less effective work of the right kidney which is located on the same side as the inoculated tumour. It is necessary to take into account the beginning of intensive Magnevist accumulation in kidneys on 25-th min at planning of irradiation sessions. Besides, fast accumulation of Magnevist in kidneys testifies that there is a fast elimination of a preparation in a blood flow and then in kidneys, which is difficult to explain in terms of diffusion pharmacokinetics model. This model was used for pharmacokinetics interpretation of others gadolinium-containing preparations. Most probably, in this case the application of classical one-compartment pharmacokinetics model is more appropriate. Present results are important for the further kerma calculations. Since in diffusion model , the reduction of preparation concentration is interpreted as simple diffusion into surrounding tissues. In this case the amount of preparation in irradiation field will change insignificantly during

exposition. In our case we observe elimination of the preparation and, hence, fast reduction of its concentration in the injection site. It was caused by preparation appearance in other organs of mice, i.e. during exposition time , the amount of preparation in the irradiation field will significantly change.

Dynamics of Magnevist at intramuscular inection on rats, which can be used for preparation delivery to bone tumours, is presented on the roentgenograms in fig. 5. In the roentgenogram in 1 minute after injection the darkening caused by Magnevist is well represented. Fast enough reduction of darkening is observed, which indicates active Magnevist elimination from an injection region, and thus 40-th min darkening is not observed any more. On these roentgenograms dependence of Magnevist concentration on time for 400 µl dose after intramuscular injection in rats is obtained (fig. 6). Thus, at intramuscular injection of Magnevist, optimal concentration of the preparation (to 80 %) is preserved within 10 min.

0 5 10 15 20 25 30 35 40Time, min

Conc

entra

tion

of g

adol

iniu

m, %

100

90

80

70

0,4 ml

50

60

FIG. 6 THE TIME DEPENDENCE OF GADOLINIUM

CONCENTRATION AT INTRAMUSCULAR INJECTION OF MAGNEVIST

Earlier, kerma is defined for biological tissue and for 1 µg of natural gadolinium in 1g of biological tissue under irradiation with ephitermal neutron beam in the WWR-SM INP AS RUz. However, our studies of Magnevist pharmacokinetics show that in order to take into account change in gadolinium amount at the irradiated region, full kerma expression for biological tissue should be presented in the following form:

Kt= Kn + Kγ + [KGdn + KGd

γ ]2

1

( )t

tt dtρ∫

Where ρ(t)- amount of Magnevist in ppm in irradiated region depending on time, t1 and tn initial and final irradiation time, respectively.

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Control - before injection 1 min after injection

5 min after injection 10 min after injection



FIG. 5 DYNAMICS OF GADOLINIUM DISTRIBUTION AT INTRAMUSCULAR INJECTION OF MAGNEVIST FOR DOSE OF 400 µL: LEFT SIDE – VIEW OF WHOLE ROENTGENOGRAM; RIGHT SIDE – MAGNIFIED VIEW OF INJECTION SITE

The preliminary analysis show that with taking into account of experimentally defined dependence - ρ(t), the full kerma value in some cases can differ on ~ 30 % from the full kerma value received without this dependence.

Conclusions

Thus, the technique of gadolinium-containing preparation (Magnevist) visualisation is developed for exact analysis of the gadolinium amount in the

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irradiated target. This technique is easy enough in operation and allows pharmacokinetics studies of the injected preparation. Magnevist pharmacokinetics at the intratumoral and intramuscular injection is studied by using this technique. Obtained data allow one to make the semiquantitative estimation of gadolinium amount in injection site. Also, it makes clear that commonly used diffusion model of pharmacokinetic for gadolinium-containing preparations is inapplicable. In this case, the one-compartment pharmacokinetics model is more appropriate.

The received results are imporant in researches on neutron capture therapy, in particular, for the definition of gadolinium amount in tumour, of irradiation duration and of absorbed dose in experiments on biological objects and in clinical tests aimed at development of cancer treatments with using epithermal neutron beam.

ACKNOWLEDGMENT

Authors are grateful to X-ray diagnostics department staff of the Republican Oncologic Scientific Center for support in measurements and to Dr. J.N. Kaharov for useful discussions.

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Gadolinium Vizualization in Vivo for Dosimetry in Neutron Capture Therapy