U.S. patent number 5,490,840 [Application Number 08/312,362] was granted by the patent office on 1996-02-13 for targeted thermal release of drug-polymer conjugates.
This patent grant is currently assigned to General Electric Company. Invention is credited to Thomas R. Anthony, Harvey E. Cline, Lorinda R. Opsahl, Egidijus E. Uzgiris, Kirby G. Vosburgh.
United States Patent |
5,490,840 |
Uzgiris , et al. |
February 13, 1996 |
Targeted thermal release of drug-polymer conjugates
Abstract
Thermal drug treatment of tumor tissue is obtained by attaching
a thermally active drug to carrier molecules which have an affinity
to tumor tissue. Localized heating is performed on the tumor
tissue, thereby activating the drug in the tumor tissue. The end
result may be concentrated delivery of a drug to a chosen tissue,
or, in the case where the drug creates a toxin when heated,
selective tissue destruction of a selected locations heated. The
localized heat may be applied by focused ultrasound heating.
Inventors: |
Uzgiris; Egidijus E.
(Niskayuna, NY), Opsahl; Lorinda R. (Clifton Park, NY),
Vosburgh; Kirby G. (Niskayuna, NY), Anthony; Thomas R.
(Niskayuna, NY), Cline; Harvey E. (Niskayuna, NY) |
Assignee: |
General Electric Company
(Schenectady, NY)
|
Family
ID: |
23211113 |
Appl.
No.: |
08/312,362 |
Filed: |
September 26, 1994 |
Current U.S.
Class: |
604/22; 128/898;
424/9.34; 600/439; 601/3 |
Current CPC
Class: |
A61M
37/0092 (20130101) |
Current International
Class: |
A61M
37/00 (20060101); A61B 017/20 () |
Field of
Search: |
;128/653.2,653.4,662.02,660.03 ;604/20,22 ;424/9 ;601/2,15,3
;607/97,901 |
References Cited
[Referenced By]
U.S. Patent Documents
Other References
Pimm, Malcolm. "Critical Reviews in Therapeutic Drug Carrier
Systems", vol. 5, issue 3 (1988). .
Lele, P. P., "Hyperthermiaby Utrasound", M.I.T. .
"The Demonstration of Human Tumors on Nude Mice Using
Gadolinium-Labelled Monoclonal Antibodies for Magnetic Resonance
Imaging by S.Gohr-Rosenthal, H. Schmitt-Willich, W. Ebert & J.
Conrad, Investigative Radiolog", vol. 28, No. 9, 789-795..
|
Primary Examiner: Rosenbaum; C. Fred
Assistant Examiner: Smith; Chalin
Attorney, Agent or Firm: Zale; Lawrence P. Snyder;
Marvin
Claims
What we claim is:
1. A method of thermal drug treatment of tumor tissue of a subject
comprising the steps of:
a) selecting drug molecules used in tumor tissue treatment of
living subjects;
b) selecting a polypeptide carrier molecule of a size such that it
will pass freely into tumor tissue but substantially none will pass
into normal tissue;
c) binding drug molecules to carrier molecules to result in
combined carrier/drug molecules;
d) introducing the carrier/drug molecules into a blood vessel of
said subject having said tumor tissue desired to be destroyed
causing the carrier/drug molecules to infuse into the tumor tissue;
and
e) heating the tumor tissue employing focused ultrasound and the
carrier/drug molecules within the tumor tissue to cause the
carrier/drug molecules to produce a toxin having a relatively
increased concentration in the tumor tissue as compared with the
concentration in other tissues of said subject.
2. The method of thermal drug treatment of claim 1 wherein the
polypeptide carrier molecules are chosen to have a plurality of
residues such that the combined charge of molecules of the selected
polypeptide and selected drug is a net negative charge.
3. The method of thermal drug treatment of claim 1 wherein the
polypeptide carrier molecules and drug molecules have a combined
molecular size chosen to selectively accumulate in the tumor
tissue.
4. The method of thermal drug treatment of claim 1 wherein the
polypeptide carrier molecules are selected to be polylysine
molecules having a plurality of attached residues.
5. The method of thermal drug treatment of claim 1 wherein the
drugs are chosen to be chemotherapy drugs.
Description
CROSS REFERENCES TO RELATED APPLICATIONS
This application is related to co-pending U.S. patent applications
"Method Of Enhanced Drug Delivery To Tumor Tissue With High Charge
Macromolecules" by Uzgiris Ser. No. 08/312,367, filed Sep. 26,
1994; and "Image Guided Thermal Release Of Drugs From Targeted
Liposomal Drug Carriers" by Opsahl, Uzgiris Ser. No. 08/312,369,
filed Sep. 26, 1994; and "Method Of Maximizing Tumor Contrast With
High Charge Macromolecules" by Uzgiris Ser. No. 08/312,361, filed
Sep. 26, 1994; "Method Of Maximizing Tumor Contrast With Contrast
Agents Of High Molecular Weight" by Uzgiris, Opsahl Ser. No.
08/312,368 filed Sep. 26, 1994 all assigned to the present assignee
and hereby incorporated by reference.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to medical treatment of tumor tissue,
and more specifically, deals with optimizing tissue destruction
with focused ultrasound heating.
2. Description of Related Art
Devices have been developed which focus ultrasonic sound waves at a
focal point deep within a subject. At the focal point, energy is
dissipated and local heating results. Of the tissue is allowed to
come to a sufficiently high temperature for a sufficiently long
period of time, the tissue will be denatured and be re-absorbed by
the body. In this manner, tumors can be killed as without the
necessity of an operation.
In some cases, it may not be possible to locally heat a tumor to a
high enough temperature without causing serious damage to the
patient. For example, a tumor tangled around the brain stem may not
be treatable by this method because of the danger of thermal damage
to the brain stem.
Another method of destroying tumor tissue is through chemotherapy.
In conventional chemotherapy, a patient is injected with a
poisonous compound that concentrates in the faster growing tissue
of a tumor. The dose of the poisonous compound is adjusted such
that the concentration in the normal tissue does not reach toxic
levels while the concentration in the tumor is high enough to
destroy it.
One alterative to simple chemotherapy is photodynamic therapy where
the body is injected with a photosensitive compound that tends to
concentrate in the tumor. The primary photosensitive compound
itself is harmless. However, when the compound is exposed to light,
it breaks down into successor compounds at least one of which is
toxic to the tissue. By concentrating light on the tumor, the
compound break down and toxicity are limited to the tumor. One
problem with this approach is that the patient is largely opaque
and any light that is transmitted by the body is highly scattered
and diffuse. Consequently, it is difficult to expose tumors in many
parts of the body to light.
In many medical procedures, it is important to accumulate a certain
chemical entity to a desired tissue type. In chemotherapy, it is
important to deliver drugs to a cancerous tumor tissue. Traditional
anti-tumor therapies, including chemotherapy and radiation
treatments, rely upon a differential response between normal tissue
and cancerous cells. However, there remains unavoidable toxicity
towards normal tissue which causes substantial side effects and
limit practical drug dosages.
Much work has been done in the area of developing specific chemical
entities attached to antibodies, that are specific to tumor
antigens. Delivery of chemical entities by this method is a
difficult task since it requires finding antibodies which are
specific to tumor antigens, and do not bind to other tissue. For
most human tumors, the associated antibodies are not specific only
to this type of tissue.
A further problem is that once antibody has been found that binds
to the type of tumor intended to be destroyed, the delivery of the
chemical entity may not be very large since the density of the
antibodies on the surface of the cells of tumor tissue is generally
not high.
Currently there is a need for a method of treatment of tumor tissue
of a subject with limited collateral damage to adjacent tissues of
the subject.
SUMMARY OF THE INVENTION
Drug molecules are accumulated in tumor tissue of a subject, then
heated by localized focused ultrasound heating to cause the drug to
be activated, or released from, a carrier causing an increased
concentration of the drug in the heated region, as opposed to other
regions of the subject. Carrier molecules may be used to facilitate
the accumulation of the drug in the tumor tissue. The carriers are
chosen to preferentially accumulate in tumors through enlarged
pores in the blood vessels of the tumor tissue, but remain in the
vessels in normal tissue. Drug molecules are conjugated to carrier
molecules through a labile bond that can be readily broken at
mildly elevated temperatures above the subject's body temperature.
Thus drug release, or toxin creation, could be adjusted depending
upon the temperature of the location being heated.
OBJECT OF THE INVENTION
It is an object of the present invention to provide a method of
selectively destroying tissue within a living subject using focused
ultrasonic heating of chemical compounds injected into the subject
at lower temperatures than are possible with focused ultrasound
heating alone.
It is another object of the present invention to provide method of
selectively destroying tissue within a living subject that reduces
collateral damage in surrounding tissue.
It is another object of the present invention to provide an
increased concentration of a drug within tumor tissue as compared
with other tissue of the patient.
It is another object of the present invention to provide a method
for selectively destroying cancerous tissue within a subject.
It is another object of the present invention to selectively
deliver large concentrations of therapeutic drugs to tumor tissue,
with limited side affects on adjacent tissue.
BRIEF DESCRIPTION OF THE DRAWINGS
While the novel features of the invention are set forth with
particularity in the appended claims, the invention, both as to
organization and content, will be better understood and
appreciated, along with other objects and features thereof, from
the following detailed description taken in conjunction with the
drawing, in which:
FIG. 1 is an illustration of drug/carrier molecule complexes
delivery to tumor tissue.
FIG. 2 is a schematic block diagram of an MR Therapy system
compatible with use of the present invention.
FIG. 3 is an illustration of a patient positioned within the bore
of the magnets of the MR Therapy system of FIG. 2 as the patient
would appear during localized heating of a desired location of the
patient.
FIG. 4 is a graph of percentage of a drug released over time at
different applied temperatures.
FIG. 5 is a graph of the accumulated amount of a drug released
after one hour as a function of temperature.
DETAILED DESCRIPTION OF THE INVENTION
Although the body is opaque to light, it is often transparent to
ultrasonic waves. If ultrasound waves are emitted from a focused
ultrasound transducer or a phased array, they can be concentrated
at any location in the body and cause local heating there. If the
body is injected with a thermally metastable compound that tends to
naturally concentrate in the faster growing tissue of the tumor
while these ultrasonic waves are concentrated on a tumor, the
compound will break down and only produce toxic reaction products
in the tumor tissue. If C.sub.T is the ratio of the concentration
of the metastable compound in the tumor as compared to normal
tissue and C.sub.R is the ratio of the decomposition rate at
temperature T in the tumor versus the normal body temperature
T.sub.0, then the concentration ratio R of toxic reaction products
in the tumor relative to normal tissues is given by:
R must be greater than 1 for the method to function. C.sub.R can be
less than 1, but preferably as high as possible. C.sub.R can vary
from 0.1-1000. Preferably C.sub.R and C.sub.T will be chosen such
that R is very high. The decomposition rate ratio is given by:
where .DELTA.G is the free energy of the chemical reaction.
The combination of equations (1) and (2) yield the ratio R of the
toxic compound in the tumor to the other tissues in the body.
As an example, consider a chemical reaction with a free energy
change of .DELTA.G=25 kcal/mole. If the temperature in the tumor is
raised by 10 degrees Centigrade by the ultrasonic heating over the
normal tissue temperature of 36 Centigrade, the enhancement of
toxic reaction products in the tumor is a factor of 3.55X. If
.DELTA.G=15 kcal/mole, the enhancement is 2.14X. This enhancement
could be used either to raise the toxicity level in the tumor or to
lower the toxicity level in the healthy tissue. Compounds would be
synthesized that had free energy of reactions that are low enough
to be thermally decomposed but large enough to significantly
increase the toxicity level in the tumor. Suitable free energies of
reaction would be from 5 to 50 Kcal/mole.
The present invention enhances drug delivery to tumor tissue and
consequently, tissue destruction, by causing an elevated
concentration of the drug in the tumor tissue. This may be done by
injecting a metastable compound and then perform localized heating
which induces breakdown of a metastable compound into a toxin only
where heated.
The present invention takes advantage of the differences in tumor
tissue from normal tissue to cause additional accumulation of the
drug in the tumor tissue. Tumors tend to have vasculature which has
much larger pores and tend to be `leaky`. The use of a small
molecule, for chemotherapy treatment causes it to pass out into the
tumor interstitial spaces and readily migrates its way back into
the vasculature and is removed from the region. The drug is
attached to a carrier molecule, with a labile bond. The carrier
molecules have an affinity to tumor tissue. In the aforementioned
U.S. patent applications, "Method Of Maximizing Tumor Contrast With
Contrast Agents Of High Molecular Weight" by Uzgiris, Opsahl Ser.
No. 08/312,368; and "Image Guided Thermal Release Of Drugs From
Targeted Liposomal Drug Carriers" by Opsahl, Uzgiris Ser. No.
08/312,369; the importance of molecular size of the carrier and
molecules, in causing them to accumulate in tumor tissue through
the enlarged pores of tumor vasculature, and thereby become
`trapped` within the tumor tissue interstitium is described. Also,
in the aforementioned U.S. patent applications "Method Of Enhanced
Drug Delivery To Tumor Tissue With High Charge Macromolecules" by
Uzgiris Ser. No. 08/312,367; and "Method Of Maximizing Tumor
Contrast With High Charge Macromolecules" by Uzgiris Ser. No.
08/312,361 it was shown that chemical entities (a drug and a
contrast agent, respectively) may be `piggybacked` on a
sufficiently charged carrier molecule to result in a
carrier/chemical entity complex having a net negative charge to
further increase accumulation of the carrier/chemical entity in the
tumor tissue, along with cause increased retention in the tumor
tissue.
The carrier molecules are chosen to have a size such that they
would not leak from the blood vasculature through pores in normal
tissue but would do so through the larger pores of tumor
vasculature and Would accumulate over a period of time in the tumor
interstitium. The carrier molecules are also of such a size that
they do not readily re-enter the post capillary circulation as do
small molecules. A size of approximately 100 nm diameter was chosen
which distribute preferentially into cancer tissue due to the leaky
nature of tumor vasculature. This, together with an ineffective
lymphatic drainage system in tumor tissue, results in the retention
of carrier molecules for an extended period of time as compared
with small molecules.
In FIG. 1, a plurality of complexes of carrier molecules attached
to drug molecules encapsulating an amount of a drug, is shown as
"C". A solution of complexes, 7a, 7b, 7c is introduced into a
patient's blood vessel 3. These complexes follow blood vessel 3 and
are contained by blood vessel 3 since pores 9 in normal tissue are
a size small enough to contain complexes 7a, 7b, 7c. Once the
complexes enter tumor tissue 5, pore size becomes enlarged shown as
pores 11. Complexes 7d and 7g pass through pores 11 and into
interstitial space of tumor 5. Complex 7e is shown working its way
through the interstitial space of tumor 5. Stroma 13 typically
develops in tumor 5 thereby further entangling and holding
complexes within the interstitial spaces. The clearance of small
molecules from the tumor interstitium is rather rapid. Complexes
according to the present invention are able to leak into the tumor
interstitium, but their clearance from the tumor is retarded due to
their size. Complexes do not readily exit the tumor interstitium by
the route of post capillary drainage, which is the dominant route
of clearance of small molecules from the interstitial space of
tumor tissue. Eventually, the complexes may be cleared through the
residual lymphatic drainage that may be present in the tumor
tissue. If the complex are chosen to be very large, however, they
may never fit through the pores of the vasculature and would be
excluded from the interstitial space of tumor 5.
Conventional Magnetic Resonance (MR) Imaging provides a radiologist
with internal views of a patient's anatomy. MR imaging provides
excellent contrast between different tissues and is useful in
planning surgical procedures. A tumor in a patient is much more
visible in an MR image than as seen in actual surgery because the
tumor and normal tissue often look similar in surgery. The tumor
can also be obscured by blood during surgery.
A view of the heated region may also be provided with the use of MR
temperature sensitive pulse sequences. MR imaging
temperature-sensitive pulse sequences are described in U.S. Pat.
No. 5,307,812 May 3, 1994 "Heat Surgery System Monitored by
Real-Time Magnetic Resonance Profiling" by C. Hardy, H. Cline which
describes capturing temperature mapped images of a subject.
In U.S. Pat. No. 5,247,935 Sep. 28, 1993 "Magnetic Resonance Guided
Focused Ultrasound Surgery" by H. Cline, R. Ettinger, K. Rohling,
R. Watkins; and U.S. Pat. No. 5,275,165 Jan. 4, 1994 "Magnetic
Resonance Guided Ultrasound Therapy System With Inclined Track to
Move Transducers in a Small Vertical Space" by R. Ettinger et al.,
assigned to the present assignee and hereby incorporated by
reference, an ultrasound transducer is positioned within an MR
Imaging magnet with the use of hydraulics so as to focus ultrasound
heat to a specific location selected by the operator. Since an MR
imaging system is employed, internal structures may be imaged.
Also, since temperature-sensitive MR pulse sequences may be used, a
heated region may also be imaged and registered with a conventional
MR image providing feedback of the location being heated.
A schematic block diagram of an MR therapy system is shown in FIG.
2. An MR imaging system 10 employs pulse sequences in the well
known manner to rapidly acquire images of a patient 15. A gradient
amplifier 40 and a radiofrequency (RF) power source 50 supply the
power for the sequences. An operator console 60 is used to control
the imaging system. Raw data is sent from receiver 20 to a control
workstation 30 that displays images on a display means 110 to a
surgeon. Control workstation 30 may compute a path from transducer
19 to a desired location within patient 15 which avoids bone and
air spaces. The surgeon indicates the desired location of the focal
point of ultrasound transducer 19 by means of an input device 120
which can be a three-dimensional pointing device such as a track
ball or a mouse.
Control workstation 30 actuates a positioning means 70 to position
ultrasound transducer 19. MR imaging system 10 then employs pulse
sequences to rapidly acquire temperature sensitive images of
patient 15. Since both the internal structures and heated regions
are imaged, the surgeon can accurately position the heated region
to correspond to a desired internal structure through input device
120.
As shown in FIG. 3, patient 15 is placed on a table 11 designed to
accommodate focused ultrasound transducer 19 in an ultrasound
conducting liquid bath 17. Ultrasound conducting liquid 17 is
chosen to be one that will conduct ultrasonic energy with little
attenuation. Ultrasound transducer 19 can be moved inside the bore
of an MR imaging magnet 13 by positioning means 70 to focus on
different locations within patient 15. The focal point of
ultrasound transducer 19 is positioned along the computed path by
positioning means 70 onto a tumor 15. The ultrasound transducer is
moved while the surgeon views temperature sensitive images.
It is now possible to accurately view tumor tissue with MR imaging,
heat deep lying tumor tissue with focussed ultrasound, and adjust
the location of heat application by viewing temperature sensitive
MR images superimposed upon conventional MR images. This would
allow the operator to adjust the location of the ultrasound focus
to correspond to the tumor tissue.
By selectively heating the tumor tissue, the labile bond is broken
and the drug is released. Release is effectuated in locations
having a high temperature, and very little where there is normal
body temperature. By specifically localizing the heat, it is
possible to achieve a much larger concentration of the drug in the
tumor tissue as compared with other tissues which are not
heated.
Carrier molecules may be polylysine, human serum albumin (HSA),
dextran, or other similar sized polypeptides. Experiments were
performed using fluorescein isothiocyanate (FITC) conjugated rabbit
imunoglobin G (IgG) molecule. The conjugation is through a
thio-urea bond, that is the isothiocyanate moiety links to an amine
group of the protein such that the bond is:
{fluorescein}-N-CS-N-{protein}. At 4.degree. C. the bond is stable,
but at elevated temperatures the FITC is released from the protein
as shown in an assay performed by filtering the test solution
through an Amicon 30,000 kDa cutoff membrane filter. The release
rate at different temperatures is shown in FIG. 4. The cumulative
release after one hour exposure to different temperatures is shown
in FIG. 5. At approximately 55.degree. C. there is an efficient
release of the FITC from the macromolecule.
The present invention may function in two different modes. It may
act primarily as a drug delivery system in which elevated dosages
of a toxic chemical are delivered to tumor tissue. It may also act
primarily as a thermal tissue destruction system which destroys
tissue at its focal point aided by the drug delivered to the tumor
tissue. Both modes minimize side effects due to drug interaction
with normal tissue. Beneficial synergistic effects are anticipated
through the simultaneous use of minimally-invasive thermal
therapies and drug release.
While specific embodiments of the invention have been illustrated
and described herein, it is realized that modifications and changes
will occur to those skilled in the art. It is therefore to be
understood that the appended claims are intended to cover all such
modifications and changes as fall within the true spirit and scope
of the invention.
* * * * *