U.S. patent application number 11/115740 was filed with the patent office on 2005-09-08 for energy-activated targeted cancer therapy.
Invention is credited to Chen, James.
Application Number | 20050196401 11/115740 |
Document ID | / |
Family ID | 40418902 |
Filed Date | 2005-09-08 |
United States Patent
Application |
20050196401 |
Kind Code |
A1 |
Chen, James |
September 8, 2005 |
Energy-activated targeted cancer therapy
Abstract
The present invention is drawn to delivery systems for
administering a therapy to a target tissue or target composition in
a mammalian subject, using an ultrasonic energy-activated targeted
agent. The claimed energy-activated targeted therapy is useful in
the treatment of specifically selected target tissues, such as
vascular endothelial tissue, the abnormal vascular walls of tumors,
solid tumors of the head and neck, tumors of the gastrointestinal
tract, tumors of the liver, tumors of the breast, tumors of the
prostate, tumors of the lung, nonsolid tumors, malignant cells of
the hematopoietic and lymphoid tissue and other lesions in the
vascular system or bone marrow, and tissue or cells related to
autoimmune and inflammatory disease.
Inventors: |
Chen, James; (Bellevue,
WA) |
Correspondence
Address: |
Stephanie Seidman
FISH & RICHARDSON P.C.
12390 El Camino Real
San Diego
CA
92130-2081
US
|
Family ID: |
40418902 |
Appl. No.: |
11/115740 |
Filed: |
April 26, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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11115740 |
Apr 26, 2005 |
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10317269 |
Dec 10, 2002 |
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10317269 |
Dec 10, 2002 |
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09271575 |
Mar 18, 1999 |
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6602274 |
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60116234 |
Jan 15, 1999 |
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Current U.S.
Class: |
424/155.1 ;
604/20 |
Current CPC
Class: |
A61K 47/6849 20170801;
A61K 41/0057 20130101; A61N 5/062 20130101; A61P 9/10 20180101;
A61K 47/6835 20170801; A61K 47/6867 20170801; A61P 9/14 20180101;
A61P 35/00 20180101; A61P 35/02 20180101; A61K 41/0061 20130101;
A61P 29/00 20180101; A61P 9/00 20180101; A61P 7/00 20180101; A61K
41/0071 20130101; A61P 37/00 20180101; A61K 47/6817 20170801 |
Class at
Publication: |
424/155.1 ;
604/020 |
International
Class: |
A61K 039/395; A61N
001/30 |
Claims
What is claimed:
1. An ultrasonic energy-activated targeted delivery system that is
selectively targeted to a target tissue, comprising: (a) an
ultrasonic energy-activated agent that absorbs energy and destroys
a target tissue to which it is bound; and (b) a ligand conjugated
to the ultrasonic energy-activated agent, the ligand binding to a
receptor on the target tissue with specificity, so that binding of
the ligand to a non-target tissue is minimized.
2. The delivery system of claim 1, wherein the energy-activated
agent comprises a prodrug.
3. The delivery system of claim 1, wherein the ligand comprises an
antibody that binds to the receptor.
4. The delivery system of claim 1, wherein the receptor is selected
from the group consisting of a vascular endothelium antigen, an
antigen that is specific for an abnormal vascular wall of a tumor
and an antigen that is specific for a non-vascular tumor
tissue.
5. The delivery system of claim 1, wherein the ligand is selected
from the group consisting of a target-specific antibody, a
target-specific antibody fragment, a target-specific peptide and a
target-specific polymer.
6. The delivery system of claim 1, wherein the ligand and the
receptor comprise a binding pair selected from the group consisting
of a biotin-streptavidin, a chemokine-chemokine receptor, a growth
factor-growth factor receptor and an antigen-antibody.
7. The delivery system of claim 1, wherein the ligand is a
target-specific antibody specific to an antigen selected from the
group consisting of tumor surface antigen, tumor endothelial
antigen, non-tumor endothelial antigen and tumor vessel wall
antigen.
8. The delivery system of claim 1, wherein the target tissue is
selected from the group consisting of a vascular endothelial
tissue, an abnormal vascular wall of a tumor, a solid tumor in one
of the head, the neck, the gastrointestinal tract, the liver, the
breast, the prostate, and the lung, a nonsolid tumor, malignant
cells in hematopoietic tissue, malignant cells in lymphoid tissue,
lesions in a vascular system, diseased bone marrow, cells afflicted
by an autoimmune disease and cells afflicted with an inflammatory
disease.
9. The delivery system of claim 1, wherein the agent is selected
from the group consisting of indocyanine green, methylene blue,
toluidine blue, aminolevulinic acid, phthalocyanines, porphyrins,
purpurins, texaphyrins, chlorins, bacteriochlorins, merocyanines,
psoralens, benzoporphyrin derivatives (BPD), porfimer sodium and
protoporphyrin IX.
10. The delivery system of claim 1, wherein the agent is selected
from the group consisting of a gallium-porphyrin complex,
protoporphyrin, hematoporphyrin, daunorubicin and adriamycin.
11. An ultrasonic energy-activated targeted delivery system,
comprising: (a) an ultrasonic energy-activated agent that absorbs
energy and destroys a target tissue to which it is bound; (b) a
liposome delivery system; and (b) a ligand that binds to a receptor
on a target tissue with specificity; wherein the ligand is
separately conjugated to the ultrasonic energy-activated agent and
to the liposomes of the liposome delivery system to provide dual
targeting of the agent to the target tissue.
12. The delivery system of claim 11, wherein the energy-activated
agent comprises a prodrug.
13. The delivery system of claim 11, wherein the ligand comprises
an antibody that binds to the receptor.
14. The delivery system of claim 11, wherein the receptor is
selected from the group consisting of a vascular endothelium
antigen, an antigen that is specific for an abnormal vascular wall
of a tumor and an antigen that is specific for a non-vascular tumor
tissue.
15. The delivery system of claim 11, wherein the ligand is selected
from the group consisting of a target-specific antibody, a
target-specific antibody fragment, a target-specific peptide and a
target-specific polymer.
16. The delivery system of claim 11, wherein the ligand and the
receptor comprise a binding pair selected from the group consisting
of a biotin-streptavidin, a chemokine-chemokine receptor, a growth
factor-growth factor receptor and an antigen-antibody.
17. The delivery system of claim 11, wherein the ligand is a
target-specific antibody specific to an antigen selected from the
group consisting of tumor surface antigen, tumor endothelial
antigen, non-tumor endothelial antigen and tumor vessel wall
antigen.
18. The delivery system of claim 11, wherein the target tissue is
selected from the group consisting of a vascular endothelial
tissue, an abnormal vascular wall of a tumor, a solid tumor in one
of the head, the neck, the gastrointestinal tract, the liver, the
breast, the prostate, and the lung, a nonsolid tumor, malignant
cells in hematopoietic tissue, malignant cells in lymphoid tissue,
lesions in a vascular system, diseased bone marrow, cells afflicted
by an autoimmune disease and cells afflicted with an inflammatory
disease.
19. The delivery system of claim 11, wherein the agent is selected
from the group consisting of indocyanine green, methylene blue,
toluidine blue, aminolevulinic acid, phthalocyanines, porphyrins,
purpurins, texaphyrins, chlorins, bacteriochlorins, merocyanines,
psoralens, benzoporphyrin derivatives (BPD), porfimer sodium and
protoporphyrin IX.
20. The delivery system of claim 11, wherein the agent is selected
from the group consisting of a gallium-porphyrin complex,
protoporphyrin, hematoporphyrin, daunorubicin and adriamycin.
Description
RELATED APPLICATIONS
[0001] This application is a divisional application of copending
U.S. patent application Ser. No. 10/317,269, filed Dec. 10, 2002,
to James Chen, entitled "ENERGY-ACTIVATED TARGETED CANCER THERAPY,"
which is a divisional application of U.S. patent application Ser.
No. 09/271,575, now U.S. Pat. No. 6,602,274, to James Chen,
entitled "TARGETED TRANSCUTANEOUS CANCER THERAPY," which claims
benefit of priority under 35 U.S.C. .sctn.119(e) to U.S.
provisional application Ser. No. 60/116,234 to James Chen, filed
Jan. 15, 1999, entitled "TARGETED TRANSCUTANEOUS CANCER THERAPY,"
and each of the above-noted applications and provisional
application are incorporated by reference in their entirety
herein.
FIELD OF THE INVENTION
[0002] This invention generally relates to the delivery to a tumor
target site of a therapeutically effective amount of a
photosensitizing agent that is activated by a relatively low
fluence rate or level of intensity of light administered over a
prolonged period of time, and more specifically, to the delivery of
a photosensitizing agent that is targeted to bind with cancerous
cells at the target site.
BACKGROUND OF THE INVENTION
[0003] One form of energy activated therapy for destroying abnormal
or diseased tissue is photodynamic therapy (PDT). PDT is a two-step
treatment process, which has received increasing interest as a mode
of treatment for a wide variety of different cancers and diseased
tissue. The first step in this therapy is carried out by
administering a photosensitive compound systemically by ingestion
or injection, or topically applying the compound to a specific
treatment site on a patient's body, followed by illumination of the
treatment site with light having a wavelength or waveband
corresponding to a characteristic absorption waveband of the
photosensitizer. The light activates the photosensitizing compound,
causing singlet oxygen radicals and other reactive species to be
generated, leading to a number of biological effects that destroy
the abnormal or diseased tissue, which has absorbed the
photosensitizing compound. The depth and volume of the cytotoxic
effect on the abnormal tissue, such as a cancerous tumor, depend in
part on the depth of the light penetration into the tissue; the
photosensitizer concentration and its cellular distribution, and
the availability of molecular oxygen which will depend upon the
vasculature system supplying the abnormal tissue or tumor.
[0004] Various types of PDT light sources and their methods of use
have been described in the prior art literature. However,
publications describing appropriate light sources and the effects
of transcutaneous light delivery to internal treatment sites within
a patient's body, for PDT purposes, are relatively limited in
number. It has generally been accepted that the ability of a light
source external to the body to cause clinically useful cytotoxicity
during PDT is limited in depth to a range of 1-2 cm or less,
depending on the photosensitizer.
[0005] Treatment of superficial tumors in this manner has been
associated with inadvertent skin damage due to accumulation of the
photosensitizer in normal skin tissue, which is a property of all
systemically administered photosensitizers in clinical use. For
example, clinically useful porphyrins such as PHOTOPHRIN.TM. (a
QLT, Ltd. brand of sodium porfimer) are associated with general
dermal photosensitivity lasting up to six weeks. PURLYTIN.TM.,
which is a brand of purpurin, and FOSCAN.TM., which is brand of
chlorin, sensitize the skin to light for at least several weeks, so
that patients to whom these drugs are administered must avoid
exposure to sunlight or other bright light sources during this time
to avoid unintended phototoxic effects on the normal dermal tissue.
Indeed, efforts have been made to develop photoprotectants to
reduce skin photosensitivity (see, for example: Dillon et al,
"Photochemistry and Photobiology," 48(2): 235-238 (1988); and
Sigdestad et al., British J. of Cancer, 74:S89-S92, (1996)).
[0006] Recently, it has been reported that a relatively intense
external laser light source might be employed transcutaneously to
cause two-photon absorption by a photosensitizer at a greater depth
within a patient's body, so that it is theoretically possible to
cause a very limited volume of cytotoxicity in diseased tissue at
greater depths than previously believed possible. However, no
clinical studies exist to support this contention. One would expect
that the passage of an intense beam of light through the skin would
lead to the same risk of phototoxic injury to non-target normal
tissues, such as skin and subcutaneous normal tissue, if this light
is applied in conjunction with a systemically administered
photosensitizer.
[0007] For example, one PDT modality discloses the use of an
intense laser source to activate a photosensitizer drug within a
precisely defined boundary (see U.S. Pat. No. 5,829,448, Fisher et
al., "Method for improved selectivity in photo-activation of
molecular agents"). The two-photon methodology requires a high
power, high intensity laser for drug activation using a highly
collimated beam, with a high degree of spatial control. For a large
tumor, this treatment is not practical, since the beam would have
to be swept across the skin surface in some sort of set, repeating
pattern, so that the beam encompasses the entire volume of the
tumor. Patient or organ movement would be a problem, because the
beam could become misaligned. Exposure of normal tissue or skin in
the path of the beam and subcutaneous tissue photosensitivity is
not addressed in the prior art literature.
[0008] Any photosensitizer absorbed by normal tissue in the path of
the beam will likely be activated and cause unwanted collateral
normal tissue damage. Clearly, it would be preferable to employ a
technique that minimizes the risk of damage to normal tissue and
which does not depend upon a high intensity laser light source to
produce two photon effects. Further, it would be preferable to
provide a prolonged exposure of an internal treatment site with
light at a lower fluence rate or lower intensity, which tends to
reduce the risk of harm to non-target tissue or skin and
subcutaneous normal tissue and reduces any collateral tissue damage
due to phototoxicity.
[0009] Other PDT modalities have employed the use of a light source
producing a low total fluence delivered over a short time period to
avoid harm to skin caused by activation of a photosensitizer and
have timed the administration of such drugs to better facilitate
destruction of small tumors in animals (see, for example, U.S. Pat.
No. 5,705,518, Richter et al.). However, although not taught or
suggested by the prior art, it would be preferable to employ a
light source that enables a relatively large total fluence PDT, but
at a lower intensity so that larger tumor volumes can more readily
be treated.
[0010] If, as is often the case, a target tumor tissue lies below
an intact cutaneous layer of normal tissue, the main drawbacks of
all transcutaneous illumination methods, whether they be external
laser or external non-laser light sources, are: (1) the risk of
damage to non-target tissues, such as the more superficial
cutaneous and subcutaneous tissues overlying the target tumor mass;
(2) the limited volume of a tumor that can be treated; and (3) the
limitation of treatment depth. Damage to normal tissue lying
between the light source and the target tissue in a tumor occurs
due to the uptake of photosensitizer by the skin and other tissues
overlying the tumor mass, and the resulting undesired
photoactivation of the photosensitizer absorbed by these tissues.
The consequences of inadvertent skin damage caused by
transcutaneous light delivery to a subcutaneous tumor may include
severe pain, serious infection, and fistula formation. The limited
volume of tumor that can be clinically treated and the limitations
of the light penetration below the skin surface in turn have led
those skilled in this art to conclude that clinical transcutaneous
PDT is only suitable for treatment of superficial, thin
lesions.
[0011] U.S. Pat. No. 5,445,608, Chen et al., discloses the use of
implanted light sources for internally administering PDT.
Typically, the treatment of any internal cancerous lesions with PDT
requires at least a minimally invasive procedure such as an
endoscopic technique, for positioning the light source proximate to
the tumor, or open surgery to expose the tumor site. There is some
risk associated with any internal procedure performed on the body.
Clearly, there would be significant advantage to a completely
noninvasive form of PDT directed to subcutaneous and deep tumors,
which avoids the inadvertent activation of any photosensitizer in
skin and intervening tissues. To date, this capability has not been
clinically demonstrated nor realized. Only in animal studies
utilizing mice or other rodents with very thin cutaneous tissue
layers have very small superficial subcutaneous tumors been treated
with transcutaneously transmitted light. These minimal in vivo
studies do not provide an enabling disclosure or even suggest how
transcutaneous light sources might safely be used to treat large
tumors in humans with PDT, however.
[0012] Another PDT modality in the prior art teaches the
destruction of abnormal cells that are circulating in the blood
using light therapy, while leaving the blood vessels intact (see,
for example: U.S. Pat. No. 5,736,563, Richter et al.; WO 94/06424,
Richter; WO 93/00005, Champan et al.; U.S. Pat. No. 5,484,803,
Richter et al., and WO 93/24127, North et al.). Instead, it might
be preferable to deliberately damage and occlude blood vessels that
form the vasculature supplying nutrients and oxygen to a tumor
mass, thus rendering a given volume of abnormal tissue in the tumor
(not circulating cells) ischemic and anoxic and thus promoting the
death of the tumor tissue serviced by these blood vessels.
[0013] To facilitate the selective destruction of the blood vessels
that service a tumor, it would be desirable to selectively bind a
photosensitizing agent to specific target tissue antigens, such as
those found on the epithelial cells comprising tumor blood vessels.
This targeting scheme should decrease the amount of
photosensitizing drug required for effective PDT, which in turn
should reduce the total light energy, and the light intensity
needed for effective photoactivation of the drug. Even if only a
portion of a blood vessel is occluded as a result of the PDT,
downstream thrombosis is likely to occur, leading to a much greater
volume of tumor necrosis compared to a direct cytotoxic method of
destroying the tumor cells, in which the photosensitizer drug must
be delivered to all abnormal cells that are to be destroyed.
[0014] One method of ensuring highly specific uptake of a
photosensitizer by epithelial cells in tumor vessels would be to
use the avidin-biotin targeting system. Highly specific binding of
a targeted agent such as a PDT drug to tumor blood vessels (but not
to the cells in normal blood vessels) is enabled by this two step
system. While there are reports in the scientific literature
describing the binding between biotin and streptavidin to target
tumor cells, there are no reports of using this ligand-receptor
binding pair to bind with cells in tumor vessels nor in conjunction
with carrying out prolonged PDT light exposure (see, for example:
Savitsky et al., SPIE, 3191:343-353, (1997); and Ruebneretal.,
SPIE, 2625:328-332, (1996)). In a non-PDT modality, the
biotin-streptavidin ligand-receptor binding pair has also been
reported as useful in binding tumor targeting conjugates with
radionuclides (see U.S. Pat. No. 5,630,996, Reno et al.) and with
monoclonal antibodies (see Casalini et al.; J Nuclear Med,
38(9):1378-1381, (1997)) and U.S. Pat. No. 5,482,698,
Griffiths).
[0015] Other ligand-receptor binding pairs have been used in PDT
for targeting tumor antigens, but the prior art fails to teach
their use in conjunction with targeting cells in blood vessels or
treatment of large, established tumors (see, for example, Mew et
al., J. of Immunol., 130(3): 1473-1477, (1983)).
[0016] High powered lasers are usually employed as a light source
in administering PDT to shorten the time required for the treatment
(see W.G. Fisher et al., Photochemistry and Photobiology,
66(2):141-155, (1997)). However, it would likely be safer to use a
low power, non-coherent light source that remains energized for two
or more hours to increase the depth of the photoactivation. This
approach is contrary to the prior art that recommends PDT be
carried out with a brief exposure from a high powered, collimated
light source.
[0017] Recently, there has been much interest in the use of
anti-angiogenesis drugs for treating cancerous tumors by minimizing
the blood supply that feeds a tumor's growth. However, targeting of
tumor vessels using anti-angiogenesis drugs may lead to reduction
in size of small tumors and may prevent new tumor growth, but will
likely be ineffective in causing reliable regression of large,
established tumors in humans. However, by using a combination of
anti-angiogenesis and a photo-sensitizer in the targeting
conjugate, it is likely that a large volume tumor can be destroyed
by administering PDT.
[0018] In treating large tumors, a staged procedure may be
preferable in order to control tumor swelling and the amount of
necrotic tissue produced as the PDT causes destruction of the tumor
mass. For example, by activating a photosensitizer bound to tumor
vessels in the center of a large tumor and then sequentially
expanding the treatment zone outward in a stepwise manner, a large
volume tumor can be gradually ablated in a controlled fashion in
order to prevent swelling due to edema and inflammation, which is
problematic in organs such as the brain.
[0019] Delivered in vivo, PDT has been demonstrated to cause vessel
thrombosis and vascular constriction, occlusion, and collapse. And
though the treatment of very superficial, thin tumors has been
reported using transcutaneous light, there are no clinical reports
of transcutaneous light activation being used to destroy deeper,
thick tumors that are disposed more than 2 cm below the skin
surface. Clearly, there is a need for a PDT paradigm that enables
large volume tumors that are disposed well below the surface of the
skin to be destroyed with transcutaneous light activation.
[0020] It is apparent that the usual method of administering PDT to
treat bulky tumors, which relies on invasive introduction of
optical fibers, is not the best approach. It would be highly
advantageous to apply light transcutaneously in a completely
noninvasive method to treat such large tumors (as well as small and
even microscopic tumors), without risking damage to non-target
tissues, such as skin and normal subcutaneous tissue. Instead of
the conventional technique, a method of photoactivation and a
series of photosensitizer constructs is needed that enable
PDT-induced cytotoxicity, on both a macro and microscopic scale,
without risk to the cutaneous layer, or any surrounding normal
tissues. Also, the therapeutic index should be enhanced if a
specific photosensitizer drug targeting scheme is employed.
[0021] Citation of the above documents is not intended as an
admission that any of the foregoing is pertinent prior art. All
statements as to the date or representation as to the contents of
these documents is based on the information available to the
applicant and does not constitute any admission as to the
correctness of the dates or contents of these documents. Further,
all documents referred to throughout this specification are hereby
incorporated by reference herein, in their entirety.
SUMMARY OF THE INVENTION
[0022] In accord with the present invention, a method is defined
for transcutaneously administering a photodynamic therapy to a
target tissue in a mammalian subject. The method includes the step
of administering to the subject a therapeutically effective amount
of either a photosensitizing agent having a characteristic light
absorption waveband, a photosensitizing agent delivery system that
delivers the photosensitizing agent, or a prodrug that produces a
prodrug product having a characteristic light absorption waveband.
The photosensitizing agent, photosensitizing agent delivery system,
or prodrug selectively binds to the target tissue. Light having a
waveband corresponding at least in part with the characteristic
light absorption waveband of said photosensitizing agent or of the
prodrug is used for transcutaneously irradiating at least a portion
of the mammalian subject. An intensity of the light used for
irradiating is substantially less than 500 mw/cm.sup.2, and a total
fluence of the light is sufficiently high to activate the
photosensitizing agent or the prodrug product, as applicable.
[0023] In one embodiment, sufficient time is allowed for any of the
photosensitizing agent, the photosensitizing agent delivery system,
or the prodrug (depending upon which one of these was administered)
that is not bound to the target tissue to clear from non-target
tissues of the mammalian subject prior to the step of irradiating
with the light.
[0024] In one application of the invention, the target tissue is
vascular endothelial tissue. In another application, the target
tissue is an abnormal vascular wall of a tumor. As further defined,
the target tissue is selected from the group consisting of: a
vascular endothelial tissue, an abnormal vascular wall of a tumor,
a solid tumor, a tumor of a head, a tumor of a neck, a tumor of a
gastrointestinal tract, a tumor of a liver, a tumor of a breast, a
tumor of a prostate, a tumor of a lung, a nonsolid tumor, malignant
cells of one of a hematopoietic tissue and a lymphoid tissue,
lesions in a vascular system, a diseased bone marrow, and diseased
cells in which the disease is one of an autoimmune and an
inflammatory disease. In yet a further application of the present
invention, the target tissue is a lesion in a vascular system. It
is contemplated that the target tissue is a lesion of a type
selected from the group consisting of atherosclerotic lesions,
arteriovenous malformations, aneurysms, and venous lesions.
[0025] The step of irradiating generally comprises the step of
providing a light source that is activated to produce the light. In
one preferred embodiment of the invention, the light source is
disposed external to an intact skin layer of the mammalian subject
during the step of irradiating. In another preferred embodiment,
the method includes the step of inserting the light source
underneath an intact skin layer, but external to an intact surface
of an organ of the mammalian subject, and the organ comprises the
target tissue.
[0026] In one embodiment, the photosensitizing agent is conjugated
to a ligand. The ligand may be either an antibody or an antibody
fragment that is specific in binding with the target tissue.
Alternatively, the ligand is a peptide, or a polymer, either of
which is specific in binding with the target tissue.
[0027] The photosensitizing agent is preferably selected from the
group consisting of indocyanine green (ICG), methylene blue,
toluidine blue, aminolevulinic acid (ALA), chlorins,
phthalocyanines, porphyrins, purpurins, texaphyrins, and other
photosensitizer agents that have a characteristic light absorption
peak in a range of from about 500 nm to about 1100 nm.
[0028] The step of irradiating is preferably carried out for a time
interval of from about 30 minutes to about 72 hours, or more
preferably, from about 60 minutes to about 48 hours, or most
preferably, from about 3 hours to about 24 hours.
[0029] In yet another application of the invention, the target
tissue is bone marrow, or comprises cells afflicted with either an
autoimmune disease or an inflammatory disease.
[0030] An additional application of the invention contemplates a
method for administering photodynamic therapy to a target
composition in a mammalian subject by transillumination. The target
composition may include one or more pathogenic agents, including:
bacteria, viruses, fungi, protozoa, and toxins as well as tissues
infected or infiltrated therewith.
[0031] In one embodiment, the total fluence of the light used for
irradiating is between about 30 Joules and about 25,000 Joules, or
between about 100 Joules and about 20,000 Joules, and in another
embodiment, between about 500 Joules and about 10,000 Joules.
[0032] Another application of the present invention uses an energy
activated compound that has a characteristic energy absorption
waveband. The energy activated compound selectively binds to the
target tissue. Energy having a waveband corresponding at least in
part with the characteristic energy absorption waveband of said
energy activated compound is used for transcutaneously irradiating
at least a portion of the mammalian subject. In one embodiment the
waveband is in the ultrasonic range of energy. Said compound is
activated by said irradiating step, wherein the intensity of said
ultrasonic energy is substantially less than that level which would
result in damage to normal tissue, but at a sufficiently high total
fluence of ultrasonic energy that is absorbed by said compound
which in turn destroys the target tissue to which it is bound. In
one embodiment, the total fluence of the ultrasonic energy used for
irradiating is between about 5 kHz and more than about 300 MHz, in
another embodiment, between about 10 kHz and more than about 200
MHz, and in another embodiment, between about 20 kHz and more than
about 100 MHz.
BRIEF DESCRIPTION OF THE DRAWING FIGURES
[0033] The foregoing aspects and many of the attendant advantages
of this invention will become more readily appreciated as the same
becomes better understood by reference to the following detailed
description, when taken in conjunction with the accompanying
drawings, wherein:
[0034] FIG. 1 is a schematic diagram illustrating an external light
source being used to administer transcutaneous cancer therapy to a
relatively large, singular tumor, and to multiple, small
tumors;
[0035] FIG. 2 is a schematic cross-sectional view of a section of a
tumor blood vessel, illustrating binding of an
antibody/photosensitive drug to endothelial tissue;
[0036] FIGS. 3A and 3B are schematic diagrams illustrating
biotin-avidin targeting of endothelial antigens for use in
rendering PDT;
[0037] FIGS. 4A-4C schematically illustrate tissue amplified
infarction downstream of photodynamic transcutaneous therapy
applied to endothelium tissue;
[0038] FIG. 5 is a schematic diagram illustrating the use of an
external ultrasound source for transcutaneous application of PDT to
a deep tumor;
[0039] FIG. 6 is a schematic diagram showing the use of an external
light source for transcutaneous treatment of intraosseous
disease;
[0040] FIG. 7 is a schematic diagram showing both an external light
source transcutaneously administering light and an intraluminal
light source position within either the terminal ileum or colon to
treat Crohn's disease with targeted PDT;
[0041] FIG. 8 is a schematic diagram illustrating an intraluminal
light source in the form of a capsule or pill for administering
light to destroy H. pylori on the gastric lining with targeted PDT;
and
[0042] FIG. 9 is a schematic diagram showing how an internal light
source administers transillumination of a deep tumor through an
organ wall to provide targeted PDT that destroys the tumor.
DETAILED DESCRIPTION
[0043] This invention is directed to methods and compositions for
therapeutically treating a target tissue or destroying or impairing
a target cell or a biological component in a mammalian subject by
the specific and selective binding of a photosensitizer agent to
the target tissue, cell, or biological component. At least a
portion of the subject is irradiated with light at a wavelength or
waveband within a characteristic absorption waveband of the
photosensitizing agent. The light is administered at a relatively
low fluence rate or intensity, but at an overall high total fluence
dose, resulting in minimal collateral normal tissue damage. It is
contemplated that an optimal total fluence for the light
administered to a patient will be determined clinically, using a
light dose escalation trial. It is further contemplated that the
total fluence administered during a treatment will preferably be in
the range of 30 Joules to 25,000 Joules, more preferably, in the
range from 100 Joules to 20,000 Joules, and most preferably, in the
range from 500 Joules to 10,000 Joules.
[0044] The terminology used herein is generally intended to have
the art-recognized meaning and any differences therefrom as used in
the present disclosure will be apparent to the ordinary skilled
artisan. For the sake of clarity, terms may also have a particular
meaning, as will be clear from their use in context. For example,
"transcutaneous" as used in regard to light in this specification
and in the claims that follow, more specifically herein refers to
the passage of light through unbroken tissue. Where the tissue
layer is skin or dermis, transcutaneous includes "transdermal" and
it will be understood that the light source is external to the
outer skin layer. However, the term "transillumination" as used
herein refers to the passage of light through a tissue layer, such
as the outer surface layer of an organ, e.g., the liver, and it
will be apparent that the light source is external to the organ,
but internal or implanted within the subject or patient.
[0045] One aspect of the present invention provides for the precise
targeting of photosensitive agents or drugs and compounds to
specific target antigens of a subject or patient and to the method
for activating the targeted photosensitizer agents by subsequently
administering to the subject light at a relatively low fluence rate
or intensity, over a prolonged period of time, from a light source
that is external to the target tissue in order to achieve maximal
cytotoxicity of the abnormal tissue, with minimal adverse side
effects or collateral normal tissue damage.
[0046] FIG. 1 illustrates transcutaneous delivery of light 12 from
an external source 10 to a relatively deep tumor 14, or to a
plurality of small, but relatively deep tumors 16. The light
emitted by external source 10 is preferably of a longer waveband,
but still within an absorption waveband of the photosensitive agent
(not shown in this Figure) that has been selectively bound to tumor
14 and smaller tumors 16. The longer wavelength of light 12 enables
it to pass through a dermal layer 18 and penetrate into the
patient's body beyond the depth of tumor(s) being treated with
targeted PDT. In these two examples, the PDT is directed
specifically at target cells in tumor 14 or in tumors 16.
[0047] As used in this specification and the following claims, the
terms "target cells" or "target tissues" refer to those cells or
tissues, respectively that are intended to be impaired or destroyed
by PDT delivered in accord with the present invention. Target cells
or target tissues take up or bind with the photosensitizing agent,
and, when sufficient light radiation of the waveband corresponding
to the characteristic waveband of the photosensitizing agent is
applied, these cells or tissues are impaired or destroyed. Target
cells are cells in target tissue, and the target tissue includes,
but is not limited to, vascular endothelial tissue, abnormal
vascular walls of tumors, solid tumors such as (but not limited to)
tumors of the head and neck, tumors of the gastrointestinal tract,
tumors of the liver, tumors of the breast, tumors of the prostate,
tumors of the lung, nonsolid tumors and malignant cells of the
hematopoietic and lymphoid tissue, other lesions in the vascular
system, bone marrow, and tissue or cells related to autoimmune
disease.
[0048] Further, target cells include virus-containing cells, and
parasite-containing cells. Also included among target cells are
cells undergoing substantially more rapid division as compared to
non-target cells. The term "target cells" also includes, but is not
limited to, microorganisms such as bacteria, viruses, fungi,
parasites, and infectious agents. Thus, the term "target cell" is
not limited to living cells but also includes infectious organic
particles such as viruses. "Target compositions" or "target
biological components" include, but are not be limited to: toxins,
peptides, polymers, and other compounds that may be selectively and
specifically identified as an organic target that is intended to be
impaired or destroyed by this treatment method.
[0049] FIG. 2 includes a section of a tumor blood vessel 20 having
a wall 22, with an endothelial lining 24. A plurality of
endothelial antigens 26 are disposed along the endothelial lining.
In this example, antibodies 28 that are specific to endothelial
antigens 26 have been administered and are shown binding with the
endothelial antigens. Coupled to antibodies 28 are PDT
photosensitive drug molecules 30. Thus, the PDT photosensitive drug
molecules are bound to the endothelial antigens via antibodies 28,
but are not bound to non-target cells, since the antibodies are
selective only to the endothelial antigens.
[0050] "Non-target cells" are all the cells of a mammal that are
not intended to be impaired, damaged, or destroyed by the treatment
method rendered in accord with the present invention. These
non-target cells include but are not limited to healthy blood
cells, and other normal tissue, not otherwise identified to be
targeted.
[0051] "Destroy" means to kill the desired target cell. "Impair"
means to change the target cell in such a way as to interfere with
its function. For example, in North et al., it is observed that
after virus-infected T cells treated with benzoporphyrin
derivatives ("BPD") were exposed to light, holes developed in the T
cell membrane and increased in size until the membrane completely
decomposed (Blood Cells 18:129-40, (1992)). Target cells are
understood to be impaired or destroyed even if the target cells are
ultimately disposed of by macrophages.
[0052] "Energy activated agent" is a chemical compound that binds
to one or more types of selected target cells and, when exposed to
energy of an appropriate waveband, absorbs the energy, causing
substances to be produced that impair or destroy the target
cells.
[0053] "Photosensitizing agent" is a chemical compound that binds
to one or more types of selected target cells and, when exposed to
light of an appropriate waveband, absorbs the light, causing
substances to be produced that impair or destroy the target cells.
Virtually any chemical compound that preferentially is absorbed or
bound to a selected target and absorbs light causing the desired
therapy to be effected may be used in this invention. Preferably,
the photosensitizing agent or compound is nontoxic to the animal to
which it is administered or is capable of being formulated in a
nontoxic composition that can be administered to the animal. In
addition, following exposure to light, the photosensitizing agent
in any resulting photodegraded form is also preferably nontoxic. A
comprehensive listing of photosensitive chemicals may be found in
Kreimer-Bimbaum, Sem. Hematol, 26:157-73, (1989). Photosensitive
agents or compounds include, but are not limited to, chlorins,
bacteriochlorins, phthalocyanines, porphyrins, purpurins,
merocyanines, psoralens, benzoporphyrin derivatives (BPD), and
porfimer sodium and pro-drugs such as delta-aminolevulinic acid,
which can produce photosensitive agents such as protoporphyrin IX.
Other suitable photosensitive compounds include ICG, methylene
blue, toluidine blue, texaphyrins, and any other agent that absorbs
light in a range of 500 nm-1100 nm.
[0054] The term "prodrug" is used herein to mean any of a class of
substances that are not themselves photosensitive agents, but when
introduced into the body, through metabolic, chemical, or physical
processes, are converted into a photosensitive agent. In the
following disclosure, an aminolevulinic acid (ALA) is the only
exemplary prodrug. After being administered to a patient, ALA is
metabolically converted into a porphyrin compound that is an
effective photosensitive agent.
[0055] "Radiation" as used herein includes all wavelengths and
wavebands. Preferably, the radiation wavelength or waveband is
selected to correspond with or at least overlap the wavelength(s)
or wavebands that excite the photosensitive compound.
Photosensitive agents or compound typically have one or more
absorption wavebands that excite them to produce the substances,
which damage or destroy target tissue, target cells, or target
compositions. Even more preferably, the radiation wavelength or
waveband matches the excitation wavelength or waveband of the
photosensitive compound and has low absorption by the non-target
cells and the rest of the intact animal, including blood proteins.
For example, a preferred wavelength of light for ICG is in the
range 750-850 nm.
[0056] The radiation used to activate the photosensitive compound
is further defined in this invention by its intensity, duration,
and timing with respect to dosing a target site. The intensity or
fluence rate must be sufficient for the radiation to penetrate skin
and reach the target cells, target tissues, or target compositions.
The duration or total fluence dose must be sufficient to
photoactivate enough photosensitive agent to achieve the desired
effect on the target site. Both intensity and duration are
preferably limited to avoid over-treating the subject or animal.
Timing with respect to the dosage of the photosensitive agent
employed is important, because (1) the administered photosensitive
agent requires some time to home in on target cells, tissue, or
compositions at the treatment site, and (2) the blood level of many
photosensitive agents decreases with time.
[0057] The present invention provides a method for providing a
medical therapy to an animal, and the term "animal" includes, but
is not limited to, humans and other mammals. The term "mammals" or
"mammalian subject" includes farm animals, such as cows, hogs and
sheep, as well as pet or sport animals such as horses, dogs, and
cats.
[0058] Reference herein to "intact animal" means that the whole,
undivided animal is available to be exposed to radiation. No part
of the animal is removed for exposure to the radiation, in contrast
with photophoresis, in which an animal's blood is circulated
outside its body for exposure to radiation. However, in the present
invention, the entire animal need not be exposed to radiation. Only
a portion of the intact animal subject may or need be exposed to
radiation, sufficient to ensure that the radiation is administered
to the treatment site where the target tissue, cells, or
compositions are disposed.
[0059] In the present invention, a photosensitizing agent is
generally administered to the animal before the animal is subjected
to radiation. Preferred photosensitizing agents include, but are
not limited to, chlorins, bacteriochlorins, phthalocyanines,
porphyrins, purpurins, merocyanines, psoralens and pro-drugs such
as delta-aminolevulinic acid, which can produce drugs such as
protoporphyrin. More preferred photosensitizing agents are:
methylene blue, toluidine blue, texaphyrins, and any other agent
that absorbs light having a wavelength or waveband in the range
from 600 nm-1100 nm. Most preferred of the photosensitizing agents
is ICG. The photosensitizing agent is preferably administered
locally or systemically, by oral ingestion, or by injection, which
may be intravascular, subcutaneous, intramuscular, intraperitoneal
or directly into a treatment site, such as intratumoral. The
photosensitizing agent also can be administered enterally or
topically via patches or implants.
[0060] The photosensitizing agent also can be conjugated to
specific ligands known to be reactive with a target tissue, cell,
or composition, such as receptor-specific ligands or
immunoglobulins or immunospecific portions of immunoglobulins,
permitting them to be more concentrated in a desired target cell or
microorganism than in non-target tissue or cells. The
photosensitizing agent may be further conjugated to a
ligand-receptor binding pair. Examples of a suitable binding pair
include but are not limited to: biotin-streptavidin,
chemokine-chemokine receptor, growth factor-growth factor receptor,
and antigen-antibody. As used herein, the term "photosensitizing
agent delivery system" refers to a photosensitizing agent
conjugate, which because of its conjugation, has increased
selectivity in binding to a target tissue, target cells, or target
composition. The use of a photosensitizing agent delivery system is
expected to reduce the required dose level of the conjugated
photosensitizing agent, since the conjugate material is more
selectively targeted at the desired tissue, cell, or composition,
and less of it is wasted by distribution into other tissues whose
destruction should be avoided.
[0061] In FIGS. 3A and 3B, an example of a photosensitizing agent
delivery system 40 is illustrated in which the target tissue is
endothelial layer 24, which is disposed along blood vessel wall 22
of tumor blood vessel 20. As shown in FIG. 3A, antibodies 28 are
coupled with biotin molecules 42 and thus selectively bound to
endothelial antigens 26 along the endothelial layer. FIG. 3B
illustrates avidin molecules 44 coupled to PDT photosensitive drug
molecules 30, where the avidin molecules bind with biotin molecules
42. This system thus ensures that the PDT photosensitive drug
molecules 30 only bind with the selectively targeted endothelial
tissue. When light of the appropriate waveband is administered, it
activates the PDT photosensitive drug molecules, causing the
endothelial tissue to be destroyed.
[0062] FIGS. 4A-4C illustrate a mechanism for amplifying the effect
on a tumor of PDT administered to destroy the endothelial tissue in
a tumor blood vessel 50. Tumor blood vessel 50 distally branches
into two smaller blood vessels 52. In FIG. 4A, the PDT administered
to activate the PDT photosensitive drug molecules has produced
substantial damage to the endothelium, creating an intravascular
thrombosis (or clot) 54. As shown in FIG. 4B, the intravascular
thrombosis is carried distally through tumor blood vessel 50 until
it reaches the bifurcation point where smaller diameter blood
vessels 52 branch. Due to the flow through smaller internal
diameter of blood vessels 52, intravascular thrombosis 54 can not
advance any further, and is stopped, creating a plug that virtually
stops blood flow through tumor blood vessel 50. The interruption of
blood flow also interrupts the provision of nutrients and oxygen to
the surrounding tumor cells, causing the tumor cells to die. In
FIG. 4C, the dying tumor cells 56 are within a zone of tumor cell
death or necrosis 58 surrounding the vessel and which zone
increases in volume over time, thereby amplifying the effects of
the PDT on the endothelium tissue of the tumor blood vessels.
[0063] A photosensitizing agent can be administered in a dry
formulation, such as pills, capsules, suppositories or patches. The
photosensitizing agent also may be administered in a liquid
formulation, either alone, with water, or with pharmaceutically
acceptable excipients, such as are disclosed in Remington's
Pharmaceutical Sciences. The liquid formulation also can be a
suspension or an emulsion. In particular, liposomal or lipophilic
formulations are desirable. If suspensions or emulsions are
utilized, suitable excipients include water, saline, dextrose,
glycerol, and the like. These compositions may contain minor
amounts of nontoxic auxiliary substances such as wetting or
emulsifying agents, antioxidants, pH buffering agents, and the
like.
[0064] The dose of photosensitizing agent will vary with the target
tissue, cells, or composition, the optimal blood level (see Example
1), the animal's weight, and the timing and duration of the
radiation administered. Depending on the photosensitizing agent
used, an equivalent optimal therapeutic level will have to be
empirically established. Preferably, the dose will be calculated to
obtain a desired blood level of the photosensitizing agent, which
will likely be between about 0.01 .mu.g/ml and 100 .mu.g/ml. More
preferably, the dose will produce a blood level of the
photosensitizing agent between about 0.01 .mu.g/ml and 10
.mu.g/ml.
[0065] The intensity of radiation used to treat the target cell or
target tissue is usually between about 5 mW/cm.sup.2 and about 100
mW/cm.sup.2. In one embodiment, the intensity of radiation employed
should be between about 10 mW/cm.sup.2 and about 75 mW/cm.sup.2. In
another embodiment, the intensity of radiation is between about 15
mW/cm.sup.2 and about 50 mW/cm.sup.2.
[0066] The duration of radiation exposure administered to a subject
is preferably between about 30 minutes and about 72 hours. In one
embodiment, the duration of radiation exposure is between about 60
minutes and about 48 hours. In another embodiment, the duration of
radiation exposure is between about 2 hours and about 24 hours.
[0067] It is contemplated that a targeted photosensitizer agent can
be substantially and selectively photoactivated in the target cells
and target tissues within a therapeutically reasonable period of
time and without excess toxicity or collateral damage to non-target
normal tissues. Thus, there appears to be a therapeutic window
bounded by the targeted photosensitizer agent dosage and the
radiation dosage. In view of problems in the prior art related to
either extracorporeal treatment of target tissues or use of high
intensity laser light irradiation intraoperatively, the present
invention offers substantial advantages. In accord with the present
invention, targeted transcutaneous PDT will be employed to treat
patients injected with a photosensitizer agent and will subject the
patients to a relatively low fluence rate, but high total fluence
dose of radiation. This approach is an attractive method for
treating target tissues that include neoplastic diseased tissue,
infectious agents, and other pathological tissues, cells, and
compositions.
[0068] One aspect of the present invention is drawn to a method for
transcutaneous energy activation therapy applied to destroy tumors
in a mammalian subject or patient by first administering to the
subject a therapeutically effective amount of a first conjugate
comprising a first member of a ligand-receptor binding pair
conjugated to an antibody or antibody fragment. The antibody or
antibody fragment selectively binds to a target tissue antigen.
Simultaneously or subsequently, a therapeutically effective amount
of a second conjugate comprising a second member of the
ligand-receptor binding pair conjugated to an energy-sensitive
agent or energy-sensitive agent delivery system or prodrug is
administered to the patient, wherein the first member binds to the
second member of the ligand-receptor binding pair. These steps are
followed by irradiating at least a portion of the subject with
energy having a wavelength or waveband absorbed by the
energy-sensitive agent, or energy-sensitive agent delivery system,
or by the product thereof. This radiation energy is preferably
provided by an energy source that is external to the subject and is
preferably administered at a relatively low fluence rate that
results in the activation of the energy-sensitive agent, or
energy-sensitive delivery system, or prodrug product.
[0069] While one embodiment of the present invention is drawn to
the use of light energy for administering PDT to destroy tumors,
other forms of energy are within the scope of this invention, as
will be understood by those of ordinary skill in the art. Such
forms of energy include, but are not limited to: thermal, sonic,
ultrasonic, chemical, light, microwave, ionizing (such as x-ray and
gamma ray), mechanical, and electrical. For example,
sonodynamically induced or activated agents include, but are not
limited to: gallium-porphyrin complex (see Yumita et al., Cancer
Letters, 112: 79-86, (1997)), other porphyrin complexes, such as
protoporphyrin and hematoporphyrin (see Umemura et al., Ultrasonics
Sonochemistry 3:S187-S191, (1996)); other cancer drugs, such as
daunorubicin and adriamycin, used in the presence of ultrasound
therapy (see Yumita et al., Japan J. Hyperthermic Oncology,
3(2):175-182, (1987)).
[0070] FIG. 5 illustrates the use of an external ultrasound
transducer head 60 for generating an ultrasonic beam 62 that
penetrates through a dermal layer 64 and into a subcutaneous layer
66. The external ultrasound transducer head is brought into contact
with dermal layer 64 so that ultrasonic beam 62 is directed toward
a relatively deep tumor 68. The ultrasonic beam activates a PDT
photosensitive drug that has been administered to the patient and
selectively targeted at tumor 68, causing the drug to destroy the
tumor.
[0071] This invention further employs an energy source, e.g., a
light source, that is external to the target tissue. The target
tissues may include and may relate to the vasculature or blood
vessels that supply blood to tumor tissue or the target tissues may
include the tumor tissue antigens, per se. These target tissue
antigens will be readily understood by one of ordinary skill in the
art to include but to not be limited to: tumor surface antigen,
tumor endothelial antigen, non-tumor endothelial antigen, and tumor
vessel wall antigen, or other antigens of blood vessels that supply
blood to the tumor.
[0072] Where the target tissue includes endothelial or vascular
tissue, a ligand-receptor binding pair includes
biotin-streptavidin. In this embodiment, the activation of
photosensitizer agents by a relatively low fluence rate of a light
source over a prolonged period of time results in the direct or
indirect destruction, impairment or occlusion of blood supply to
the tumor resulting in hypoxia or anoxia to the tumor tissues.
Where the target tissue includes tumor tissue other than
endothelial or vascular, the activation of photosensitizer agents
by a relatively low fluence rate of a light source over a prolonged
period of time results in the direct destruction of the tumor
tissue due to deprivation of oxygen and nutrients from the tumor
cells.
[0073] The ordinary skilled artisan would be familiar with various
ligand-receptor binding pairs, including those known and those
currently yet to be discovered. Those known include, but are not
limited to: biotin-streptavidin, chemokine-chemokine receptor,
growth factor-growth factor receptor, and antigen-antibody. The
present invention contemplates at least one preferred embodiment
that uses biotin-streptavidin as, the ligand-receptor binding pair.
However, the ordinary skilled artisan will readily understand from
the present disclosure that any ligand-receptor binding pair may be
useful in practicing this invention, provided that the
ligand-receptor binding pair demonstrates a specificity for the
binding by the ligand to the receptor and further provided that the
ligand-receptor binding pair permits the creation of a first
conjugate comprising a first member of the ligand-receptor binding
pair conjugated to an antibody or antibody fragment. In this case,
the antibody or antibody fragment selectively binds to a target
tissue antigen and permits the creation of a second conjugate
comprising a second member of the ligand-receptor binding pair
conjugated to an energy-sensitive or photosensitizing agent, or
energy-sensitive or photosensitizing agent delivery system, or
prodrug. The first member then binds to the second member of the
ligand-receptor binding pair.
[0074] Another embodiment of the present invention includes a
photosensitizing agent delivery system that utilizes both a
liposome delivery system and a photosensitizing agent, where each
is separately conjugated to a second member of the ligand-receptor
binding pair, and where the first member binds to the second member
of the ligand-receptor binding pair. In one embodiment, the
ligand-receptor binding pair is biotin-streptavidin. In this
embodiment, the photosensitizing agent as well as the
photosensitizing agent delivery system may both be specifically
targeted through selective binding to a target tissue antigen by
the antibody or antibody fragment of the first member binding pair.
Such dual targeting is expected to enhance the specificity of
uptake and to increase the quantity of uptake of the
photosensitizing agent by the target tissue, cell, or
compositions.
EXAMPLES
[0075] Having now generally described the invention, it will be
more readily understood through reference to the following
examples, which are provided by way of illustration and are not
intended to be limiting in regard to the scope of the invention,
unless specified.
Example 1
[0076] Transcutaneous Photodynamic Therapy of a Solid Type
Tumor
[0077] A patient in the terminal phase of recurrent malignant colon
cancer presented with a protruding colon carcinoma tumor mass of
approximately 500 grams and approximately 13 cm in diameter, which
extended through the patient's dermis. Due to the advanced state of
the patient's disease and due to the highly vascularized nature of
this tumor mass, resection was not feasible. Further, this large
tumor mass presented a significant amount of pain and discomfort to
the patient, as well as greatly impairing the patient's ability to
lie flat.
[0078] Six separate light source probes, each including a linear
array of LEDs, were surgically implanted in this large human tumor
using standard surgical procedures. An intensity of about 25-30 mW
of light from each light source probe (650 nm peak wavelength) was
delivered to the tumor for 40 hours following oral administration
to the patient of a single dose of an ALA photosensitizer agent (60
mg/kg). However, after 18 hours, two of the light source probes
became unseated from the tumor mass and were disconnected from the
electrical power supply used to energize the LEDs on each probe.
The total fluence delivered to the tumor bed during this single
extended duration treatment was in excess of 20,000 Joules.
Extensive tumor necrosis in a radius of up to 5 cm around each of
the light source probes was observed after 40 hours of PDT, with no
collateral damage to surrounding normal tissue. The extent of this
PDT-induced necrotic effect in a large volume of tumor tissue was
totally unexpected and has not been described before in any PDT
studies in subjects in vivo or clinically. Over the course of four
weeks following PDT, the necrotic tumor tissue was debrided from
the patient resulting in a reduction of approximately 500 grams of
tumor tissue. The patient noted a significant improvement in his
quality of life, with a resurgent level of energy and improved well
being.
[0079] The average thickness of human skin is approximately 1 cm.
Therefore, if this same method of prolonged, relatively low fluence
rate, but overall high total fluence of light delivery is utilized
to deliver the light transcutaneously, a therapeutic effect well
below the skin surface, to a depth of is contemplated.
[0080] The fluence rate employed in this Example represented about
150-180 mW/cm.sup.2, with a total fluence more than 20,000 Joules.
The preferable fluence rate contemplated more broadly by the
present invention is between about 5 mW/cm.sup.2 and about 100
mW/cm.sup.2, more preferably, between about 10 mW/cm.sup.2 and
about 75 mW/cm.sup.2, and most preferably, between about 15
mW/cm.sup.2 and about 50 mW/cm.sup.2.
[0081] It is further contemplated that the optimal total fluence be
empirically determined, using a light dose escalation trial, and
will likely and preferably be in the range of about 30 Joules to
about 25,000 Joules, and more preferably be in the range from about
100 Joules to about 20,000 Joules, and most preferably be in the
range from about 500 Joules to about 10,000 Joules.
Example 2
[0082] Transcutaneous Photodynamic Therapy of lntraosseous
Disease
[0083] The current accepted therapy for treating leukemia and other
malignant bone marrow diseases employs a systemic treatment
utilizing chemotherapy and/or radiotherapy, sometimes followed by a
bone marrow transplant. There are significant risks associated with
non-discriminative ablative therapies that destroy all marrow
elements, including the risks of infections, bleeding diathesis,
and other hematological problems.
[0084] There is a definite need for alternative therapies that do
not subject patients to procedures which may be risky and which
inherently cause pain and suffering. This example is directed to a
method of treating intraosseous malignancy that has major
advantages over the prior art techniques for treating this
disease.
[0085] A targeted antibody-photosensitizer conjugate (APC) is
constructed, which binds selectively to antigens present on
leukemic cells. This ligand-receptor binding pair or APC is infused
intravenously and is taken up in the marrow by circulating leukemic
cells, and by stationary deposits that may reside in other organs.
When unbound to leukemic cells, APC is eliminated from the body.
Internal or external light sources may be used to activate the
targeted drug. For example, light bar probes disclosed in U.S. Pat.
No. 5,445,608 may be inserted into bone marrow to treat the
intraosseous disease. The devices disclosed in U.S. Pat. No.
5,702,432 may be used to treat disease cells circulating in the
patient's lymphatic or vascular system. An external device
transcutaneously activating the targeted drug, for example, a light
source that emits light that is transmitted through the dermal
layer may also be used in treating the marrow compartment in accord
with the present invention.
[0086] PDT targeting has been described for leukemic cells (see
U.S. Pat. No. 5,736,563),but not with the capability of treating
marrow in situ. Without this capability, simply lowering the
leukemic cell count would have little clinical benefit, since the
marrow is a major source of new leukemic clones, and the marrow
must be protected from failure, which will lead to the death of the
patient regardless of how well the pathologic cell load in the
circulation is treated. Specific APC promotes the selective damage
of leukemic cells in marrow, while reducing collateral and
non-target tissue damage. Further, the use of a relatively low
fluence rate but overall high total fluence dose is particularly
effective in this therapy. Optimal fluence rates and dosing times
are readily empirically determined using dose escalation for both
drug and light dose as is often done in a clinical trial. Any of a
number of different types of leukemia cell antigens may be
selected, provided that the antigen chosen is as specific as
possible for the leukemia cell. Such antigens will be known to
those of ordinary skill in this art. The selection of a specific
photosensitizer agent may be made, provided that the
photosensitizer agent chosen is activated by light having a
waveband of from about 500 nm to about 1100 nm, and more
preferably, a waveband from about 630 nm to about 1000 nm, and most
preferably, a waveband from about 800 nm to about 950 nm or
greater. The photosensitizer agents noted above are suitable for
use in this Example.
[0087] With reference to FIG. 6, external light source 10 is
administering light 12 transcutaneously through dermal layer 18.
Light 12 has a sufficiently long wavelength to pass through a
subcutaneous layer 70 and through a cortical bone surface 74, into
a bone marrow compartment 76. Leukemia cells 78 have penetrated
bone marrow compartment 76 and are distributed about within it. To
provide targeted PDT treatment that will destroy the leukemia
cells, antibodies 82 bound with PDT photosensitive drug molecules
84 have been administered to the patient and have coupled with
leukemia antigens 80 on the leukemia cells 78. The light provided
by external light source 10 thus activates the PDT photosensitive
drug, causing it to destroy the leukemia cells. This targeted PDT
process is carried out with minimal invasive or adverse impact on
the patient, in contrast to the more conventional treatment
paradigms currently used.
Example 3
[0088] Transcutaneous Photodynamic Therapy of Crohn's Disease
[0089] Crohn's disease is a chronic inflammation of the
gastrointestinal tract thought to be mediated in large part by
dysfunction of CD4+ T cells lining the gut mucosa, especially in
terminal ileum. The current accepted therapy for Crohn's disease
provides for surgical removal of the inflamed bowel segment and the
use of anti-inflammatory agents, steroids and other
immunosuppressive drugs. None of these measures is entirely
satisfactory due to surgical risk, recurrence of disease,
medication side effects, and refractoriness of the disease. There
is a clear need for alternative therapies useful in treating this
immune dysfunction that offer greater efficacy and reduced side
effects and risk. This Example, details of which are illustrated in
FIG. 7, indicates the drug compositions and methodologies useful in
accord with the present invention to selectively destroy the
dysfunctional cells or inhibit their function. In the illustrated
example, external light source 10 is administering light 12 that
has a sufficiently long wavelength to penetrate dermal tissue 18,
which is disposed over a patient's abdomen, and pass through a
subcutaneous layer 90, into a terminal ileum or colon 92. The light
passes through wall 94 of the terminal ileum or colon.
Alternatively (or in addition), light 12' can be administered from
an intraluminal probe 96, from sources (not separately shown) that
are energized with an electrical current supplied through a lead
98.
[0090] Ligand-receptor binding pairs 100, or more specifically,
APCs, are created that bind selectively to CD4+ T cell antigens 102
of T cells 104, which are disposed along the interior, intraluminal
surface of the terminal ileum or colon. For example, the CD4+
antigen itself may be targeted by those antibodies 106 that bind
specifically to the CD4+ antigen. Many of the photosensitizer
agents noted above may be used for photosensitizing drug molecules
108, in the therapy of this Example. The APC is preferably
formulated into a pharmaceutically acceptable compound that can be
released in the terminal ileum and colon in a manner similar to
that known to be used for the orally delivered form of
Budesonide.TM. also known as Entocort.TM.. The APC compound is
ingested and releases the conjugate into the terminal ileum and
colon. At the time of therapy, the bowel should have been prepped
in much the same manner as done in preparing for a colonoscopy, so
that it is cleared of fecal material. The targeted photosensitizer
will bind to the pathologic T cells and any unbound APC is removed
via peristaltic action. The sensitizer bound to the T cells is
activated by intraluminally positioned light source probe 96,
details of which are disclosed in any one of U.S. Pat. Nos.:
5,766,234; 5,782,896; 5,800,478; and 5,827,186, each of which is
hereby incorporated by reference herein in its entirety; or by a
flexible intraluminal optical fiber (not shown) that is passed via
the nasopharynx; or, by the transcutaneous light illumination
provided by external light source 10. Transcutaneous light
illumination is preferred because it is entirely noninvasive.
[0091] In this exemplary treatment, the following protocol may be
utilized:
[0092] Step 1 Patient is NPO ("non per os" or nothing by mouth) and
the bowel has been prepped or cleansed by administering an enema to
clear it of fecal material;
[0093] Step 2 Specially formulated APC conjugate compound 100 is
ingested;
[0094] Step 3 The APC conjugate is released to the terminal ileum
and colon;
[0095] Step 4 If transcutaneous illumination is not used, one or
more light source probes 96 are ingested or passed into the GI
tract and advanced to the terminal ileum or colon.
[0096] Step 5 The APC conjugate is bound to target T cells 104 and
any unbound conjugate fraction passes distally via peristalsis (and
is subsequently eliminated from the body).
[0097] Step 6 If an internal light source is used, the light source
should preferably be imaged using ultrasound or computer assisted
topography (i.e., a CT scan--not shown) to confirm its location and
the light source can then be activated while positioned in the
ileum. Once activated, the light source will deliver light at the
appropriate waveband for the photosensitizing agent selected, at a
relatively low fluence rate, but at a high total fluence dose, as
noted above. The optimal drug dose and fluence parameters will be
determined clinically in a drug and light dose escalation trial.
The light dose and drug dose are such that T cell inactivation
occurs, leading to decreased regulation of the immune process and a
reduction of any pathologic inflammation--both of which are factors
characteristic of this disease.
[0098] Step 7 The light source is deactivated. It is particularly
important to deactivate an internal light source before withdrawing
it from the treatment site to prevent nonspecific APC
activation.
[0099] The present invention can also be employed to target other
types of immunologic cells, such as other T cells, macrophages,
neutrophils, B cells, and monocytes. A tiered approach can thus be
employed, starting with CD4+ T cells, then moving to CD8+ T cells,
and then monocytes and neutrophils. By inhibiting or preventing
interaction and/or secretion of inflammatory cell products, the
pathologic process is controlled at the lumenal site, completely
avoiding systemic side effects and major surgery. The same process
can be applied to treat ulcerative colitis with the same benefits.
As indicated above, the APC can be activated with light
administered transcutaneously, using any number of different types
of external light sources such as LEDs, laser diodes, and lamps
that emit light with a wavelength or waveband sufficiently long to
penetrate through the overlying dermal and internal tissue, and
into the intestine. The optimal wavelength or waveband of this
light is determined by both the light absorption properties of the
photosensitizer and the need to use light with as long a wavelength
as possible to ensure adequate penetration into the patient's body.
A desirable photosensitizer is preferably one that absorbs in the
range from about 700 nm to about 900 nm, which optimizes tissue
penetration. The appropriate fluence rate and total fluence
delivered is readily determined by a light dose escalation clinical
trial. The light dose and drug dose are such that T cell
inactivation occurs, leading to reduced regulation of the immune
process and a reduction in pathologic inflammation.
Example 4
[0100] Intraluminal Transcutaneous PDT Targeted at Helicobacter
pylon Targeting of photosensitizers to bind with bacterial cells is
known in the prior art. Many antigens that can serve as targets for
ligand-receptor binding pairs, and more specifically, APC, have
been identified, and the techniques to construct such conjugates
are well known to those of ordinary skill in this art. What is not
apparent from the prior art are the steps necessary to apply such
conjugates in the treatment of a clinical disease. This Example
describes the clinical application of APC to the treatment of an
infection using PDT. FIG. 8 illustrates details of the example, as
described below.
[0101] Helicobacter pylori is reportedly associated with tumors of
the stomach in mice and as a putative agent of ulcerative pathology
in humans. However, it appears that the use of PDT for destroying
an H. pylori infection in human patients has not been carried out,
although proposals to use laser light for PDT destruction of
bacteria have been set forth (Millson et al., J. of Photochemistry
and Photobiology, 32: 59-65 (1996)).
[0102] In this Example, a capsular or pill-shaped and sized light
source 120 is administered orally to a patient, so that it passes
into the stomach 118 of the patient, where it administers light
122. Alternatively, an optical fiber (not shown) may be passed into
the stomach via the nasopharynx to administer light 122 to the
treatment site. In order to implement targeted PDT for treating
ulcers in humans, an APC 124, which antibody 131 is targeted
against a suitable Helicobacter pylori antigen 126 is formulated
into an ingestible compound that releases the APC to a gastric
mucus/epithelial layer 128 where the bacterium is found. The APC is
ingested at a time when the stomach and duodenum is substantially
empty in order to promote binding of the APC to bacterium 130. Any
unbound APC is diluted by gastric juice and carried distally by
peristalsis to be eliminated from the body in fecal matter. Light
sources suitable for intraluminal passage are disclosed in any one
of U.S. Pat. Nos.: 5,766,234; 5,782,896; 5,800,478; and 5,827,186,
the disclosure of each being specifically hereby incorporated
herein in its entirety. Alternatively, light source 120 in capsule
or pill form, e.g., as disclosed in copending commonly assigned
U.S. patent application, Ser. No 09/260,923, entitled, "Polymer
Battery for Internal Light Device," filed on Mar. 2, 1999 (now U.S.
Pat. No. 6,273,904, issued Aug. 14, 2001) is used for activating
the APC. The light source is preferably energized just prior to its
ingestion or remotely after ingestion, when in the stomach or in a
desired intraluminal passage. If necessary, multiple light sources
are ingested to insure that adequate photoactivation of the
localized APC occurs sufficient to kill the bacterium. Light is
delivered at a relatively low fluence rate but at a high total
fluence dose, as discussed above. The light source(s) may be
deactivated after passage beyond the duodenum to avoid unwanted
distal photoactivation. In this manner, a photosensitizing agent
132 comprising the APC is activated topically without the need for
a procedure such as endoscopy with fiberoptic gastric illumination
in order to provide the activating light. Since the APC is
targeted, nonspecific uptake by normal tissue and other normal
compositions of the body is minimized in order to prevent injury to
normal gastric tissue and problems with the gastric system.
[0103] In this exemplary treatment, the following protocol may be
utilized:
[0104] Step 1 Patient is NPO for six hours to insure that the
stomach is empty.
[0105] Step 2 The APC is ingested.
[0106] Step 3 One hour elapses to allow for bacterial binding and
distal passage of unbound APC. The optimal period can be longer or
shorter and is readily determined by measuring the clinical
response; for example, response can be determined endoscopically by
observation and biopsy.
[0107] Step 4 One or more light sources are ingested sequentially
and activated in the stomach. The length of time that light is
administered by these sources and the number of sources that are
ingested will be determined clinically in a light dose escalation
study. The churning action of the stomach serves to translocate the
light source(s) so that the light is distributed more evenly prior
to passage of the source(s) into the duodenum. Since each light
source is small (the size of a pill or tablet), it passes easily
out through the GI system via peristalsis.
[0108] Step 5 The light sources are deactivated after distal
passage beyond the gastroduodenal area and excreted in fecal
matter.
[0109] Note that it is also contemplated that an external light
source located over the gastric area can be used to
transcutaneously administer light to the treatment site, and that
an ultrasonic transducer (not shown here, but generally like that
shown in FIG. 5) can alternatively be employed to activate the APC,
provided that photosensitizer agent 132 comprising the APC is
activated by the frequency of ultrasonic energy transmitted by the
transducer. The use of an external light source requires that the
APC and the light source absorb and emit in the near infrared to
infrared range, respectively, so that the light will efficiently
penetrate the patient's skin and reach the treatment site. Examples
of long waveband photosensitizers are ICG, toluidine blue, and
methylene blue, as disclosed herein.
Example 5
[0110] Transcutaneous PDT for Targeting Pulmonary Tuberculosis
[0111] An APC is formulated to bind with great affinity to
Mycobacterium tuberculosis in a selective and specific manner.
Preferably, the APC is formulated as an aerosol, which can be
easily inhaled, enabling distribution into all lung segments. Steam
is then inhaled to solubilize any unbound APC and facilitate its
removal from the lung by exhalation. Alternatively, the APC is
formulated as an injectable compound and administered
intravenously. Either way, the bound APC is photoactivated by an
external light source disposed on the chest and/or back.
[0112] Step 1 The APC is inhaled or injected.
[0113] Step 2 Time is allowed to elapse to allow binding of the APC
with the Mycobacterium tuberculosis, followed by steam inhalation
to remove any unbound APC (if inhaled). The time required to ensure
a therapeutically effective dose of bound APC may be routinely
determined clinically using standard clinical practices and
procedures.
[0114] Step 3 The light source is disposed adjacent to the thorax
and activated for a sufficient time to ensure that therapeutic
irradiation has occurred, which may be routinely determined
clinically using conventional clinical practices and procedures.
The fluence rate and total fluence dose may be determined as noted
above.
[0115] Note that alternatively, an internal light source disposed
within the thoracic area can be used to administer the light. A
further alternative would be the use of an external ultrasonic
transducer to produce ultrasonic sound waves that activate the APC.
The use of an external light source requires that the APC and the
light source respectively absorb and emit light in the near
infrared to infrared range to ensure efficient skin penetration of
the light. Examples of long waveband photosensitizers are ICG,
toluidine blue, and methylene blue.
Example 6
[0116] Transcutaneous PDT for Targeting Otitis Media
[0117] A photosensitizer conjugate is formulated which binds with
great affinity to Streptococcus pneumoniae and Hemophilus
influenzae in a selective manner. The APC is formulated into an
injectable compound, which can be administered intravenously or
instilled topically into the middle ear via a previously placed
tympanostomy tube. The drug is activated using light emitted by a
small light source about the size, shape, and weight of a hearing
aid, which is disposed behind the ear and aimed at the middle ear,
so that the light passes into the middle ear transcutaneously.
[0118] Step 1 The APC fluid formulation is instilled into the
middle ear.
[0119] Step 2 Sufficient time is allowed to elapse to allow binding
of the APC with the disease organisms, and then, any excess fluid
is drained away by gravity or actively aspirated using a needle and
syringe.
[0120] Step 3 The light source is positioned behind the ear and
activated. The light source need not be very intense since the
middle ear cavity is small. Further, the fluence rate and total
fluence dose may be followed as discussed above.
Example 7
[0121] Transcutaneous PDT for Targeting Antibiotic Associated
Pseudo membranous Colitis
[0122] In cases where Clostridium difficile causes pseudomembranous
colitis, the same scheme disclosed above for the treatment of H.
pylori may be applied. The difference is that the APC is targeted
toward C. difficile and the ingested light source is activated in
the colon rather than in the stomach. Alternatively, the
photosensitive agent can be activated with transcutaneously
transmitted light from an external light source, or by ultrasonic
energy produced by an ultrasonic transmitter.
Example 8
[0123] Transcutaneous PDT for Targeting Septic Shock Disease
[0124] A number of anti-endotoxin antibodies and peptides have been
developed and synthesized that can be bound to photosensitizers to
form anti-endotoxin APCs. These APCs are injected, allowed to bind
and then activated transcutaneously with light, or by using the
intracorporeal light emitting devices disclosed in U.S. Pat. No.
5,702,432. For transcutaneous activation, an external light source
is placed over a major vessel, preferably an artery, but most
preferably a vein where the blood flow is slower, to allow more
time for APC activation.
Example 9
[0125] Liver Cancer Photodynamic Therapy by Transillumination
[0126] This Example uses the present invention for the treatment of
an organ infiltrated with tumor tissue. Reference is made to FIG.
9. Specifically, light 140 is administered by transillumination
through liver tissue 148 from an implanted light source 144 that is
disposed external to the surface of liver 142, but within the
patient's body underneath the skin layer 18. In this embodiment, a
patient is injected intravenously with a photosensitizer agent ICG,
conjugated to an antibody that is specific to vascular endothelial
antigen (not separately shown) on a tumor 146, so that the antibody
binds with the antigen, but not to other tissue in the liver. The
optimal dose of ICG will be empirically determined, for example,
via a dose escalation clinical trial as is so often performed to
evaluate chemotherapeutic agents. One or more light source probes
144 are surgically implanted (e.g., endoscopically) adjacent to,
but not invading parenchymal tissue 148 of liver 142. After
delaying a time sufficient to permit clearing of the
photosensitizer conjugate from the non-target tissues, the light
source(s) is(are) activated, irradiating the target tissue with
light 140 at a relatively low fluence rate, but administering a
high total fluence dose of light in the waveband from about 750 nm
to about 850 nm.
[0127] The specific dose of photosensitizer conjugate administered
to the patient is that which will result in a concentration of
active ICG in the blood of between about 0.01 .mu.g/ml and about
100 .mu.g/ml and more preferably, between about 0.01 .mu.g/ml and
about 10 [.mu.g/ml. It is well within the skill of the ordinary
skilled artisan to determine the specific therapeutically effective
dose using standard clinical practices and procedures. Similarly, a
specific acceptable fluence rate and a total fluence dose may be
empirically determined based upon the information provided in this
disclosure.
[0128] Although the present invention has been described in
connection with the preferred form of practicing it, those of
ordinary skill in the art will understand that many modifications
can be made thereto within the scope of the claims that follow.
Accordingly, it is not intended that the scope of the invention in
any way be limited by the above description, but instead be
determined entirely by reference to the claims that follow.
* * * * *