WO1991015240A1

WO1991015240A1 - Method of preparing an iron oxide composition for therapeutic treatment of a living body and iron oxide composition

Info

Publication number: WO1991015240A1
Application number: PCT/HU1990/000025
Authority: WO
Inventors: Péter Teleki
Original assignee: Teleki Peter
Priority date: 1990-04-11
Filing date: 1990-04-11
Publication date: 1991-10-17

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 and decaying after the period 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 and decaying after the period to an isotope of short life time radiating with high activity before transforming into a stable isotope, the stable isotope being not toxic.

Description

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

FIELD OF INVENTION

l The invention refers to the field of the medicine and especially to the means to be applied in the therapeutic processes of oncology and proposes a method of preparing an iron oxide composition for therapeutic treatment of a living body and an iron oxide composition. The method as proposed

^Λ- ^~ 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

2.^' according to the invention includes a liquid carrier medium, the liquid carrier medium being applicable in in vivo con¬ ditions 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 5 dispersion in the liquid carrier medium.

BACKGROUND OF THE INVENTION

The scientific investigations carried out in order to C 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 stated that practically the normal cells take up very small 5 amounts of iron oxides, i. e. ferrous oxide (FeO), ferric oxide (FepOη) and mixed iron oxide (ferroferric oxide - Fe-,0. ). Of course, this recognition is very interesting per se and offers a possibility of elaborating different methods of influencing the cancer cells by making use of the ircr. atoms bound in the 5 parts of the living body suffering from this enormous state.

The first investigations reported e.g. in the book "Bio¬ physical 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,

'I the whole edition publishing papers of an international conference held on the problems of the mag etic 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

'5 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 no mal cells. The radiation

21 results also in exciting the iron atoms which emit then electrons and gamma fotons. The surmarized effect of the in¬ creased temperature and the emitted radiation can follow in the desired therapeutic effect if the cancer cells are localized in a relatively small area. The problem is here that the blood 5 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.

3- A further problem should be seen in the fact that the K—edge energy characterizing the iron atoπs 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, 5 however a value lying slightly under this limit can be applied, too. The narrow excitation spectrum is not ensured by the known means.

SUMMARY GF THE INVENTION

The object of the present invention is to improve and widen the therapeutic possibilities offered by the neutral fluids containing iron oxide by ensuring a very narrow excitation spectrum of iron present in the fluid in the form of 'Z an iron oxide.

The invention is based on the recognition that the the¬ rapeutic 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 *Z iron atoms in the required narrow range.

Hence, the invention consititutes a method of preparing an iron oxide composition and an 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 therapeutic purposes and dispersing the fine grain iron oxide in the liquid carrier medium, with the novel feature of including the step of cccpleting the fine grain iron oxide with at least one isotope shopwing low 5 activity for a first period sufficient for introducing the fine grain iron oxide into an organ targeted of the living body and decaying after the first period to a high activity isotope of short life time constituting a second period before trans¬ forming into a stable isotope, the stable isotope being not 2 toxic to the living body. This method is intended to influence the biologic activity of the cancer cells during the high activity period.

In a preferred embodiment of the method as proposed by the invention the at least one isotope is selected from the 5 group consisted of Ti 52 (titanium), Ru 9 (ruthenium), Cd 104 (cadmium), Lu 178 and Lu 179 (lutetium), for limiting the bio¬ logic activity of the cancer cells. The isotopes mentioned can be introduced into the iron oxide among other possibilites by ion bombardment. Because of the short life time (second period) of the isotopes preferably applied in the invention 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 com- position for therapeutic treatment of a living body, comprising a liquid carrier medium, the liquid carrier medium being app¬ licable 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 fi e grain iron oxide constitutes a solid carrier medium for bearing 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 and decaying after the first period to an isotope of short life time constituting a second period, the isotope after decay 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.

As mentioned in connection with the proposed method, in the preferred embodiments of the iron oxide composition ac¬ cording 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 (lutetium).

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. The object of the invention is further a method of mak- ing use of the nickel isotope Ni 28, which added to the iron can be excited by X-ray radiation or by synchrotron radiation. The synchrtron radiation is per se also capable of exciting iron also without application of nickel. The nickel isotope Ni 28 excited emits K radiation with energy 8.331 keV and with two edges (K alpha and K alphap) 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 ob¬ ject of the present invention.

DETAILED DESCRIPTION OF THE INVENTION AND SOME PREFERRED EMBO¬ DIMENTS

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 should be exploited in a novel manner. The excitation of the iron bound in the cancer cells by their presence in the iron oxide 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 the 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 by X-ray or synchrotron radiation. This •is rather a very local method, not applicable in the later stages of the cancer diseases attacking extended body areas. The excitation can be ensured either by iirmediate 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 in local treatments of the cancer diseases when a small area should be taken into account. The more advantageous solution should be seen in the method of completing the microscopic grains of the iron oxides, i.e. the grains consisting of ferrous oxide (FeO), ferric oxide (FepO and mixed iron oxide (ferroferric oxide - Fe^O^) by an isotope which being present in the microstructure of the iron oxide constitutes the instrument of weakening the biologic activity of or killing the cancer cells. These grains are rather very small, their size is^'about 10 nm or less and they can be produced by known methods.

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 solution. The micrograins means generally particles of average size being rather below 10 nm. The preparation of physilogic solutions with grains of this average size are solved and can not constitute the 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 is done e.g. by ion bombardment introducing into the material system comprising the iron oxide an isotope capable of multiple transformation, the transformation meeting special requirements. The requirements mean that the isotope should issue at the beginning in a first period radiation of very low 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 a stable isotope 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 there¬ from, if necessary, by simple medical means.

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 perhaps used also without iron with regard to the intensive chemical similarity of the two elements. This isotope of the _ΛΛRU emits K radiation and decays thereby to the technetium isotope Tc 43 with half-period 57 minutes emitting intensive hard gamma-radiation and K radiation of energy 0.874 MeV with dose rate constant 10.12 together with e radiation of relatively low intensity. The intermediate isotope Tc 94 of -TC has half-period about 53 minuts and transforms into the stable molybdenum isotope Mo 42. Molybdenum can be repelled from the organism of the living body by knwon 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 (ΛqCd). This isotope transforms with half-period about 59 minutes to the intermediate silver (,₇Ag) isotope Ag 47 having half-period about 69 minutes and emitting weak e radiation together with intensive gamma radiation in the frequency range of 0.56 MeV to 0.94 MeV. The process ter- minates in the stable palladium ^-Pd) isotope Pd 104. Palla¬ dium is not dangereous for the human body ar 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 and composition of the invention are τhe Ti 52 isotope of the tita¬ nium ( pTi) having half-period about 12 minutes, the Lu 178 and Lu 179 isotopes of lutetium -.Lu). The first of the mentioned . r isotopes decays to vanadium (p_oV isotope V 52 and the last with half-period 4 minutes transforms into the chromium (_o^Cr) isotope Cr 52. The lutetium isotopes arrive to the stable haf¬ nium (₇pHf) isotopes Hf 178 and Hf 179 over the intermediate iscτopes Hf 17o and Hf 17S* being characterized by the half- I —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 method and the composition of the invention are ob¬ viously realizable on the present stage of the technical deve¬ lopment. The materials introduced into the living body are ac-

2. tive only for a short time and they can be transported to the organ targeted by the means of the iron oxides. The compounds comprising the required elements can be removed from the or¬ ganism, i.e. of the human being, by the means of a physiologic solution. The main advantage is, however, that the living body

25 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 on the localizations wherein this is really required.

Claims

CLAIMS:

1. Method of preparing an iron oxide composition for therapeutic treatment of a living body, ccmprising the steps of providing fine grain iron oxide, introducing the fine grain iron oxide into a liquid carrier medium applicable for thera¬ peutic purposes and dispersing the fine grain iron cxide in the liquid carrier medium, characterized in the step of completing the fine grain iron oxide with ar least one isotope of low activity for a first period sufficient for introducing the fine grain iron oxide int. an organ targeted of the living body and decaying after the first period to a high activity isotope of short life time before transforming into a stable isotope, the stable isotope being r.ot toxic to the living body, for influencing the biologic activity cf the cancer cells during the high activity sec:r.d period.

2. The method as set forth in clain 1 , characterized in that the at least one isotope 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 clai__ 1 , characterized in carrying out the completing step by ion bombardment.

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

5. Iron oxide composition for therapeutic treatment of a living body, comprising a liquid carrier medium, the liquid carrier medium being applicable in in vivc conditions in a liv- ing body and fine grain iron oxide made of at least one iron oxide selected from the group consisted of ferrous oxide, fer¬ ric 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 bearir-g at least one isotope of lew activity for a first period sufficient for introducing the fine grain iron oxide into an organ targeted of the living body and decaying after the first period 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, for influencir-g the biologic life conditions cf the cancer cells in the orgar. targeted during the high activity radiation second period.

6. The iron oxide composition as set forth in claim 5, characterized in that the at least one isotope introduced into the grains is selected from the group consisted of Ti 52, Ru 94, Cd !0 , Lu 178 and Lu 179.

7. The iron oxide composition as set forth in claim 6, characterized in that the fine grain iron oxide consists of particles of size dimensions about 10 nm.