U.S. patent application number 14/270579 was filed with the patent office on 2014-08-28 for system for defining energy field characteristics to illuminate nano-particles used to treat invasive agents.
This patent application is currently assigned to Actium BioSystems, LLC. The applicant listed for this patent is Karl M. Frantz, Martin A. Huisjen, Daniel B. McKenna, Andrew C. Updegrave. Invention is credited to Karl M. Frantz, Martin A. Huisjen, Daniel B. McKenna, Andrew C. Updegrave.
Application Number | 20140243733 14/270579 |
Document ID | / |
Family ID | 46544662 |
Filed Date | 2014-08-28 |
United States Patent
Application |
20140243733 |
Kind Code |
A1 |
McKenna; Daniel B. ; et
al. |
August 28, 2014 |
SYSTEM FOR DEFINING ENERGY FIELD CHARACTERISTICS TO ILLUMINATE
NANO-PARTICLES USED TO TREAT INVASIVE AGENTS
Abstract
The Invasive Agent Treatment System incorporates the pairing of
energy fields with nano-particles to cause a thermal effect in the
nano-particles, which thermal effect is transmitted into the
biological cells of the invasive agent. The energy fields are
derived from at least one or a combination of the following: an
electric field, a magnetic field, an electromagnetic field (EM), an
acoustic field, and an optical field. The Invasive Agent Treatment
System provides the necessary coordination among the
characteristics of the nano-particles, concentration of
nano-particles, duration of treatment, and applied fields to enable
the generation of precisely crafted fields and their application in
a mode and manner to be effective with a high degree of
accuracy.
Inventors: |
McKenna; Daniel B.; (Detroit
Lakes, MN) ; Frantz; Karl M.; (Broomfield, CO)
; Updegrave; Andrew C.; (Boulder, CO) ; Huisjen;
Martin A.; (Boulder, CO) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
McKenna; Daniel B.
Frantz; Karl M.
Updegrave; Andrew C.
Huisjen; Martin A. |
Detroit Lakes
Broomfield
Boulder
Boulder |
MN
CO
CO
CO |
US
US
US
US |
|
|
Assignee: |
Actium BioSystems, LLC
Detroit Lakes
MN
|
Family ID: |
46544662 |
Appl. No.: |
14/270579 |
Filed: |
May 6, 2014 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
13012560 |
Jan 24, 2011 |
8757166 |
|
|
14270579 |
|
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Current U.S.
Class: |
604/20 ;
607/103 |
Current CPC
Class: |
A61K 41/0052 20130101;
A61N 1/325 20130101; A61N 2/002 20130101; A61N 2/004 20130101; A61N
2/02 20130101; A61N 1/406 20130101 |
Class at
Publication: |
604/20 ;
607/103 |
International
Class: |
A61N 1/32 20060101
A61N001/32; A61N 2/00 20060101 A61N002/00 |
Claims
1. An invasive agent treatment system for use in dynamically
defining characteristics of energy fields which are used in
activating target particles, which are inserted into a living
organism in a manner to associate with invasive agents, to destroy
invasive agents in the living organism, comprising: target particle
databases for maintaining a listing of characteristics of at least
one type of target particle; and an energy field controller,
responsive to a user selecting at least one type of said target
particles and identifying a portion of a target living organism
which contains an invasive agent and at least one type of said
target particles, for automatically selecting energy field
characteristics from the characteristics of energy fields
including, but not limited to, at least one of: field type,
frequency, field strength, duration, field modulation, repetition
frequency, polarization, beam size, and focal point, necessary to
energize the selected type of target particles in a predetermined
manner in the portion of the target living organism to destroy the
invasive agent.
2. The invasive agent destruction system of claim 1 wherein said
energy field controller is responsive to said selected type of
target particle to differentially heat said portion of said target
living organism by selecting a frequency of said energy field which
energizes the selected type of target particles greater than the
surrounding living tissue.
3. The invasive agent destruction system of claim 2 wherein said
energy field controller is responsive to said selected type of
target particle to linearly decrease the field strength of an
E-Field as the frequency of the E-Field increases to realize the
same power absorbed at the target particle.
4. The invasive agent destruction system of claim 3 wherein said
energy field controller is responsive to said selected type of
target particle for selecting an E-Field strength where the power
absorbed at the target particle is a function of the E-Field
strength squared.
5. The invasive agent destruction system of claim 2 wherein said
energy field controller is responsive to said selected type of
target particle which has a relative permittivity which is a
complex value, having both real and imaginary values, where the
imaginary portion of the permittivity changes with frequency and
determines the loss a given material has in an E-Field, for
dynamically adjusting the E-Field strength as a function of
frequency.
6. The invasive agent destruction system of claim 2 wherein said
energy field controller is responsive to said selected type of
target particle having a permittivity and polarity which are
temperature dependent, for dynamically changing the E-Field
strength during the process of heating of the target particles.
7. The invasive agent destruction system of claim 2 wherein said
energy field controller is responsive to said selected type of
target particle for selecting an energy field strength as a
function of target particle radius cubed for E-Fields and target
particle radius to the fifth power for H-Fields.
8. The invasive agent destruction system of claim 1 wherein said
energy field controller is responsive to said selected type of
target particle which is made of material types responsive to both
magnetic and electric fields for illuminating the nano-particle
with a magnetic field and an electric field.
9. The invasive agent destruction system of claim 1 wherein said
energy field controller is responsive to said selected type of
target particle to linearly decrease the field strength of an
E-Field as the frequency of the E-Field increases to realize the
same power absorbed at the target particle.
10. The invasive agent destruction system of claim 9 wherein said
energy field controller is responsive to said selected type of
target particle for selecting an E-Field strength where the power
absorbed at the target particle is a function of the E-Field
strength squared.
11. The invasive agent destruction system of claim 9 wherein said
energy field controller is responsive to said selected type of
target particle which has a relative permittivity which is a
complex value, having both real and imaginary values, where the
imaginary portion of the permittivity changes with frequency and
determines the loss a given material has in an E-Field, for
dynamically adjusting the E-Field strength as function of
frequency.
12. The invasive agent destruction system of claim 9 wherein said
energy field controller is responsive to said selected type of
target particle having a permittivity and polarity which are
temperature dependent, for dynamically changing the E-Field
strength during the process of heating of the target particles.
13. The invasive agent destruction system of claim 9 wherein said
energy field controller is responsive to said selected type of
target particle for selecting an energy field strength as a
function of target particle radius cubed for E-Fields and target
particle radius to the fifth power for H-Fields.
14. The invasive agent destruction system of claim 1, further
comprising: a target particle location database for storing data
indicative of the presence and locus of target particles which are
located in a living organism.
15. The invasive agent destruction system of claim 1, further
comprising: destruction databases for storing data relevant to the
destruction of invasive agents, comprising at least one of: a
target particle location database for storing data indicative of
the presence and locus of target particles which are located in a
living organism, a patient data database for maintaining living
organism-specific data which provides data regarding at least one
of: age, sex, weight, prior surgeries, or other conditions relevant
to the destruction of invasive agents, an empirical and analytical
data database for maintaining information, which has been collected
via at least one of: modeling, testing, theoretical computations,
and past experiences, relating to destruction of invasive agents in
a living organism, a reflection characteristics database for
maintaining data which represents the percentage of an incident
signal which is reflected at the interface between two materials, a
penetration depth database for maintaining data which represents
the attenuation of an incident signal as it passes through a
selected material, and a living organism characterization database
for storing data which defines a three-dimensional physical
composition of at least one characteristic of a living organism
selected from the set of characteristics comprising: material,
shape, size, density, and surface treatment.
16. The invasive agent destruction system of claim 15 wherein said
energy field controller comprises: a target energy field
calculator, responsive to said data stored in said destruction
databases, for determining characteristics of an energy field
incident on said target particles required to activate said target
particles located in the target living organism to respond in a
pre-determined detectable manner to destroy invasive agents in the
living organism.
17. The invasive agent destruction system of claim 16 wherein said
energy field controller comprises: a correlation process for
correlating said determined characteristics of an energy field with
said empirical and analytical data to generate refined determined
characteristics.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 13/012,560 filed on Jan. 24, 2011, which is
incorporated by reference herein in its entirety for all purposes.
This application is also related to U.S. patent application Ser.
No. 13/012,496 filed Jan. 24, 2011, titled "System For Correlating
Energy Field Characteristics With Target Particle Characteristics
In The Application Of An Energy Field To A Living Organism For
Treatment Of Invasive Agents"; U.S. patent application Ser. No.
13/012,509 filed Jan. 24, 2011, titled "System For Correlating
Energy Field Characteristics With Target Particle Characteristics
In The Application Of An Energy Field To A Living Organism For
Imaging Of Invasive Agents"; U.S. patent application Ser. No.
13/012,527 filed Jan. 24, 2011, tided "System For Correlating
Energy Field Characteristics With Target Particle Characteristics
In The Application Of An Energy Field To A Living Organism For
Imaging and Treatment Of Invasive Agents"; U.S. patent application
Ser. No. 13/012,539 filed Jan. 24, 2011, titled "System For
Automatically Amending Energy Field Characteristics In The
Application Of An Energy Field To A Living Organism For Treatment
Of Invasive Agents"; and U.S. patent application Ser. No.
13/012,572 filed Jan. 24, 2011, titled "Low Temperature
Hyperthermia System For Therapeutic Treatment Of Invasive
Agents".
FIELD OF THE INVENTION
[0002] The invention relates generally to the field of treatment of
invasive agents, such as pathogens and cancers, in living organisms
and, more particularly, to a system that matches input energy field
characteristics, as applied to the living organism, with the
characteristics of nano-particles which are infused into the living
tissue that is to be treated.
BACKGROUND OF THE INVENTION
[0003] It is a problem to both accurately detect the presence of
and determine the locus of invasive agents, such as pathogens and
cancers (malignant neoplasm), (collectively termed "invasive
agents" herein) in a living organism (ex.--human, animal), as well
as treat these invasive agents. Present cancer diagnostic and
treatment methods (such as chemo-therapy and radiation therapy) are
imprecise and can result in damage to the living organism in order
to destroy the cancer cells.
[0004] Presently, a procedure is being used where nano-particles
are directed to invasive agents (cancer cells) by the use of
passive and active targeting methods. The passive targeting
approach uses the size and shape of the nano-particles to enhance
their uptake into cancer cells while the active targeting approach
uses coatings applied to the nano-particles (such as an antigen) to
enable the targeted uptake of the nano-particles by only those
cells, cancer cells for instance, that are susceptible to the
antigen coating. The size of the nano-particles is selected to
enable the cancer cells to ingest the nano-particles, yet not be
able to excrete the ingested nano-particles. The nano-particles can
be heated via the use of a magnetic field to raise the temperature
of the cancer cells, thereby killing the cancer cells; or the
nano-particles can be formed to encapsulate cancer-killing drugs,
which are released into the cancer cell by the application of the
magnetic field.
[0005] However, this process is in the early stages of development
and has yet to reach a level of maturity where the physical
processes and their limitations are well understood. Existing
cancer treatment techniques using nano-particles fail to provide
the necessary coordination among the characteristics of the
nano-particles, concentration of nano-particles, duration of
treatment, and applied fields to enable the generation of precisely
crafted fields and their application in a mode and manner to be
effective with a high degree of accuracy.
[0006] Thus, there presently is no procedure that can be used to
accurately detect the presence of cancer cells in a living organism
or treat the cancer cells, once detected, to destroy the cancer
cells, without serious negative effects on the living organism.
Present diagnostic and treatment procedures are macro and
non-specific in their approach and are ineffective or can result in
damage to the living organism in order to destroy the cancer
cells.
BRIEF SUMMARY OF THE INVENTION
[0007] The above-described problems are solved and a technical
advance achieved by the present System For Defining Energy Field
Characteristics To Illuminate Nano-Particles Used To Treat Invasive
Agents (termed "Invasive Agent Treatment System") which creates the
pairing of energy fields with nano-particles to cause a thermal
effect in the nano-particles, which thermal effect is transmitted
into the biological cells of the invasive agent. The energy fields
are derived from at least one or a combination of the following: an
electric field, a magnetic field, an electromagnetic field (EM), an
acoustic field, and an optical field. The Invasive Agent Treatment
System provides the necessary coordination among the
characteristics of the nano-particles, concentration of
nano-particles, duration of treatment, and applied fields to enable
the generation of precisely crafted fields and their application in
a mode and manner to be effective with a high degree of accuracy.
The energy field frequencies are in the hundreds of kilohertz or
millions or billions of hertz, with energy field strengths ranging
from a few hundred volts per meter to thousands of volts per meter,
if an E-Field; alternatively, the magnetic fields (H-Field) are in
the hundreds of kilohertz and higher with field strengths in the
10-20 thousand amps/meter. These energy field parameters are
typical and nothing herein precludes other types of energy field
parameters.
[0008] The nano-particles which are excited by these energy fields
have characteristics which make them responsive to excitation
typically by a given energy field type. Some nano-particles are
responsive to only an E-Field; others are only responsive to an
H-Field, while some are responsive to both. The induced effects in
the nano-particle can be numerous; however, the predominant effect
of interest is a thermal effect, where the exciting energy field
causes the temperature of the particle, hence the surrounding
biological material, to rise in temperature.
[0009] Two modes of cancer treatment are embodied herein: ablation
and low temperature hyperthermia. In the ablation method, the
nano-particles are illuminated by an energy field and the
nano-particles thereby are heated to a temperature (for example
greater than 42.degree. C.) which causes the cells of the invasive
agent to be heated to a temperature which kills the cancer cells
over a given timeframe. The second method of cancer treatment uses
Low Temperature Hyperthermia (LTH) to bring the nano-particles and
the associated cancer cells to a temperature of 42.25.degree. C. or
cooler. This temperature causes the cancer cells, particularly
cancer stem cells, to be stressed by a number of mechanisms which
include: re-oxygenation, increased blood flow, change of acidity,
and so on--environments that are harmful to cancer stem cells. By
the application of the energy field to the nano-particles for a
sufficient period of time, the heated cancer cells are destroyed
with minimal production of Heat Shock Proteins, which enable cancer
stem cells to survive normal killing temperatures.
[0010] This Invasive Agent Treatment System identifies
nano-particle--energy field pairings which cause the optimal
excitation of the nano-particles, based on a number of theoretical
and analytical criteria, including the characteristics of the
nano-particles, concentration of nano-particles, duration of
treatment, and applied fields to enable the generation of precisely
crafted energy fields and their application in a mode and manner to
be effective with a high degree of accuracy where the net effect is
a thermal rise in the nano-particles. In the case of ablation, the
thermal rise is to a temperature which directly kills cancer cells.
In the case of LTH, the objective is to stress and kill cancer stem
cells, cells which are very resistant to heat ablation due to the
production of Heat Shock Proteins, which protect the cancer cell
from damage. LTH also kills in other ways, such as
oxygenation--cancer stem cells prefer and live in a hypoxic
environment; increasing the level of oxygen is one way to kill
cancer stem cells that may have been already pre-stressed by a
treatment of ionizing radiation or chemotherapy.
[0011] The description of the Invasive Agent Treatment System uses
cancer as an example of an invasive agent, since much research has
been done in this field and the diversity of cancers that are found
in a living organism is extensive. Of note, while the methods and
techniques described herein focus on breast cancer treatment, the
technology is applicable to any type of cancer or other biological
invasive agent, such as HIV or even the common cold. Since
nano-particles are as small as the smallest of biological
structures, these techniques are not limited to just cancer and
treating cancer cells to a physical extent; but rather, the methods
described herein could be used to treat virtually any type of
invasive agent or non-normal biological material, behavior,
mechanism, or process.
[0012] Note that the locus of the cancer cells may be dynamic, such
as in the case of a blood-borne cancer. In this example, the
movement of the cancer cells within the blood stream creates an
added complexity to the treatment process. In cancers that are in
the process of metastasizing, the blood system and the lymph system
create pathways for the cancer to spread to other loci. Thus, there
is a time domain component in conjunction with a spatial domain
component for the treatment protocol. For most cancers, and breast
cancer in particular, the time domain component can often be
ignored and just the spatial domain component is of interest.
However, even for breast cancer, depending on the type of energy
field, the chest wall movement caused by breathing must be
considered and extracted from the treatment process, if the
illumination of the breast by the energy field is in a narrow
range. In the case of breast cancer, placing the breasts between
plates, as is done in present day mammograms, helps remove the
breathing motion artifact. As discussed herein, treatment methods
that use pulsed field excitation, where the pulses are relatively
short in time, say one microsecond long, would help remove motion
artifacts.
[0013] The target nano-particles are activated by a precisely
crafted energy field to provide illumination of the target
nano-particles with the minimum required energy to create the
selected effects. Since there is a great diversity in cancer cells,
there must be a corresponding diversity in the target
nano-particles which are designed to be implanted in the specific
cancer cells and be responsive to the applied energy fields.
Furthermore, the site of the cancer can vary in terms of depth
within the living organism; and this has significant implications
in terms of the strength and focus of the energy fields, since each
interface in the living organism encountered by the incident energy
field(s) can cause dissipation, diffraction, and reflection of the
incident energy field(s). Also, each living organism has
characteristics that define the illumination environment and
limitations on the type and duration of the energy fields that are
used.
[0014] Certain energy field types, such as a magnetic field, are
less susceptible to tissue interaction as the energy field
propagates into the in vivo body to the nano-particle locus.
However, if the magnetic field construct of field strength
multiplied by the excitation frequency is too high, eddy currents
can be induced in the tissue of the living organism, which can
cause unintended heating. There is a balancing of illumination
attributes that must be considered. While a magnetic field has less
tissue artifacts to deal with, a magnetic field cannot be used when
metallic objects are embedded in the living organism, such as pace
makers, orthopedic screws/pins, and the like. An electric or
electromagnetic field may be better suited for situations where
metallic objects are present since it may be easier to highly
target the illumination to just the area of interest versus a large
macro region of the living organism.
[0015] Thus, the pairing of nano-particles to energy fields
requires the consideration of a number of field illumination
factors to include: energy field type, frequency, energy field
strength, duration, energy field modulation, repetition frequency,
beam size, and focal point. The determined energy field
characteristics then are used to activate one or more energy field
generators to generate an energy field having the selected energy
field characteristics for application to the portion of the target
living organism to treat the presence and locus of invasive agents
in the living organism by the excitation of introduced
nano-particles.
[0016] It is important to note that the activation of
nano-particles is highly deterministic, meaning that a given
nano-particle is optimally activated or excited by a given energy
field of pre-defined characteristics. Generic or random energy
field excitations do not optimally excite a given nano-particle. In
fact, certain nano-particle types do not respond at all to certain
energy fields, as is shown herein.
[0017] The following description provides a brief disclosure of
these elements in sufficient detail to understand the teachings and
benefits of the pairing energy fields with nano-particles. The
description of the Invasive Agent Treatment System also teaches how
to determine what type of energy field in which a nano-particle is
optimally excited. It is expected that many other applications can
be envisioned by one of ordinary skill in the art, and the methods
described herein for field-particle pairing are simply one
application of treatment methods, ablation and LTH, which is
delimited by the appended claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] FIG. 1A illustrates, in flow chart form, the typical
treatment steps used in both ablation or LTH treatment
protocols;
[0019] FIG. 1B illustrates the types of nano-particles paired with
a responsive energy field type for ablation or LTH treatment
protocols;
[0020] FIG. 2A is an example, in table format, of target particle
characteristics for nano-particles;
[0021] FIG. 2B illustrates, in table format, the various
nano-particle types as paired with energy field types;
[0022] FIG. 3 is a diagram of a water molecule, showing its dipolar
nature;
[0023] FIG. 4 is diagram of a water molecule in an electric or
EM-Field;
[0024] FIG. 5 is diagram of a dumbbell shaped nano-particle having
dipolar attributes;
[0025] FIG. 6 illustrates a diagram of a generic dipolar
particle;
[0026] FIG. 7 illustrates a diagram of a generic dipolar particle
in an electric or EM-Field;
[0027] FIG. 8 depicts a diagram of a particle that has both
magnetic and electric responsive material types;
[0028] FIG. 9 illustrates a diagram of a nano-particle that has a
uniform distribution of both magnetic and electric field responsive
materials;
[0029] FIG. 10 illustrates a graphical representation of the
Arrenhius curve of cellular death over time versus temperature;
[0030] FIG. 11 illustrates the measured real and imaginary parts of
the permittivity response of a surfactant versus frequency at
different surfactant concentrations;
[0031] FIG. 11A illustrates the plots of FIG. 11 with an
identification of two regions for discussion;
[0032] FIG. 12 illustrates a graphical representation of
permittivity versus frequency for two sizes of gold
nano-particles;
[0033] FIG. 13A illustrates a graphical representation of a
surfactant in the presence of an electric field (strong response)
and a magnetic field (no response);
[0034] FIG. 13B illustrates a graphical representation of the
effect of nano-particle concentration on induced temperature in an
electric field using PEG200;
[0035] FIG. 13C illustrates a graphical representation of the
nano-particle's temperature dependence on electric field strength
for PEG200 in an electric field;
[0036] FIG. 13D illustrates a graphical representation of the
temperature of a surfactant in different electric field
intensities;
[0037] FIG. 13E illustrates a graphical representation of the
temperature of a surfactant in different electric field intensities
as shown in FIG. 13D, labeled to show the actual values of file
parameters;
[0038] FIG. 13F illustrates a graphical representation of the
PEG200 nano-particle's heating dependence on the exciting energy
field frequency;
[0039] FIG. 14A illustrates a graphical representation of an
Fe.sub.3O.sub.4 iron oxide nano-particle in both magnetic and
electric fields where the nano-particle only thermally responds to
the magnetic field;
[0040] FIG. 14B illustrates a graphical representation of a number
of materials in a magnetic field, where only the iron oxide
responds to the magnetic field with a temperature increase;
[0041] FIG. 14C illustrates a graphical representation of the
temperature dependence of iron oxide at different concentrations in
a magnetic field;
[0042] FIG. 14D illustrates a graphical representation of the
temperature dependence of iron oxide at different concentrations at
different point in the heating cycle time frame;
[0043] FIG. 14E illustrates a graphical representation of the iron
oxide temperature dependence on field strength and on the duration
of the illumination;
[0044] FIG. 15 illustrates a graphical representation of the LTH
nano-particle types, their energy field type, their energy field
dependence, and temperature dependence;
[0045] FIG. 16 illustrates the Magneto-caloric Effect nano-particle
temperature effect when in a magnetic field;
[0046] FIG. 17 illustrates the Electro-caloric Effect nano-particle
temperature effect when in an electric field;
[0047] FIG. 18 illustrates the combined Magneto-caloric and
Electro-caloric Effect effects;
[0048] FIG. 19 illustrates the Curie temperature effect when
nano-particles are situated in a magnetic field;
[0049] FIG. 20 illustrates a typical cancer cell which has a
plurality of nano-particles implanted within the cancer cell;
[0050] FIG. 21 illustrates, in block diagram form, the typical
architecture of an Energy Field and Target Correlation System in
which the present Invasive Agent Treatment System can be
implemented; and
[0051] FIGS. 22A and 22B illustrate, in flow diagram form, the
operation of the Energy Field and Target Correlation System to
image and treat invasive agents in a target portion of a living
organism.
DETAILED DESCRIPTION OF THE INVENTION
[0052] FIG. 21 illustrates, in block diagram form, the typical
architecture of Energy Field and Target Correlation System 2100 as
used with a specific instance of a living organism 2110. In
operation, the target portion of the living organism 2110 is
populated with target particles of a predetermined type or types.
This population of target particles could be delivered in a variety
of fashions to include, but not limited to: intravenous delivery,
injected delivery, a skin cream and the like. The target particles
themselves can take on at least two generic forms of delivery after
initial administration: active and passive. Active delivery
particles are particles which are selectively taken up by the
invasive agent or cancer cells because of a preferred antigen (or
other substance), while passive particles use their shape, size, or
physical configuration to be selectively taken up by the cancer
cells. Alternatively, it is possible for all cell types, healthy
and cancerous, to take up the target particles; and the cancer
cells can cause the target particle to change, such as "melt" an
outer layer off of the target particle because the pH of a cancer
cell is typically different than the pH of a healthy cell. In this
case, the two target particle types are now different: a modified
target particle in the cancer cell and an original target particle
in a healthy cell. Thus, in the healthy cell, where the shell did
not melt or dissolve, the cytotoxin, for example, would not be
released (but it would be released in the cancerous cell).
[0053] These target particles are designed to attach to or be
absorbed by the cancer cells (invasive agents) of interest to
enable treatment of the cancer cells. For the sake of simplicity of
description, the target particles used herein as an illustration
are nano-particles and these terms are used interchangeably,
without intending to limit the scope of target particles that could
be used. Some empirical evidence suggests that a higher uptake
probability in cancer cells occurs if both IV and injection
delivery are utilized simultaneously. The first is via Intravenous
(IV) delivery of the target particle solution to the bloodstream.
The second is via injecting the target particles directly at the
tumor site. Nothing herein precludes any method of delivery of
target particles to the cancer site; and all delivery methods,
whether active or passive, are considered covered by this systems
level approach to cancer treatment. Active delivery involves the
use of targeting molecules or coatings on the exterior of the
target particle that are preferred by cancer cells and rejected by
other healthy cells. Passive delivery uses the unique physical
attributes of the target particle, such as length or width, to only
be taken up by cancer cells and not by other healthy cells. It is
possible to use both Active and Passive methods in a concurrent
fashion as well. Furthermore, healthy cells can uptake
nano-particles, either the same as taken up by the cancer cells or
other nano-particles specifically targeted to healthy cells.
[0054] After a sufficient preparation time to enable the target
particles to reach their desired destination, the living organism
2110 is illuminated by energy fields which are automatically
selected and produced by the Energy Field and Target Correlation
System 2100 to enable the Activated Target Particle Detector 2107,
which is responsive to activation of the target particles, for
producing a human interpretable representation of the targeted
portion of the living organism 2110 to illustrate the presence and
locus of the activated target particles.
[0055] The Activated Target Particle Detector 2107 could take on a
number of forms. The first form could be an ultra-sonic array that
is designed to pick up or receive the emitted acoustical signature
of the tissue and target particles when under a pulsed
illumination, such as in thermal acoustic or photo acoustic
imaging. The second form could be a microwave antenna receiving
array that picks up the back scatter or scattering components of
the tissue and target particles. These detectors, while not shown
in FIG. 21, would reside at the input of Activated Target Particle
Detector 2107.
[0056] In particular, there are a number of databases which
maintain information which is relevant to the treatment process. In
particular, a Target Particle Database 2101 maintains a listing of
characteristics of at least one type of target particle from the
characteristics of target particles including: size, shape,
material composition, surface coating, geometry, and contents. The
Invasive Agent-To-Detection Characteristics Database 2108 maintains
data which characterizes the relationship between the invasive
agent and the detection characteristics needed to produce a
detectable effect for a selected type of target particle. In
addition, Patient Data Database 2109 maintains patient-specific
data which provides data regarding the age, sex, weight, prior
surgeries, or other conditions relevant to the detection process.
The Empirical And Analytical Data Database 2113 maintains
information which has been collected via modeling, testing,
theoretical computations, and the like. The Reflection
Characteristics Database 2111 contains data which represents the
percentage of an incident energy field which is reflected at the
interface between two materials: biological, water, air, or the
like. Finally, the Penetration Depth Database 2112 contains data
which represents the attenuation of an incident energy field as it
passes through a selected material. The number and contents of
these databases are selected to illustrate the concepts of the
Energy Field and Target Correlation System 2100 and are not
intended to limit the application of the Energy Field and Target
Correlation System 2100.
[0057] There are also one or more Field Generators 2103-2105, 2118,
and 2119 for generating an energy field. An Electric Field
Generator 2103 is shown for producing an electric field; a Magnetic
Field Generator 2104 is shown for producing a magnetic field; an
Electromagnetic Field Generator 2105 is shown for producing an
electromagnetic field; an Optical Generator 2118 is shown for
producing NIR, IR Optical, and UV inputs; and an Acoustical
Generator 2119 is shown for generating sonic and ultrasonic inputs.
Any combination of these Field Generators 2103-2105, 2118, and 2119
may be present and can be activated individually or simultaneously,
as required. At the outputs of each of these field generators,
2103-2105, 2118, 2119, there are illumination radiators which may
comprise antennas, antenna arrays, magnetic coils, and so on. The
purpose of these radiators (not shown in FIG. 21 for clarity) is to
provide the energy field or the energy impulse that excites the
tissue and the target particles. The radiators could be linearly
polarized, such as in horizontal and/or vertical; or they could be
elliptically polarized; or they could be circularly polarized such
as in Left Hand or Right Hand Circular. The output energy field
might consist of continuous, modulated, or pulsed energy in any
frequency band from acoustic through RF and microwave through
infrared and optical.
[0058] An Energy Field Controller 2102, which is responsive to a
user selecting, via the User Interface 2106, at least one type of
the target particles and identifying a portion of a target living
organism which contains these target particles, automatically
selects energy field characteristics from the characteristics of
energy fields including: field type, frequency, field strength,
duration, field modulation, repetition frequency, beam size, and
focal point, to energize the selected target particles in a
selected manner in the identified portion of the target living
organism. Thus, the user inputs data relating to the class of
target particles and the portion of the living organism that is
being analyzed, which causes the Energy Field Controller 2102 to
automatically determine the appropriate set of energy field
characteristics which are required for application to the
designated portion of the target living organism to activate the
target particles to respond in a detectable manner to enable the
identification, via an Activated Target Particle Detector 2107, of
a presence and locus of invasive agents in the living organism (as
disclosed in further detail below). The Energy Field Controller
2102 uses the automatically determined set of energy field
characteristics to activate the corresponding Energy Field
Generator(s) 2103-2105, 2118, and 2119 to output the corresponding
energy fields as defined by the set of energy field
characteristics. It should be noted that an automated system would
help improve accuracy and prevent human imaging errors; but nothing
herein prevents this system from being operated in a manual form,
should a special case arise wherein a manually-entered algorithm
could potentially enable higher imaging contrast or resolution; or
better, a more efficacious treatment protocol.
Energy Field Controller
[0059] The Energy Field Controller 2102 executes a process which
automatically selects energy field characteristics from the
characteristics of energy fields including, but not limited to:
field type, frequency, field strength, field modulation, repetition
frequency, beam size, and focal point, to energize the implanted
target particle in a selected manner in a portion of the target
living organism. The present Invasive Agent Treatment System
comprises this process as illustrated in steps 2206-2214 of FIG.
22A and also comprises the Target Particle Database 2101, Invasive
Agent-To-Detection Characteristics Database 2108, Patient Data
Database 2109, Empirical And Analytical Data Database 2113,
Reflection Characteristics Database 2111, and the Penetration Depth
Database 2112, along with the data illustrated in FIGS. 10-19
herein.
[0060] There are a number of logical feedback loops, where the
feedback enables the system to have an optimum response. This
feedback largely takes place between the Activated Target Particle
Detector 2107 and the Energy Field Controller 2102. FIGS. 22A and
22B show numerous feedback, as well as feed-forward, loops.
[0061] FIGS. 22A and 22B illustrate in flow diagram form the
operation of the Energy Field and Target Correlation System 2100 to
treat invasive agents in a target portion of a living organism. The
Energy Field and Target Correlation System 2100 receives a set of
user-provided input data to define the protocol and equipment
configuration in the living organism, as well as the target
particles that have been deployed in the living organism. This data
then is used by the Energy Field and Target Correlation System 2100
to automatically build a set of illumination functions and compute
the sequence of energy field controls that are required for the
invasive agent detection and treatment protocols. In addition, the
Energy Field and Target Correlation System 2100 makes use of
dynamic feedback to adjust the energy fields during the execution
of a selected protocol.
[0062] At step 2201, the user inputs data via User Interface 2106
to the Energy Field and Target Correlation System 2100 to define
target particles deployed in the living organism 2110, such as in
the breast of the woman 2110. At step 2202, the user optionally
inputs data via User Interface 2106 to the Energy Field and Target
Correlation System 2100 to define the configuration of the
equipment, such as the two table configurations shown in FIGS. 8
and 9. If the equipment configuration is invariant, this step can
be skipped. The user also can input data via User Interface 2106 to
the Energy Field and Target Correlation System 2100 to define the
procedure being executed. The user then can input data into the
Energy Field and Target Correlation System 2100 at step 2204 via
User Interface 2106 to define an invasive agent (such as breast
cancer) presumed to be in the target portion of the living organism
2110. At step 2205, the user optionally inputs data via User
Interface 2106 to the Energy Field and Target Correlation System
2100 that identifies a selected living organism 2110 and the
attributes of this living organism 2110. This pairing of input
information defines the particular application that must be
addressed by the Energy Field Controller 2102 in automatically
generating an illumination protocol that is effective for this
application, yet not excessive and potentially damaging to the
living organism 2110.
[0063] In response to these data inputs, at step 2206, the Energy
Field Controller 2102 retrieves data from the Target Particle
Database 2101; and, at step 2207, the Energy Field Controller 2102
retrieves data from the Invasive Agent Database 2108. This
retrieved data, in conjunction with the user input data, is used by
the Energy Field Controller 2102 at step 2208 to automatically
select energy field characteristics; this also could be set
manually, depending on specific circumstances. The energy field
characteristics include: field type, frequency, field strength,
field modulation, repetition frequency, beam size, focal point, and
the like. These energy field characteristics are needed to produce
a precisely crafted energy field with is mapped to the target
particle characteristics and the target portion of the living
organism 2110.
[0064] At step 2209, the Energy Field Controller 2102 retrieves
reflection coefficient data from the Reflection Characteristic
Database 2111 and also retrieves penetration depth data at step
2210 from the Penetration Depth Database 2112 (this is for an
E-Field component; the H-Field excitation is less susceptible to
these issues as previously discussed herein). This data enables the
Energy Field Controller 2102 to account for the particular tissues
that the generated energy fields will traverse to reach the
deployed target particles. This information is used to adjust the
selected energy field characteristics as computed at step 2208.
[0065] At step 2211, the Energy Field Controller 2102 accesses the
Empirical And Analytical Data Database 2113 that maintains
information which has been collected via modeling, testing,
theoretical computations, and the like. This data represents the
experiential knowledge that can be used by the Energy Field and
Target Correlation System 2100 to automatically set the
illumination functions and energy field generator controls. Thus,
at step 2212, the Energy Field Controller 2102 extracts whatever
data is relevant to the proposed protocol from the Empirical And
Analytical Data Database 2113. This step completes the data input,
collection, and extraction functions.
[0066] At step 2213, the Energy Field Controller 2102 proceeds to
automatically build a set of treatment illumination functions which
are used to detect the presence and locus of the invasive agents in
the living organism. These illumination functions are then used by
the Energy Field Controller 2102 to compute a sequence of treatment
energy field controls, which are the control signals used to
activate selected Energy Field Generators 2103-2105, 2118, and 2119
to produce the illumination energy fields necessary to activate the
target particles to produce a desired and detectable effect via the
application of the treatment energy field controls at step
2215.
[0067] The energy field generator(s) produce one or more energy
fields corresponding to the selected energy field characteristics
to illuminate the target portion of the living organism 2110. At
step 2216, the target particles in the living organism are
activated to produce a predetermined effect which can be detected
at step 2217 by the Activated Target Particle Detector 2107 and
which enable differentiation between the activated target particles
in their associated invasive agents and the surrounding normal
cells in the living organism. Then at step 2218, the Activated
Target Particle Detector 2107 compares the detected excitations
with what is expected and, at step 2219, determines whether the
detected effects are within predetermined limits. As an example, if
the image shows the entire breast as being cancerous, there is
likely an error somewhere that needs to be resolved. If so, the
Activated Target Particle Detector 2107 produces a human sensible
output at step 2222 indicative of the presence and locus of
invasive agents as signified by the predetermined effects produced
by the activated target particles. If not, processing advances to
step 2220 where a determination is made whether the illumination
functions need to be adjusted by routing back to step 2213. If not,
processing advances to step 2221 where a determination is made
whether the treatment energy field controls need to be adjusted by
routing back to step 2214. If not, processing advances to step
2222. The process then terminates after step 2222. An image of the
invasive agent, and the treatment results, is realized at step
2222. This image can be used by doctors and treatment teams to
understand the spatial extent of cancer and propose likely further
treatment methods for the imaged cancer.
Invasive Agent Pairing with Target Nano-Particles
[0068] Each target nano-particle to living organism to invasive
agent sequence is unique, to some degree, and this is part of the
system's process implemented by the Invasive Agent Treatment
System, as executing in Energy Field Controller 102, to recognize
and adapt for this uniqueness or variability to create a custom or
semi-custom illumination regimen or protocol. While certain
nano-particles behave differently under illumination, a number of
theoretical characteristics, verified by empirical data, describe
parameters that can be controlled in the energy field domain to
induce certain thermal behaviors in the nano-particle domain. The
two generic thermal realms are Ablation and Low Temperature
Hyperthermia (LTH).
[0069] In FIG. 1A, the process steps of Ablation and LTH are
described. At step 100, the nano-particles are administered in vivo
(in the body) via intravenous (IV) means, by direct injection
means, by a combination, or by other means to include a skin
cream.
[0070] These target particles are designed to attach to or be
absorbed by the cancer cells (invasive agents) of interest to
enable the destruction of the cancer cells. For the sake of
simplicity of description, the target particles used herein as an
illustration are nano-particles, and these terms are used
interchangeably without intending to limit the scope of target
particles that could be used. Some empirical evidence suggests that
a higher uptake probability in cancer cells occurs if both IV and
injection delivery are utilized simultaneously. The first is via
IntraVenous (IV) delivery of the target particle solution to the
bloodstream. Some research is showing as much as 8% to 10% of the
delivered particle count is getting to and residing in cancer
cells. The second is via injecting the target particles directly at
the tumor site. Nothing herein precludes any method of delivery of
target particles to the cancer site; and all delivery methods,
whether active or passive, are considered covered by this approach
to cancer treatment. Active delivery involves the use of targeting
molecules or coatings on the exterior of the target particle that
are preferred by cancer cells and rejected by other healthy cells.
Passive delivery uses the unique physical attributes of the target
particle, such as length or width, to only be taken up by cancer
cells and not by other healthy cells. It is possible to use both
active and passive methods in a concurrent fashion as well.
[0071] At step 101, there are a number of possible invasive agents
identified that can be found in a living organism; and these can
include viruses, bacterial, cancers, and the like. An infection is
the detrimental colonization of a host organism by a foreign
parasite species. Infecting organisms seek to utilize the host's
resources to multiply, usually at the expense of the host. The
immune system of mammalian hosts reacts to infections with an
innate response, often involving inflammation, followed by an
adaptive response. Colloquially, a pathogen is usually considered a
microscopic organism though the definition is broader, including
macro parasites, fungi, viruses, prions, bacteria, and viroids. A
further class of invasive agents is cancers, which is a class of
diseases in which a cell or a group of cells display uncontrolled
growth, invasion (intrusion on and destruction of adjacent
tissues), and sometimes metastasis. A separate class of agents is
not strictly "invasive" in nature, such as fat cells, uric acid
"crystals", kidney stones, etc., but is included in the
classification of invasive agents herein for simplicity of
description. Cancer (medical term: malignant neoplasm) is a class
of diseases in which a cell, or a group of cells, display
uncontrolled growth, invasion (intrusion on and destruction of
adjacent tissues), and sometimes metastasis (spread to other
locations in the body via lymph or blood). These three malignant
properties of cancers differentiate them from benign tumors, which
are self-limited, and do not invade or metastasize. Most cancers
form a tumor but some, like leukemia, do not.
[0072] At step 101 in FIG. 1A, the nano-particles are now residing
in the cancer cells. At step 102, the cancer cell region now
holding nano-particles is illuminated with an energy field in a
predetermined fashion: E-Field, H-Field, EM-Field, and so on. At
step 103, the nano-particles absorb energy from the illuminating
field and the result is a rise in temperature of the nano-particles
themselves, which in turn causes a rise in temperature of the
cancer cells in which they are residing or in the proximity.
[0073] At step 104, thermal ablation occurs where the temperature
of the cancer cells exceeds 43.degree. C. and, over time, the
cancer cells are killed. FIG. 10 shows the cell death rate versus
temperature versus time. Above 43.degree. C., the cancer cell death
rate versus time becomes very steep, meaning that the cancer cells
are dying rapidly. Note that the temperature rise from an ambient
human body of 37.degree. C. to a cancer cell killing temperature of
at least 43.degree. C. is only 6.degree. C. of temperature rise.
The cancer cell death region is the left of line 1010 and describes
the region opposite of the direction of arrows 1030.
[0074] In contrast, at step 105, the LTH method is realized. Here
the desired temperature of the cancer cells is 42.25.degree. C. and
cooler. Note that the exact temperature can be person dependent, so
adjustment may be necessary to optimize the LTH process for any
given person. This is the region in FIG. 10 as indicated by arrows
1030 to the right of line 1010 as described by 1040. In this
region, a number of positive biological things happen to maximize
the probability that heat resistant cells, such as cancer stem
cells, are killed. Things like re-oxygenation and minimization of
Heat Shock Proteins are key attributes of the LTH process.
[0075] FIG. 1B shows the corresponding nano-particles for the two
thermal treatment modalities: Ablation and LTH. For ablation, there
are five generic nano-particle types that are thermally responsive
to a given energy field type: E, H, EM, acoustic, and optical
fields. For LTH, three nano-particles and one method realize the
creation of an LTH environment: a Curie nano-particle, a
magneto-caloric nano-particle, and an electro-caloric
nano-particle. The systems method uses a feedback approach to
modify the excitation function to realize a target temperature
using a nano-particle that might have nominally come from the
ablation family of nano-particles.
[0076] FIG. 2A is a target particle database that describes
nano-particles conducive to the ablation process. These
nano-particles are made of various materials and are responsive to
energy field types as described. FIG. 2B is again for
nano-particles in the ablation method being used, for example, in
breast and lung cancer. The nano-particles for the LTH methods are
described later herein.
Particles in Electric Fields
[0077] For virtually all metals, an H-Field excitation produces
stronger heating. However, in those compounds that have an odd
number of oxygen atoms, the heating is faster with the E-Field.
This is because a single oxygen atom or odd numbers of oxygen atoms
are dipolar in nature, and heat faster in an E-Field (vs. an
H-Field). A dipolar substance is highly susceptible to heating in
an electric field; the molecule of water for example, H.sub.2O,
having a single oxygen, due to uneven sharing of electrons in time
in the H.sub.2O structure, creates a polar spatial extent that is
physically rotated as the electrical phase of the E- or EM-Field
passes over or through the substance. This is how standard
microwave ovens work, in particular exciting water molecules where
the rotation of said water molecules causes inter-molecule friction
and thereby heat.
[0078] In FIG. 3, a water molecule is shown with its corresponding
dipolar charges. It is this non-uniform sharing of electrons when
the atoms form the molecule where, in time, the non-uniform
electron sharing causes a dipolar charge. When this dipolar charge
is placed in an electric field, as shown in FIG. 4, it causes the
water molecule to rotate with the phase of the applied energy
field. This rotation or partial rotation (frequency dependent)
causes molecular friction which causes heat.
[0079] The Debeye response defines how a polar molecule behaves in
the presence of an electric field of a given frequency. It is the
imaginary part of the complex permittivity which defines the
relative ability of a substance to heat faster than its water
counter part. In FIG. 11 in graph 1140, the imaginary part of the
permittivity of water is plotted. Note that if the excitation
E-Field frequency (or EM-Field) is below 300 MHz, there is
virtually no heating of water. In the lower 20 GHz range, the
heating of water is maximized. While this is discussed in greater
detail later in this specification, what is desired are materials
that exhibit a significant delta over water in their imaginary part
of their permittivity. In this way, the nano-particles heat faster
than the water of the tissue of the living organism, thereby not
harming the tissue while causing the nano-particles to heat and
kill cancer cells. For example, if the excitation frequency were
below 300 MHz, virtually no water heating occurs, meaning tissue
does not heat up. So nano-particles that are responsive at 3000 MHz
and below in an electric field are not competing with the tissue
also being heated.
[0080] In FIG. 5, a generic nano-particle shape is envisioned which
has a polar charge as well as rotatable mass. This type of
nano-particle configuration heats faster than other types of
nano-particles when in an electric field or an EM-Field.
Alternatively, an example nano-particle is shown in FIG. 6 where
the entire half of the particle is polar. FIG. 7 shows how this
type of nano-particle behaves in an illuminating electric field or
an EM-Field wave. Since a nano-particle has greater mass than a
water molecule, for example, a rotating nano-particle causes
greater thermal creation than a rotating water molecule.
[0081] Note also that the heating mechanism can also be caused by
eddy currents in the nano-particle, even if the nano-particle does
not physically rotate. This generally is true for metallic
nano-particles but could also be embodied in other material types
such as dielectrics.
[0082] FIG. 8 contemplates a nano-particle which is made of
material types responsive to both magnetic and electric fields.
This nano-particle is illuminated by a magnetic field which causes
heating in the half of the nano-particle susceptible to a magnetic
field; similarly the electric field causes heating in the half of
the nano-particle susceptible to an electric field. An EM-Field,
since it contains both energy field types, naturally heats the
combination nano-particle. FIG. 9 is a more uniform distribution of
the material types which are inductive to heating by a given energy
field type.
[0083] In particular, both PEG (PolyEthyleneGycol) nano-spheres and
iron ferrite (Fe.sub.3O.sub.4) nano-rods have been shown to greatly
enhance tissue heating upon the application of quasi steady state
energy (after tens to hundreds of seconds)--PEG being susceptible
to an electric field while iron ferrite being susceptible to a
magnetic field. An iron ferrite sphere coated with PEG would
ostensibly be susceptible to both E- and H-Fields, as well as an
EM-Field. The size, shape, and material composition of
nano-particles (target particles) that lead to maximum heating at
RF frequencies have not been investigated in the literature. These
relationships are described in detail herein.
Target Particle Heating
[0084] Materials that have bound electrons preferably are heated
using an electric field, and this is also the case for dielectrics
which have bound electrons. Materials with free electrons generally
are heated better in a magnetic field. In addition, materials that
have an odd number of oxygen atoms always heat better in an
electric field. This is because of the manner in which the
electrons are shared in the orbital of the molecule describing the
material, thereby making the molecule dipolar in its charge,
further making it susceptible to physical rotation in an electric
field as the phase of the wave changes as it passes over and
through the molecule. This creates molecular motion, hence
friction, hence heat. Thus, materials having a single oxygen atom,
three oxygen atoms, five oxygen atoms, and so on are better heated
in an electric field, while materials with an even number of oxygen
atoms are better heated in a magnetic field.
[0085] To heat a target particle with electric or electromagnetic
energy, it is clear that the particle must have some non-zero value
of the imaginary part of the permittivity (and perhaps
conductivity, in some situations). Effective heating means that in
the material permittivity
.epsilon.=.epsilon.'-j.epsilon.''=(.epsilon..sub.r-j.sigma./.omega..epsil-
on..sub.0).epsilon..sub.0, all loss mechanisms are described by
finite, non-zero .epsilon.'', associated with .sigma., regardless
of the nature of the loss (conduction, dipolar friction, etc.).
Thus, the imaginary part of the effective permittivity must be
non-zero at the frequency of illumination.
[0086] In general, any material may be heated by electric or
electromagnetic energy, but the degree to which that happens is
dependent on:
[0087] Frequency of the electromagnetic energy,
[0088] Intensity of the electromagnetic energy,
[0089] Proximity to the source of the electromagnetic energy,
[0090] Conducting or non-conducting nature of the material,
[0091] Nature of the material: how glossy, complex permittivity
(real and imaginary), complex permeability (real and
imaginary).
[0092] The induced power (power dissipated), or heating, in a
particle is: [0093] A multiplier of angular excitation frequency,
where it is dependent on the angular frequency and the value of the
imaginary part of the permittivity at the given angular frequency;
[0094] A function of field strength squared (E or H); [0095]
Particle size dependent: the selection of using E or H is also
particle-size dependent (for a larger gold particle, 10 nm vs. 5
nm, the 10 nm particle favors H-Field excitation as the key
imaginary part of the "polarization" is higher by a factor of about
10.times.; [0096] Some particles of smaller sizes will not heat in
an electric field, while larger sized particles will substantially
heat; [0097] A function of particle radius cubed for E-Fields, and
radius to the fifth power for H-Fields (for metallic spheres);
[0098] Is a linear multiplier of .epsilon..sub.0 for E-Fields;
[0099] Is a linear multiplier of .mu..sub.0 for H-Fields; and
[0100] Does not depend on skin depth in the nanoparticle sized
realm.
[0101] The magnetic heating is also a function of complex magnetic
dipoles and the excitation and realization of those dipoles in the
material itself. Even a non-magnetic metallic sphere in a magnetic
field has eddy currents induced which cause heating.
Electric Field Heating
[0102] The relative static permittivity of a solvent is a good
measure of its polarity, and the dielectric constant, hence
polarity, is temperature dependent. This means that, as a material
heats up, its relative .epsilon..sub.r changes, as does its
polarity, further meaning that the illumination function needs to
change to maintain a constant rate of heating. Thus, the excitation
field is not static and changes during the process of heating,
based partially on the change in polarity and .epsilon..sub.r. This
could be as simple as a lookup table mapping tissue temperature to
illuminated power, or it could involve active temperature feedback
where the temperature is measured and that temperature is reported
to the system controller which then adjusts its illumination power
level accordingly.
[0103] Nano-particles that exhibit, either naturally or via a
coating, a polarity in the spatial domain get hot via the "dipolar
heating" effect in an E-Field. In addition, if the nano-particles
were, over time, to become less dipolar as the temperature rose,
the maximum defined temperature would be reached naturally and any
further excitation would not cause an increase in temperature. This
would be a natural limiting function, offering an added degree of
heating safety.
[0104] For a treatment protocol, the heating of the nano-particles
in the cancer cells must exceed the heating of healthy tissue in
the vicinity of the location of the nano-particles. For an imaging
protocol, the heating of the nano-particles in the cancer cells
just needs to be different than neighboring healthy tissue. If the
frequency of the applied energy field is low, the E-Field component
of the applied energy field provides a low level of heating of the
surrounding healthy tissue; and the tissue heating increases when
the frequency of the applied energy field is raised to higher
levels. Thus, one method to develop a temperature differential
between nano-particles and healthy tissue is to use a lower RF
frequency.
[0105] By examining the well-known equations which define the
illumination function for both E- and H-Fields, the key drivers can
be identified to maximize the particle-illumination mapping
function; that is, which illumination functions are optimal for
maximum heating of a given target particle material type. Equations
1 and 2, below, define the power dissipated in a metallic target
particle that is contained in an electric field. Equation 1 defines
the electric field heating of a nano-particle in watts. As
previously mentioned, the absorbed power is a function of the
E-Field squared (actually, this is the complex E-Field). The power
is a linear function of the excitation frequency, in this case
.omega. or angular frequency, including the imaginary part of the
permittivity at the given excitation frequency.
[0106] Thus, in an electric field, the objective is to find target
particle material types which heat faster than the surrounding
healthy tissue. In this manner, cancerous tissue containing target
particles (such as nano-particles) is heated without harming
healthy tissue.
P abs E ( .omega. ) = .omega. 2 Im ( .alpha. E ) o E -> 2 2 ( 1
) ##EQU00001##
[0107] The relative permittivity of the target particle being
illuminated, as shown in Equation 2, which dovetails into Equation
1 as .alpha..sub.E, provides insight into the behavior of material
with differing dielectric constants. As an example, in an electric
field, the heating of the target particles must exceed the heating
of tissue in the vicinity of the location of the target particle.
The heating of tissue is dispersive with the illumination
frequency; as the frequency changes, the relative conductivity and
permittivity of tissue changes. Different tissue types also have
different permittivity and conductivity, again changing with
frequency. Cancer also has its own unique dispersive electrical
properties.
.alpha. E = 4 .pi. R 3 r - 1 r + 2 ( 2 ) ##EQU00002##
[0108] In Equation 2, the relative permittivity is a complex value,
having both real and imaginary values. It is the imaginary portion
of the complex permittivity that determines the loss a given
material has in an electric field. Another defining factor is the
loss tangent, which is a function of the ratio of the imaginary
part to the real part of the relative permittivity; again, a
dispersive complex value always changing with frequency. For
Equation 2, the relative dielectric constant of a conductor in
general has a real value that is negative and an imaginary value
that is very large. For example, silver's complex dielectric
constant is -85+j8*10.sup.12. Note that the real part is negative
and the imaginary part is rather large. The magnitude of
.epsilon..sub.r is >> greater than 1, as is the case for
metals, meaning Equation 2 does not permit heating of a conductive
metal such as silver. In this case, a magnetic field is the
preferred field for materials with properties like silver.
[0109] If the excitation frequency goes from 13.56 MHz (a common
frequency band allocated by the FCC for medical devices) to 3 GHz,
the power absorbed by the target particle goes up by a factor of
221 times, a linear relationship, provided that the imaginary part
of the permittivity does not change with frequency. This means
that, all other variables being equal, illuminating a target
particle at 3 GHz has 221 times the power absorbed if the
illumination were at 13.56 MHz. This is important. It means that
the electric field strength at 3 GHz can be almost 15 times less
strong than the electric field at 13.56 MHz to obtain the same
results. This is because of the squared relationship of the field
strength. Thus, illuminating at a higher frequency offers a safety
factor in terms of illumination energy field strength, where human
tissue is involved, to offer significantly lower illumination
levels. Thus, higher frequencies realize the same power absorbed at
the target particle level as lower frequencies, but with much lower
electric field strengths. Similar relationships exist for magnetic
field excitation of nano-particles.
[0110] Tissue has three major frequency vs. permittivity dispersive
regions: alpha-beta-gamma, all of which are frequency dependent.
Alpha dispersion is at low frequencies and has very little
engineering impact. Beta dispersion occurs at frequencies from
around 1 KHz to the GHz region, and gamma dispersion begins around
10 GHz. This behavior affects the complex permittivity which
affects its heating rate in an electric field. Without going into a
lot of detail regarding tissue heating, it is sufficient to say
that the target particle heating rate must exceed the tissue
heating rate when the illumination function is an electric field.
To be clear, the heating by-product of tissue, with or without
nano-particles, in an electric field is not governed by Equations 1
and 2. It is governed by other equations and the general Specific
Absorption Rate (SAR) equation, shown as Equation 3 below.
Equations 1, 2, 4, and 5 are for heating of particles. Thus, tissue
containing particles would have two sets of equations governing the
overall heating: one set for the particles and the second set for
the tissue alone.
[0111] The Specific Absorption Rate is governed by the following
Equation 3, which describes the heating of tissue in general. For
this to work, Particle Absorption with associated thermodynamic
heat transfer to the cancer cell must be greater than the SAR for
the surrounding healthy tissue; and the SAR temperature of healthy
tissue cannot exceed that for harming healthy tissue, say in the
upper 30's.degree. C. or very low 40's.degree. C.
SAR = .sigma. E 2 .rho. m ( 3 ) ##EQU00003##
where SAR is in watts per kilogram, and where .sigma. equals the
bulk electrical conductivity (S/m), and p.sub.m is the mass density
kg/m.sup.3, and E.sup.2 is V/m.
Imaginary Part of Permittivity
[0112] Next, measured laboratory data empirical verifies the
previous E-Field equations, trends, and dependencies. These tests
show that the field-particle relationship is governed by definable
and measurable results, where the results can be used to predict
which nano-particle is responsive to which field, at what
frequency, and to what relative heating level.
[0113] In FIG. 11, there are two sets of plots, both having the
same material but of differing material concentrations. The
material was tested using a Time Domain method to remove boundary
artifacts to ensure the most accurate possible permittivity
measurements. On the left side are two plots 1110, 1120 for a 10
mg/ml concentration of a surfactant, cocamidopropyl betaine. The
upper left plot 1110 is the complex permittivity while the lower
left plot 1120 is the product of epsilon zero, omega, and the
imaginary part of the permittivity, same material, and same
concentration. Plot 1117 in graph 1110 is the real part of the
surfactant's permittivity, while plot 1112 in graph 1110 is the
imaginary part. Water's real part is plot 1118 in graph 1110, and
water's imaginary part is plot 1114 in graph 1110. We are
interested in two things: the imaginary part value plot 1112 in
graph 1110 and how that value relates to the imaginary part of
water, plot 1114 in graph 1110. Thus, at around 3 GHz, the
surfactant starts to separate going leftward from water (imaginary
part plots). At 3 GHz, if the surfactant were in nano-form within
the cancer, it would not heat any faster than the water in the
surrounding tissue cells. At 1E08 or 100 MHz, water's imaginary
part is virtually zero, meaning water does not heat at this
frequency, while the surfactant is at 50 for its imaginary value,
meaning it heats very rapidly at this frequency. Note that the
imaginary part of the surfactant appears to go up asymptotically in
plot 1112 of graph 1110. However, if the plot were extended to the
left, it may come back down.
[0114] The Debeye plot for water is shown as plot 1114 in graph
1110. Water has a certain relaxation frequency of around 24 GHz
(peak of plot 1114). If the molecule is larger, such as in
surfactant, then the relaxation frequency is lower.
[0115] As the concentration is increased, as shown in the right
hand graphs,upper right graph 1130 is 100 mg/ml for permittivity
and lower right graph 1140 is 100 mg/ml conductivity, both for the
surfactant. Note how the imaginary part of the surfactant in plot
1132 of graph 1130 shifts up and to the right. This means that, at
a given frequency, the response is enhanced and, at higher
frequencies, the response may become sufficiently different from
water to be viable in terms of differential heating. Note also the
real part of the surfactant plot 1137 of graph 1130 changed also.
This is further illustrated in FIG. 11A by the vertical boxes. Note
that, in the left plot ,the imaginary part goes through the lower
middle of the box; in contrast, on the right plot, the imaginary
part just touches the right hand side at the top of the box and
doesn't go through it. This is the result of the change in
concentration from 10 mg/ml to 100 mg/ml.
[0116] Going back to FIG. 11 for a moment, only when plot 1112 in
graph 1110 as compared to plot 1114 in graph 1110, and plot 1132 of
1130 compared to plot 1134 in graph 1130, having a substantial
difference in value, do the nano-particles heat greater than tissue
(which is largely water). Thus, the permittivity measurement test
enables a very accurate assessment of whether a nano-material heats
at all and whether it heats greater than the heating of water (or
tissue). The next permittivity plot offers clarity to this
concept.
[0117] FIG. 12 shows permittivity measurements for gold
nano-particles. The left-hand two plots 1210, 1220 are for gold
nano-particles at 0.05 mg/ml for 5 nm gold spheres. The right-hand
two plots 1230, 1240 are for 80 nm (nanometer) gold spheres with a
same concentration of 0.05 mg/ml. Note that, for the left plot
1210, line 1212, the imaginary permittivity of the 5 nm gold
spheres versus frequency, it almost exactly tracks the imaginary
part for water line 1214 of graph 1210. This means that 5 nm gold
spheres are not heated by an illuminating electric field from 10
MHz to 20+Ghz. In fact, this has been shown to be correct;
laboratory excitations of 5 nm gold spheres do not heat at any
frequency. In contrast, 80 nm gold spheres, upper right graph 1230,
at line 1232, diverges from the imaginary part of water at around
250 MHz. Thus, at frequencies below 250 MHz, and more particularly
at 10-30 MHz, 80 nm gold spheres get hot in an illuminating
electric field. This is due to the non-zero imaginary value of the
imaginary part of the permittivity of 80 nm gold spheres, with
respect to water's imaginary part which is zero in this spectral
region. In addition, where water has a zero imaginary value, it
does not get hot, meaning tissue does not get hot.
[0118] FIG. 13A shows the responsive nature of materials is field
dependent, sometimes in a binary manner. The material being tested
is cocamidopropyl betaine. Plot line 1310 is the material thermally
responding to an illuminating electric field. Over 180 seconds of
time, the material's temperature is increased 26.degree. C.
Remember, to get to 43.degree. C. where cell death occurs rapidly,
it only takes around 6.degree. C. of change. The electric field
strength is 1,000 V/m (volts per meter), and the excitation
frequency is 3200 MHz (or 3.2 GHz). Note that this material does
not exhibit a rise in temperature in the presence of a magnetic
field 1320. The frequency of the magnetic field is 290 KHz. Thus, a
surfactant, having a non-zero value for the imaginary part of the
permittivity, is only heated in an electric field and not a
magnetic field.
[0119] FIG. 13B illustrates the heating effect on a concentration
of nano-particles. This is for PEG 200 (polyethylene glycol)
nano-particles in a 1,000 V/m electric field at 3200 MHz. For the
1.0.times. concentration, the 30-second temperature is a little
over 2.degree. C. At twice the concentration for 30 seconds, the
temperature is just shy of 4.degree. C., showing the linear heating
relationship with particle concentration in an electric field. This
is relevant to the level of particles that can be delivered to a
cancer cell. If the concentration of nano-particles in the cancer
cell is known, the illuminating field and time can be determined
for a given temperature rise.
[0120] FIG. 13C illustrates the heating effect on a concentration
of PEG 200 nano-particles having a size of 1.65 nm to 2.001 nm.
These nano-particles are in an electric field at 7,000 MHz (or 7.0
GHz). At 0.9.times. concentration, the field strength is 450 V/m;
at 1.8.times. concentration, the field strength is 900 V/m. The
temperature rise at 0.9.times. concentration is 1.2.degree. C.,
while at 1.8.times. concentration, the temperature rise is
4.8.degree. C. This is a temperature rise ratio of 4 times. Thus,
when the field strength is doubled from 450 V/m to 900 V/m, the
temperature increases by a factor of 4, or a squared relationship,
as predicted by theory. The nano-particle concentration for this
test is 1000 mg/ml.
[0121] FIG. 13D illustrates the thermal response as a function of
electric field intensity, and 13E illustrates the temperature
change as a function of the applied electric filed. FIGS. 13D and
13E illustrate the response of the surfactant cocamidopropyl
betaine at a concentration of 313 mg/ml at a frequency of 3200 MHz.
The field strengths are shown in FIG. 13E. Note the non-linear
shape of the temperature curves for different field strengths. If
we look at 500 V/m or 1.0.times. electric field strength
(7.0.degree. C.) compared to 1,000 V/m or 2.0.times. electric field
strength (26.0.degree. C.), for 180 seconds, we see the temperature
ratio is around 3.7 times. At 30 seconds, the rise in the
temperatures of the cocamidopropyl betaine in the different
electric fields are 1.9.degree. C. to 7.5.degree. C. or a ratio of
3.95. Thus, within experimental error, the squared temperature rule
for a doubling of field strength applies to a surfactant.
[0122] FIG. 13F illustrates a plot of the thermal response of
PEG200 nano-particles in an electric field of 1,000 V/m with a
concentration of 1,000 mg/ml as a function of the frequency of the
applied electric field. The frequency heating dependence stated by
the equations is dependent on the excitation frequency in
combination with the value of the imaginary permittivity at the
stated frequency; the measured results here suggest something at
least squared or likely greater. From a 5.3.degree. C. temperature
rise at 1.0.times., the baseline frequency (180 second plot), to
21.5.degree. C. temperature rise at 2.0.times., the baseline
frequency (180 second plot), this has a ratio of 4.0. At
1.0.times., the baseline frequency (2.2 GHz) and at 1.7.times. the
baseline frequency (3.7 GHz), the rise in temperature ratio was 4
times for a 1.7 times change in frequency, suggesting a
relationship greater than a squared one.
Magnetic Field-Particle Data
[0123] FIG. 14A shows a plot of one material, iron oxide
Fe.sub.3O.sub.4, in both a magnetic field and an electric field.
The nano-particle concentration is 50 mg/ml. The magnetic field
frequency is 290 KHz. This is plotted as line 1410, which shows a
strong thermal response to being exposed to a magnetic
field--upwards of 40.degree. C. temperature change at 180 seconds.
In contrast, this material does not heat in an electric field, line
1420. The E-Field is at 3.2 GHz at 1,000 V/m. There is a light
temperature rise of 1420, but this is because the iron ferrite
particles are in a colloidal solution of water. It is the small
portion of water that is actually heating here versus the
nano-particles. Thus, like the electric field example in FIG. 13A,
the nano-particle can exhibit very selective heating based on the
correct pairing of the field-to-particle relationship.
[0124] In FIG. 14B, again in a magnetic field of around 20,000 A/m,
only the iron ferrite (circled boxes and upper three plotted lines)
gets hot. Note that the iron ferrite of 02 mg/ml barley moves in
temperature; that is because, like for the electric field, there is
a minimum nano-particle concentration necessary to get the
particles to begin heating. In this case, 2 mg/ml is too low and it
doesn't heat.
[0125] FIG. 14C shows the linear relationship effect of
concentration when using a magnetic field and nano-particles
susceptible to magnetic fields. Again, the particle is
Fe.sub.3O.sub.4 and the nano-particle size is around 55 nm. The
excitation frequency is 340 KHz. For the two dashed boxes outlining
the two bar graphs, at a 1.0.times. concentration, the temperature
is around 19.2.degree. C.; at 2.0.times. concentration, the
temperature is at 40.degree. C. This is a ratio of 2.08 or
effectively a linear relationship. Thus, like the electric field
data set, the magnetic field versus particle relationship is a
linear one with respect to particle concentration.
[0126] In FIG. 14D, there are four sets of circled data point
pairs, between a concentration of 25 mg/ml and 50 mg/ml. For all
four of these pairings, the temperature relationship is a factor of
two. Thus, this confirms FIG. 14C--the temperature rise is linear
with a change in nano-particle concentration. Again, like the
electric field example of concentration, the importance of this
relationship is actually at a cellular level; that is, how many
nano-particles are delivered to a cancer cell. The excitation
temperature is dependent on how many particles arrive at a given
cell. The more particles, the hotter the cancer cell will get.
Alternatively, if a given nano-particle administration protocol is
known to deliver X particles per cell, then, the excitation
function, time/field strength/frequency can all be pre-determined a
priori to actual treatment.
[0127] Now we look at magnetic field strength. FIG. 14E shows a
test of varying magnetic field strength. This is using
nano-particles that are composed of Fe.sub.3O.sub.4 at 25 mg/ml at
290 KHz excitation frequency. The nano-particles were placed within
a material that emulated the electrical characteristics of human
muscle at the given frequency. The two black circled regions show a
ratio of on the low end 1.0.degree. C. to 3.9.degree. C. (ratio of
3.9) to on the high end 2.2.degree. C. to 8.0.degree. C. (ratio of
3.6). This is for a field strength change of almost 2 times, which
produces a temperature change of close to 4 times, thereby
experimentally confirming the field squared relationship on heating
in the magnetic domain. This holds similar to when the electric
field is squared and the temperature goes up by a factor of 4
times.
Magnetic Field Heating
[0128] In general, there are three types or regions of magnetic
heating: Brown, Neel, and Rayleigh. The Brown region is at lower
frequencies, and the heating is caused by the magnetic
nano-particle physically rotating in the medium, such as in a
cancer cell. Since the Brown region is at such a low frequency, not
much heating energy can be imparted using this mode. The Neel and
Rayleigh regions are characterized by the creation and relaxation
of magnetic domains or dipoles in the nano-particle itself. When
the magnetic domains or dipoles are random and then forced to
become ordered and then random again, as when occurs in an
alternating phase magnetic field, heat is released by the
nano-particle. Both the Neel and Rayleigh regions are much higher
in frequency than the Brown region, and the nano-particle itself
does not rotate.
[0129] The Neel region, for a variety of reasons not discussed
herein, is extremely sensitive to the size of the nano-particle in
terms of the highest heating state with respect to the excitation
frequency. Thus, a log normal distribution of nano-particle sizes
would mean that only a portion of the nano-particles, say 45%,
would be optimally heated. The falloff rate of heating is orders of
magnitude: an example would be a change of nano-particle size by
4-5 nanometers results in a heating change of up to four orders of
magnitude. This is not optimal for single frequency illumination if
the nano-particle sample size is not tightly controlled. One
possible positive or advantageous use of this characteristic is to
use nano-particles that have two different sizes, which are
targeted to two different material types, where the nano-particle
size distribution is tightly controlled. The excitation then is
done at two different frequencies sequentially applied with a
waiting period between each excitation. The two regions or extents
of nano-particles, located in healthy tissue vs. cancerous tissue,
then could be easily mapped.
[0130] For a broader size distribution of nano-particles, a more
broadband frequency magnetic field is required to ensure that all
the nano-particles are heated. In this manner, the log normal
nano-particle size distribution is still optimally heated because
the excitation frequencies are broadband, thus ensuring that all
nano-particles have the optimal frequency. The selected frequency
spectrum should match the nano-particle size distribution so the
time or temporal space for a given frequency matches the relative
number of nano-particles for that given frequency.
[0131] Alternatively, if the nano-particle sample size distribution
is highly varied and cost implications make it difficult to tighten
this up (it is difficult and costly to get 100% of the
nano-particles exactly at a 20 nm diameter for instance), then
working in the Rayleigh region removes this size vs. frequency
dependence. There is also some evidence that suggests that heating
of the magnetic nano-particles in the Rayleigh region could be an
H.sup.3 function, which would clearly be advantageous.
[0132] It is clear that nano-particle heating in the Rayleigh
region is less dependent on nano-particle size, as it is in the
Neel region. As discussed, this could be both an advantage and a
disadvantage. The advantage is that it removes the nano-particle
size dependence on frequency for heating, meaning the nano-particle
size distribution can be less tightly controlled (lowering the cost
of the nano-particle). On the flip side, the disadvantage is that
the ability to use nano-particle size as a differentiator in the
heating process is now gone, where one size is used for healthy
tissue and a second size is used for cancerous tissue, each having
their own optimal heating frequency.
[0133] When using a pure magnetic field (H-Field), tissue heating
is generally very low, almost non-existent, provided the product of
frequency and A/m magnetic field strength is kept below certain
levels where eddy currents, hence heat, are introduced to the body.
This product has been experimentally determined to be 4.85*10.sup.8
where, after an hour at these levels, human subjects have suggested
they were feeling "warm-ish" in the illuminated region. Clearly, an
image can be extracted much faster than that timeframe, especially
when magnetic field susceptible nano-particles are used, such as
iron ferrite, where 45 nm iron ferrite Fe.sub.3O.sub.4
nano-particles have been heated to very high temperatures of
90.degree. C. in a matter of 180 seconds. For the differential
temperature imaging method, the temperatures needed are
significantly lower since the body is around 37.degree. C.
[0134] Equations 4 and 5 govern the power absorbed (in watts) by a
nano-particle in the presence of a magnetic field. Like the
equations for the electric field contribution to power absorbed,
the magnetic field power absorbed contribution is a function of the
field squared (H.sup.2) and a linear effect with angular frequency,
.omega., in addition to the effect of frequency on the imaginary
part of the relative permittivity. Similar frequency dependence and
field strength dependencies exist with the magnetic field. For
conductors, surface charges at the interface prevent the electric
field from penetrating efficiently in the metallic particle. This
"screening" occurs at a scale defined by the Thomas-Fermi length.
This is not dependent on skin depth. However, in contrast, the
magnetic fields are continuous at the interface and, therefore, can
penetrate into the material itself (a conductor). Nano-particle
conductors, in general, are best paired with a magnetic field.
[0135] In general, materials that are conductors or have free
electrons are best illuminated by a magnetic field. An exception
would be aluminum, which is not responsive to magnetic field
heating. Molecular compositions that have an even number of oxygen
atoms, such as Fe and Fe.sub.3O.sub.4, are best heated with a
magnetic field.
P abs M ( .omega. ) = .omega. 2 Im ( .alpha. H ) .mu. o H r 2 2 ( 4
) .alpha. H = 2 .pi. 15 R 3 ( 2 .pi. R .lamda. ) 2 ( r - 1 ) ( 5 )
##EQU00004##
[0136] The magnetic field does not heat tissue like the electric
field does because the magnetic field has no impact on materials
that are dipolar or exhibit a strong permittivity. This has
inherent advantages in terms of creating a detectable heating
difference between healthy tissue and cancerous tissue where
nano-particles reside.
[0137] There are empirical and theoretical equations that describe
the heating of nano-particles for each of these three regions. For
brevity, these equations are not included herein.
Both Sets of E and H Equations
[0138] The above-presented sets of equations have a dependence on
nano-particle size. The electric field heating has an R.sup.3
dependence, while the magnetic field has an R.sup.5 dependence.
Thus, for very small nano-particles, 5 nm (nanometers) and below,
the imaginary parts of the E and H equations (Equation 1 and
Equation 4, respectively) are almost identical. However, as the
particle size increases to 10 nm and bigger, the magnitude of the
imaginary part of the H-Field becomes bigger than the E-Field. One
example, calculated at optical frequencies, has the magnitudes of
the two respective components alpha E and alpha H varying by an
order of magnitude (10 times).
[0139] Materials that work well in both fields are those that have
a physical distribution in a powder form of two substances, such as
zinc oxide-cobalt (ZnO--Co) in a composite sample. For example,
when in the E-Field, the ZnO heats to high temps (900.degree. C.)
while the cobalt only goes to 50.degree. C. In a magnetic field,
the cobalt heats to 700.degree. C. while the ZnO (zinc oxide) only
goes to 50.degree. C. Thus, an electro magnetic field (EM) heats
both substances to their respective highs of 900.degree. C. for
zinc oxide (ZnO) (from the electric field portion) and 700.degree.
C. for the cobalt (CO) in the magnetic field portion of the
composite EM wave.
Material Properties
[0140] The heating of tissue is dispersive with frequency; as the
frequency changes the relative permittivity and conductivity of the
tissue changes. Different tissue types have different
permittivities and conductivities, again changing with frequency.
Cancer also has its own dispersive electrical properties, which are
unique. This is yet another method of particle location detection,
or cancerous vs. healthy tissue detection. By using a very
broadband illumination source, such as UWB or Ultra-Wideband
energy, the material properties change significantly from the
lowest frequency to the highest frequency-these material properties
can be detected and spatially mapped. Thus, the material properties
greatly differ from F(low) to F(high)-, for healthy tissue, for
cancerous tissue, and for nano-particles. These differences in
material properties offer a means to distinguish and spatially map
the cancerous regions containing nano-particles.
Particle Properties
[0141] Characteristics of particles include size, shape, material
composition, density, surface coating, geometry, contents, and
behavior in the presence of an energy field have predetermined
characteristics. In addition, the data can contain a listing of
cancer types for which the particular target particle is
effective.
[0142] FIG. 2A is an example, in table format, of target particle
characteristics for nano-particles. These particles are for
Ablation versus Low Temperature Hyperthermia. For example, for a
predetermined model of nano-particle (ex. -9736C) there are
relevant characteristics, such as: geometry (cylinder); material
which is used to fabricate the nano-particle (IronOxide);
dimensions (10 diameter, 75 length); coating (PEG, Poly Ethylene
Glycol); concentration (85 picograms per cell (per cancer cell));
and excitation response function of 1000 V/m and 15000 A/m. Two
fields are used since the nano-particle has two materials which are
susceptible to differing field types: the iron ferrite
Fe.sub.3O.sub.4 is susceptible to a magnetic or H-Field only (given
in A/m), while the PEG coating is susceptible to an E-Field only
(given in V/m). The frequency for the E-Field is in the upper
S-band range, or 2.5 to 3.0 GHz, while the magnetic field is lower,
in the MHZ range, 14 MHz. These selected frequencies are
representative and in no manner are limiting. For example, the
magnetic field could be in the 200-300 KHz range, where heating has
shown to be very responsive. Frequency selection is chosen based on
the area being treated, the particle type, the level of reflections
and penetration depth, and so on. For instance, selecting the
magnetic frequency extremely low puts the magnetic excitation in
the Brown region, which does not induce as much energy into the
nano-particle, hence, heat into the tissue. For some cases, this
may be desirable on the Imaging side of the process, but less
desirable on the Treatment side of the process. At frequencies that
are not resonant for the nano-particles, frequencies in the MHz or
GHz region, the illumination polarization is less important, since
nano-particles are resonant in the terahertz region (light
spectra). However, the illumination polarization for tissue does
have importance; and certain tissue artifacts may show up using
different polarizations. At optical or laser excitation, the
nano-particle shape and size become important, since the
nano-particle size becomes a substantial part of the illuminating
wavelength. In addition, at optical or laser frequencies,
nano-particles can begin to exhibit meta-material behaviors such as
SPR, or Surface Plasmon Resonances. The excitation phase can be
controlled to ensure that all energy impinging on the skin, for
example, arrives in phase so it is additive. In other cases, the
electrical phase of the energy can be adjusted to steer the
exciting beam over the region to illuminate, thereby causing a
moving energy field over the breast, for example.
[0143] Other nano-particles such as 6754Z in FIG. 3 are designed to
have an enhanced acoustical response when excited with an energy
pulse, RF/microwave, or optical. The PEG shell is more easily
compressed since it has a surfactant filling (fluid-like filling)
thereby being more easily compressed/expanded and thereby emitting
a stronger acoustical response which is unique from either healthy
tissue or cancerous tissue. This material is also unique in terms
of its permittivity and conductivity in an E-Field or
E(M)-Field.
[0144] These entries define the responsiveness of the selected
nano-particle to a preferred applied energy field, as well as the
physical and chemical characteristics of the nano-particle that can
be used with a particular invasive agent. For example, a
nano-particle of long linear aspect ratio, long and skinny, often
is susceptible of being consumed by a cancer cell, yet also is too
large or shape specific to be excreted by the cancer cell. A
coating of carbodilimide conjugated polyethylene glycol-iron
oxide-impregnated dextran can be used as the "composite" deposited
on the nano-particle to make it attractive to human breast cancer
cells.
Energy Fields
[0145] An energy field is comprised of fields in the
electromagnetic spectrum which range from kilohertz to optical
frequencies (terahertz). Radio Frequency (RF) and Microwave energy
is contained within this spectrum. The fields can follow or be
bounded or be explained by Maxwell's equations, and they can
exhibit quantum behavior (light, for example, exhibits both wave
and quantum particle behavior simultaneously). The innovation
described herein focuses on electromagnetic energy that exhibits
more wave-like behavior. However, it should be noted that the
nano-particles that are being excited by the Maxwellian waves may
themselves exhibit linear or stepped behavior (which is quantum
like in its nature). So, while the illumination function is
described by Maxwell's equations, the nano-particle, which is
activated under the Maxwellian illumination, may very well exhibit
behavior that is non-linear in its nature.
[0146] The Maxwellian fields used for illumination functions
generally can take the form of three types of fields: an
electromagnetic field (EM) which has both types of waves, magnetic
and electric, in a spatially orthogonal relationship; an electric
field (E); and a magnetic field (H). It is important to recognize
that any combination of these three basic field types are possible;
and, in fact, may be desirable. Thus, the illumination may be
multifold vs. a single illumination type. In addition, the
combinations of fields can be arranged to include spatial and
temporal domains. Therefore, it is possible (for example) to have a
magnetic field for 2 seconds, followed by an electric field for 5
seconds, in a time or temporal sequential fashion. As another
example, 65% of the illumination space could be covered by an
electric field while the entire illumination space is illuminated
by a magnetic field, all in a concurrent fashion; or a baseline
electromagnetic field (EM) could illuminate the target region with
a pulsed magnetic field covering the same region. Separately, a
given illumination function may only be the electric field, or it
may only be the magnetic field, or it may only be an
electromagnetic field. Nothing contained herein limits the
possibilities or modes of illumination by given field types.
[0147] An example of both field types, E and H, being concurrently
active is an electromagnetic (EM) field; and a further example is
an electromagnetic wave that is propagating through the air
carrying a signal, with both field types, electric E and magnetic
M. In an EM wave, the electric and magnetic fields are spatially
orthogonal to each other and propagate together. In contrast, a
"pure" electric field has an electric field only and a "pure"
magnetic field has a magnetic field only. As already described, an
electric field is denoted by the letter E, while a magnetic field
is denoted by the letter H, while an electromagnetic field is
denoted by EM.
[0148] When a material is illuminated by a given energy field type,
the material "absorbs" energy from the field and exhibits that
"absorption" by exhibiting a temperature rise, or converts the
field to an electrical current, or exhibits other modes of
excitation such as an electro-fluidic force, mechanical motion, and
so on. The pairing of the target particle type and the energy field
type is managed to control or produce by design a given behavior in
the target particle. One desirable illumination energy
field-to-target particle trait or property is the presence of a
thermal rise in the target particle. When the target particle is
placed in an energy field, the target particle, through a mechanism
described in the following sections, exhibits a thermal rise to a
higher energy state. The thermal rise in the target particle is
highly dependent on the pairing of the composition of the target
particle (including size, shape, material composition, density,
surface coating, geometry, contents, or behavior in the presence of
an energy field having predetermined characteristics, etc.) with
the illumination function, E-Field, H-Field, or EM-Field. Another
desirable trait in the particle under illumination is the
propensity to exhibit a strong acoustical response such as that
when illuminated via a pulse of energy, RF/Microwave, or laser. In
the first case, thermal, this delta increase can be mapped and used
to differentiate the cancerous tissue with particles vs. healthy
tissue. In the second case, acoustical response from material
compression/expansion would be used to enhance or differentiate the
acoustical signature of both healthy and cancerous tissue from
cancerous tissue containing nano-particles.
[0149] Target particles contained within a given energy field
exhibit certain behaviors. Most important, different target
particles and their associated composition respond uniquely in a
given energy field type. In fact, certain target particles do not
respond to a specific field type whatsoever; that is, no energy is
absorbed by the target particle in that given energy field. An
example is a target particle formed of zinc oxide responds
dramatically to an electric field with a sharp temperature rise but
has virtually no thermal response to a magnetic field. In contrast
and in converse, a target particle formed of Fe.sub.3O.sub.4 (iron
oxide) exhibits a very steep temperature rise in a magnetic field
and has virtually no temperature rise in an electric field. Target
particles manufactured from other materials respond in varying
degrees to either E- or H-Fields. Target particles manufactured
from copper, for example, respond almost equally to either energy
field type, E or H. For materials that respond to both E- and
H-Fields (such as copper), an optimal excitation source may be an
electromagnetic wave (EM), since it simultaneously contains both
energy field types in an orthogonal configuration.
[0150] Thus, the energy field type used for heating materials needs
to be optimally matched to the composition of the target particle.
Existing prior art does not recognize the importance of this
pairing, that is, the pairing of illumination energy field type to
composition of the target particle.
[0151] It is even more important to precisely pair the energy field
type for nano-particles, because they have virtually no mass, to
thermodynamically convert their "absorbed" energy to heating of
tissue where the nano-particles are residing. Without this precise
pairing of illumination function with nano-particles' material
type, the nano-particles do not reach a high enough temperature to
thermodynamically transfer their thermal energy to surrounding
material (cytoplasm, nucleus, membrane). Separately, the physical
composition of the target particle (size, shape, material
composition, density, surface coating, geometry, contents, and
behavior in the presence of an energy field having predetermined
characteristics) makes a difference in how the target particle
behaves under illumination. The concentration of the energy field
strength is an important parameter. In fact, equations show that
the heating phenomenon is a function of the energy field strength
squared. This is true for both E- and H-Fields, with H-Field
illumination being driven by even more complex equations, where
sometimes the function could move up to an H-cubed relationship.
This cubed relationship has been proposed for specific, unique
circumstances by some authors. Thus, for example, devices that
realize "induction heating" methods, which use a very concentrated
H-Field, heat metals to melting points, while a more distributed
H-Field won't have the same heating effect. Therefore, how the
field is constructed and presented or delivered to the body or
tissue is an additional parameter that is important and
controllable.
[0152] The prior art has extremely limited understanding of the
mechanisms occurring in terms of the thermal heating or other
processes of nano-particles in fields of any type. This rather
blind approach, presently in use, has no design consideration of
energy field/target particle pairing optimization whatsoever.
Low Temperature Hyperthermia Particles
[0153] The Low Temperature Hyperthermia method uses specially
designed nano-particles that exhibit a specific temperature rise in
a given illumination energy field and then have no further
temperature rise even if the applied illumination energy field
increases beyond the optimal level. Alternatively, the
nano-particles exhibit a tightly controlled temperature rise based
on a pre-determined or pre-designed a priori temperature rise for a
given illumination energy field strength. The illumination energy
field that is applied is either an electric field (E-Field) or a
magnetic field (H-Field) or a combination of both, as an E- and
H-Field or via an orthogonal field such as an EM-Field. The
nano-particles exhibit the property of not getting any hotter than
a pre-determined, pre-designed temperature even if the exciting
illumination energy field strength continues to rise. This ensures
that an optimal temperature, which for the purpose of this
description is selected to be 42.degree. C., is not exceeded in the
tissue which minimizes the release of Heat Shock Proteins while
further stressing the cancer cells so that they die, versus
emitting cancer stem cells/other cells. It also ensures that
healthy tissue is not harmed, should an errant nano-particle end up
in healthy tissue. This treatment approach is called Low
Temperature Hyperthermia.
[0154] This Low Temperature Hyperthermia System first uses
radiation or chemotherapy to kill the majority of the cancerous
cells followed by the application of E-Field or H-Field or EM-Field
radiation with on-site nano-particles to realize a temperature rise
to 42.degree. C. in the cancer cells. The advantages realized by
this treatment protocol are significant: virtually any tumor
location can be treated; the release of Heat Shock Proteins is
minimized (at 42.degree. C.); an errant nano-particle in a healthy
cell will not harm a healthy cell at 42.degree. C.; and cancerous
cells are kept at a nominal 42.degree. C. (or some other optimum
temperature) to ensure that the already stressed cancer (from
radiation or chemotherapy) is continuing to die and that cancer
stem cells are not released. Separately, a third killing element
can be added--if the nano-particle is a temperature sensitive
liposome, the liposome shell will "melt" at a design temp which is
less than 42.degree. C., wherein a cytotoxin can be released. This
third killing method, the released cytotoxin, is the third step of
a multi-pronged approach to kill deep seated cancer tumors.
[0155] The Low Temperature Hyperthermia System realizes many
advantages over the existing art: [0156] It is no longer necessary
to pre-image to ensure the nano-particles are in the correct
location since the temperature rise is limited to a safe 42.degree.
C. Healthy tissue is not harmed even if a nano-particle errantly
resides in a healthy cell. [0157] The targeting capability of
multi-dimensional radiation technology enables the exact shape of
the tumorous region plus some extended boundary volume to be
treated with radiation. This precision is difficult with other
types of treatment technologies. [0158] The Low Temperature
Hyperthermia System realizes up to three stepped methods of cancer
cell killing: radiation and/or chemotherapy, low temperature
hyperthermia, and cytotoxin. This ensures a very high kill rate and
significantly lowers the probability that the cancer will reappear
after treatment. [0159] Cancer cells that may have realized a low
nano-particle uptake concentration can be further treated with a
cytotoxin. This is of particular use when the cancer is of a more
deadly variety or if it is known that the uptake of a given cancer
cell for a given nano-particle type is naturally low. [0160] If for
some reason nano-particles cannot be used for a given patient, it
is possible to use RF- or microwave-based hyperthermia without
particles but with very tight temperature feedback controls for the
second level of treatment to realize the target 42.degree. C. in
the cancerous tissue and surrounding tissue. In this case, there is
no temperature discrimination between cancer and healthy tissue in
terms of heating. This approach isn't optimal, since heating fields
can cause hot spots, such as in healthy tissue, but it is a
fallback if nano-particles can't be used. [0161] Tumors in any
location, ranging from on or near the skin to deep in the abdomen
or lungs, can be treated easily and safely. [0162] Nano-particles
are safely removed by the body's natural filtering systems after
radiation and field treatment is complete. Thus, residual
nano-particles do not stay in the body. [0163] At 42.degree. C.,
Heat Shock Protein production is reduced, thereby minimizing the
level of cancer stem cells/other cells emitted by the resident
cancer.
[0164] This Low Temperature Hyperthermia System takes advantage of
many treatment modalities, each having distinct advantages, wherein
the combined treatment protocol is safe and efficacious. The
combined approach of multiple killing steps can be optimized
further based on the specifics of a given cancer and the
individual. This level of flexibility and control has heretofore
not been available. The approach taken is one of optimizing the
relationship between the exciting energy field and the
nano-particle characteristics, where the optimization is in this
case one of behavior at a given specified temperature. Certain
properties are designed into the nano-particles to enable a
pre-determined, pre-designed a priori temperature rise based on the
strength of the illumination energy field: E, H, E and H, or
EM.
[0165] In FIG. 20, a cancer cell 410 has a locus of nano-particles
resident 420. When the nano-particles 420 are heated by the
external illumination energy field, a heat transfer loss occurs at
430 between the nano-particles and the cancer cell. In order to
realize an optimal temperature distribution across the cancer
cell's extent, where such temperature profile is somewhat dependent
on whether the nano-particles have clumped in the cancer cell, the
target temperature of the nano-particle could be the same as the
target temperature of the cancer cell or it could be different to
account for the thermal loss between the nano-particles and the
cancer cell. In this example, the nano-particles are heated to a
temperature higher than that of the cancer cell due to a thermal
loss at the particle/cell interface, where the heat loss is shown
as 430. To determine the particle temperature, the desired cancer
cell temperature and the loss parameters are determined. In this
example, the desired cancer cell temperature is 42.degree. C., and
that is equivalent to the nano-particle temperature minus the
temperature loss.
Methods of Controlling Nano-Particle Temperature
[0166] There are at least three methods for accurately controlling
the nano-particle temperature: the Curie temperature, the
magneto-caloric effect, and the electro-caloric effect. As shown in
FIG. 15, there are minimally four attributes of interest: the
Effect (450), the Field Type (460), the Field Dependence (470), and
the Temperature Dependence (480). For the Effects (450), there are
minimally three approaches to realize a controlled temperature rise
in a nano-particle: the Magneto-caloric Effect (451), the
Electro-caloric Effect (452), and the Curie Temperature (453). Now,
looking horizontally, the attributes of each Effect can be studied.
For the magneto-caloric effect, the field type is Magnetic (461)
and the field dependence is Field Strength (471) with temperature
dependence on H-Field Strength (481). Similarly, for the
electro-caloric effect, the field type is Electric (462) with the
field dependence being Field Strength (472), and the temperature
dependence on E-Field Strength (482). Last of the three, Curie
temperature, has a field type of Magnetic (463) with a field
dependence of a Field Strength Cut-off (473), and a temperature
dependence of a given H-Field strength and nothing higher.
[0167] Alternatively, it is possible to use a heating method where
"regular" nano-particles that heat up in a field, whether the field
is electric or magnetic or a combination of the two, are used to
heat up cancer cells. This approach does not have the precision of
using specially designed nano-particles. Some feedback mechanism
must be employed to accurately manage the applied energy field to
not exceed the desired cancer cell temperature. This is a very
complex process, albeit not impossible, that requires some way of
accurately measuring the cancer cells' temperature. The field
excitation must be anticipated to not overshoot the heating of the
cancer to a non-Low Temperature Hyperthermia range. For cancers
other than skin cancer, this could be very complex and ultimately
not very accurate.
Magneto-Caloric Effect in the Low Temperature Hyperthermia
System
[0168] The magneto-caloric effect was originally envisioned for
magnetic cooling or refrigeration. Since the magneto-caloric
effect's cooling stage happens after the magnetic field is removed,
it can be used to bring substances very close to absolute zero
(after the initial ambient heat rise is removed by other
environmental cooling means). This is called adiabatic
demagnetization. While at the moment we do not anticipate using the
cooling phase of magnetic refrigeration for cancer treatment, it is
certainly available to us as part of this system (presently not
used but claimed herein).
[0169] The magneto-caloric effect heating during the adiabatic
magnetization phase is due to the application of a Direct Current
(DC) magnetic field. This is in contrast to the heating of
ferromagnetic particles in an Alternating Current (AC) magnetic
field. This is an important distinction between the multiple
methods described herein which are used to heat nano-particles to a
given temperature; magneto-caloric is a DC magnetic field, while
particles in the ferromagnetic state are best heated using an AC
magnetic field.
[0170] What is of particular interest to the cancer treatment
envisioned herein is the precise rate of temperature rise when
magneto-caloric materials are subjected to a magnetic field of
given strength, measured in Amps per Meter. While "regular"
nano-materials such as iron ferrite Fe.sub.3O.sub.4 heat in an
Alternating Current magnetic field, where the frequency of the
magnetic field varies from hundreds of kilohertz to megahertz, the
rate of rise is less precisely correlated to magnetic field
strength. For iron ferrite in a high frequency magnetic field, the
nano-particle does heat, and the heating is correlated to magnetic
field strength, it is not specifically correlated to a set number
of degrees of temperature rise for a given increase in magnetic
field strength (such as the case for magneto-caloric nano-particles
in a DC field of a given field strength). For iron ferrite, the
linear, squared, or cubed relationship to the magnetic field is
prevalent as it relates respectively to being in the Brownian,
Neel, or Rayleigh magnetic regions (Rayleigh can be both squared
and cubed, variable dependent). Thus, an iron ferrite particle
could be used, but it does not have the precise heating
characteristics of a magneto-caloric nano-particle.
[0171] Certain materials exhibit the magneto-caloric effect. One
such chemical element is gadolinium, which is also used in an alloy
form as a contrast agent in Magnetic Resonance Imaging (MRI). Thus,
this material is safe for use in humans and simply needs to be
processed in nano-meter dimensions. The gadolinium alloy
Gd.sub.5(Si.sub.2Ge.sub.2) has a much stronger magneto-caloric
effect. Praseodymium alloy with nickel PrNi.sub.5 has a very strong
magneto-caloric response, so strong that it has enabled
temperatures to within one thousandth of a degree of absolute zero.
This particular "cooling" application is somewhat different from
the approach described herein.
[0172] The Low Temperature Hyperthermia System uses the Adiabatic
Magnetization stage of magnetic cooling, wherein the nano-particles
exhibiting a magneto-caloric effect residing in a cancer cell then
are exposed to a magnetic field with specific field strength. This
field strength is determined a priori for the given particle's
material composition based on a specified desired temperature rise.
The magnetic field causes the magnetic dipoles of the atoms to
align, which means the particle's magnetic entropy must decline (go
down). Since no energy is lost yet, thermodynamics teaches us that
the nano-particles' temperature must go up. It is this very tightly
controlled temperature rise, based on a given magnetic field
strength, which is of great interest in realizing Low Temperature
Hyperthermia.
[0173] Clearly, for the cancer cell treatment application of Low
Temperature Hyperthermia, what is desired is a nano-particle
fabricated from a material that offers around 5.degree. C. to
10.degree. C. of temperature rise in a reasonable magnetic field.
Since the normal temperature of the human body is around 37.degree.
C., to reach a nominal cellular target temperature of 42.degree. C.
plus some heat loss, the nano-particle must be capable of a
5.degree. C. to 10.degree. C. temperature rise in a specified
magnetic field. For example, 37.degree. C. ambient body temperature
plus 10.degree. C. of nano-particle temperature rise yields a
nano-particle temperature of 47.degree. C. Then subtract 5.degree.
C. of thermal loss in this example to yield a cancer cell
temperature of 42.degree. C. Other levels of thermal loss are
possible and are used in this document as other examples of how
this system works.
[0174] For the Magneto-caloric Effect`, as shown in FIG. 16,
nano-particles are designed to exhibit this effect at the desired
field strength and per degree temperature rise correlation. As
illustrated in element 505, the magnetic dipoles of the
nano-particle exhibit random alignment when not in the presence of
a magnetic field. As illustrated in element 515, when exposed to a
magnetic field, the magnetic diploes of the nano-particle align,
and nano-particle heating occurs at a specified rate per the
applied magnetic field strength; the rate of heating is measured in
degrees per incremental field of some value. The process described
herein uses a portion of the magnetic refrigeration cycle and
discards the unneeded steps of the cycle. Thus, at step 510, the
nano-particles are located in the cancer cell but are not in a
magnetic field; the magnetic field is off. Thus, the particle
temperature is at ambient, which is the temperature of the cancer
cell. This is illustrated in elements 525 and 526. When the
magnetic field is applied to the cancerous region, the
nano-particles in the cancer cells have their magnetic dipoles
align at step 520. The temperature rise is specified by the
Magneto-caloric Effect's properties, and the rise is shown at level
531 as illustrated in element 530 (ambient temperature was level
526 ). The Low Temperature Hyperthermia System achieves a tightly
controlled thermal rise based on the magnetic field's exciting
strength at the region or locus of the cancer cells where the
nano-particles reside under the precise control of the system.
Since the remaining steps are the magnetic refrigeration process,
the process terminates at step 535, and steps 540 and 545 are not
executed.
[0175] For room temperature adiabatic magnetization heating, a
number of materials exhibit properties of interest; most are alloys
of gadolinium. This is advantageous since gadolinium alloys are
being used as contrast agents for MRIs, meaning the material has
been approved for use in humans. Gadolinium is strongly
paramagnetic at room temperature and exhibits ferromagnetic
properties below room temperature. It's Curie temperature, as a
pure element, is 17.degree. C.-above 17.degree. C., gadolinium is
paramagnetic, meaning it only has magnetic properties when it is
placed in a magnetic field (the magnetic spins or dipoles are
random until a magnetic field is applied). Alloys of gadolinium may
have different Curie points. Gadolinium exhibits a magneto-caloric
effect where its temperature rises when placed in a DC magnetic
field, and the temperature decreases when it is removed from the DC
magnetic field.
Electro-Caloric Effect in the Low Temperature Hyperthermia
System
[0176] Similarly, for the Electro-caloric Effect, when a specially
designed nano-particle which exhibits an Electro-caloric Effect is
placed in a DC electric field, the temperature rise of the
nano-particle is dependent on the field strength of the electric
field. Like the magnetic cooling cycle, the Low Temperature
Hyperthermia System 150 uses the first steps of the process and
does not use the remaining cooling steps. Like the Magneto-caloric
Effect with magnetic fields, the Electro-caloric Effect realizes a
specified temperature increase when exposed to an electric field.
As an example material, PZT, a mixture of oxygen, zirconium, lead,
and titanium with a 12.degree. C-temperature response in a field
voltage as low as 25 volts was used; the ambient temperature in
this example was 220.degree. C. At room temperature, ferroelectric
polymers have shown 12.degree. C. of temperature change when
exposed to a DC electric field. Sometimes this effect is called the
Giant Electro-caloric Effect.
[0177] FIG. 17 shows the Electro-caloric Effect. As illustrated in
element 605, a nano-particle is shown not in an electric field,
while the nano-particle is illustrated in element 615 as in the
electric field. At step 610, the nano-particle is not in the DC
electric field and has an ambient temperature of level 626 as
illustrated in element 625. When the DC electric field is applied
to the nano-particle at step 620, the temperature rises to .DELTA.T
at level 631 which is greater than the ambient temperature of T at
level 626 (is illustrated in element 630). The remaining steps of
the Electro-caloric cooling process, steps 640 and 645, are not
used and the process stops at step 635. Of course, like the
magnetic cooling process, the electric cooling process has
additional steps which offer cooling to cancer cells--for now, only
heating is desired.
Combined Magneto- and Electro-Caloric Effect in the Low Temperature
Hyperthermia System
[0178] FIG. 18 illustrates the use of a nano-particle 705 that is
susceptible to both Magneto-caloric 700 and Electro-caloric 701
Effects. When the nano-particle is located in the body and is not
in an electric field as illustrated in element 710 and not in a
magnetic field as illustrated in element 720, the ambient
temperature of level 735 (T) is realized. When the nano-particle is
illuminated by an electric field as illustrated in element 715 and
a magnetic field as illustrated in element 725, the corresponding
temperature rise in the nano-particle has two components, one from
the electric field nano-particle response as indicated by level 740
.DELTA.T.sub.Electric and the second from the magnetic field
response as indicated by level 745 .DELTA.T.sub.Magnetic. These two
responses create or enable a "doubling" of the temperature rise
over the ambient temperature. Both of these fields, magnetic and
electric, are DC in nature.
Curie Temperature
[0179] The Curie temperature of a material is the physical
temperature where the material transitions from a ferromagnetic
state to a paramagnetic state. Below the Curie temperature, the
material is ferromagnetic; above the Curie temperature, the
material is paramagnetic. This means that the magnetic dipoles or
spins of the atoms of the material go from an aligned, ordered
state (ferromagnetic) to a purely random state (paramagnetic) (in
the absence of an applied magnetic field). This effect is
reversible in certain materials as the material moves back and
forth across, or above and below, the Curie temperature.
[0180] Above the Curie temperature, the thermal energy overcomes
the ion magnetic moments resulting in disordered or random magnetic
dipoles (the spins) and the material is no longer ferromagnetic. It
is now paramagnetic. Paramagnetic materials, in absence of a
magnetic field, do not exhibit any magnetic effect. Paramagnetic
materials, even in the presence of a magnetic field, only have a
relatively small induced magnetization because of the difference
between the number of spins aligned with the applied field and the
number of spins aligned in the opposing direction.-Only a small
percentage of the total number of spins are oriented by the field
flux lines.
[0181] How does a nano-material behave when in a magnetic field
when the temperature is above the Curie point and it is now
paramagnetic? This depends on whether the magnetic field is AC or
DC. Below the Curie temperature, a ferromagnetic material in an
Alternating Current (AC) magnetic field results in nano-particle
heating. This is due to the "forced" alignment and re-alignment of
the magnetic dipole with the phase of the magnetic field; as the
phase changes with time (AC), the dipole attempts to re-align. This
creates heating in the ferromagnetic nano-particle. If this field
were DC, or a static magnetic field, no steady state heating
occurs.
[0182] Above the Curie temperature, the material is now
paramagnetic. This means the magnetic dipoles are random in the
nano-particle. When placed in a DC field, no steady state heating
occurs. When placed in an AC or Alternating Magnetic field, there
is only a small fraction of the magnetic dipoles or spins that are
affected, meaning the "induced" magnetization is low. This is
proportional (linear) to the applied field strength. Since the
magnetic dipole re-ordering is not anywhere near the magnitude of
the magnetic dipole re-ordering in a ferromagnetic particle in an
AC magnetic field, the heating of a paramagnetic material past its
Curie temperature is considerably less.
[0183] Some paramagnetic materials are also Magneto-caloric, but
only a few. Magneto-caloric materials are paramagnetic with special
behavior associated with being Magneto-caloric. This should not be
confused with materials that are hotter than their Curie
temperature and have now become paramagnetic. This particular
paramagnetic state is not Magneto-caloric.
[0184] Magnetic materials of a certain design exhibit a Curie
temperature effect wherein, after a certain magnetic field strength
is realized, the material (or nano-particle in this case) no longer
continues to heat. Paramagnetic materials, even in the presence of
a magnetic field, only have a relatively small induced
magnetization because of the difference between the number of spins
aligned with the applied field and the number of spins aligned in
the opposing direction is only a small percentage of the total
number of spins. The paramagnetic spins still align along the field
lines, but there are not that many that have to be flipped when the
field direction is reversed.
[0185] FIG. 19 illustrates the Curie temperature effect when
nano-particles are situated in a magnetic field, where elements 860
and 870 are illustrative of this process. Element 870 illustrates
that past the Curie temperature the spins of the magnetic material
of the nano-particles are not aligned and the domains are random in
nature. At 860, the dipoles are aligned even without an applied
magnetic field; and element 860 is meant to illustrate the effect
of adding a magnetic field. The temperature where this occurs is
material dependent and, thus, can be designed to occur at specific
temperatures, thereby offering a means to precisely control cancer
cell heating. As illustrated in element 805, a nano-particle is
shown which is susceptible to heating as a result of being exposed
to a magnetic field. As illustrated in element 810, the
nano-particle is not in the magnetic field (i.e., the field is
turned off) and the nano-particle temperature is stable with its
ambient surroundings as illustrated in element 830. For the
nano-particle that has been introduced into a cancer cell, this
temperature is approximately the ambient body temperature of
37.degree. C. (as illustrated in element 830). When a magnetic
field is applied as illustrated in element 820, the nano-particle
heats until the Curie temperature is reached wherein the heating
essentially stops. This is illustrated as level 850 in element 840.
The ambient temperature of level 845 is elevated to a new
temperature of level 850, which shows the temperature rise due to
the Curie temperature of the nano-particle material.
Thermal Response to Low Temperature Hyperthermia System
[0186] The Magneto-caloric Effect example discussed next has the
body temperature at 37.degree. C., the nano-particle at
44.5.degree. C., and having thermodynamic losses of 2.5.degree. C.
to produce the resultant temperature in the cancer cell of
42.degree. C. This value of 42.degree. C. resides in the Low
Temperature Hyperthermia range and is highly desirable for reasons
stated herein to include the minimization of the release of cancer
stem cells. Gadolinium has been shown to have a strong
Magneto-caloric Effect with 21.degree. C. of temperature change
starting at room temperature or around 21.degree. C. ( 70.degree.
F.). Gadolinium has been shown to support up to 60.degree. C. of
temperature change. In the Magneto-caloric example, the magnetic
nano-material rises 1.5.degree. C. per 3 kA/m of magnetic field. By
using the temperatures just discussed, we need 7.5.degree. C. of
temperature rise over ambient. This means that the magnetic field
needed is 15 kA/m, as shown in the following calculation:
(7.5.degree. C.* 3 kA/m)/1.5.degree. C.=15 kA/m
[0187] An Electro-caloric effect example is next with the same
temperature ranges as the magnetic example, where the temperature
here is a function of the electric field and the nano-particle
material. The target cancer cell temperature is 42.degree. C. and a
nano-particle exhibiting 2.degree. C. temperature rise per 0.75
kV/m electric field strength requires a total DC electric field
strength of 2.81 kV/m in order to realize the desired particle
temperature rise of 7.5.degree. C. as shown in the following
calculation:
(7.5.degree. C.*0.75 V/m)/2.0.degree. C.=2.81 kV/m
[0188] This raises the temperature of the nano-particle from an
ambient temperature of 37.degree. C. to 44.5.degree. C. less
2.5.degree. C. of loss to arrive at the target temperature of 42
.degree. C. for the cancer cells. An example Electro-caloric
material is a ferroelectric polymer which has up to 12.degree. C.
of temperature change at room temperature.
[0189] Last is an example to illustrate the Curie Temperature
process. At a temperature of 44.5.degree. C., it is desired to have
the nano-particle heating largely stop at the Curie point of
44.5.degree. C. The nano-material is selected to have this
temperature characteristic. Thus, for example, the magnetic field
strength (DC) may be raised to 25 kA/m, even though the Curie point
is reached with a magnetic field of 20 kA/m. This small overage of
field strength insures that the Curie point is reached for all
particles, and the target particle temperature of 44.5.degree. C.
is realized. The additional field strength from 20 to 25 kA/m does
not cause significant temperature rise above the Curie temperature
of 44.5.degree. C. Subtract 2.5.degree. C. of heat loss, and the
target cancer cell temp of 42.degree. C. is realized. Example Curie
temperatures for selected nano-particle materials include: chromium
bromide=37.degree. C.; europium oxide=77.degree. C.
[0190] Arrhenius Curve for Low Temperature Hyperthermia
[0191] It is important to stay in the 42.degree. C. to
42.25.degree. C. temperature range or cooler as shown in FIG. 10,
lines 1030. Note the cell death rate is very small for this Low
Temperature Hyperthermia range. At 42.degree. C., the probability
of cell death almost flattens out and is relatively independent of
time. In contrast, the cell death rate at 46.5.degree. C. is almost
vertical, meaning cell death occurs almost instantaneously. Thus,
in just a 4.5.degree. C. span, the cell death rate goes from
virtually zero to 100%. Thus, it is paramount that the cellular
temperature be tightly controlled-; and be targeted at 42.degree.
C. or less. Observe how dramatic the cell death rate is from
42.0.degree. C. to 43.0.degree. C. This underscores how important
tight temperature control is and, correspondingly, how critical the
particle design is in conjunction with the applied field strength.
Being off by even as much as 1.0.degree. C. causes this process to
fail. Thus, designing the temperature control largely into the
material properties of the nano-particle is the critical inventive
step necessary for success.
[0192] The Arrhenius curve is independent of whether the cells are
in vivo (in the body) or in vitro (in the glass). Thermodynamic
equations which describe the heat loss from the nano-particles,
whether the nano-particles are clumped in the cancer cell or
whether the nano-particles are evenly distributed in the cancer
cell, enable the incorporation of heat loss to determine the
optimal particle temperature. The physiological benefits of Low
Temperature Hyperthermia, primarily the minimization of the release
of cancer stem cells, require that the temperature range stay at
42.degree. C. and cooler. Certain conditions affect the positioning
of the Arrhenius curve and include acidification or step down
hyperthermia and post thermal tolerance induction. These also need
to be considered for a given patient treatment protocol.
[0193] Benefits of Low Temperature Hyperthermia
[0194] The benefits of Low Temperature Hyperthermia are realized
between the temperature range of 41.degree. C. to 41.5.degree. C.
in skin. The optimal temperature is different for different tissue
types, and this description has used the target temperature of
42.degree. C.; but in practice, this temperature could be anything
that is optimal for a given tissue type.
[0195] Of note, cancer cells can adapt to heat stress by becoming
thermo-tolerant. This is caused by the release of Heat Shock
Proteins. Thermo-tolerance tends to shift the Arrhenius curve down
and to the right, indicating higher temperatures are needed along
with greater times at that temperature to realize the same effect.
Thus, minimizing the level of Heat Shock Proteins reduces the level
of resistance to hyperthermia treatment. Low Temperature
Hyperthermia has a number of beneficial effects: it improves
perfusion where skin perfusion can be 10-fold while tumor perfusion
can be 1.5- to 2.0-fold. Increased blood vessel pore size is
realized, where both of these effects improve drug delivery
performance, such as via liposomes (lipid). Increased profusion and
blood vessel size also enhance re-oxygenation 1380, which is
critical since cancer stem cells prefer a hypoxic environment.
Thus, this helps kill cancer cells. Enzymes for aerobic metabolism
are more heat sensitive than those for anaerobic metabolism. Thus,
during Low Temperature Hyperthermia, there is a concomitant
reduction in tumor respiration. Respiration inhibition is caused by
this process. Minimizing the level of heat shock proteins is
important since cancer cells with Heat Shock Proteins are
relatively resistant to hyperthermia treatment. In addition, acute
acidification of cancer cells below their resting pH leads to
catastrophic cell death.
Summary
[0196] The Invasive Agent Treatment System provides the necessary
coordination among the characteristics of the nano-particles,
concentration of nano-particles, duration of treatment, and applied
fields to enable the generation of precisely crafted fields and
their application in a mode and manner to be effective with a high
degree of accuracy.
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