U.S. patent application number 12/363793 was filed with the patent office on 2009-05-28 for method of and system for selective cell destruction.
This patent application is currently assigned to Yeda Research And Development Co., Ltd.. Invention is credited to Dan Oron, Yaron SILBERBERG, Dvir Yelin.
Application Number | 20090137999 12/363793 |
Document ID | / |
Family ID | 32587669 |
Filed Date | 2009-05-28 |
United States Patent
Application |
20090137999 |
Kind Code |
A1 |
SILBERBERG; Yaron ; et
al. |
May 28, 2009 |
METHOD OF AND SYSTEM FOR SELECTIVE CELL DESTRUCTION
Abstract
Method and apparatus for the ionization of living cells where an
optical device (14) delivers an optical pulse having an optical
field power which is modified locally by an optical field power
modifying means (18) to effect ionization and destruction of living
cells (16).
Inventors: |
SILBERBERG; Yaron; (LeHavim,
IL) ; Yelin; Dvir; (Jerusalem, IL) ; Oron;
Dan; (Rechovot, IL) |
Correspondence
Address: |
MARTIN D. MOYNIHAN d/b/a PRTSI, INC.
P.O. BOX 16446
ARLINGTON
VA
22215
US
|
Assignee: |
Yeda Research And Development Co.,
Ltd.
Rehovot
IL
|
Family ID: |
32587669 |
Appl. No.: |
12/363793 |
Filed: |
February 2, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
10562001 |
May 1, 2006 |
7498565 |
|
|
PCT/IL2004/000491 |
Jun 9, 2004 |
|
|
|
12363793 |
|
|
|
|
Current U.S.
Class: |
606/15 ;
606/14 |
Current CPC
Class: |
A61B 18/22 20130101;
A61B 2018/00982 20130101; A61B 18/1482 20130101; A61B 18/20
20130101 |
Class at
Publication: |
606/15 ;
606/14 |
International
Class: |
A61B 18/18 20060101
A61B018/18 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 24, 2003 |
IL |
156626 |
Claims
1. A light transmitting device for directing light to living cells
present in a body of a subject, the device comprising: an optical
device for emitting at least one optical pulse having a duration in
a femtosecond time scale; and a waveguide for guiding said optical
pulses into a body of a subject; said waveguide having an emission
face, through which said optical pulses are emitted to the living
cells.
2. The light transmitting device of claim 1, wherein said optical
pulses are selected so as to destroy the cells via ionization.
3. The light transmitting device of claim 1, wherein said optical
pulses have a peak power which is below the ionization threshold of
the cells.
4. The light transmitting device claim 3, wherein the ionization
threshold is from about 10.sup.10 Watts/cm.sup.2 to about 10.sup.14
Watts/cm.sup.2.
5. The light transmitting device of claim 1, wherein said at least
one optical pulse is characterized by a peak power of from about
10.sup.5 Watts to about 10.sup.10 Watts.
6. The light transmitting device of claim 1, wherein said pulses
have a average-intensity which is below a heating damage threshold
of the living cells.
7. The light transmitting device of claim 6, wherein said
average-intensity is below 1 Watt/cm.sup.2.
8. The light transmitting device of claim 1, wherein said optical
pulses have a wavelength from about 400 nm to about 1300 nm.
9. The light transmitting device of claim 1, wherein said optical
pulses have a wavelength from about 800 nm to about 1300 nm.
10. The light transmitting device of claim 1, wherein said optical
pulses have a wavelength from about 400 nm to about 800 nm.
11. The light transmitting device of claim 1, wherein said
waveguide comprise a fiber optic bundle.
12. The light transmitting device of claim 1, further comprising a
lens for focusing a beam of said at least one optical pulse onto
the cells.
13. The light transmitting device of claim 1, wherein said
waveguide is sterile.
14. The light transmitting device of claim 1, wherein said
waveguide is covered by a disposable sterile coat.
15. The light transmitting device of claim 1, wherein said at least
one optical pulse is characterized by a repetition-rate from about
10 pulses per second to about 10.sup.10 pulses per second.
Description
RELATED APPLICATIONS
[0001] This application is a Divisional of U.S. patent application
Ser. No. 10/562,001, filed on May 1, 2006, which is a US National
Phase Patent Application of PCT Application No. PCT/IL2004/000491
having International Filing Date of Jun. 9, 2004, which claims the
benefit of Israel Patent Application No. 156626, filed on Jun. 24,
2003. The contents of the above Applications are all incorporated
herein by reference.
FIELD AND BACKGROUND OF THE INVENTION
[0002] The present invention relates to a method and system for
destruction of biological tissues and/or cells via selective
ionization and, more particularly, to a method of ionizing
biological tissues and/or cells using metallic nano-particles and
electromagnetic irradiation.
[0003] Cancer is a major cause of death in the modern world.
Effective treatment of cancer is most readily accomplished
following early detection of malignant tumors. Most techniques used
to treat cancer (other than chemotherapy) are directed against a
defined tumor site in an organ, such as brain, breast, ovary and
colon tumors, etc. When a mass of abnormal cells is consolidated
and is sufficiently large, either surgical removal, destruction of
the tumor mass using either heating, cooling, radiative or chemical
ablation becomes possible because the target is readily
identifiable and localizable. However, it is not uncommon for a
cancer that has initially occurred at a primary site to metastasize
and spread into adjacent organs as diffuse clusters of abnormal
cells. These small clusters of cells, which are more properly
referred to as microscopic diffuse metastatic deposits, are not
localizable and are virtually impossible to treat other than by
systemic chemotherapy or radiotherapy. Yet, because of the diverse
nature of cancer cells, only a portion of the metastatic abnormal
cells will likely be susceptible to chemotherapy or radiotherapy,
leaving abnormal cells that are resistant to the therapy to
multiply until the patient dies from the concomitant effects of the
malignant cells.
[0004] Recently, light and more specifically laser light has been
used for non-invasive detection as well as destruction of malignant
cells. Laser technology has found many applications in medicine and
biology including destruction of cells or tissues, e.g., for the
purpose of cancer treatment. Destruction of unwanted cells can be
achieved either through a direct interaction between the laser beam
and the tissue, or through activation of some photochemical
reactions using light-activated molecules which are injected into
or otherwise administered to the tissue.
[0005] Photo-dynamic therapy (PDT) is a relatively new approach for
treating many cancers. At the first step of treatment, one or more
drugs that bind to rapidly dividing cells are administered either
directly to a tissue or organ or systemically to the treated
subject. The drugs administered for PDT are commonly known as
photosensitizers due to their inherent ability to absorb photons of
light and transfer that energy to oxygen which then converts to a
cytotoxic or cytostatic species. Approximately 24-48 hours after
the injection, a narrow-band laser is used to excite the
photosensitive drug, inducing a chemical reaction which results in
a production of free radicals and/or other reactive products that
destroy the abnormal tissue or cell with relatively small damage to
the surrounding healthy tissue.
[0006] To date, POT has been used to treat esophageal cancer, early
stage lung cancer, Kaposi's sarcoma, an AIDS related condition,
atherosclerotic plaques, lesions of surface skin diseases,
overgrowth of blood vessels in the eye (macular degeneration) and
unwanted pathogens in the blood.
[0007] The effectiveness of the PDT process depends on the amount
of photosensitizer at the target, the absorption properties of the
environment neighboring the target and photosensitizer, and a
number of physiologic factors such as temperature, pH, oxygen
content, and the sensitivity of the target to the photosensitizer
generated reaction.
[0008] Known PDT techniques suffer from a number of drawbacks and
limitations. It is necessary to deliver a large amount of light
radiation to the tumor at specific wavelengths to activate the
photosensitive agent. Most photosensitive agents are activated at
wavelengths that can only penetrate through three or less
centimeters of tissue. Hence, non- or minimal-invasive PDT can be
used for cancerous growths that are on or near the surface of the
skin, or on the lining of internal organs.
[0009] Typical prior art PDT light delivery systems have used
monochromatic lasers in combination with fiber optic catheters, for
example by providing a monochromatic light to a fiber optic bundle,
which in turn transmits the light through a light diffuser to the
tumor. One disadvantage of such PDT delivery system is that a
typical fiber optic catheter transmits only about 30% to 50% of
available light energy. Additional energy losses occur in the
diffuser which surrounds the light-emitting end of the catheter and
diffuses the light emanating from the catheter. The blood and the
surrounding tissue also attenuate a substantial portion of the
input power. The net result is that only about 25% to 30% of the
power is available to activate the photosensitive agent. Besides
increasing the required size and cost of the light source, these
energy losses also reduce the effectiveness of the treatment since
the depth of radiation penetration into the tissue is reduced. With
reduced penetration, surgical techniques are required to remove
much of the malignant tissue before photodynamic therapy commences,
and the likelihood that all malignant tissue is destroyed is
lessened.
[0010] Another drawback of PDT techniques is that the
photosensitizing drug remains in the bloodstream for six weeks or
more, causing patients to be extremely light sensitive during that
time period.
[0011] The present invention provides solutions to the problems
associated with prior art cell destruction techniques.
SUMMARY OF THE INVENTION
[0012] According to one aspect of the present invention there is
provided a method of destroying living cells, the cells being
characterized by an ionization threshold, the method comprising:
providing at least one optical pulse having an optical field power
smaller than the ionization threshold of the cells; and generating
conditions for locally increasing the optical field power per unit
area beyond the ionization threshold of the cells, thereby
destroying the cells via ionization.
[0013] According to further features in preferred embodiments of
the invention described below, the generating conditions for
locally increasing the optical field power per unit area is by a
plurality of particles, at least a portion of each of the plurality
of particles is made of a conducting material.
[0014] According to another aspect of the present invention there
is provided a method of destroying living cells, the cells being
characterized by an ionization threshold, the method comprising:
administrating a plurality of particles to the cells, at least a
portion of each of the plurality of particles is made of a
conducting material; and directing at least one optical pulse
toward at least a portion of the cells; the particles and the at
least one optical pulse are selected and designed so as to provide
a local enhancement of an optical field to a power per unit area
which is beyond the ionization threshold of the cells, thereby
destroying the cells via ionization.
[0015] According to further features in preferred embodiments of
the invention described below, the method further comprising
focusing a beam of the at least one optical pulse, so as to
increase the optical field power per unit area.
[0016] According to still further features in the described
preferred embodiments the focusing is done by a converging
lens.
[0017] According to yet another aspect of the present invention
there is provided a system for destroying living cells, the cells
being characterized by an ionization threshold, the system
comprising: an optical device for providing at least one optical
pulse having an optical field power which is smaller than the
ionization threshold of the cells; and a mechanism for locally
increasing the optical field power per unit area beyond the
ionization threshold of the cells, thereby destroying the cells via
ionization.
[0018] According to further features in preferred embodiments of
the invention described below, the mechanism for locally increasing
the optical field power per unit area comprises a plurality of
particles, at least a portion of each of the plurality of particles
is made of a conducting material.
[0019] According to still further features in the described
preferred embodiments the system further comprising at least one
optical element for focusing a beam of the at least one optical
pulse, so as to increase the optical field power per unit area.
[0020] According to still another aspect of the present invention
there is provided an ablative procedure for destroying living cells
present in a body of a subject, the cells being characterized by an
ionization threshold, the ablative procedure comprising:
administrating a plurality of particles to the body of the subject,
at least a portion of each of the plurality of particles is made of
a conducting material; directing at least one optical pulse toward
at least a portion of the cells; the particles and the optical
pulses are selected and designed so as to provide a local
enhancement of an optical field to a power per unit area which is
beyond the ionization threshold of the cells, thereby destroying
the cells via ionization.
[0021] According to further features in preferred embodiments of
the invention described below, the directing at least one optical
pulse is by inserting a light transmitting device into the body of
the subject; and using the light transmitting device for
[0022] According to still further features in the described
preferred embodiments inserting the light transmitting device into
the body is by endoscopy.
[0023] According to still further features in the described
preferred embodiments inserting the light transmitting device into
the body is by laparoscopy.
[0024] According to an additional aspect of the present invention
there is provided a light transmitting device for destroying living
cells present in a body of a subject, the device comprising: an
optical device for emitting a at least one optical pulse having a
duration in a femtosecond time scale; and a waveguide for guiding
the optical pulses into a body of a subject; the waveguide having
an emission face, through which the optical pulses are emitted to
the living cells, thereby destroying the cells via ionization.
[0025] According to further features in preferred embodiments of
the invention described below, the waveguide comprise a fiber optic
bundle.
[0026] According to still further features in the described
preferred embodiments the waveguide is sterile.
[0027] According to still further features in the described
preferred embodiments the waveguide is covered by a disposable
sterile coat.
[0028] According to still further features in the described
preferred embodiments the cells form a part of an organ.
[0029] According to still further features in the described
preferred embodiments the cells form a part of a tumor.
[0030] According to still further features in the described
preferred embodiments the cells form a part of a malignant
tumor.
[0031] According to still further features in the described
preferred embodiments the cells form a part of a blood vessel.
[0032] According to still further features in the described
preferred embodiments the cells form a part of a pathological
tissue.
[0033] According to still further features in the described
preferred embodiments the cells form a part of a restenotic
tissue.
[0034] According to still further features in the described
preferred embodiments the ionization threshold is from about
10.sup.10 Watts/cm.sup.2 to about 10.sup.14 Watts/cm.sup.2.
[0035] According to still further features in the described
preferred embodiments the light transmitting device comprises a
fiber optic bundle.
[0036] According to still further features in the described
preferred embodiments a duration of the at least one optical pulse
is selected so as to avoid heating of the cells by linear
absorption.
[0037] According to still further features in the described
preferred embodiments the duration is in a femtoseconds time
scale.
[0038] According to still further features in the described
preferred embodiments a wavelength of the at least one optical
pulse is from about 400 nm to about 1300 nm.
[0039] According to still further features in the described
preferred embodiments a repetition-rate of the at least one optical
pulses is from a 10 pulses/second to about 10.sup.10
pulses/second.
[0040] According to still further features in the described
preferred embodiments the pulses having a high peak-power.
[0041] According to still further features in the described
preferred embodiments the pulses having a low
average-intensity.
[0042] According to still further features in the described
preferred embodiments the peak-power is below the ionization
threshold of the living cells.
[0043] According to still further features in the described
preferred embodiments the average-intensity is below a heating
damage threshold of the living cells.
[0044] According to still further features in the described
preferred embodiments the average-intensity is lower than 1
Watt/cm.sup.2.
[0045] According to still further features in the described
preferred embodiments the light transmitting device comprises at
least one optical element for focusing a beam of said at least one
optical pulse, so as to increase said optical field power per unit
area.
[0046] According to still further features in the described
preferred embodiments the at least one optical element is a
converging lens.
[0047] According to still further features in the described
preferred embodiments each of the plurality of particles comprises
an affinity component having affinity to the living cells.
[0048] According to still further features in the described
preferred embodiments a size of each of the plurality of particles
is from 1 nm to 200 nm.
[0049] According to still further features in the described
preferred embodiments the particles are biocompatible.
[0050] According to still further features in the described
preferred embodiments the particles are metallic particles.
[0051] According to still further features in the described
preferred embodiments the conducting material is comprised of at
least one metal selected from the group consisting of coinage
metals, noble metals, transition metals and synthetic metals.
[0052] According to still further features in the described
preferred embodiments the synthetic metals are selected from the
group consisting of polyacetylene and polyanaline.
[0053] According to still further features in the described
preferred embodiments the conducting material is gold.
[0054] According to still further features in the described
preferred embodiments the conducting material comprises a
metal-like material.
[0055] According to still further features in the described
preferred embodiments the conducting material comprises a metal
alloy.
[0056] According to still further features in the described
preferred embodiments the affinity component comprises a moiety
selected from the group consisting of an antibody, an antigen, a
ligand and a substrate.
[0057] According to still further features in the described
preferred embodiments the moiety is selected so as to ensure
attachment of the particles to a predetermined part of the cell,
which is selected from the group consisting of nucleus, nucleolus,
mitochondria, membrane, DNA, RNA, proteins, endoplasmic reticulum
and Golgi apparatus.
[0058] According to still further features in the described
preferred embodiments the particles comprise a conducting shell
layer characterized by a shell-thickness, having a first radius and
a second radius.
[0059] According to still further features in the described
preferred embodiments a ratio between the first radius and the
second radius is selected so as to obtain a predetermined
plasmon-resonance frequency of the particles.
[0060] According to still further features in the described
preferred embodiments the predetermined resonance frequency is a
near infrared resonance frequency.
[0061] According to still further features in the described
preferred embodiments the thickness is from 1 nm to 100 nm.
[0062] According to still further features in the described
preferred embodiments the conducting shell layer immediately
adjacent to and independently layered upon a non-conducting core
layer.
[0063] According to still further features in the described
preferred embodiments the non-conducting core layer comprises a
dielectric material.
[0064] According to still further features in the described
preferred embodiments the dielectric material is selected from the
group consisting of silicon dioxide, titanium dioxide, PMMA,
polystyrene, and dendrimers.
[0065] According to still further features in the described
preferred embodiments the non-conducting core layer comprises a
semi-conducting material.
[0066] According to still further features in the described
preferred embodiments the non-conducting core layer comprises at
least one molecule selected from the group consisting of an organic
molecule and an organic super-molecular structure.
[0067] According to still further features in the described
preferred embodiments the non-conducting core layer comprises a
mixture of non-conducting materials.
[0068] According to still further features in the described
preferred embodiments the non-conducting core layer comprises an
optically absorbing material.
[0069] According to still further features in the described
preferred embodiments the non-conducting core layer comprises a
fluorescent material.
[0070] According to still further features in the described
preferred embodiments the optical device has a peak-power from
about 10.sup.5 Watts to about 10.sup.10 Watts.
[0071] The present invention successfully addresses the
shortcomings of the presently known configurations by providing a
method and system for destroying living cells far exceeding prior
art.
BRIEF DESCRIPTION OF THE DRAWINGS
[0072] The invention is herein described, by way of example only,
with reference to the accompanying drawings. With specific
reference now to the drawings in detail, it is stressed that the
particulars shown are by way of example and for purposes of
illustrative discussion of the preferred embodiments of the present
invention only, and are presented in the cause of providing what is
believed to be the most useful and readily understood description
of the principles and conceptual aspects of the invention. In this
regard, no attempt is made to show structural details of the
invention in more detail than is necessary for a fundamental
understanding of the invention, the description taken with the
drawings making apparent to those skilled in the art how the
several forms of the invention may be embodied in practice.
[0073] In the drawings:
[0074] FIG. 1 is a system for destroying living cells, according to
the present invention; and
[0075] FIG. 2 is a nanoparticle captured in a cell, according to
the present invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0076] The present invention is of a method and a system for
destroying living cells by ionization, which can be used for
tissue/cell ablation. Specifically, the present invention can be
used to remove clusters of cells either by invasive or non-invasive
medical procedures.
[0077] The principles and operation of a method and a system for
destroying living cells according to the present invention may be
better understood with reference to the drawings and accompanying
descriptions.
[0078] Before explaining at least one embodiment of the invention
in detail, it is to be understood that the invention is not limited
in its application to the details of construction and the
arrangement of the components set forth in the following
description or illustrated in the drawings. The invention is
capable of other embodiments or of being practiced or carried out
in various ways. Also, it is to be understood that the phraseology
and terminology employed herein is for the purpose of description
and should not be regarded as limiting.
[0079] Referring now to the drawings, FIG. 1 illustrates a system
10 for destruction of living cells 12. According to the present
invention, cells 12 are characterized by an ionization threshold,
measurable in units of energy per time unit per area unit, e.g.,
Watts/cm.sup.2. Cells 12 may form any part of the human body, for
example, an organ or a part of an organ, e.g., a blood vessel or
part thereof, a tumor (malignant or benign) and any other
pathological tissue, e.g., a restenotic tissue. A typical
ionization threshold for cells 12 is, in terms of orders of
magnitude, from 10.sup.10 Watts/cm.sup.2 to 10.sup.14
Watts/cm.sup.2.
[0080] According to a preferred embodiment of the present invention
system 10 includes an optical device 14 for providing an optical
field power smaller than the ionization threshold and a mechanism
16 for locally increasing the optical field power per unit area
beyond the ionization threshold of the cells. The optical filed, as
provided by optical device 14 is in a form of at least one light
pulse (e.g., a sequence of laser pulses), the duration and the
repetition-rate of which are chosen so as to avoid heating of the
cells by linear absorption. A typical pulse duration is in a
femtoseconds time scale, e.g., about 10-100010.sup.-15 seconds.
[0081] As used herein, the term about refers to .+-.10%.
[0082] Optical device 14 provides a laser beam having a high
peak-power with a low average-intensity. According to a preferred
embodiment of the present invention, the peak-power of the laser is
below the ionization threshold and the average-intensity is below
the heating damage threshold for bodily tissues.
[0083] The desired peak and average intensities may be achieved in
more than one way. Hence, in one embodiment of the present
invention, device 14 may be provided as an amplified, low
repetition-rate femtosecond laser system having a peak-power of
about 10.sup.10 Watts. In another embodiment of the present
invention, device 14 may be a high repetition-rate femtosecond
laser system having a peak power of about 10.sup.5 Watts. It is to
be understood that in the latter embodiment the illuminated area
should be sufficiently small and the beam should be focused by at
least one optical element 18 to achieve high optical field power
per unit area at the cell. Optical element 18 may be any known
element for focusing (e.g. collimating) an optical beam, such as,
but not limited to a converging lens.
[0084] Typical repetition rates are from about 10 pulses/second for
a low repetition-rate laser system to about 10.sup.10 pulses/second
for a high repetition-rate femtosecond laser system. One ordinarily
skilled in the art would appreciate that a penetration depth of the
laser beam into the body depends on the wavelength of the optical
field. It is known that human tissues are relatively transparent to
light in the near-infrared region (NIR) of the spectrum. When deep
penetration is desired, a preferred wavelength of the laser beam is
from about 800 nm to about 1300 nm, however, shorter wavelengths
(e.g. 400 nm to 800 nm) may also be used, for abnormal cells
growths that are on or near the surface of the skin, or on the
lining of internal organs.
[0085] Unlike prior art teachings, where the power of the laser
beam is above the ionization threshold, optical device 14 provides
a pulse power which is below ionization threshold hence there is no
global cell destruction across the entire illumination area, along
its efficient penetration depth.
[0086] Mechanism 16 serves, according to the gist of the present
invention, for increasing the laser field beyond the ionization
threshold only within a limited volume where unwanted cells are
present. Thus, system 10 has the advantage of selectively
destroying unwanted cells by ionization, while leaving other
neighboring cells substantially undamaged.
[0087] According to a preferred embodiment of the present invention
mechanism 16 may be any mechanism capable of locally increasing the
optical field. Thus, for example, mechanism 16 may include a
plurality of particles, at least a portion of each of the particles
is made of a conducting material. Hence, the particles may be, for
example, metallic particles.
[0088] Each of the particles may also include an affinity
component, whereby the affinity component has affinity to the
living cells to be destroyed. The particles have a diameter which
is preferably from 1 nm to 200 nm, so as to allow a substantial
increment of the nearby optical field, which increment is larger
for smaller particles. The affinity component of the particles
ensures a short distance between the particles and the unwanted
cells, hence when the optical field is increased near the
particles, a selective destruction of the cells occurs. When
ionization occurs at a living cell, it is destroyed irrespectively
to the location at which the ionization is initiated. Thus, the
affinity of the particles may be selected so that the particles
will attach to any part of the cell, e.g., nucleus, nucleolus,
mitochondria, membrane, DNA, RNA, proteins and the like.
[0089] As used herein, the term nanoparticle refers to a particle
or particles of nano-meter size range, e.g., 1-20010.sup.-9 m.
[0090] The physical process of strong field enhancement very close
to metal nanoparticles is a well known phenomenon and has been
described in detail in the literature. To this end, see, for
example, R. H. Doremus and P. Rao, J. Mater. Res., 11, 2834 (1996);
M. Quinten, Appl Phys. B 73, 245 (2001) and R. D. Averitt, S. L.
Westcott and N. J. Halas, J. Opt. Soc. Am. B 16, 1824 (1999), the
contents of which are hereby incorporated by reference.
[0091] In metal nanoparticles, resonant collective oscillations of
conduction electrons, also known as particle plasmons, are excited
by an optical field. The resonance frequency of a particle plasmon
is determined mainly by the dielectric function of the metal, the
surrounding medium and by the shape of the particle. Resonance
leads to a narrow spectrally selective absorption and an
enhancement of the local field confined on and close to the surface
of the metal particle. The spectral width of absorption and
near-field enhancement depends on the decay time of the particle
plasmons.
[0092] When the laser wavelength is tuned to the plasmon resonance
frequency of the particle, the local electric field in proximity to
the nano-particles could be enhanced by several orders of
magnitude.
[0093] Reference is now made to FIG. 2, which illustrates a
nanoparticle 22 which is captured by one of living cells 12.
Nanoparticle 22 includes affinity component 26, which specifically
attaches nanoparticle 22 to cell 12. Cell 12 and nanoparticle 22
are illuminated by laser beam 28. The optical field of beam 28 is
increased in a volume 24 neighboring nanoparticle 22.
[0094] When the optical field interacts with atoms or molecules
present in volume 24, the electrons are oscillating due to the
force exerts by the field oscillations. When the field power per
unit area reaches above the ionization threshold, the electrons
detach from the atoms. The free electrons that are formed after the
initial ionization are accelerated by the optical field and
interact with other molecules, leading to the creation of local
damage. Because the pulse power of laser beam 28 is below the
ionization threshold of cells 12, the damage is constrained only to
volume 24.
[0095] The structure size and shape of the nanoparticles are
designed in accordance with the specific application for which
system 10 is used. Specifically, the size of the nanoparticles is
selected so that the resonance frequency of the nanoparticles and
the frequency of the optical pulses substantially coincide. Hence,
in preferred embodiments in which the pulses are of short
wavelengths (e.g., 400-800 nm for near-skin treatments), the
nanoparticles are about 1-50 nm in diameter. Longer wavelengths
(e.g., near infrared), which allow deep penetration depth of the
optical pulses into the body, require larger nanoparticles, about
100-200 nm in diameter.
[0096] It is often desired to further minimize the nanoparticles
size, for example, to enhance the effect of optical field increment
or to allow the nanoparticles to penetrate into the cells. This may
be done, by providing nanoparticles which include a dielectric core
and a conducting shall layer. Nanoparticles having such structure
are called nanoshells. Although nanoshells are especially useful in
cases of near infrared wavelengths applications, they may also be
used for short wavelengths applications.
[0097] The process of manufacturing nanoshells having a dielectric
core and a conducting shell, is known in the art and is described
in, for example, WO 01/06257 and WO 02/28552, the contents of which
are hereby incorporated by reference.
[0098] For any given core and shell materials, the ratio between
the core radius and the total radius of nanoshells can be chosen
for maximum scattering and minimum absorption at a specific
resonance frequency. Based on the core to total radii ratios, the
nanoshells manifesting plasmon resonances extending from
ultraviolet to infrared can be readily fabricated. Hence, the core
diameters of the nanoshells may range from about 1 nm to about 400
nm or more, and the shell thickness may range from about 1 nm to
about 100 nm. For a near infrared light, the total diameter of the
nanoshells may be reduced down to 20 nm.
[0099] According to a preferred embodiment of the present invention
the non-conducting core layer may be, for example, a
semi-conducting material, an organic molecule, an organic
super-molecular structure, or any mixture of non-conducting
materials. Optionally, the non-conducting core layer may include an
optically absorbing material, and/or a fluorescent material.
[0100] According to another aspect of the invention there is
provided a method of destroying living cells, characterized by an
ionization threshold. The method comprises the following steps
which may be executed using an appropriate system, device or
apparatus, e.g., system 10, as described hereinabove. Hence, at
least one optical light pulse is provided, having an optical field
power smaller than the ionization threshold of the cells, while
generating conditions for locally increasing the optical field
power per unit area beyond the ionization threshold of the cells.
Hence the cells are destroyed via ionization. The conditions for
locally increasing the optical field may be generated, for example,
by administrating particles such as, e.g., nanoparticles 22 to the
cells, as is further detailed hereinabove.
[0101] According to an additional aspect of the invention there is
provided a light transmitting device for destroying living cells
present in a body of a subject. The device may be used, e.g., by
system 10, as optical device 14 (FIG. 1). According to a preferred
embodiment of the present invention the device includes an optical
device for emitting at least one optical pulse having a duration
which is preferably in a femtosecond time scale. The device further
includes a waveguide, e.g., fiber optic bundle, for guiding the
optical pulses into a body of a subject. The waveguide having an
emission face, through which the optical pulses are emitted to the
living cells, hence the cells are destroyed as detailed above. The
device may be used either in an invasive medical procedure or in
non-invasive medical procedure. In any case, the waveguide is
preferably sterile. The sterilization of the waveguide may be, for
example by a disposable sterile coat, which covers at least a
portion of the waveguide.
[0102] The present invention successfully provides an ablative
procedure for destroying living cells present in a body of a
subject. The ablative procedure includes the following steps, which
may be executed, for example, using system 10. In a first step of
the procedure a plurality of particles are administrated to the
body of the subject. The particles are similar to the nanoparticles
described hereinabove. In a second step, at least one optical pulse
is directed toward at least a portion of the cells.
[0103] According to a preferred embodiment of the present invention
the second step may be done by a light transmitting device which
may inserted into the body of the subject. The light transmitting
device may be any device known in the art for transmitting, e.g., a
laser beam, e.g., a fiber optic bundle. In a third step of the
procedure the light transmitting device is used for.
[0104] Similarly to the above embodiments, the particles and the
pulse (or pulses) are selected and designed so as to provide a
local enhancement of an optical field to a power per unit area
which is beyond the ionization threshold of the cells, thereby
destroying the cells via ionization.
[0105] According to a preferred embodiment of the present invention
the light transmitting device is inserted into the body by either
endoscopy or laparoscopy. In addition, the ablation procedure may
be executed in parallel to another surgical procedure, while the
unwanted cells of the subject are exposed.
[0106] Suitable metals for forming the metallic nanoparticles or
the outer layer of the nanoshells include the noble and coinage
metals, but other electrically conductive metals may also be
employed. Metals that are particularly well suited for use in
shells include but are not limited to gold, silver, copper,
platinum, palladium, lead, iron or the like. Gold and silver are
preferred. Alloys or non-homogenous mixtures of such metals may
also be used.
[0107] Gold nanoparticles are suitable markers in biotechnological
systems because specific activities of micro-molecules can be
retained when coupling micro-molecules to gold nanoparticles. In
addition, gold nanoparticles can be easily visualized by electron
microscopy. Since gold is inert, gold nano-particles are highly
biocompatible.
[0108] Suitable dielectric core materials of the nanoshells used in
the present invention include, but are not limited to, silicon
dioxide, goldsulfide, titanium dioxide, polymethyl methacrylate
(PMMA), polystyrene, andmacromolecules such as dendrimers. The core
of the nanoparticle may also be a combination or a layered
combination of dielectric materials such as those listed above.
[0109] According to a preferred embodiment of the present invention
the living cells may form a part of a tumor. Typical tumors
include, but are not limited to, breast tumor, brain tumor,
neuroblastoma, thyroid gland tumor, gestational trophoblastic
tumor, uterine sarcoma, carcinoid tumor, colon carcinoma,
esophageal carcinoma, hepatocellular carcinoma, liver carcinoma,
lymphoma, plasma cell neoplasm, mesothelioma, thymoma, alveolar
soft-part sarcoma, angiosarcoma, epithelioid sarcoma, extraskeletal
chondrosarcoma, fibrosarcoma, leiomyosarcoma, liposarcoma,
malignant fibrous histiocytoma, malignant hemangiopericytoma,
malignant mesenchymoma, malignant schwannoma, synovial sarcoma,
melanoma, neuroepithelioma, osteosarcoma, leiomyosarcoma, Ewing
sarcoma, osteosarcoma, rhabdomyo-sarcoma, hemangiocytoma,
myxosarcoma, mesothelioma (e.g., lung mesothelioma), granulosa cell
tumor, thecoma cell tumor and Sertoli-Leydig tumor.
[0110] Hence, the present invention can be used to treat many types
of cancers, such as, but not limited to, vaginal cancer, vulvar
cancer, cervical cancer, endometrial cancer, ovarian cancer, rectal
cancer, salivary gland cancer, laryngeal cancer, nasopharyngeal
cancer, many lung metastases and acute or chronic leukemia (e.g.,
lymphocytic, Myeloid, hairy cell).
[0111] According to a preferred embodiment of the present
invention, the affinity component of the nanoparticles includes a
moiety which may be, for example an antibody, an antigen, a ligand
or a substrate. The techniques of attaching proteins and other
chemicals, to the surfaces of metal nanoparticles, are well known
in the art. To this end, see, e.g., C. Zhang et al., Anal. Chem.
74, 96 (2002); J. Ni et. al. Anal. Chem. 71, 4903 (1999); L. Lyon,
et al, Anal. Chem. 70, 5177 (1998), the contents of which are
hereby incorporated by reference.
[0112] The following lists some primary antibodies known to
specifically bind their associated cytological markers and which
are presently employed as affinity components in
immunohistochemical stains used for research and, in limited cases,
for diagnosis and therapy of various diseases. Anti-estrogen
receptor antibody (breast cancer), anti-progesterone receptor
antibody (breast cancer), anti-p53 antibody (multiple cancers),
anti-Her-2/neu antibody (multiple cancers), anti-EGFR antibody
(epidermal growth factor, multiple cancers), anti-cathepsin D
antibody (breast and other cancers), anti-Bcl-2 antibody (apoptotic
cells), anti-E-cadherin antibody, anti-CA125 antibody (ovarian and
other cancers), anti-CA15-3 antibody (breast cancer), anti-CA19-9
antibody (colon cancer), anti-c-erbB-2 antibody,
anti-P-glycoprotein antibody (MDR, multi-drug resistance), anti-CEA
antibody (carcinoembryonic antigen), anti-retinoblastoma protein
(Rb) antibody, anti-ras oncoprotein (p21) antibody, anti-Lewis X
(also called CD15) antibody, anti-Ki-67 antibody (cellular
proliferation), anti-PCNA (multiple cancers) antibody, anti-CD3
antibody (T-cells), anti-CD4 antibody (helper T cells), anti-CD5
antibody (T cells), anti-CD7 antibody (thymocytes, immature T
cells, NK killer cells), anti-CD8 antibody (suppressor T cells),
anti-CD9/p24 antibody (ALL), anti-CD10 (also called CALLA) antibody
(common acute lymphoblasic leukemia), anti-CD11c antibody
(Monocytes, granulocytes, AML), anti-CD13 antibody (myelomonocytic
cells, AML), anti-CD14 antibody (mature monocytes, granulocytes),
anti-CD15 antibody (Hodgkin's disease), anti-CD19 antibody (B
cells), anti-CD20 antibody (B cells), anti-CD22 antibody (B cells),
anti-CD23 antibody (activated B cells, CLL), anti-CD30 antibody
(activated T and B cells, Hodgkin's disease), anti-CD31 antibody
(angiogenesis marker), anti-CD33 antibody (myeloid cells, AML),
anti-CD34 antibody (endothelial stem cells, stromal tumors),
anti-CD35 antibody (dendritic cells), anti-CD38 antibody (plasma
cells, activated T, B, and myeloid cells), anti-CD41 antibody
(platelets, megakaryocytes), anti-LCA/CD45 antibody (leukocyte
common antigen), anti-CD45RO antibody (helper, inducer T cells),
anti-CD45RA antibody (B cells), anti-CD39, CD100 antibody,
anti-CD95/Fas antibody (apoptosis), anti-CD99 antibody (Ewings
Sarcoma marker, MIC2 gene product), anti-CD106 antibody (VCAM-1;
activated endothelial cells), anti-ubiquitin antibody (Alzheimer's
disease), anti-CD71 (transferrin receptor) antibody, anti-c-myc
(oncoprotein and a hapten) antibody, anti-cytokeratins (transferrin
receptor) antibody, anti-vimentins (endothelial cells) antibody (B
and T cells), anti-HPV proteins (human papillomavirus) antibody,
anti-kappa light chains antibody (B cell), anti-lambda light chains
antibody (B cell), anti-melanosomes (HMB45) antibody (melanoma),
anti-prostate specific antigen (PSA) antibody (prostate cancer),
anti-S-100 antibody (melanoma, salvary, glial cells), anti-tau
antigen antibody (Alzheimer's disease), anti-fibrin antibody
(epithelial cells), anti-keratins antibody, and anti-Tn-antigen
antibody (colon carcinoma, adenocarcinomas, and pancreatic
cancer).
[0113] It is appreciated that certain features of the invention,
which are, for clarity, described in the context of separate
embodiments, may also be provided in combination in a single
embodiment. Conversely, various features of the invention, which
are, for brevity, described in the context of a single embodiment,
may also be provided separately or in any suitable
subcombination.
[0114] Although the invention has been described in conjunction
with specific embodiments thereof, it is evident that many
alternatives, modifications and variations will be apparent to
those skilled in the art. Accordingly, it is intended to embrace
all such alternatives, modifications and variations that fall
within the spirit and broad scope of the appended claims. All
publications, patents and patent applications mentioned in this
specification are herein incorporated in their entirety by
reference into the specification, to the same extent as if each
individual publication, patent or patent application was
specifically and individually indicated to be incorporated herein
by reference. In addition, citation or identification of any
reference in this application shall not be construed as an
admission that such reference is available as prior art to the
present invention.
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