WO1991010452A1

WO1991010452A1 - Improved method of preparing an iron oxide composition for therapeutic treatment of a living body and iron oxide composition

Info

Publication number: WO1991010452A1
Application number: PCT/HU1990/000024
Authority: WO
Inventors: Péter Teleki
Original assignee: Teleki Peter
Priority date: 1990-01-22
Filing date: 1990-04-11
Publication date: 1991-07-25
Also published as: AU5423490A; HU900222D0

Abstract

The invention refers to a method of preparing an iron oxide composition and an iron oxide composition for therapeutic treatment of a living body. The method comprises the steps of providing fine grain iron oxide, introducing the fine grain iron oxide into a liquid carrier medium applicable for therapeutic purposes and dispersing the fine grain iron oxide in the liquid carrier medium, including the novel step of completing the fine grain iron oxide with at least one isotope of low activity for a period sufficient for introducing the fine grain iron oxide into an organ targeted of the living body or at least one isotope capable of being activated by neutrons and decaying after the period or transforming under influence of the neutrons to a high activity isotope of short life time before transforming into a stable isotope. The composition as proposed comprises a liquid carrier medium, the liquid carrier medium being applicable in a living body and fine grain iron oxide made of at least one iron oxide selected from the group consisted of ferrous oxide, ferric oxide and ferroferric oxide forming a dispersion in the liquid carrier medium, wherein the fine grain iron oxide constitutes a solid carrier medium for bearing at least one isotope of low activity for a period sufficient for introducing the fine grain iron oxide into an organ targeted of the living body or at least one isotope capable of being activated by neutrons and decaying after the period or transforming under influence of the neutrons to an isotope of short life time radiating with high activity before transforming into a stable isotope, the stable isotope being not toxic.

Description

IMPROVED METHOD OP PREPARING AN IRON OXIDE COMPOSITION FOR THERAPEUTIC TREATMENT OF A LIVING BODY AND IRON OXIDE COMPOSITION

FIELD OF INVENTION

The invention refers to the field of the medicine and especially to the means to be applied in the therapeutic processes of the oncology and proposes an improved method of preparing an iron oxide composition for therapeutic treatment of a living body and a novel kind of the iron oxide compositions applicable in the oncology. The method as proposed comprises the known steps of providing fine grain iron oxide, introducing the fine grain iron oxide into a liquid carrier medium applicable for therapeutic purposes and dispersing the fine grain iron oxide in the liquid carrier .medium..The iron oxide composition for therapeutic treatment of', a living body according to the invention includes a liquid carrier medium, the liquid carrier medium being applicable in in vivo conditions in a living body and fine grain iron oxide made of at least one iron oxide selected from the group consisted of ferrous oxide, ferric oxide and ferroferric oxide forming a dispersion in the liquid carrier medium.

BACKGROUND OF THE INVENTION The scientific investigations carried out in order to analyse the problems of different methods of the therapy of cancer diseases resulted in the middle of the eighties in the conclusion that the cancer cells developed in the living body bind much more iron oxide than the normal cells and it can be

69047-5903/2/NE-Ko stated that practically the normal cells take up very small amounts of iron oxides, i . e . ferrous oxide (FeO), ferric oxide (Fe₂O₃) and mixed iron oxide (ferroferric oxide - Fe₃O₄). Of course, this recognition is very interesting per se and offers possibilities of elaborating different methods of influencing the biologic activity of the cancer cells by making use of the iron atoms bound in the parts of the living body suffering from this enormous state.

The first investigations reported e.g. in the book en- titled "Biophysical Effects of Magnetic Field. Studies" (Springer Verlag, Heidelberg, New-York, 1986) or in a special edition of the Journal of Magnetism and Magnetic Materials (march 1987, 65, the whole edition publishing papers of an international conference held on the problems of the magnetic liquids) show the possibility of introducing an iron oxide containing fluid medium into the living body which fluid has pH value 7, i.e. is chemically neutral. The iron oxide transported by this fluid to the organs of the living body is after a predetermined time period exposed to X-ray radiation and the increased temperature of the iron oxide component realizes an effect which has become known since longer time: the cancer cells are more sensitive to increased temperature than the normal cells. The radiation absorbed results also in exciting the iron atoms which emit then electrons and gamma fotons. The summarized effect of the increased temperature and the emitted radiation can follow in the desired relatively active therapeutic effect if the cancer cells are localized in a small area. The problem is here that the blood cells of the human beings comprise also iron. The X-ray radiation exciting the iron oxide component of the fluid can obviously cause the excitation of the iron containing cells of the blood. Thus, the therapeutic treatment may not be applied on extended areas.

A further problem should be seen in the fact that the K-edge energy characterizing the iron atoms is relatively low, it makes out about 7.111 keV and of course, the excitation of iron can be done at this relatively low energy. Thus, radiation (quantums) of energy slightly exceeding this value is required, however a value lying slightly under this limit can be applied, too. The narrow excitation spectrum is not ensured by the known means.

SUMMARY OF THE INVENTION

The object of the present invention is to improve and widen the therapeutic possibilities offered by the neutral fluids containing iron oxide. The invention proposes to ensure a very narrow excitation spectrum of iron present in the fluid in the form of an iron oxide or to make use of the iron oxide to transport some of substances capable of influencing the cancer cells.

The invention is based on the recognition that the therapeutic effect of the iron oxide containing neutral fluids should be ensured by completing it with isotopes showing no or very limited toxic influence and being capable of exciting the iron atoms in the required narrow range or of becoming an active radiation source issuing intensive radiation for a short time.

Hence, the invention consititutes an improved method of preparing an iron oxide composition and a novel iron oxide composition for the therapeutic treatment of a living body. The method as proposed comprises the steps of providing fine grain iron oxide, introducing the fine grain iron oxide into a liquid carrier medium applicable for oncologic therapeutic purposes and dispersing the fine grain iron oxide in the liquid carrier medium, with the novel feature of including the step of completing the fine grain iron oxide with at least one isotope characterized by low activity for a first period sufficient for introducing the fine grain iron oxide into an organ targeted of the living body or at least one isotope capable of being activated by neutrons and decaying after the first period or transforming in result of neutron activation to a high activity isotope of short life time constituting a second period before transforming into a stable isotope, the stable isotope being not toxic to the living body. The method of the invention is intended to influence, i.e. lower the biologic activity of the cancer cells as much as possible, up to killing them during the high activity period.

In a preferred embodiment of the method as proposed by the invention the at least one isotope of low activity is advantageously Ti 52 (titanium), Ru 94 (ruthenium), Cd 104 (cadmium), Lu 178 and Lu 179 (lutetium), and the at least one isotope capable of being activated by neutrons, especially of thermal and/or resistance energy range is B 10 or Rh 103, for limiting the biologic activity of the cancer cells. In the first method the composition can be prepared in a relatively expensive and sophisticated manner improved in an advantageous way by the second method. The isotopes mentioned can be introduced into the iron oxide among other possibilites by ion bombardment or alloying. Because of the short life time in the second period of the isotopes characterized by low activity in the first period it is very advantageous to prepare the at least one isotope immediately before carrying out the step of completing by it the fine grain iron oxide.

The invention proposes further also an iron oxide composition for therapeutic treatment of a living body, comprising a liquid carrier medium, the liquid carrier medium being applicable in in vivo conditions in a living body and fine grain iron oxide made of at least one iron oxide selected from the group consisted of ferrous oxide, ferric oxide and ferroferric oxide forming a dispersion in the liquid carrier medium, wherein the novel element of the invention is that the fine grain iron oxide constitutes a solid carrier medium for bearing at least one isotope of low activity for a first period which is sufficient for introducing the fine grain iron oxide into an organ targeted of the living body or at least one isotope capable of being activated by neutrons and decaying after the first period or transforming under influence of thermal and/or resonance neutrons to an isotope of short life time, the short life time constituting a second period, the isotope after decay or transformation radiating with high activity before transforming into a stable isotope, the stable isotope being not toxic, for influencing the biologic life conditions of the cancer cells in the organ targeted during the high activity radiation period in order to lever their biologic activity up to killing.

As mentioned in connecticr. with the proposed method, in the especially advantageous embodiments of the iron oxide composition prepared .according to the invention, the isotope applied and introduced into the grains is Ti 52 (titanium), Ru 94 (ruthenium), Cd 104 (cadmium), Lu 178 and/or. Lu 179 (lutetiixi), when applying the isotopes of low activity in the first period or it is either B 10 or Rh 103, when the neutron activation is preferred. The last two isotopes are activated by neutrons.

Advantageously, in the iron oxide composition realized according to the invention the fine grain iron oxide consists of particles of size dimensions about 10 nm.

In another preferred emtcdiment of the invention the iron component of the composition is prepared by neutron activation of the isotope of mar-ganium Mn 55 which transforms into the isotope Fe 56 crossing the intermediate stage of the isotope Mn 56. This manganium isotope emits gamma-radiation and shows beta-decay with half-period about 2.56 hours.

The object of the invention is further a method of making use of the nickel isotope Ni 28, which added to the iron can be excited by X-ray radiation or by synchrotron radiation. The synchrotron radiation is alone also capable of exciting iron without application of nickel. The nickel isotope Ni 58 when excited emits K radiation with energy 8.331 keV and with two edges (K alpha₁ and K alpha₂) characterized by the energy values 7.48 keV and 7.46 keV, respectively.

The invention will be further described in more detail with reference to some preferred realizations and embodiments, wherein the methods of application of the composition proposed according to the invention will not be described in any way, because the methods of the medical treatments are not the object of the present invention.

DETAILED DESCRIPTION OF THE INVENTION ATD SOME PREFERRED EMBODIMENTS

The invention is based, as it follows from the features mentioned above, on the recognition that the tendency of the cancer cells to bind more intensively the different kinds of iron oxide than the normal cells do it should be exploited in a novel, non-conventional manner. The excitation of the iron atoms bound in the cancer cells and being present in the iron oxide comppounds can be applied to weakening the biologic activity of and killing the cancer cells and this can be done after introducing iron oxide into the living body after being bound with the targeted organ of the living body, especially of a human being. The means of excitation are either the radiation issued from an outer . source or isotopes added to the iron oxide.

The first possibility means that the iron present in the iron oxide is excited either by any one of X-ray and synchrotron radiation or by a neutron flux consisted of low energy neutrons of thermal or resonance range preferably with energy from about 0.025 eV (these electrons propagate with speed about 2200 m/s) up to. about 1 eV.

The methods applying the X-ray or synchrotron radiation offer rather the possibilities of local intervention into the living body suffering from the cancer disease, likely to be not applicable in the later stages of the cancer diseases attacking extended body areas. The excitation can be ensured either by immediate excitation of the iron atoms or by that of nickel atoms emitting with energy very near to the required value 7.111 keV being characteristic for the iron. The application of this kind of excitation can be very advantageous when local treatments are prescribed and only small areas should be taken into account.

When applying the method of activating selected isotopes by a neutron flux consisted of neutrons of energy from the thermal up to the resonance range it is very important that the particles cannot cause harmful ionization. This means, the selected isotopes introduced into the living body are activated only, the neutron flux results practically in no significant changes of the biologic organs, tissues and cells it crosses. The investigations proved that especially two isotopes are convenient. These isotopes are the B 10 isotope of boron (₅B) and the Rh 103 isotope of rhodium (₄₅Rh). The boron decays mainly to lithium isotope Li 7 (₃Li) and alpha particles are deliberated in this decay process. Under influence of the neutrons a small amount of the lithium isotope li 8 comes also into being together with the boron isotope B 11. Both processes are characterized with low probability and these isotopes produced show very short life time. Hence, in this case the process ¹⁰B (n, alpha) ⁷Li determines mainly the biologic effects. The alpha particles can penetrate the living body only with very small depth but they are very active. They take up electrons and the ionization caused by electron capture results in free energy about 2.8 MeV.

The other isotope proposed to be activated by a neutron flux is the rhodium isotope Rh 103. The neutrons cause the reaction of transforming this isotope into the isotope Rh 104 showing beta decay with half-time about 42 sec. The decay. results in the palladium isotope Pd 104. Hence, in this case the reaction schedule can be summarized according to the following: ¹⁰³Rh (n, gamma) ¹⁰⁴Rh (e-, gamma) Pd. The palladium (₄₆Pd) is believed to be not harmful for the living body at all. The neutron reaction can be ensured by thermal neutrons but the cross-section of the Rh 103 isotope against resonance neutrons (having energy about 1.0 eV) is much higher than that against the thermal neutrons. It is to be taken into account that the resonance neutrons are slowed down in the environment formed by the living body.

The processes depicted above are capable of killing the cancer cells but the radiation emitted can not penetrate the distal parts of the body. This radiation has thereby no long distance influence.

The neutron flux can be moderated and regulated by known means, e.g. by applying paraffin.

The most important constituent elements of the living body are the hydrogen, carbon, nitrogen, oxigene, magnesium, fluorine, sodium, phosphorus, potassium, calcium and iron. They all have effective cross-section against neutrons below aboout 3-38 barn (for the K 39 isotope of potassium) and rather below 0.5 barn for the most important elements. This means that the neutron flux cause activation of the elements mentioned with very low probability and it practically cannot be harmful for the living tissues, cells and organs of the body.

In order to avoid the neutron activation of elements not desired to be activated it is very advantageous to apply isotopes of iron which can be activated only with low probability and other isotopes which transform after activation to a stable component. This means that in the case of applying iron the iron isotopes Fe 54 and Fe 58 are rather less advantageous because of relatively high probability of their neutron activation. The isotope separation is a known method but with regard to the iron it is expensive. The preferred, most advantageous isotope Fe 56 can be producecd by the neutron activation of the manganium isotope Mn 55 transforming into the manganium isotope Mn 56 which shows beta decay and results in the isotope Fe 56. Under influence of the neutron flux the radioactive isotope Fe 56 produces the stable isotope Fe 57. The similar schedule can be drawn in the case of calciur. produced from the potassium isotope K 41 by neutrons wherefrcπ first the calcium isotope Ca 42 is received which is activated with short half-time to the stable isotope Ca 43. The isotope separation can be applied in the case of nitrogen, chlorine and potassium to be used together with the iron oxides in the physiologic fluid medium in order to prepare the isotopes N 15, Cl 37, X 41 showing low effective cross-section against neutron activation. By selecting the mentioned isotopes produced the neutron load of the living body can be reduced as much as possible.

The solutions based on neutron activation make use of at least one iron oxide constituting carriers for isotopes to be activated and the ircn oxides themselves take rather no part in the radioactive processes. A further solution of this kind can be seen in the method of completing the microscopic grains of the iron oxides, i.e. the grains consisting of at least one of the iron oxides - ferrous oxide (FeO), ferric oxide (Fe₂O₃) and mixed iron oxide (ferroferric oxide - Fe₃O₄) - by an isotope which being active when present in the microstructure of the iron oxide constitutes the instrument of weakening the biologic activity of or killing the cancer cells. The iron oxide grains are rather very small, their size is about 10 nm or less and they can be prepared by known methods. The sarr.e size magnitude characterizes the iron oxide grains also in the neutron activation method.

The micrograins of the iron oxide should be introduced into the interior of a living body, generally of a human being by the means of a physiological liquid. As mentioned, the micrograins constitute generally particles of average size being rather below 10 nm. The preparation of physiologic solutions with grains of this average size are known and constitute no object of the present invention.

The micrograins of the iron oxide should be completed — according to the present invention - by the isotopes forming the desired instrument of weakening the biologic activity of or killing the cancer cells. The completion can be done e.g. by ion bombardment or alloying introducing into the material system comprising the iron oxide an isotope capable of being activating by a neutron flux of thermal or resonance energy range as shown above.

It is also preferred to apply the iron oxide grains for carrying isotopes being active in the moment of introducing into the living body and taking later part in a multiple transformation process, the transformation meeting special requirements. The requirements mean that the active isotope should emit at the beginning of the treatment in a first period radiation of very lew intensity being not harmful for the living body, than undergo transformation and arrive thereby to another - let's say - intermediate isotope emitting intensive radiation for a second period lasting short time, rather below 1 hour. After the short life time of this intermediate isotope the process should terminate with corring a stable isotope into being which is not toxic or show low toxicity in the conditions of the living body, in the body of a human being and can be expelled therefrom, if necessary, by simple medical methods.

Some isotopes can fulfill the requirements mentioned above.

According to the investigations carried out the first of the isotopes to be applied is the ruthenium isotope Ru 94 which can be probably used also without iron with regard to the intensive chemical similarity of the two elements. This isotope of the ₄₄Ru emits K radiation and decays thereby to the isotope Tc 43 of the technetium with half-period 57 minutes emitting intensive (hard) gamma-radiation and K radiation showing energy 0.874 MeV with dose rate constant 10.12 together with e radiation of relatively low intensity. The intermediate isotope To 94 of ₄₃ Tc has half-period about 53 minuts and undergoes transformation into the stable molybdenum isotope Mo 42. The molybdenum can be repelled from the organism of the living body of a human being-by known means. This means, the first period lasts in this case about 57 minutes and the second period about 53 minutes.

The similar schedule can be drawn when selecting the isotope Cd 104 of cadmium (₄₉Od). This isotope transforms with half-period about 59 minutes to the intermediate silver (₄₇Ag) isotope Ag 47 having half-perioi about 69 minutes and erritting weak e radiation together with intensive gamma radiation in the frequency range of 0.56 MeV to 0.94 MeV. The process terminates in the stable palladium (₄₆Pd) isotope Pd 104. Falladium seems to be not dangerecus for the human body an all. This means, the first period lasts in this case about 59 minutes and the second period about 69 minutes.

The mentioned isotopes of rutenium and cadmium show in both decay stages first and second periods about 1 hour. These periods can be regarded sometimes to be disadvantageous, and especially when the intensive radiation is applied so long. Of course, the first period must not be too short because if it is short the iron oxide will not be bound by the targeted organ and no real effect is ensured.

The further isotopes applicable in the process ar.d composition of the invention are the Ti 52 isotope of the titanium (₂₂Ti) having half-period about 12 minutes, the Lu 178 and Lu 179 isotopes of lutetiun (₇₁ lu). The first of the mentioned isotopes decays to vanadium (₂₃V) isotope V 52 and the last with half-period 4 minutes transforms into the chromium (p_.Cr) isotope Cr 52. The lutetium isotopes arrive to the stable hafnium (₇₂Hf) isotopes Hf 178 and Hf 179 over the intermediate isotopes Hf 178^m and Hf 179^m being characterized by the half- -periods 5 sec and 29 sec, respectively. This means, the second periods are rather short when applying the mentioned isotopes of lutetium and titanium.

In the last three possibilities it is required rather to prepare the isotopes in situ because of the short duration of the first period, i.e. the nuclear arrangement and the medical treatment means should be arranged near to one another. The development of the medical sciences show the amplification of the tendency of equipping some kinds of medical centers with nuclear means.

The method and the composition of the invention are obviously realizable on the present stage of the technical development. The materials introduced into the living body are capable of being activated from an outer neutron source emitting low energy (thermal or rescrsnce neutrons) or they are active only for a short time and they can be transported to the crgan targeted by the means of the iron oxides. The compounds comprising the required elements can be introduced into the organism, i.e. of the human being, by the means of a physiologic solution and the products of the radioactive processes can be simply removed or they are not toxic. The main advantage is, however, that the living body can be exposed to the action of a radioactive radiation very locally, no general radiation is necessary and the isotope can be made the radiation act exactly in the localizations wherein this is really required.

Claims

CLAIMS:

1. Improved method of preparing an iron oxide composition for therapeutic treatment of a living body, comprising the steps of providing fine grain iron oxide, introducing the fine grain iron oxide into a liquid carrier median applicable for therapeutic purposes and dispersing the fine grain iron oxide in the liquid carrier medium,

characterized in the

step of completing the fine grain iron oxide with at least one isotope of low activity for a first period sufficient for introducing the fine grain iron oxide into an organ targeted of the living body or at least one isotope capable of being activated by neutrons and decaying after the first period or transforming by neutron activation to a high activity isotope of short life time before transforming into a stable isotope, the stable isotope being not toxic to the living body, for influencing the biologic activity of the cancer cells during the high activity second period.

2. The method as set forth in claim 1, characterized inthat the at least one isotope of low activity is selected from the group consisted of Ti 52, Ru 94, Cd 104, Lu 178 and Lu 179.

3. The method as set forth in claim 1 , characterized in that the at least one isotope capable of being activated by neutrons is selected from the group consisted of B 10 and Rh 103.

4. The method as set forth in claim 3, characterized in carrying out the activation by the means of neutrons with energy in the range from the thermal to the resonance values making out from about 0.025 eV to about 1 eV.

5. The method as set forth in claim 1, characterized in carrying out the completing step by ion bombardment or alloying the iron basic material before transforming it into one of the oxides.

6. The method as set forth in claim 1, characterized in preparing the at least one isotope before completing by it the fine grain iron oxide.

7. The method as set forth in claim 1 , characterized in that the at least one iron oxide is prepared from the isotope Fe 56 produced from the isotope of manganiur. Mn 55 by neutron bombardment, the neutrons having energy in the range of thermal and/or resonance neutrons.

8. The method as set forth in any of claims 1 to 7, characterizedin that the fine grain iron oxide is prepared from particles of ferrous oxide, ferric oxide and ferroferric oxide of average size about 10 nm or less.

9. Iron oxide composition for therapeutic treatment of a living body, comprising a liquid carrier medium, the liquid carrier medium, being applicable in in vivo conditions in a living body and fine grain iron oxide made of at least one iron oxide selected from the group consisted of ferrous oxide, ferric oxide and ferroferric oxide forming a dispersion in the liquid carrier medium,

characterized in that

the fine grain iron oxide constitutes a solid carrier medium for transporting at least one isotope showing low activity during a first period sufficient for introducing the fine grain iron oxide into an organ targeted of the living body or at least one isotope capable of being activated by neutrons and decaying after the first period or transforming by neutron activation to an isotope of short life time radiating with high activity through a second period before transforming into a stable isotope, the stable isotope being not toxic in the living body, for influencing the biologic life conditions of the cancer cells in the organ targeted during the high activity radiation second period in order to lower their biologic activity up to killing them.

10. The iron oxide composition as set forth in claim 9, characterized in that the at least one isotope of low activity introduced into the grains is selected from the group consisted of Ti 52, Ru 94, Cd 104, Lu 178 and Lu 179.

11. The iron oxide composition as set forth in claim 9, characterized in that the fine grain iron oxide consists of particles of size dimensions about 10 n m .

12. The iron oxide composition as set forth in claim 9, characterized in that the at least one isotope capable of beng activated by neutrons is selected from the group consisted of B 10 and Rh 103.

13. The iron composition as set forth in any of claims 9 to 12 , characterized in that the iron oxide carrier of the at least one isotope is consituted substantially by the iron isotope Fe 56 having small effective cross-section against neutron activation.

14. The iron composition as set fo rth in any of claims 9 to 13, characterized in that the irin oxide grains are completed by nickel isotope Ni 58.