JP2009196914A - Medicine having magnetism, guiding system for medicine and magnetism-detecting system - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To realize a drug delivery system that solves conventional technical problems and can be readily put into practice. <P>SOLUTION: The medicine having magnetism includes a pharmaceutical compound contained in apoferritin. As the medicine itself has magnetism, it can be guided to an affected part in the body utilizing the magnetism of the medicine itself without using a carrier composed of a magnetic substance as before. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a drug having magnetism, a drug guidance system, and a magnetic detection device.

  In general, drugs are administered in vivo to reach the affected area and cause a therapeutic effect by exerting a pharmacological effect in the affected area, but even if the drug reaches tissues other than the affected area (that is, normal tissues) Don't be. Therefore, how to efficiently guide the drug to the affected area is important in the treatment strategy. Such a technique for guiding a drug to an affected area is called drug delivery, and research and development have been actively conducted in recent years. This drug delivery has at least two advantages. One is that a sufficiently high drug concentration is obtained in the affected tissue. This is because the pharmacological effect does not appear unless the drug concentration in the affected area is above a certain level, and a therapeutic effect cannot be expected at a low concentration. The second is to induce the drug only to the affected tissue and not unnecessarily to normal tissue. Thereby, a side effect can be suppressed.

  Such drug delivery is most effective in cancer treatment with anticancer agents. Most anticancer drugs inhibit cell proliferation of cancer cells with active cell division, so that even normal tissues, such as bone marrow or hair roots, gastrointestinal mucosa, etc. It will be suppressed. For this reason, side effects such as anemia, hair loss, and vomiting occur in cancer patients who receive anticancer drugs. Since these side effects are a heavy burden on the patient, the dosage must be limited, and the pharmacological effect of the anticancer drug cannot be obtained sufficiently. In the worst case, side effects can cause the patient to die. Therefore, it is expected that cancer treatment can be effectively performed while suppressing side effects by inducing anticancer drugs to cancer cells by drug delivery and concentrating on cancer cells to exert pharmacological effects. Has been.

  Other than anticancer agents, for example, it can be applied to male erectile dysfunction drugs. Male erectile dysfunction drugs cause serious systemic hypotension when used in combination with nitro drugs, leading to death, and are particularly problematic for men with middle-aged and older heart disease. This is because the drug for erectile dysfunction does not necessarily concentrate on the affected part, but acts on the blood vessels throughout the body to amplify the vasodilatory action of the nitro preparation. Therefore, it is considered that side effects caused by the combined use with a nitro preparation can be suppressed by inducing a drug for male erectile dysfunction to the affected area by drug delivery and concentrating on the affected area to exert a pharmacological effect.

  As a specific method of drug delivery, for example, guidance to a diseased tissue using a carrier (carrier) is being studied. This is because a drug is placed on a carrier that tends to concentrate on the affected area, and the drug is placed on the carrier to the affected area. It is meant to be carried. The use of various antibodies, microspheres, or magnetic substances as the carrier has been studied. Among them, a magnetic material is regarded as promising, and a method of attaching a carrier, which is a magnetic material, to a drug and accumulating it in an affected area by a magnetic field has been studied (for example, see Patent Document 1 below). This method is considered to be a particularly effective method for anti-cancer agents having high cytotoxicity because of the simplicity of the induction method and the possibility of treatment targeting the affected area.

  Further, it has been reported that iron oxide is encapsulated with apoferritin (for example, Non-Patent Documents 1 to 3), but there is no report that a pharmaceutical compound is encapsulated with apoferritin.

JP 2001-10978 A Fiona C. Meldrum, Brigid R. Heywood, Stephen Mann, 'Magnetoferritin: In Vitro Synthesis of a Novel Magnetic Protein', Science, 257 (1992) 522-523 Jeff WM Bulte, Trevor Douglas, Stephen Mann, Richard B. Frankel, Bruce Vymazal, Marie-Paule Strub, and Joseph A. Frank, 'Magnetoferritin: Characterization of a Novel Superparamagnetic MR Contrast Agent', JMRI, 4 (1994) 497- 505 Fiona C. Meldrum, Vanessa J. Wade, Duncan L. Nimmo, Brigid R. Heywood and Stephen Mann, 'Synthesis of inorganic nanophase materials in supermolecular protein cages', Nature, 349 (1991) 684-687

  However, as described above, when a carrier that is a magnetic substance is used as a carrier, it is difficult to administer orally, the carrier molecule is generally huge, or the binding strength and affinity with drug molecules are technical. Problems have been pointed out, making it difficult to put to practical use.

  The present invention has been made in view of the above-described circumstances, and an object of the present invention is to realize a drug delivery system that can solve the conventional technical problems and can be easily put into practical use.

The present invention relates to (1) a magnetic drug encapsulating a pharmaceutical compound with apoferritin;
(2) The drug having magnetism according to (1), wherein the pharmaceutical compound is an iron-salen complex represented by the following formula (I) or a derivative thereof;
(3) The drug having magnetism according to (1) or (2), which is configured to be guided to a target tissue or affected area by a magnetic field applied to the individual when administered to the individual;
(4) The magnetic drug according to (3), wherein a magnetic field is applied to the tissue or affected area from the outer surface of the individual so as to be induced in the tissue or affected area;
(5) The magnetic agent according to (4), wherein a magnetic force generating means is applied in the tissue or the affected part of the individual so as to be guided to the tissue or the affected part;
(6) The magnetic force generating means is disposed in the middle of the path of a blood vessel or the like for supplying the body fluid of the individual into the tissue or the affected part of the individual so as to be guided to a downstream tissue or affected part. 3) a drug having magnetism according to 3);
(7) A guidance system for guiding the magnetic drug according to (1) or (2) administered into the body to a predetermined affected area using the magnetic property of the drug, the surface of the individual or the individual A drug induction system in which means for generating a magnetic field is disposed on the tissue or affected area of the patient;
(8) A guidance system for guiding the magnetic drug according to (1) or (2) administered into the body to a predetermined affected area using the magnetic property of the drug, wherein a magnetic field is applied to an individual. A drug induction system comprising: means for generating; and means for guiding the magnetic field to the target tissue or affected area for fixation;
(9) The means for generating the magnetic field is configured so that two magnets are paired and the target tissue or affected part is placed between the two magnets, and the magnetic flux is concentrated on the tissue or affected part. The drug induction system according to (7) or (8);
(10) The drug induction system according to any one of (7) to (9), wherein the target tissue or affected area is identified by MRI or CT;
(11) A magnetic detection device that detects the pharmacokinetics of the drug by detecting the magnetism of the drug having magnetism according to (1) or (2) administered into the body;
(12) The magnetic detection device according to (11), wherein the magnetism is detected by magnetic resonance induction.

According to the present invention, since the drug itself can be magnetized, the drug can be guided to the affected part in the body by using the magnetic property of the drug itself without using a carrier made of a magnetic material as in the prior art. it can.
By providing the drug itself with magnetism, a high magnetic susceptibility can be obtained, so that it can be applied to drug delivery over a wide range without being limited to the affected area existing on the body surface.
It is also possible to kill cancer cells by increasing the temperature by applying an alternating magnetic field after guiding the drug to the affected area.
As a result, it can be solved that conventional oral administration is difficult, the carrier molecule is generally huge, or there are technical problems in binding strength and affinity with drug molecules. It is possible to realize a drug delivery system that can be easily realized.

  Next, an embodiment of the present invention will be described. The following embodiment is an example for explaining the present invention, and is not intended to limit the present invention only to this embodiment. The present invention can be implemented in various forms without departing from the gist thereof.

(Drug)
The drug of the present invention is a magnetic drug encapsulating a pharmaceutical compound with apoferritin.

Ferritin is known as an iron storage protein and has a molecular weight of 450 kD. Ferritin has an outer diameter of about 12 nm, consists of 24 subunits, and encloses trivalent iron in a hollow of 8 nm in diameter. Apoferritin can be obtained by removing the encapsulated trivalent iron.
Apoferritin can be converted to apoferritin by filtering ferritin in a sodium acetate solution under a nitrogen atmosphere.

Any drug can be used as the pharmaceutical compound to be encapsulated, and for example, a commercially available drug or organic magnetic substance having no magnetism can be used. When an organic magnetic substance is used as the encapsulated pharmaceutical compound, the magnetic properties of the pharmaceutical compound itself can be utilized even after apoferritin as a carrier is separated from the pharmaceutical compound.
The pharmaceutical compound to be encapsulated is preferably an iron-salen complex represented by the following formula (I) or a derivative thereof.

The magnetic drug of the present invention may be an in vivo marker.
As an example of use of the drug of the present invention, since the drug itself has magnetism, after administration to an individual, a magnetic field can be applied to the individual to induce the drug to the target tissue or affected area.
In another use example, a magnetic field can be applied to the tissue or affected area from the outer surface of the individual to induce the drug to the tissue or affected area.
As another example of use, a magnetic force generating means can be applied to the tissue or affected area of the individual to induce the drug to the tissue or affected area.
As another example of use, magnetic force generating means may be disposed in the path of a blood vessel or the like for supplying body fluid of the individual into the tissue or affected part of the individual to induce the drug to a downstream tissue or affected part. it can.

(Drug guidance system)
The magnetic drug of the present invention is a guidance system that guides the drug administered into the body to a predetermined affected area using the magnetic property of the drug, and applies a magnetic field to the surface, tissue, or affected area of an individual. The present invention can be applied to a drug guidance system in which a generating means is arranged.
The magnetic drug of the present invention is a guidance system for guiding the drug administered into the body to a predetermined affected area using the magnetism of the drug, the means for generating a magnetic field for an individual, and the magnetic field And a means for guiding the target to the target tissue or affected area of the individual.
It is preferable that the means for generating the magnetic field is configured so that two magnets are paired and the target tissue or affected part is placed between the two magnets, and the magnetic flux is concentrated on the tissue or affected part. .
The target tissue or affected area is preferably identified by MRI or CT.

(Magnetic detection device)
The magnetic drug of the present invention can be applied to a magnetic detection device that detects the pharmacokinetics of the drug by detecting the magnetism of the drug administered into the body.
The magnetic drug of the present invention is a magnetic detection device that detects the distribution of the drug in the body by detecting the magnetism of the drug administered into the body and quantifies the biological function (such as brain function) exhibited by the drug. Can be applied.
The magnetism of the drug is preferably detected by magnetic resonance induction.

(Functional diagnosis, cancer chemotherapy)
As another example of use of the magnetic drug of the present invention, by applying electromagnetic waves to a drug induced in cancer tissue, the temperature can be locally increased and cancer cells can be specifically killed.
Thus, when the drug of the present invention is used, functional diagnosis and cancer chemotherapy can be performed simultaneously with one drug. For example, an MRI diagnostic apparatus capable of cancer chemotherapy and a magnetic field induction drug delivery system can be provided.

EXAMPLES Hereinafter, although an Example demonstrates this invention further in detail, this invention is not limited to these Examples.
Example 1

Apoferritin synthesis:
The synthesis of apoferritin using horse spleen ferritin will be described. Apoferrin was filtered through a sodium acetate solution (0.2 M) adjusted to pH 5.5 under a nitrogen atmosphere, and then trivalent iron contained in the solution was removed using triglycolic acid using a reducing chelate method. . Subsequently, trivalent iron completely contained was removed by repeated filtration with a sodium chloride solution (0.15M).

Synthesis in which apoferritin encapsulates a compound of formula (I):
Apoferrin was dispersed in either a solution of pH 7.5-8.5 using 0.05 M 4- (2-hydroxyethyl) -1-piperazineethane-sulfonic acid (HEPES) or 0.25 M AMPSO. Subsequently, 0.1 M iron complex acetic acid aqueous solution of chemical formula (I) was added and stirred at a temperature of 35-50 ° C. Subsequently, reduction was performed using sodium borohydride. As a result, a compound in which the iron complex of the formula (I) was encapsulated in the core of apoferritin was synthesized.

(Example 2)
When the rat L6 cells were 30% confluent, the medium was photographed after 48 hours after sprinkling the medium so that the iron complex powder represented by the above formula (I) could be visually attracted to the magnet. .
FIG. 1 shows a state in which a bar magnet is brought into contact with a rectangular flask having a culture medium of rat L6 cells. Then, 48 hours later, the results were obtained by photographing the bottom of the square flask from one end to the other end and calculating the number of cells. In FIG. 2, “proximal to magnet” means within the projected area of the magnet end face on the bottom of the square flask, and “distal from magnet” means a region on the bottom face of the square flask opposite to the magnet end face.

As shown in FIG. 2, it can be seen that the iron-salen complex is attracted near the magnet, the concentration of the iron-salen complex is increased, and the number of cells is extremely lower than that of the distal due to the DNA suppression action of the iron-salen complex. As a result, the system including the magnetic drug and the magnetism generating means according to the present invention enables the drug to be concentrated on the target affected area or tissue of the individual.
Next, another example of the guidance device according to the present invention will be described. As shown in FIG. 3, in this guidance device, a pair of magnets 230 and 232 facing each other in the direction of gravity are supported by a stand 234 and a clamp 235, and a metal plate 236 is placed between the magnets. By placing a metal plate, particularly an iron plate, between a pair of magnets, a locally uniform and strong magnetic field can be created.

This induction device can change the generated magnetic force by using an electromagnet instead of a magnet. Further, the pair of magnetic force generating means can be moved in the XYZ directions, and the magnetic force generating means can be moved to the target position of the solid on the table.
By placing solid tissue in the area of this magnetic field, the drug can be concentrated in this tissue. A mouse having a body weight of about 30 grams was intravenously injected with the aforementioned metal complex (drug concentration 5 mg / ml (15 mM)), and the mouse was placed on an iron plate so that the right kidney was between the pair of magnets. Put.
The magnet used was Shin-Etsu Chemical Co., Ltd., product number: N50 (neodymium permanent magnet), residual magnetic flux density: 1.39-1.44 T. At this time, the magnetic field applied to the right kidney is about 0.3 (T), and the magnetic field applied to the left kidney is about 1/10. Together with the left kidney and the kidney to which no magnetic field was applied (control), a magnetic field was applied to the right kidney of the mouse, and 10 minutes later, SNR was measured by MRI in T1 mode and T2 mode. As a result, as shown in FIG. 4, it was confirmed that the right kidney (RT) to which a magnetic field was applied can retain the drug in the tissue as compared with the left kidney (LT) and the control.

  Further, when an alternating magnetic field having a magnetic field strength of 200 Oe (Oersted) and a frequency of 50 kHz to 200 KHz was applied to the drug, the temperature of the drug rose from 2 ° C. to 10 ° C. (FIG. 5). This was equivalent to 39 ° C to 47 ° C when converted to the temperature at the time of administration in the body, and was confirmed to be a temperature range in which cancer cells can be killed.

It is a block diagram which shows the outline | summary of the experimental system which verifies the location of the chemical | medical agent in a magnetic field. It is a characteristic view which shows the measurement result of the cell number based on the fluctuation | variation of the chemical | medical agent density | concentration in a magnetic field. It is a perspective view which shows other embodiment of the guidance device concerning this invention. It is a graph of a MRI measurement result (T1-weighted signal) for the kidney of a mouse. It is a graph of the temperature rise when applying an alternating magnetic field to a medicine.

Claims (12)

  A magnetic drug encapsulating a pharmaceutical compound with apoferritin. The drug having magnetism according to claim 1, wherein the pharmaceutical compound is an iron-salen complex represented by the following formula (I) or a derivative thereof.
  The magnetic drug according to claim 1 or 2, wherein when administered to an individual, the agent has a magnetic property according to claim 1 or 2 so as to be guided to a target tissue or affected area by a magnetic field applied to the individual.   The drug having magnetism according to claim 3, wherein a magnetic field is applied to the tissue or affected area from the outer surface of the individual so as to be guided to the tissue or affected area.   The magnetic agent according to claim 4, wherein a magnetic force generating means is applied to the individual or the affected part of the individual so as to be guided to the tissue or the affected part.   The magnetic force generation means is arranged in the middle of a path of a blood vessel or the like for supplying the body fluid of the individual into the tissue or the affected part of the individual so as to be guided to a downstream tissue or affected part. Drug with magnetic properties. A guidance system for guiding the magnetic drug according to claim 1 or 2 administered into a body to a predetermined affected area using the magnetic property of the drug,
A drug induction system in which means for generating a magnetic field is arranged on the surface of an individual or on the tissue or affected area of the individual. A guidance system for guiding the magnetic drug according to claim 1 or 2 administered into a body to a predetermined affected area using the magnetic property of the drug,
A drug guidance system comprising: means for generating a magnetic field for an individual; and means for guiding the magnetic field to the fixed target tissue or affected area.   The means for generating the magnetic field is configured so that two magnets are paired, the target tissue or affected part is placed between the two magnets, and the magnetic flux is concentrated on the tissue or affected part. Or the drug guidance system according to 8,   The drug induction system according to any one of claims 7 to 9, wherein the target tissue or affected area is identified by MRI or CT.   A magnetic detection device for detecting the pharmacokinetics of a drug by detecting the magnetism of the drug having magnetism according to claim 1 or 2 administered into the body.   The magnetic detection apparatus according to claim 11, wherein the magnetism is detected by magnetic resonance induction.