JP2009280505A - Iron oxide nanoparticles - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide iron oxide nanoparticles suitable for thermotherapy for destruction of cancer cells according to applied magnetic field, frequency and viscosity, and to provide a method for determining particle diameters of the iron oxide nanoparticles suitable for the thermotherapy for destruction of the cancer cells according to the applied magnetic field, the frequency and the viscosity. <P>SOLUTION: The iron oxide nanoparticles are usable for the thermotherapy for the destruction of lesion cells by the heating to a prescribed temperature by generating the heat in a prescribed dispersion medium in the body by an external high-frequency magnetic field. The iron oxide nanoparticles are regulated so that the SAR value (specific absorption rate) defined by equation 1 under a condition of the external magnetic field of 600 kHz frequency and 3.2 kA/m magnetic field strength may be a calorific value required according to the lesion cells, that is ≥5.0 W/g and ≤28.3 W/g per unit time. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to iron oxide nanoparticles used for thermotherapy, and particularly to iron oxide nanoparticles suitable for thermotherapy determined from the viewpoint of exothermic characteristics and magnetic characteristics.

  Conventionally, so-called thermotherapy is known in which iron oxide particles are disposed (dispersed) in the vicinity of cancer tissue, and a high-frequency magnetic field is applied from the outside to cause iron oxide to generate heat, thereby killing the cancer tissue (Patent Document 1). ~ 4).

  Such hyperthermia is a treatment method that utilizes the property that cancer cells tend to be warmer than normal cells and is weak against heat, and more specifically, by heating a lesion site to about 40 ° C. or higher. It is intended to kill only cancer cells without damaging peripheral normal cells as much as possible.

  Here, it is known that iron oxide particles typified by magnetite or the like generate heat due to hysteresis loss in a high-frequency magnetic field, and the heat generation due to this hysteresis loss depends on the particle diameter of the iron oxide particles.

  More specifically, when the particle diameter is smaller than the predetermined diameter, the iron oxide particles such as magnetite do not generate hysteresis because no hysteresis loss occurs. On the other hand, if the particle diameter is larger than the predetermined diameter, aggregation occurs due to the magnetism of the particles themselves, and the solvent dispersibility of the magnetite colloid is impaired.

In the above sense, it has been known that there is a predetermined numerical range for the particle diameter of iron oxide particles suitable for thermotherapy.
Japanese Patent No. 3983843 JP 2006-307126 A Special table 2007-521109 gazette JP 2007-256151 A

  The present invention was created based on the above findings. That is, the objective of this invention is providing the iron oxide nanoparticle suitable for the thermotherapy which kills a cancer cell according to an applied magnetic field, a frequency, and a viscosity.

  Furthermore, this invention is providing the determination method of the particle size of the iron oxide nanoparticle suitable for the thermotherapy which kills a cancer cell according to an applied magnetic field, a frequency, and a viscosity.

  In order to solve the above-mentioned problems, the present inventors have found that the heat generation mechanism of superparamagnetic magnetite nanoparticles is roughly classified into so-called Neel relaxation and Brownian relaxation, and the following points are focused on these two relaxations. did.

First, the balance between the two relaxations depends on the particle size of the magnetite. More specifically, the larger the magnetite particle size, the more dominant the Brownian relaxation.
Secondly, regarding the relationship between the viscosity of the environment where the magnetite nanoparticles are placed and the heat generation, the higher the viscosity, the lower the heat generated by Brownian relaxation.

  Thirdly, regarding the relationship between the shift of the blocking temperature to the high temperature side and the particle size, the larger the particle size of the magnetite, the more the shift of the blocking temperature to the high temperature side due to the frequency change is suppressed.

  In particular, in relation to the first and second points, the influence of the magnetic relaxation mechanism on the heat generation characteristics is evaluated using the SAR value defined by the following equation, particularly the influence of the viscosity of the dispersion medium. And found an appropriate numerical range.

（ここで、Ｃは：分散媒および酸化鉄ナノ粒子の各比熱、ｍは：分散媒および酸化鉄ナノ粒子の各重量、△Ｔ／△ｔは：初期温度変化率）

(Where C is the specific heat of the dispersion medium and iron oxide nanoparticles, m is the weight of the dispersion medium and iron oxide nanoparticles, and ΔT / Δt is the initial temperature change rate)

The present inventor has created the following invention based on the above knowledge.
(1) Iron oxide nanoparticles that are used in thermotherapy to cause heat generation in a predetermined dispersion medium in the body by an external high-frequency magnetic field and kill the diseased cells by heating to a predetermined temperature, with a frequency of 600 kHz and a magnetic field Under the condition of an external magnetic field with an intensity of 3.2 kA / m, the SAR value defined by the following formula is the calorific value required according to the diseased cell, that is, 5.0 W / g or more and 28.3 W / g or less per unit time It is an iron oxide nanoparticle characterized by becoming.

ここでＳＡＲ値が２８．３を超えると、酸化鉄ナノ粒子のブラウニアン緩和が支配的になるので、局所的な作用（血液等による粘度の影響、臓器等への粒子の固着）によって発熱が抑制される可能性がある。

Here, when the SAR value exceeds 28.3, the Brownian relaxation of the iron oxide nanoparticles becomes dominant, so that the heat generation is suppressed by local action (the influence of the viscosity due to blood, etc., the adhesion of the particles to the organ, etc.). There is a possibility that.

  On the other hand, when the SAR value is less than 5.0, there is a possibility that a desired calorific value does not occur unless a large amount of iron oxide nanoparticles are added. In addition, the time for applying the magnetic field is relatively long, and there is a concern about adverse effects on the human body.

(2) The iron oxide nanoparticles according to (1), wherein the iron oxide nanoparticles are mainly formed of magnetite.
If magnetite is the main component, it may be a mixture with other iron oxide nanoparticles. For example, a mixture of γFe ₂ O ₃ and Fe ₃ O ₄ may be used.

(3) The iron oxide nanoparticles according to (1) or (2), wherein the iron oxide nanoparticles have a particle size of 11 nm or more and 14 nm or less.
The particle diameter of the iron oxide nanoparticles referred to here may be the particle diameter of an individual, or may be the average particle diameter in the case of an aggregate of a plurality of iron oxide nanoparticles.
In addition, the one where the distribution range of the average particle diameter is narrower is easier to manage in practical situations such as temperature control, and the heat generation efficiency is better.

The present inventor considered the influence of the magnetic relaxation mechanism on the heat generation characteristics in finding iron oxide nanoparticles having excellent heat generation characteristics.
That is, there is a concept of Neel relaxation and Brownian relaxation as a heat generation mechanism of iron oxide nanoparticles. Here, Neel relaxation is relaxation by rotation of a magnetic moment, and is expressed by the following equation.

他方、ブラウニアン緩和は磁性粒子の回転による緩和であり、以下の式で表わされる。

On the other hand, Brownian relaxation is relaxation caused by rotation of magnetic particles, and is expressed by the following equation.

In the exothermic property of iron oxide nanoparticles, it has been known that there is a difference in calorific value between the case of In-Vitro and the case where it is actually used in thermotherapy.
This is because in thermotherapy, iron oxide nanoparticles are taken into the body, so that it is necessary to obtain an appropriate calorific value in the gel. For this purpose, in the case of iron oxide nanoparticles in which the Brownian relaxation is dominant in the heat generation characteristics, there is a possibility that the heat generation amount is reduced in a high viscosity medium.

Next, the iron oxide nanoparticles used in the present invention will be described.
The iron oxide nanoparticles of the present invention may be iron oxide containing oxygen and iron as magnetic particles. Examples thereof include ferrite such as γ iron oxide called maghemite, magnetite, cobalt ferrite, and barium ferrite. Among these, magnetite is particularly preferable.
Here, the calorific value is expressed by the following equation.

ここで、Ｐ：発熱量、μ₀：真空下における透磁率、χ''：交流磁界率の虚数部、ｆ：
周波数、Ｈ₀：磁界強度を表わす。

Here, P: calorific value, μ ₀ : permeability under vacuum, χ ″: imaginary part of AC magnetic field ratio, f:
Frequency, H ₀ : represents magnetic field strength.

About the iron oxide nanoparticle, the particle diameter which shows each calorific value and the maximum heat generation characteristic was calculated | required from the said type | formula using four types, maghemite, magnetite, cobalt ferrite, and barium ferrite.
From the viewpoint of dispersion stability, it was found that magnetite is optimal as the iron oxide nanoparticles.

A method for producing iron oxide nanoparticles used in the present invention will be described.
Iron oxide nanoparticles are generally produced by a pulverization method, a coprecipitation method, a vapor deposition method, or other similar methods. Among them, the coprecipitation method is usually preferable from the viewpoint of productivity.

(Production method)
A specific method for producing particles by coprecipitation will be described with an example of magnetite. The following production method is an example and does not limit the iron oxide nanoparticles of the present invention.
First, 13.0 g of ferrous sulfate heptahydrate and 24.0 g of ferric chloride hexahydrate are dissolved in water, and the total amount of the solution is adjusted to 70 cc with water. 30 cc of 28% aqueous ammonia is added to the salt iron solution to precipitate Fe ₃ O ₄ particles.

Next, an oleic acid solution consisting of 2.1 g of oleic acid and 27 cc of 3% aqueous ammonia heated to 70 ° C. is prepared. Such an oleic acid solution is added to the suspension of Fe ₃ O ₄ particles, and the mixture is allowed to stand for about 1 hour while the particles are covered with oleate ions.
Next, 30 cc of heptane is poured into the suspension of particles covered with oleic acid and the entire suspension is stirred and allowed to stand. The particles coated with oleic acid are peptized in heptane, and a magnetic fluid containing heptane as a dispersion medium is put into a 200 cc beaker.
In this way, magnetite nanoparticles can be obtained.

Magnetite nanoparticles were obtained by the above production method. At this time, the particle size and particle distribution of the nanoparticles were controlled by changing the pH immediately after the addition of ions and during the reaction.
Sample No. 1 had an average particle diameter of 12 nm, sample No. 2 had 13 nm, and sample No. 3 had 14 nm. The nanoparticles of sample No. 3 are conventional products.
When the heat generation characteristics of the samples No. 1 to 3 were measured under the conditions of an external magnetic field having a frequency of 600 kHz and a magnetic field strength of 3.2 kA / m, the graph of FIG. 1 was obtained.

As is clear from FIG. 1, the sample having the best heat generation characteristics was the sample No. 2 nanoparticles. The sample with the lowest exothermic property was the sample No. 3 nanoparticles. When the SAR values of the two samples were determined based on the following formula, the sample No. 2 was 15.7 [W / g] and the sample No. 3 was 4.6 [W / g].

  Two types of magnetite nanoparticles having different particle diameters were produced by the production method described above. Sample No. 4 had an average particle size of 12.5 nm, and Sample No. 5 had an average particle size of 15.7 nm.

  Sample No. 4 and sample No. 5 nanoparticles dispersed in water with a specific heat of 4.2 J / K · g and when dispersed in a hydrogel with a specific heat of 2.8 J / K · g. The heat generation characteristics were measured under conditions of an external magnetic field having a frequency of 600 kHz and a magnetic field strength of 3.2 kA / m. 2 is a graph showing the measurement results in water and hydrogel of sample No. 4. 3 is a graph showing the measurement results in water and hydrogel in No. 5.

As apparent from FIGS. 2 and 3, it can be seen that Sample No. 5 is inferior to No. 4 in heat generation characteristics in the hydrogel.
Further, when the specific heat of magnetite was 0.92 J / K · g, the initial temperature change rate was calculated from the slope of the graph at 60 seconds, and the SAR value was obtained, the results shown in Tables 1 and 2 below were obtained.

From the above results, it is considered that the sample No. 5 having an average particle diameter of 15.7 nm has a decrease in the SAR value due to suppression of Brownian relaxation. In addition, the SAR value is lowered by the magnetic interaction between particles, that is, the nanoparticles are fixed in the hydrogel as compared with the nanoparticles in the aqueous dispersion medium that can freely rotate, and the magnetic force between the particles is reduced. It is thought that the interaction became stronger and affected the magnetic relaxation and heat generation characteristics.
In the nanoparticle of sample No. 4, since the Neel relaxation is dominant, the temporal interaction (magnetic interaction) between the particles is small, and it is considered that the heat generation due to the Brownian relaxation is small.

Next, observation results regarding the relationship between the block temperature and the SAR value are shown.
It is said that particle sizes such as iron oxide nanoparticles have superparamagnetic properties, but in reality it is known that the relaxation of the magnetic moment is delayed with the increase of the frequency of the alternating magnetic field, resulting in minute hysteresis. It has been.
Here, it is known that the blocking temperature is a temperature at which superparamagnetism starts to be observed, and below that temperature, a hysteresis occurs because the relaxation time of the magnetic moment is longer than the observation time.

Therefore, the blocking temperature varies depending on the frequency of the alternating magnetic field, which is the observation time. As the observation time decreases (the frequency of the alternating magnetic field increases), the blocking temperature shifts to the higher temperature side.
Actually, it is possible to measure up to 10 kHz, but it is difficult to measure the blocking temperature of 600 kHz, and it is necessary to make a prediction based on the measurement result performed at 10 kHz or less.
Therefore, in the sample No. 5 obtained in Example 2 above, the blocking temperature at 600 kHz, which is the experimental condition, was predicted from the plot of the observation time and the reciprocal of the blocking temperature at the observation time.

Moreover, as a result of observing the relationship between the blocking temperature of each sample and the SAR, the SAR increased as the blocking temperature increased.
However, when the blocking temperature is higher than room temperature, depending on the degree, not only hysteresis loss due to delay of Neel relaxation, but also hysteresis loss is added to Brownian relaxation.
The observation results of the above observation are shown in FIGS. FIG. 4 is a graph showing AC magnetic susceptibility measurement results (LH), FIG. 5 is a graph showing the prediction of the blocking temperature at 600 kHz, and FIG. 6 is a graph showing the relationship between the blocking temperature and SAR. .

It is a graph which shows the heat_generation | fever measurement result in Example 1 (sample No. 1-3). It is a graph which shows the heat_generation | fever measurement result in Example 2 (sample No. 4). It is a graph which shows the heat_generation | fever measurement result in Example 2 (sample No. 5). It is a graph which shows an alternating current magnetic susceptibility measurement result (LH). It is a graph which shows prediction of the blocking temperature in 600 kHz. It is a graph which shows the relationship between blocking temperature and SAR.

Claims (3)

2. Iron oxide nanoparticles that are used in thermotherapy to generate heat in a predetermined dispersion medium in the body by an external high-frequency magnetic field and kill the diseased cells by heating to a predetermined temperature, with a frequency of 600 kHz and a magnetic field strength of 3. Under the condition of an external magnetic field of 2 kA / m, the SAR value defined by the following formula should be a calorific value required for a diseased cell, that is, 5.0 W / g or more and 28.3 W / g or less per unit time. Iron oxide nanoparticles characterized by.

(Where Ci: specific heat of dispersion medium and iron oxide nanoparticles, mi: weight of dispersion medium and iron oxide nanoparticles, ΔT / Δt: initial temperature change rate) The iron oxide nanoparticles according to claim 1, wherein the iron oxide nanoparticles are mainly formed of magnetite. The iron oxide nanoparticles according to claim 1 or 2, wherein the iron oxide nanoparticles have a particle size of 11 nm or more and 14 nm or less.

Images