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BACKGROUND OF THE INVENTION
There are presently a number of methods and techniques for the treatment of
cancer, among which may be included: radiation therapy, chemotherapy,
immunotherapy, and surgery. The common characteristics for all of these
techniques as well as any other presently known technique is that they are
extracellular in scope, that is, the cancer cell is attacked and attempted
to be killed through application of the killing force or medium outside of
the cell.
This extracellular approach is found to be less effective and efficient
because of the difficulties of penetrating the tough outer membrane of the
cancer cell that is composed of two protein layers with a lipid layer in
between. Of even greater significance is that to overcome the protection
afforded the cell by the cell membrane in any extracellular technique, the
attack on the cancer cells must be of such intensity that considerable
damage is caused to the normal cells resulting in severe side effects upon
the patient. These side effects have been found to limit considerably the
effectiveness and usefulness of these treatments.
A safe and effective cancer treatment has been the goal of investigators
for a substantial period of time. Such a technique, to be successful in
the destruction of the cancer cells, must be selective in effect upon the
cancer cells and produce no irreversible damage to the normal cells. In
sum, cancer treatment must selectively differentiate cancer cells from
normal cells and must selectively weaken or kill the cancer cells without
affecting the normal cells.
It has been known that there are certain physical differences that exist
between cancer cells and normal cells. One primary physical difference
that exists is in the temperature differential characteristics between the
cancer cells and the normal cells. Cancer cells, because of their higher
rates of metabolism, have higher resting temperatures compared to normal
cells. In the living cell, the normal temperature of the cancer cell is
known to be 37.5.degree. Centigrade, while that of the normal cell is
37.degree. Centigrade. Another physical characteristic that differentiates
the cancer cells from the normal cells is that cancer cells die at lower
temperatures than do normal cells. The temperature at which a normal cell
will be killed and thereby irreversibly will be unable to perform normal
cell functions is a temperature of 46.5.degree. Centigrade, on the
average. The cancer cell, in contrast, will be killed at the lower
temperature of 45.5.degree. Centigrade. The temperature elevation
increment necessary to cause death in the cancer cell is determined to be
at least approximately 8.0.degree. Centigrade, while the normal cell can
withstand a temperature increase of at least 9.8.degree. Centigrade.
It is known, therefore, that with a given precisely controlled increment of
heat, the cancer cells can be selectively destroyed before the death of
the normal cells. On the basis of this known differential in temperature
characteristics, a number of extracellular attempts have been made to
treat cancer by heating the cancer cells in the body. This concept of
treatment is referred to as hyperthermia. To achieve these higher
temperatures in the cancer cells, researchers have attempted a number of
method including inducing high fevers, utilizing hot baths, diathermy,
applying hot wax, and even the implantation of various heating devices in
the area of the cancer.
At this time, none of the various approaches to treat cancer have been
truly effective and all have the common characteristic of approaching the
problem by treating the cancer cell extracellularly. The outer membrane of
the cancer cell, being composed of lipids and proteins, is a poor thermal
conductor, thus making it difficult for the application of heat by
external means to penetrate into the interior of the cell where the
intracellular temperature must be raised to effect the death of the cell.
If, through the extracellular approaches of the prior hyperthermia
techniques, the temperatures were raised so high as to effect an adequate
intracellular temperature to kill the cancer cells, many of the normal
cells adjacent the application of heat could very well be destroyed.
OBJECT OF THE INVENTION
It is therefore the purpose and principal object of the present invention
to kill the cancer cells selectively by intracellularly generating a
temperature and by changing biophysical characteristics that will kill the
cancer cells while producing no harmful effects upon the normal cells.
DESCRIPTION OF THE INVENTION
The present invention achieves a precise increment of heat rise within the
cancer cell and within the cytoplasm. The thermal barrier that
characteristically exists as the outer membrane or cell wall of the cell
is now utilized as a means of retaining the heat produced within the cell,
rather than, as in the past, preventing any heat build-up within the cell.
On the basis of the cell resting temperatures and the temperature
necessary to produce cell death, the increment that the cell temperature
must be raised to cause the cell death is critical. For the normal cell,
the temperature rise is 9.5.degree. Centigrade, while in the cancer cell
the temperature rise is approximately 8.0.degree. Centigrade. Thus, any
temperature rise in the cancer cell or in the normal cell that is at least
8.0.degree. Centigrade and not more than 9.5.degree. Centigrade above the
normal cell temperature will result in a selective destruction of the
cancer cell without any harmful effects to the normal cell.
In accordance with the present invention, there are found to be a number of
approaches that can successfully achieve the end result of an
intracellular heat rise and an intracellular destruction of the cancer
cell.
In its simplest and broadest aspect, the present invention contemplates the
introduction into the cancer cell of a minute particle, such as a
ferromagnetic, diamagnetic, or a paramagnetic material, and then
subjecting all the cells generally, including the normal cells, to a
high-frequency alternating electromagnetic field.
This principle on which the present invention is based is also grounded
upon the known fact that cancer cells have a far greater affinity for
particles and for foreign substances such as these minute particles that
are to be introduced, than do the normal cells. Due to this phagocytic
characteristic of cancer cells, such particles tend to concentrate in
significantly greater numbers within the cancer cells, as compared to the
normal cells. Electronmicrographs have been taken of tissue following the
introduction of such particles and clearly illustrate the selective
concentration of the particles in the cancer cells. This is expected due
to the higher rate of metabolism of the cancer cells and because tumors
develop neo-vascularization. The new capillaries and blood vessels formed
in tumors have increased permeability to foreign particles when compared
to the capillaries and the blood vessels of normal tissues.
The particles which are useful in accordance with the present invention,
are those such as the ferromagnetic particles compatible with living
tissue may be useful. Similarly, the diamagnetic and paramagnetic
materials that may be useful include the following: gallium, indium,
technetium, strontium, iodine, and any other diamagnetic and paramagnetic
materials compatible with living tissue. The particle size of the
particles should be not greater than about 1 micron. Preferable particle
size would be less than the 1 micron size.
The minute particles described are to be injected intravenously into the
patient through the use of any suitable compatible liquid vehicles.
Aqueous solutions of any such bodyacceptable materials as dextran,
dextrose, saline or blood, as well as water alone, can be used. The liquid
vehicle should sustain the particles in suspension for the subsequent
injection. Concentrations of such body-acceptable materials that may be
useful are those that are up to about 50% by weight in water. Usually a
solution of about 1% to 10% is adequate. The concentration of the
particles in the solution is not critical and is usually in a range
between 50 to 75 mg/cc of the solution.
The intravenous injection into the patient generally is in an amount such
that between 1 to 10 mg. of the particles per kg of body weight of the
patient are injected at one time; however, up to approximately 20 - 45 mg.
total dosage per kg. of body weight is possible. The greater weight of the
patient, the higher the permissible dosage. The total amount of the dosage
is not critical though 2 to 3 injections, may be injected within a 24 to
72 hour period. The time span for the injections may vary greatly for
various patients and for various objectives.
The minute particles contained in the aqueous medium are transported
through the bloodstream and have been found to be phagocytized by the
cancerous cells to a far greater degree than, and in fact in some cases to
the possible exclusion of, their admittance into the normal cells.
Electronmicrographs of the cancerous tissue have proven the selective
pickup of the magnetic particles by the cancer cells.
The intracellular characteristics of the present technique are evident. It
has been found that the intracellular temperature of the cells may be
raised between 8.0.degree. Centigrade and 9.5.degree. Centigrade to cause
death in the cancer cell without damage being caused to the normal cells.
The next stage of the present invention is to bring about by inductive
heating with high-frequency alternating electromagnetic field a precise
rise in the temperature of the cell. The principle of inductive heating
through the use of hysteresis is a known principle. Similarly, the
monitoring of the temperatures of the living cells is a presently
available technique well-known to the medical science.
The inductive heating of the minute particles is achieved by using an
electronic oscillator operating in the high-frequency range which heats
the particles by subjecting them to an intense high-frequency field within
a large but otherwise conventional helical coil, field energy being
converted to heat through hysteresis losses and the resistive dissipation
of eddy currents. The helical inductive coil is of sufficient internal
diameter to permit the patient to pass within and of such length to
encompass the length of the patient. Generally, the internal diameter
should be at least 2 feet, but preferably would be greater than 3 - 6 feet
in diameter. No maximum diameter is known to exist except that required
from practical and economical considerations. Diameters of inductive coils
of greater than 6 feet have a preferential effect in the overall process
by providing a more uniform flux gradient to the patient.
The frequency of the electromagnetic alternating high-frequency field will
range from 50 kilohertz to 10 megahertz and the power input of the
oscillator-generator will range from 0.5 kilowatts to 1.0 kilowatts per
kg. of patient body weight 0.75 kilowatts of power per 1.0 kilograms of
body weight has been found to be particularly useful. In this power and
frequency range, the coil is selected to produce from 400 to 800 oersteds,
preferably 550 - 650 oersteds.
The time necessary to inductively heat the minute particles held within the
cells to be treated depends substantially upon the frequency and the power
producing the alternating electromagnetic field and ultimately the
strength of the field produced. In general, it has been found that
subjecting the patient to 5 to 12 minutes or preferably 8 to 10 minutes of
the alternating electromagnetic field would be adequate to bring about the
necessary temperature rise of at least 8.0.degree. Centigrade. It should
be clearly understood that it is only necessary to raise the temperature
of the cancer cell above 8.0.degree. Centigrade and that the variables
with respect to the type and concentration of the particles in the vehicle
and the electromagnetic treatment are not critical provided that the
necessary temperature is achieved.
EXAMPLE I
As a specific example of the simplest form of the present invention, ferric
hydroxide particles of 0.7 micron size are suspended in a 5% dextrose
aqueous solution in an amount of about 50 mg of the particles per cc.
Dosages in the amount of 30 mg. per kg. of body weight each of the
particles should be made twice, by intravenous injections, each being 24
hours apart. The patient is then ready for the electromagnetic treatment
by insertion entirely within an inductive coil 3 feet in diameter. The
coil is connected to an alternating current generator, producing a
frequency of 3 megahertz and a field of 600 oersteds. The patient is to be
subjected to the electromagnetic treatments about 12 hours after the last
injection. The inductive heating of the particles within the cancer cells
is between 8 and 10 minutes, during which time the temperature within the
cell will have been increased 8.5.degree. Centigrade. At this temperature,
the cancerous cells in the living tissue will have been killed while the
normal cells will recover normal cellular functions.
While the simplest aspect of the invention has been described in detail,
the selectivity of the magnetic particles for the cancer cells may be
increased through the use of several techniques.
The addition of a cancer cell seeking agent such as radioisotopes or a
tumor specific antibody is useful in directing the minute particles more
selectively to the cancer cells. It is known that both radioisotopes and
tumor specific antibodies have an affinity for the cancer cells and it is
for this reason that the radioisotopes and antibodies have been found to
have some application in the treatment of certain tumors. It is also
possible that the radioisotopes may be used to substitute for the magnetic
particles and be injected intravenously so as to be selectively taken up
by the cancerous cells. Many of these radioisotopes are inherently
paramagnetic or diamagnetic and whether chemically or physically combined
with other particles or used alone, the effect of the alternating
electromagnetic field upon the magnetic particles and/or the radioisotopes
would be to raise the temperature of the cancerous cell to the destructive
temperature. Typical examples of useful radioisotopes are such as
gallium-67, indium-113m, technetium-99m, fluorine, selenium-75. A great
many other radioisotopes are useful and the above are only examples. The
size and concentration of the radioisotopes alone or attached to the
minute particles and the manner of injection is precisely the same as
previously described.
These radioisotopes or antibodies may be bound to the particles as
iodine-131 (the radioisotope) has been bound to albumin for lung scanning
in the past. Antibodies, for instance, may be attached to the
ferromagnetic, paramagnetic, or diamagnetic particles by use of an
intermediate reducing glucose unit or its derivative such as
metasaccharinic acid, in a conventional manner and as described in Example
III, much as high molecular weight dextran is bound to ferric hydroxide.
It is known that antibodies can be formed by injection of cancer cells
removed from one patient with cancer and injected into another patient.
The injection of the cancer cells will in turn form antibodies in the
substitute host as a defense against the foreign tumor cells from the
original donor. These antibodies can be then selectively isolated and in
the past have been used to treat selected specific tumors. These
antibodies have usefulness in the present invention as a selective cancer
cell seeking agent.
These antibodies may be bound chemically or physically to the minute
particles and then re-injected into the patient to be treated. Due to the
antibodies' specificity for the original tumor cells, the antibodies bound
to the particles will even more selectively induce the particles to be
phagocytized by the cancer cells.
Antibodies with radioactive isotopes may be produced by feeding the animals
producing the antibodies, labeled amino acids. This labeled amino acid is
then incorporated into the antibody.
Large chemical entities can be attached to antibody molecules. Large
proteins may be attached via diagotized atoxyl (p-amino-benzene arsenic
acid). Antibodies may be bound while they are attached to a hapten or to
an antigen. This protects the immunologically specific site of the
antibody during the binding procedure.
It should be understood that the entire purpose of selective direction of
the particles or the radioisotopes is that the presence of an alternating
electromagnetic field will produce heat intracellularly to raise the
temperature of the cell between the 8.0.degree. Centigrade and the
9.5.degree. Centigrade range. Thus, even if all of the cells were to
possess an equal concentration of the particles, the application of the
induction heating would produce a similar rise in temperature in all
cells, which within the range desired, would do no harm to the normal
cells while killing the cancer cells. There does not appear to be any
danger in an increased concentration of the particles in the normal cells
in view of the phagocytic characteristics of the cancer cells, but to
efficiently use all of the magnetic particles and to permit the smallest
dosage possible, it is desirable to utilize where beneficial a selective
cancer cell seeking agent such as the radioisotopes or the antibodies. In
this manner, an even greater concentration of the magnetic particles
should be found in the cancer cells and a very minor amount if not an
exclusion of such particles in the normal cells.
A specific example of the use of a radioisotope in accordance with the
present invention is as follows:
EXAMPLE II
Gallium citrate - gallium-67 is incorporated into a sterilized isotonic 5%
saline solution, the concentration being 1 millicurie of gallium-67 per cc
of the total composition. The amount to be injected could vary between
0.02 millicuries up to 0.1 millicuries per kg. of body weight. Upon
injection, a 12-hour period is allotted for the gallium to isolate itself
and selectively concentrate within the cancerous cells. Thereafter, the
same alternating electromagnetic field is applied in exactly the same
manner as previously described in Example I. The amount of intracellular
temperature increase is above 8.0.degree. Centigrade and below 9.5.degree.
Centigrade and produces selective killing of the cancer cells without
harming the normal cells.
When the gallium-67 is to be utilized as a cancer cell seeking agent, it
may be bound to the particle in accordance with the manner in which
iodine-131 has been bound to albumin. This combined gallium particle may
be injected into the patient in precisely the same manner and it would be
found that the gallium selectively delivers the particles to the cancer
cells. Thereafter, when the cancer cell is subjected to the alternating
electromagnetic field, the intracellular temperature of the cancer cell is
raised above the critical increase of 8.0.degree. Centigrade to
selectively destroy the cancer cell.
It is also possible that the known utility of the tumor specific cancer
agents such as the chemotherapeutic agents, the radioisotopes or tumor
specific cancer antibodies may be utilized in accordance with the present
invention. For example, chemotherapeutic agents include 5-flurouracil,
nitrogen mustard, actinomycin D, methotrexate, cytoxon and vincristine
amongst a number of other agents known for similar utility. It is an
aspect of the present invention that such known chemotherapeutic agents in
a size less than 1 micron may be coated with ferromagnetic material to
produce a total particle of a size less than the approximate 1 micron
particle size. The particles in effect encapsulate the chemotherapeutic
agent and form a micro-sphere around the chemotherapeutic agent. The
coating thickness of the magnetic particle should be approximately 0.1
micron. Thus, the size of the chemotherapeutic agent particle should be
about 0.1 micron or less in order to to bring about the total particle
size of not greater than 1 micron and preferably less.
EXAMPLE III
The following is an example of the method of coating 5-flurouracil with a
ferromagnetic material: 5-flurouracil, a known acknowledged effective
chemotherapeutic agent against cancer, is taken in its solid state and
pulverized into particles 0.5 micron in size. These particles, in turn,
are then coated with ferric hydroxide approximately .1 micron in
thickness, in accordance with any of the conventional methods of coating
submicron particles as described in U.S. Pat. No. 3,294,686
These particles are then colloidally suspended in a 6% by weight aqueous
dextran solution. This solution is introduced intravenously to the patient
with the result that due to the phagocytic characteristics of the cancer
cells, most of these particles will be deposited in the cytoplasm inside
the cancer cells. This would take place about 4 to 8 hours after the
intravenous injection. After the particles' deposition into the cytoplasm,
the ferric hydroxide is acted upon by the cytoplasm and is converted to an
organic iron complex (ferritin) which is then absorbed.
After approximately 24 hours, the ferric hydroxide coating is thus
solubilized and the chemotherapeutic agent 5-flurouracil is released
within the cancer cell where it can effectively kill the cell. Time is not
critical, and may vary from 1 to 48 hours or more. The other tumor
specific cancer agents may be similarly utilized.
EXAMPLE IV
The chemotherapeutic agent as encapsulated in a ferromagnetic material, as
described in Example III, may be injected in precisely the same manner and
alternatively subjected to the high frequency alternating electromagnetic
field of Example I which then is capable of breaking up the micro-sphere
of the magnetic material by a vibrational frequency produced by the
electromagnetic field at which the outer surface resonates and its
integrity is destroyed. Upon breakup of the micro-spheres the
chemotherapeutic agent is released intracellularly and selectively within
the cancer cells. The same example may be applied in the same manner to
the other tumor specific cancer agents.
EXAMPLE V
The encapsulating material may also contain a low melting solid such as wax
having a melting point higher than the temperature of the cells but below
the death temperature of the normal cell. This temperature range may be
therefore between about 37.degree. and 46.5.degree. Centigrade. This wax
is in combination with the ferromagnetic material and applied as in
Example III. In this alternative embodiment the application of the
alternating electromagnetic field, as in Example I, would melt the low
melting solid due to the induction heating of the ferromagnetic material
and release the chemotherapeutic agent within the cancer cells. Similarly,
the other tumor specific cancer agents may be similarly utilized.
As previously stated, a cancer cell seeking agent such as the radioisotope
or antibodies may be utilized to more selectively direct the micro-sphere
containing the chemotherapeutic agent to the particular cancer cell. As is
known, chemotherapeutic agents sometimes have adverse side effects upon
normal cells, but the present procedure would selectively release the
chemotherapeutic agent intracellularly and selectively. Compared to the
presence of the chemotherapeutic agent in the cancerous cell, the
concentration of the chemotherapeutic agent in the normal cell would be
minimal. The undesirable side effects upon the normal cells should
therefore be greatly minimized if not totally avoided.
A further embodiment of the present invention which typifies the broad
nature of the invention is the incorporation of any tumor specific cancer
antibody or cancer treating radioisotope within the encapsulating
ferromagnetic micro-sphere in the manner previously described in Example
III. Thereafter the antibody or radioactive isotope so coated may be
introduced within the cell walls of the cancer cell and the alternating
electromagnetic field applied as in Example IV to cause the micro-spheres
of the ferromagnetic material to release the antibody or the radioisotope
intracellularly. It is also possible that the release of the encapsulated
material may be by solubilizing the spheres within the cell, as previously
described in Example III.
One of the important features of the present invention is that there is
destruction of the cancerous cells wherever they are located in the
patient. Cells that may have become detached from the tumor and drift in
the vascular system or lymphatic system would be killed by the present
process.
There are many variations of the invention as described and this invention
should be limited solely by the scope of the following claims.
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