U.S. patent application number 16/913592 was filed with the patent office on 2020-12-24 for interventional drug delivery system and associated methods.
The applicant listed for this patent is The University of North Carolina at Chapel Hill. Invention is credited to James Byrne, Joseph DeSimone, Mary Napier, Matt Parrott, Jonathan Pillai, Lukas Miller Roush, Jen Jen Yeh.
Application Number | 20200398049 16/913592 |
Document ID | / |
Family ID | 1000005066258 |
Filed Date | 2020-12-24 |
View All Diagrams
United States Patent
Application |
20200398049 |
Kind Code |
A1 |
DeSimone; Joseph ; et
al. |
December 24, 2020 |
INTERVENTIONAL DRUG DELIVERY SYSTEM AND ASSOCIATED METHODS
Abstract
A delivery system for local drug delivery to a target site of
internal body tissue is provided. The delivery system comprises a
source electrode adapted to be positioned proximate to a target
site of internal body tissue. A counter electrode is in electrical
communication with the source electrode, and is configured to
cooperate with the source electrode to form a localized electric
field proximate to the target site. A reservoir is configured to be
disposed such that the reservoir is capable of interacting with the
localized electric field. The reservoir is configured to carry a
cargo capable of being delivered to the target site when exposed to
the localized electric field. Associated methods are also
provided.
Inventors: |
DeSimone; Joseph; (Chapel
Hill, NC) ; Napier; Mary; (Carrboro, NC) ;
Pillai; Jonathan; (Chapel Hill, NC) ; Byrne;
James; (Chapel Hill, NC) ; Roush; Lukas Miller;
(Chapel Hill, NC) ; Yeh; Jen Jen; (Chapel Hill,
NC) ; Parrott; Matt; (Carrboro, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
The University of North Carolina at Chapel Hill |
Chapel Hill |
NC |
US |
|
|
Family ID: |
1000005066258 |
Appl. No.: |
16/913592 |
Filed: |
June 26, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14748361 |
Jun 24, 2015 |
10695562 |
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16913592 |
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13202810 |
Aug 23, 2011 |
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PCT/US10/25416 |
Feb 25, 2010 |
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14748361 |
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61155880 |
Feb 26, 2009 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61N 1/36002 20170801;
A61N 1/044 20130101; A61L 31/16 20130101; A61N 1/0507 20130101;
A61B 2018/00898 20130101; A61B 18/1492 20130101; A61N 1/0428
20130101; A61N 1/05 20130101; A61N 1/303 20130101; A61N 1/30
20130101; A61N 1/325 20130101; A61N 1/0448 20130101; A61N 1/00
20130101; A61K 9/0024 20130101; A61N 1/0444 20130101; A61N 1/327
20130101; A61B 2018/00214 20130101; A61K 9/0009 20130101; A61N
1/306 20130101; A61K 9/0002 20130101 |
International
Class: |
A61N 1/30 20060101
A61N001/30; A61N 1/32 20060101 A61N001/32; A61N 1/04 20060101
A61N001/04; A61N 1/00 20060101 A61N001/00; A61N 1/05 20060101
A61N001/05 |
Goverment Interests
FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
[0002] This invention was made with government support under Grant
Number CHE-9876674 awarded by the National Science Foundation. The
government has certain rights in the invention.
Claims
1. A delivery system for local drug delivery to a target site of
internal body tissue, comprising: a source electrode adapted to be
positioned proximate to a target site of internal body tissue; a
counter electrode in electrical communication with the source
electrode, the counter electrode being configured to cooperate with
the source electrode to form a localized electric field proximate
to the target site; and a reservoir capable of interacting with the
localized electric field, the reservoir being configured to carry a
cargo capable of being delivered to the target site when exposed to
the localized electric field formed between the source electrode
and the counter electrode.
2. A delivery system according to claim 1, further comprising an
electrode deployment device configured to insert at least one of
the source electrode and the counter electrode proximate to the
target site of internal body tissue in vivo.
3. A delivery system according to claim 2 further comprising a
control system in communication with the electrode deployment
device, the control system being configured to guide the electrode
deployment device with placement of the source electrode and the
counter electrode.
4. A delivery system according to claim 2 wherein the electrode
deployment device comprises one of a catheter device, an endoscopic
device, a laparoscopic device, an implantable device, and
combinations thereof.
5. A delivery system according to claim 4 wherein the catheter
device comprises a first and second expandable member serially
disposed along a longitudinal axis of the catheter device, the
source electrode being axially disposed between the first and
second expandable members such that, upon inflation of the first
and second expandable members to occlude the target site, the
target site is isolated and the delivery of the cargo is contained
to the target site.
6. A delivery system according to claim 4 wherein the catheter
device comprises a perforated polymer sheath, the cargo being
capable of exiting the catheter device through a plurality of
perforations defined by the perforated polymer sheath, and the
source electrode comprising an array of probes terminating at
different lengths and being independently powered such that the
probes are capable of being variably controlled, the source
electrode further comprising a plurality of insulating members
disposed about and between the probes so as to form cargo delivery
zones substantially aligned with the perforations of the perforated
polymer sheath.
7. A delivery system according to claim 4 wherein the endoscopic
device comprises a proximal end and a distal end having the source
electrode disposed thereabout for positioning proximate to the
target site, the source electrode comprising a hollow needle member
forming the reservoir, the proximal end having a port to fluidly
connect the proximal and distal ends such that the reservoir is
capable of being remotely filled with the cargo.
8. A delivery system according to claim 1 wherein the cargo
comprises at least one of small ionic molecules, nucleic acids,
proteins, organic nanoparticles, therapeutic agents, and imaging
agents.
9. A delivery system according to claim 1 wherein the source
electrode includes an array of probes comprising one of thin wires,
foil, mesh, pellets, disks, stents, clamps, prongs, clips, needles,
hollow tubes, and combinations thereof.
10. A delivery system according to claim 1 wherein the source
electrode and the counter electrode are comprised of one of a
metallic material, a conductive polymer material, and combinations
thereof.
11. A delivery system according to claim 1 further comprising at
least one insulating member at least partially disposed about the
source electrode, the at least one insulating member being
configured to confer directionality to the transport profile of the
cargo released from the reservoir.
12.-25. (canceled)
26. A method of delivering a cargo to a target site of internal
body tissue, the method comprising: disposing a source electrode
proximate to a target site of internal body tissue in vivo;
disposing a counter electrode in electrical communication with the
source electrode, the counter electrode being configured to
cooperate with the source electrode to form a localized electric
field proximate to the target site; disposing a reservoir such that
the reservoir is capable of interacting with the localized electric
field, the reservoir being configured to carry a cargo capable of
being delivered to the target site when exposed to the localized
electric field formed between the source electrode and the counter
electrode; and applying a voltage potential across the source and
counter electrodes to form an electric field, thereby delivering at
least a portion of the cargo to the target site.
27. A method according to claim 26, wherein disposing the source
electrode comprises disposing the source electrode proximate to the
target site of internal body tissue in vivo using an electrode
deployment device.
28. A method according to claim 27 further comprising guiding the
electrode deployment device with a control system in communication
therewith, the control system being configured to guide the
electrode deployment device for positioning of the source electrode
and the counter electrode.
29. A method according to claim 27 wherein disposing a source
electrode further comprises disposing a source electrode with an
electrode deployment device comprising one of a catheter device, an
endoscopic device, a laparoscopic device, an implantable device,
and combinations thereof.
30. A method according to claim 29 wherein disposing a source
electrode further comprises disposing a source electrode with an
electrode deployment device comprising a catheter device having a
first and second expandable member serially disposed along a
longitudinal axis of the catheter device, the source electrode
being axially disposed between the first and second expandable
members such that, upon inflation of the first and second
expandable members to occlude the target site, the target site is
isolated and the delivery of the cargo is contained to the target
site.
31. A method according to claim 29 wherein disposing a source
electrode further comprises disposing a source electrode with an
electrode deployment device comprising a catheter device having a
perforated polymer sheath, the cargo being capable of exiting the
catheter device through a plurality of perforations defined by the
perforated polymer sheath, and the source electrode comprising an
array of probes terminating at different lengths and being
independently powered such that the probes are capable of being
variably controlled, the source electrode further comprising a
plurality of insulating members disposed about and between the
probes so as to form cargo delivery zones substantially aligned
with the perforations of the perforated polymer sheath.
32.-48. (canceled)
49. A method of treating a target site of body tissue, the method
comprising: delivering a therapeutic agent to a body cavity of a
patient for storage thereof; positioning a first electrode
proximate to a target site of internal body tissue; positioning a
second electrode such that the second electrode is in electrical
communication with the first electrode; and applying a voltage
potential across the first and second electrodes to drive the
therapeutic agent from the body cavity to the target site.
50. A method according to claim 49 wherein delivering a therapeutic
agent to a body cavity further comprises implanting a device within
the body cavity, the device being configured to carry and release
the therapeutic agent upon the voltage potential being applied
between the first and second electrodes.
51. A method according to claim 49 wherein delivering a therapeutic
agent to a body cavity further comprises delivering a therapeutic
agent to one of a peritoneal cavity, a cranial cavity, an oral
cavity, a pleural cavity, an abdominopelvic cavity, and a pelvic
cavity.
52.-53. (canceled)
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This is a continuation application of U.S. application Ser.
No. 14/748,361, filed Jun. 24, 2015, which is a continuation of
U.S. application Ser. No. 13/202,810, filed Aug. 23, 2011, which is
a national phase application of International Application No.
PCT/US2010/025416, filed Feb. 25, 2010, which claims priority to
U.S. Provisional Application No. 61/155,880, filed Feb. 26, 2009,
the entire contents of each of which are incorporated by reference
herein in their entireties for all purposes.
BACKGROUND
Field of the Invention
[0003] Embodiments of the present invention relate to an
interventional drug delivery system, and more particularly, to a
system for facilitating delivery of various cargos, such as, for
example, therapeutic agents, to target sites of internal body
tissue in vivo, and methods associated therewith, wherein the
system implements an electric field to drive cargo through tissue
as in iontophoretic approaches.
Description of Related Art
[0004] Many techniques exist for the delivery of drugs and
therapeutic agents to the body. Traditional delivery methods
include, for example, oral administration, topical administration,
intravenous administration, and intramuscular, intradermal, and
subcutaneous injections. With the exception of topical
administration which permits more localized delivery of therapeutic
agents to particular area of the body, the aforementioned drug
delivery methods generally result in systemic delivery of the
therapeutic agent throughout the body. Accordingly, these delivery
methods are not optimal for localized targeting of drugs and
therapeutic agents to specific internal body tissues.
[0005] As a result, other methods, such as endovascular medical
devices, Natural Orifice Translumenal Endoscopic Surgery
(NOTES)-based devices, and iontophoresis, have been developed to
provide localized targeting of therapeutic agents to a particular
internal body tissue. Iontophoresis is a form of drug delivery that
uses electrical current to enhance the movement of charged
molecules across or through tissue. Iontophoresis is usually
defined as a non-invasive method of propelling high concentrations
of a charged substance, normally therapeutic or bioactive-agents,
transdermally by repulsive electromotive force using a small
electrical charge applied to an iontophoretic chamber containing a
similarly charged active agent and its vehicle. In some instances,
one or two chambers are filled with a solution containing an active
ingredient and its solvent, termed the vehicle. The positively
charged chamber (anode) repels a positively charged chemical, while
the negatively charged chamber (cathode) repels a negatively
charged chemical into the skin or other tissue. Unlike traditional
transdermal administration methods that involve passive absorption
of a therapeutic agent, iontophoresis relies on active
transportation within an electric field. In the presence of an
electric field, electromigration and electroosmosis are the
dominant forces in mass transport. As an example, iontophoresis has
been used to treat the dilated vessel in percutaneous transluminal
coronary angioplasty (PTCA), and thus limit or prevent restenosis.
In PTCA, catheters are inserted into the cardiovascular system
under local anesthesia and an expandable balloon portion is then
inflated to compress the atherosclerosis and dilate the lumen of
the artery.
[0006] The delivery of drugs or therapeutic agents by iontophoresis
avoids first-pass drug metabolism, a significant disadvantage
associated with oral administration of therapeutic agents. When a
drug is taken orally and absorbed from the digestive tract into the
blood stream, the blood containing the drug first passes through
the liver before entering the vasculature where it will be
delivered to the tissue to be treated. A large portion of an orally
ingested drug, however, may be metabolically inactivated before it
has a chance to exert its pharmacological effect on the body.
Furthermore it may be desirable to avoid systematic delivery all
together in order to allow high doses locally while avoiding
potential side effects elsewhere, wherein local delivery is
desirable for localized conditions. Existing medical device
technologies that enable localized placement of therapeutics fail
to provide the opportunity to embed/secure therapeutics in the
tissue(s) of interest.
[0007] Accordingly, it would be desirable to provide an improved
system and method for selectively and locally targeting delivery of
various drugs and therapeutic agents to an internal body tissue,
and fixing such cargos in the tissue(s) of interest in vivo.
SUMMARY
[0008] The above and other needs are met by aspects of the present
invention which provide, in one instance, a delivery system, and in
particular, a delivery system for local drug delivery to a target
site of internal body tissue. The delivery system comprises a
source electrode adapted to be positioned proximate to a target
site of internal body tissue. A counter electrode is in electrical
communication with the source electrode. The counter electrode is
configured to cooperate with the source electrode to form a
localized electric field proximate to the target site. An electrode
deployment device may be used and is configured to insert at least
one of the source electrode and the counter electrode proximate to
the target site of internal body tissue in vivo. A reservoir is
capable of interacting with the localized electric field. The
reservoir is configured to carry a cargo capable of being delivered
to the target site when exposed to the localized electric field
formed between the source electrode and the counter electrode. In
some aspects, the drug reservoir is capable of being remotely
filled with the cargo.
[0009] Another aspect provides a method for delivering a cargo to a
target site of internal body tissue. Such a method comprises
disposing a source electrode proximate to a target site of internal
body tissue in vivo using an electrode deployment device, and
disposing a counter electrode in electrical communication with the
source electrode, wherein the counter electrode is configured to
cooperate with the source electrode to form a localized electric
field proximate to the target site. The method further comprises
disposing a reservoir such that the reservoir is capable of
interacting with the localized electric field. The reservoir is
configured to carry a cargo capable of being delivered to the
target site when exposed to the localized electric field formed
between the source electrode and the counter electrode. In some
aspects, the drug reservoir is capable of being remotely filled
with the cargo. The method further comprises applying a voltage
potential across the source and counter electrodes to form an
electric field, thereby delivering at least a portion of the cargo
to the target site.
[0010] Yet another aspect provides a method of treating a target
site of internal body tissue. Such a method comprises delivering a
therapeutic agent to a body cavity of a patient for storage
thereof. The method further comprises positioning a first electrode
proximate to a target site of body tissue, and positioning a second
electrode such that the second electrode is in electrical
communication with the first electrode. The method further
comprises applying a voltage potential across the first and second
electrodes to drive the therapeutic agent from the body cavity to
the target site.
[0011] As such, embodiments of the present invention are provided
to enable highly targeted and efficient delivery of various cargos
to predetermined target sites. In this regard, aspects of the
present invention provide significant advantages as otherwise
detailed herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] In order to assist the understanding of embodiments of the
invention, reference will now be made to the appended drawings,
which are not necessarily drawn to scale. The drawing is exemplary
only, and should not be construed as limiting the invention.
[0013] FIGS. 1A-1G are schematic drawings of various embodiments of
a delivery system having a source electrode and counter electrode
configured to cooperate to form an electric field for delivering a
cargo, according to one embodiment of the present disclosure;
[0014] FIG. 2 is a partial view of a delivery system having a
source electrode 200 with an array of probes 200a, 200b and 200c,
according to an alternative embodiment of the present
disclosure;
[0015] FIG. 3 is a partial view of a delivery system having a
source electrode with an array of probes, according to yet another
embodiment of the present disclosure;
[0016] FIG. 4 is a partial view of a delivery system according to
one embodiment of the present disclosure, illustrating a source
electrode having a plurality of insulating members engaged
therewith;
[0017] FIG. 5 is a partial view of a delivery system disposed
within a tissue lumen, the delivery system having a plurality of
independently controlled source electrodes and a plurality of
insulating members configured to provide controlled delivery zones
for specific targeting of target sites of the tissue lumen,
according to one embodiment of the present disclosure;
[0018] FIG. 6 is a partial view of a delivery system employing a
catheter device for positioning of a source electrode 200, wherein
the delivery system includes a plurality of independently
controlled source electrodes 200a, 200b and 200c and a plurality of
insulating members 250a, 250b, 250c and 250d configured to provide
controlled delivery zones for specific targeting of target sites,
according to one embodiment of the present disclosure;
[0019] FIG. 7 is a partial view of a delivery system having a
source electrode encapsulated by a polymer matrix reservoir having
a cargo contained therein, according to one embodiment of the
present disclosure;
[0020] FIGS. 8A and 8B are partial views of a delivery system
having a source electrode with at least one insulating member
engaged therewith, the source electrode and at least one insulating
member being encapsulated by a polymer matrix reservoir having a
cargo contained therein;
[0021] FIG. 9 is a partial view of a delivery system having a
plurality of independently controlled source electrodes 200a, 200b
and 200c and a plurality of insulating members 250a, 250b, 250c,
and 250d arranged to provide controlled delivery zones, wherein the
source electrodes and the insulating members are encapsulated in a
polymer matrix, according to one embodiment of the present
disclosure;
[0022] FIG. 10 is a partial view of a delivery system having a
source electrode serially disposed between a pair of expandable
members configured to occlude a target site, wherein the expandable
members are in a relaxed state, according to one embodiment of the
present disclosure;
[0023] FIG. 11 is a partial view of the delivery system of FIG. 10,
illustrating the expandable members in an expanded state so as to
occlude the target site such that delivery of a cargo is limited
thereto;
[0024] FIG. 12 is a partial view of a delivery system having a
source electrode comprising a hollow tube needle member configured
to deliver a cargo to a target site of internal body tissue,
according to one embodiment of the present disclosure;
[0025] FIGS. 13A and 13B are partial views of a delivery system
having a counter electrode positioned at various orientations with
respect to the source electrode so as to target delivery of a cargo
to a target site to predetermined in vivo locations;
[0026] FIG. 14 is a partial view of a delivery system having a
coolant device extending about a counter electrode to provide
cooling thereto, the coolant device having a membrane portion
disposed about the counter electrode, according to one embodiment
of the present disclosure;
[0027] FIG. 15 is a partial view of a delivery system having a
coolant device extending about a counter electrode to provide
cooling thereto, wherein the counter electrode is disposed between
an insulating member and a membrane portion of the coolant device,
according to one embodiment of the present disclosure;
[0028] FIG. 16 is a partial view of a delivery system having a
coolant device extending about a counter electrode to provide
cooling thereto, the coolant device having an aperture disposed at
a distal end thereof for permitting a coolant substance to exit
therefrom;
[0029] FIGS. 17A and 17B are images illustrating an experimental
implementation of a delivery system in accordance with one aspect
of the present disclosure;
[0030] FIGS. 18A and 18B are images illustrating an experimental
implementation of a delivery system in accordance with another
aspect of the present disclosure;
[0031] FIGS. 19A-19C are images illustrating an experimental
implementation of a delivery system in accordance with yet another
aspect of the present disclosure;
[0032] FIGS. 20A and 20B are images illustrating an experimental
implementation of a delivery system in accordance with still
another aspect of the present disclosure;
[0033] FIG. 21 is an image illustrating an experimental
implementation of a delivery system in accordance with another
aspect of the present disclosure;
[0034] FIG. 22 is an image illustrating an experimental
implementation of a delivery system in accordance with still yet
another aspect of the present disclosure;
[0035] FIGS. 23A and 23B are images illustrating an experimental
implementation of a delivery system in accordance with one aspect
of the present disclosure;
[0036] FIGS. 24A and 24B are images illustrating an experimental
implementation of a delivery system in accordance with yet another
aspect of the present disclosure;
[0037] FIG. 25 is an image illustrating an experimental
implementation of a delivery system in accordance with one aspect
of the present disclosure;
[0038] FIGS. 26A and 26B are images illustrating an experimental
implementation of a delivery system in accordance with yet another
aspect of the present disclosure;
[0039] FIG. 27 is an image illustrating an experimental
implementation of a delivery system in accordance with one aspect
of the present disclosure;
[0040] FIGS. 28A and 28B are images illustrating an experimental
implementation of a delivery system in accordance with one aspect
of the present disclosure;
[0041] FIG. 29 is an image illustrating an experimental
implementation of a delivery system in accordance with another
aspect of the present disclosure;
[0042] FIGS. 30A-30C are images illustrating an experimental
implementation of a delivery system in accordance with another
aspect of the present disclosure;
[0043] FIGS. 31A and 31B are images illustrating an experimental
implementation of a delivery system in accordance with one aspect
of the present disclosure;
[0044] FIG. 32A illustrates an experimental implementation of a
delivery system in accordance with one aspect of the present
disclosure;
[0045] FIG. 32B shows results of an evaluation of the experimental
implementation of FIG. 32A according to one aspect of the present
disclosure;
[0046] FIGS. 33A-33D depict various perspective views of a delivery
system in accordance with another aspect of the present
disclosure;
[0047] FIG. 34 shows experimental results of an evaluation of an
experimental implementation according to one aspect of the present
disclosure;
[0048] FIG. 35 illustrates experimental results of an evaluation of
an experimental implementation according to one aspect of the
present disclosure;
[0049] FIG. 36 is an image illustrating an experimental
implementation of a delivery system in accordance with an
additional aspect of the present disclosure; and
[0050] FIG. 37 depicts exemplary dimensions of an experimental
implementation of a delivery system in accordance with one aspect
of the present disclosure.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0051] Embodiments of the present invention now will be described
more fully hereinafter with reference to the accompanying drawings.
The invention may be embodied in many different forms and should
not be construed as limited to the embodiments set forth herein;
rather, these embodiments are provided so that this disclosure will
satisfy applicable legal requirements. Like numbers refer to like
elements throughout.
[0052] Embodiments of the present invention are directed to systems
and methods for delivering treatment or therapeutic agents
(otherwise referred to herein as "cargo") to specific locations,
including intracellular locations in a safe and effective manner.
Such systems may deliver the agents to a diseased site in effective
amounts without endangering normal tissues or cells and thus reduce
or prevent the occurrence of undesirable side effects. Further,
such systems may electrically enhance the local delivery of
treatment agents into the wall tissues or cells of the living body.
These systems are designed to target certain tissue and cell
locations and deliver the treatment agents directly to those
locations, while minimizing any effects on non-targeted tissues and
cells. In particular, embodiments of the present invention relate
to systems which provide an electrical driving force that can
increase the rate of migration of drugs and other therapeutic
agents out of a reservoir into body tissues and cells using
iontophoresis and other approaches.
[0053] More particularly, embodiments of the present invention rely
on the transport of charged and uncharged species under the
influence of a localized electric field generated at the site of
interest. The overall transport of charged and uncharged species is
based upon three characteristic driving forces, which includes
passive diffusion, electroosmosis, and electromigration. Passive
diffusion involves the movement of a chemical species from a region
of high concentration to an area of low concentration.
Electroosmosis is the movement of a solute species via a solvent
flow accompanied by the movement of an extraneous charged species.
Electroosmosis encompasses the solvent flow referred to as
hydrokinesis. Electromigration is the movement of a charged species
through an applied electric field to an electrode of opposite
polarity. Transport of a neutrally charged species is driven by
passive diffusion and electroosmosis only, whereas all transport
modalities, passive diffusion, electroosmosis, and electromigration
contribute to the flux of a charged species.
[0054] In this regard, embodiments of the present invention may
provide an interventional drug delivery system and methods for
localized delivery of therapeutic agents to internal locations in
the human body using a controlled electrical field. The systems may
be constructed to deliver the agents specifically to the site of
interest, improving penetration of the agent while limiting effect
upon non-targeted tissue. Embodiments of the present invention may
be fashioned to deliver the agents via intravascular,
intraperitoneal, minimally invasive surgery, and natural orifice
transluminal endoscopic surgery (NOTES) modalities. The action of
the electric field may be controlled through a programmable power
supply or a function generator. By using various electrode designs
and placement configurations, highly localized and focused delivery
of cargo to the tissue of interest may be achieved. The overall
controlled release characteristics of the delivery system may be
dependent upon the charge, size, conductivity, concentration, and
pK.sub.a of the chemical species and nanoparticles, pH of the
surrounding environment, resistance of the site of interest,
current and voltage applied, electrode design and amount of
extraneous ions at site of interest.
[0055] Embodiments of the present invention may be implemented in
the delivery of therapeutic agents for such diverse areas as
oncology, pulmonary, gastrointestinal (GI), and neurology
applications. Embodiments of the present invention find application
in the field of interventional oncology for the treatment of
various cancers, which may include, for example, pancreatic
cancers, lung cancer, esophageal cancers, bladder cancers,
colorectal cancers, liver cancers, hepatic metastases, bile duct
cancers, renal cancers, cervical cancers, prostate cancers, ovarian
cancer, thyroid cancers, uterine cancers, and leukemia. In
particular, accessing bone marrow tissue may be advantageous. Other
applications may cover pulmonary diseases, neurological disorders
as well as cardiovascular applications.
[0056] In some instances, embodiments of the present invention may
employ an approach using iontophoresis. As used herein, the term
"iontophoresis" means the migration of ionizable molecules through
a medium driven by an applied low level electrical potential. This
electrically mediated movement of molecules into tissues is
superimposed upon concentration gradient dependent diffusion
processes. If the medium or tissue through which the molecules
travel also carries a charge, some electro-osmotic flow occurs.
However, generally, the rate of migration of molecules with a net
negative charge towards the positive electrode and vice versa is
determined by the net charge on the moving molecules and the
applied electrical potential. The driving force may also be
considered as electrostatic repulsion. Iontophoresis usually
requires relatively low constant DC current in the range of from
about 2-5 mA. The applied potential for iontophoresis will depend
upon number of factors, such as the electrode configuration and
position on the tissue and the nature and charge characteristics of
the molecules to be delivered.
[0057] The present invention relates to the delivery of cargo
including, but not limited to, therapeutic agents such as drug
molecules, proteins, peptides, antibodies, antibody scaffolds or
fragments of antibodies, nucleotides, contrast agents and dyes
(including radiolabels, fluorophores and chelated magnetic
species), liposomes, micelles, nanoparticles, multi-molecular
aggregates (such as, for example, albumin/paclitaxel or
Abraxane.TM.) and combinations thereof, with or without cargo
and/or targeting capabilities. Small molecules may include
chemotherapeutic agents such as alkylating agents,
anti-metabolites, plant alkaloids and terpenoids, vinca alkaloids,
podophyllotoxin, taxanes, topoisomerase inhibitors, and antitumor
antibiotics, as well as analgesics and local anesthetics.
Embodiments of the present invention also covers the delivery of
pro-drugs, small molecules and nanoparticles, in some instances
having neutral charge before delivery, that may be subsequently
charged or triggered to release cargo under physiological
conditions.
[0058] Furthermore, the cargo may include small ionic molecules,
nucleic acids, proteins, therapeutic agents, diagnostic agents, and
imaging agents as well as organic nanoparticles which may
encapsulate a wide range of therapeutic, diagnostic, and imaging
agents. The cargo may be configured to traffic preferentially based
on size, shape, charge and surface functionality; and/or
controllably release a therapeutic. Such cargos may include but are
not limited to small molecule pharmaceuticals, therapeutic and
diagnostic proteins, antibodies, DNA and RNA sequences, imaging
agents, and other active pharmaceutical ingredients. Further, such
cargo may include active agents which may include, without
limitation, analgesics, anti-inflammatory agents (including
NSAIDs), anticancer agents, antimetabolites, anthelmintics,
anti-arrhythmic agents, antibiotics, anticoagulants,
antidepressants, antidiabetic agents, antiepileptics,
antihistamines, antihypertensive agents, antimuscarinic agents,
antimycobacterial agents, antineoplastic agents,
immunosuppressants, antithyroid agents, antiviral agents,
anxiolytic sedatives (hypnotics and neuroleptics), astringents,
beta-adrenoceptor blocking agents, blood products and substitutes,
cardiac inotropic agents, contrast media, corticosteroids, cough
suppressants (expectorants and mucolytics), diagnostic agents,
diagnostic imaging agents, diuretics, dopaminergics
(antiparkinsonian agents), haemostatics, immunological agents,
therapeutic proteins, enzymes, lipid regulating agents, muscle
relaxants, parasympathomimetics, parathyroid calcitonin and
biphosphonates, prostaglandins, radio-pharmaceuticals, sex hormones
(including steroids), anti-allergic agents, stimulants and
anoretics, sympathomimetics, thyroid agents, vasodilators,
xanthines, and antiviral agents. In addition, the cargo may include
a polynucleotide. The polynucleotide may be provided as an
antisense agent or interfering RNA molecule such as an RNAi or
siRNA molecule to disrupt or inhibit expression of an encoded
protein.
[0059] Other cargo may include, without limitation, MR imaging
agents, contrast agents, gadolinium chelates, gadolinium-based
contrast agents, radiosensitizers, such as, for example,
1,2,4-benzotriazin-3-amine 1,4-dioxide (SR 4889) and
1,2,4-benzotriazine-7-amine 1,4-dioxide (WIN 59075); platinum
coordination complexes such as cisplatin and carboplatin;
anthracenediones, such as mitoxantrone; substituted ureas, such as
hydroxyurea; and adrenocortical suppressants, such as mitotane and
aminoglutethimide.
[0060] In other embodiments, the cargo may comprise Particle
Replication In Non-wetting Templates (PRINT) nanoparticles
(sometimes referred to as devices) such as disclosed, for example,
in PCT WO 2005/101466 to DeSimone et al.; PCT WO 2007/024323 to
DeSimone et al.; WO 2007/030698 to DeSimone et al.; and WO
2007/094829 to DeSimone et al., each of which is incorporated
herein by reference. PRINT is a technology which produces
monodisperse, shape specific particles which can encapsulate a wide
variety of cargos including small molecules, biologics, nucleic
acids, proteins, imaging agents. Cationically charged PRINT
nanoparticles smaller than 1 micron are readily taken up by cells
over a relatively short time frame, but penetration of the
particles throughout the tissue is a longer process. For the
delivery of PRINT nanoparticles throughout the tissue to be
effective, the penetration needs to occur within a reasonable
operational time frame. As such, the delivery system may be used to
achieve such penetration by employing iontophoresis, in which
charged PRINT nanoparticles are driven into body tissue using
repulsive electromotive forces. The PRINT particles may or may not
contain a therapeutic. In some instances, the particle may be
comprised of PLGA. In addition, the PRINT nanoparticles may be
engineered to achieve a certain mission, and design-in handles that
permit remote control for externally turning the cargo "on" or
switching it "off". As such, the cargo may be manipulated using
ultrasound, low-dose radiation, magnetics, light and other suitable
mechanisms. The particles may be coated with gold such as, for
example, gold nano-shells for thermal ablation therapy.
[0061] FIGS. 1-15 illustrate various embodiments and aspects of a
delivery system 100 in accordance with the present invention. In
general, the delivery system is provided for delivering a cargo to,
or through, a localized area of a passageway or other internal body
tissue in order to treat the localized area of the passageway or
tissue with minimal, if any, undesirable effect on other body
tissue. Such a system may be implemented intraluminally, through
natural orifices, or by minimally invasive surgery such that the
system may be used in vivo. The delivery system 100 may generally
include a source electrode, a counter electrode, a reservoir for
carrying a cargo (e.g., a therapeutic agent), and an electrode
deployment device.
[0062] As described previously, the delivery apparatus 100 which
may deliver cargo iontophoretically to target sites for localized
treatment. In general, iontophoresis technology uses an electrical
potential or current across a target site (e.g., a semipermeable
barrier) to drive ionic fixatives or drugs (or drive nonionic
fixatives or drugs) in an ionic solution. Iontophoresis facilitates
both transport of the fixative or drug across the target site and
enhances tissue penetration. In the application of iontophoresis,
two electrodes, a source electrode and a counter electrode (in some
instances, the electrodes may be positioned on opposing sides of
the target site, though such a configuration or arrangement is not
required), are utilized to develop the required potential or
current flow. The positioning of the electrodes may be accomplished
using an electrode deployment device 150. The electrode deployment
device 150 may be capable of positioning the source electrode, the
counter electrode, and the reservoir such that the therapeutic
agents may be delivered through intravascular, intraperitoneal, and
natural orifice transluminal endoscopic surgery (NOTES) modalities.
Some embodiments of the present invention may employ the technique
of reverse iontophoresis, wherein a small molecule or other
substance may be extracted from the surrounding medium. In this
manner, toxic substances or excess cargo materials may be removed
from locations in vivo.
[0063] In some instances, the electrode deployment device 150 may
comprise a catheter device to be deployed in vivo using the
intravascular route. In other embodiments, the electrode deployment
device 150 may comprise an endoscopic device for deployment via
natural orifices in the body. In other instances, the electrode
deployment device 150 may comprise a laparoscopic device for
minimally invasive surgical intervention. In other embodiments, the
electrode deployment device 150 may be surgically implanted in a
suitable location in vivo, such as, for example, the peritoneal
cavity. In yet other instances, the electrode deployment device 150
may implement combinations of two or more of the embodiments listed
above. According to some embodiments, the electrode deployment
device 150 may locate the source electrode, counter electrode,
and/or reservoir at the target site of interest through use of an
imaging system.
[0064] FIGS. 1-11 illustrate various embodiments of a source
electrode 200 implemented by the delivery system 100. The repulsive
force for driving the charged cargo through the target site tissue
is generated by placing the source electrode 200 at or proximate to
the target site of interest. The delivery system 100 may include
one or more source electrodes 200. By optimizing the placement and
geometric profile of the source electrode(s) 200, considerable
control may be achieved over the penetration depth, direction and
overall area of delivery of the cargo to the target site. The
source electrode(s) 200 may be configured as a single probe or an
array of probes comprised, for example, of thin wires, foil, mesh,
pellets, disks, stents, clamps, prongs, clips, needles, hollow
tubes or combinations thereof. For example, as shown in FIG. 1, the
source electrode 200 may include a mesh arrangement 225 (see also
FIGS. 1B, 1C, and 18B) opposably positioned with respect to a
counter electrode 500. In accordance with such an embodiment, in
some instances, the counter electrode 500 may be positioned, for
example, on an exterior surface of the pancreas/organ of interest.
The source electrode 200 having the mesh arrangement 225 may also
be placed on the exterior surface to cover a specific target tissue
such as, for example, a tumor, as shown in FIG. 1B.
[0065] In another embodiment, the mesh arrangement 225 source
electrode 200 may be configured to encase part or a portion of the
target tissue (e.g., a conical mesh encasing the tail of the
pancreas, as shown in FIG. 1C). In other instances, the source
electrode 200 may be configured or arranged as foil or patch
electrodes 235, as shown in FIG. 1D, wherein the drug reservoir 300
is coupled to the source electrode 200. The patch source electrode
235 may be configured as clamps or prongs situated at the end of
the electrode deployment device 150, such as, for example, an
endoscopic or laproscopic device, as shown in FIG. 2, wherein an
intermediary prong 208 may include the patch source electrode 235.
In this regard, the configuration may be modified to be internally
deployed by the electrode deployment device 150, wherein the mesh
arrangement 225 may be replaced by a stent device 245 (acting as
the source electrode 200), as shown in FIG. 1E, that is positioned
within the pancreatic duct 20, while the counter electrode 500 may
be positioned within an alternate branch of the same duct or,
alternatively, the bile duct 25 for example, as shown in FIG. 1F.
In some instances, the source electrode may include a reservoir 300
coupled or otherwise attached thereto for holding the cargo to be
delivered to the target site. In this manner, the reservoir 300
and/or the tissue of interest may be at least partially disposed
between the source electrode 200 and the counter electrode 500. The
source electrode(s) 200 may be fabricated from various materials
including, but not restricted to, conducting metals, such as
silver, silver chloride, platinum, aluminum, or conducting polymers
such as polypyrrole, polyaniline, or polyacetylene. In some
instances, both the source electrode 200 and the counter electrode
500 may be patch source electrodes 235, which may be positioned in
a side-by-side or otherwise proximally positioned on an organ,
tissue, or other target site, as shown in FIG. 1G. That is, the
cargo of the reservoir 300 may penetrate the target site to reach,
for example, a tumor when the voltage potential is applied between
the source electrode 200 and the counter electrode 500. Of course,
the patch source electrodes 235 may be on opposite sides of the
organ, tissue, or target site, or may be otherwise appropriately
configured to deliver the cargo to the target site.
[0066] According to some embodiments, the source electrode 200 may
include an array of multi-functional probes, combining imaging and
drug delivery functionalities, as illustrated in FIGS. 2 and 3 and
indicated by reference numbers 200a, 200b and 200c. In this regard,
the use of paramagnetic or radio-opaque materials in the probe body
may be used for imaging purposes. In other instances, catheter
devices may be capable of simultaneous delivery of imaging agents.
According to other embodiments, the incorporation of a light source
and camera may be incorporated into the probe for endoscopic
devices. Various combinations of such imaging and delivery probes
may be implemented by the delivery system 100. For example, as
illustrated in FIG. 2, the intermediary prong 208 may include the
electrode element 204, while the outer prongs 210, 212 include
imaging devices and/or agents capable of assisting with positioning
of the source electrode 200. With reference to FIG. 3, the
electrode element 204 may be radially surrounded by imaging devices
210 or agents, other source electrodes 200 or other probe members,
which may be configured as dependent on the location of the target
site within a patient's body.
[0067] In some instances, the source electrode 200 may have one or
more insulating layers or members 250a, 250b, 25c and 250d
attached, connected, or otherwise engaged therewith. The insulating
members 250a, 250b, 25c and 250d are provided to confer
directionality to the transport profile of the cargo 60 with
respect to the target site, as shown in FIG. 4, illustrating the
source electrode 200 disposed within a tissue lumen 50. That is,
the flux of the cargo will be attenuated corresponding to the
insulated areas of the source electrode 200. In this regard, a
partially insulated source electrode 200 may be for control over
targeted delivery to specific in vivo locations. That is, by
insulating a portion of the source electrode surface, control over
delivery to the tissue or organ systems may be accomplished in a
well defined manner. In this regard, the extent of transport from
the sections of the target site exposed to the unshielded sections
of the source electrode 200 may be greater than that of the
transport from the shielded or insulated region of the source
electrode 200.
[0068] According to some aspects of the present invention, a
plurality of source electrodes and indicated by reference numbers
200a, 200b and 200c may be provided, wherein each source electrode
200a, 200b or 200c is independently controlled with respect to the
other source electrodes 200a, 200b and 200c. In this manner, the
delivery system 100 may be manipulated to target various sites for
delivery of the cargo 60, as shown in FIG. 5, illustrating the
source electrodes 200a, 200b and 200c disposed within a tissue
lumen 50. That is, by allowing independent control over parameters
for iontophoretic delivery such as current, voltage and time,
variable delivery zones may be created at distinct sites within the
same tissue lumen. In addition, the source electrodes 200 may
terminate at various lengths to further provide control over
deliver of the cargo to the target site(s). Furthermore, in some
instances, the plurality of source electrodes 200a, 200b and 200c
may have the insulating members 250a, 250b, 250c and 250d disposed
therebetween and thereabout to also specifically designate delivery
regions 260 for delivery of the cargo 60 to the target site(s).
According to an alternative embodiment, the source electrodes may
be disposed within the electrode deployment device 150, such as,
for example, a catheter device 350, as illustrated in FIG. 6. The
catheter device 350 may be comprised of a perforated polymer sheath
352. That is, the catheter device 350 may have a plurality of
perforations 354 defined thereby such that the cargo 60 may exit
the catheter device 350. In one particular embodiment, the source
electrodes 200a, 200b and 200c terminate at different lengths and
may be independently powered such that the probes are capable of
being variably controlled. The source electrodes 200a, 200b and
200c may include the insulating members 250 disposed about and
between the source electrodes 200a, 200b and 200c so as to form
cargo delivery zones substantially aligned with the perforations
354 of the catheter device 350. In this regard, the cargo 60 may be
fed through the catheter device 350 proximate to the target site at
the terminal portion of the catheter device 350, where the cargo 60
may be drawn therefrom due to the electrical field applied across
the source electrode 200a, 200b and 200c and the counter
electrode.
[0069] Referring to FIG. 7, in some instances, the source electrode
200 (and/or the counter electrode) may be encapsulated in a
gelatinous solid, such as, for example, a soft polymer matrix 280,
that prevents injury from the insertion and extraction of the
source electrode 200 (and/or the counter electrode). The polymer
matrix 280 may also serve as a cargo reservoir 300 from where the
therapeutic agent(s) may be mobilized. That is, the cargo 60 may be
incorporated in the polymer matrix 280 such that, upon actuation of
the electric field, the cargo 60 may diffuse out of the polymer
matrix 280 and be delivered to the target site. FIGS. 8A and 8B
illustrate the source electrode 200 having one or more insulating
members 250 disposed thereabout such that both the source electrode
200 and the insulating members 250 are encapsulated in the polymer
matrix 280. FIG. 8A shows a single insulating member 250 disposed
longitudinally along the source electrode 200 such that the cargo
60 may be directed toward the target site. FIG. 8B shows a
plurality of insulating members 250 engaged with the source
electrode 200 such that various cargo delivery regions or zones are
defined for delivering the cargo 60 to specific areas of the target
site. In this regard, there may be a region or regions 290 of
depleted cargo within the polymer matrix 280 and a normal region or
regions 295 at some duration after actuation of the electric field
to drive the cargo 60 toward the target site.
[0070] FIG. 9 illustrates an embodiment of the delivery system 100
similar to that of FIG. 5, wherein a plurality of independently
controlled source electrodes and indicated by reference numbers
200a, 200b and 200c may be provided such that various target sites
and/or regions may be targeted for delivery. As described
previously, the length at which the source electrodes 200a, 200b
and 200c terminate may alter (as shown by reference numbers 201a,
201b and 201c in FIGS. 2, 6 and 9) and the insulating members 250a,
250b, 250c and 250d may be provided to further control delivery of
the cargo 60. In some instances, as shown in FIG. 9, the source
electrodes 200a, 200b and 200c and insulating members 250a, 250b,
250c and 250d may be encapsulated in a gelatinous solid such as,
for example, the polymer matrix 280 carrying the cargo 60
therewith. In this manner, there may be a region 290 of depleted
cargo within the polymer matrix 280 and a normal region 295 at some
duration after actuation of the electric field to drive the cargo
60 toward the target site.
[0071] In one embodiment, as illustrated in FIGS. 10 and 11, a
catheter device, such as, for example, a balloon catheter 400
having a pair of expandable members 402 may be used to deliver the
cargo 60 to the target site. The source electrode 200 may be
serially disposed between the pair of expandable members 402, which
are configured to occlude a target site. In this regard, the
expandable members 402 may be used to enclose or occlude an
intraluminal area before and/or after the source electrode 200, to
limit the delivery of the cargo (e.g., therapeutic agent) to the
area of interest. That is, the expandable members 402 may be in a
relaxed state (FIG. 10) during positioning of the catheter and/or
source electrode 200 proximate to the target site. Thereafter, the
expandable members 402 may be inflated to an expanded state (FIG.
11) so as to contact a duct or other passageway 410 to enclose the
target site such that the cargo delivery is isolated to the target
site, thereby limiting exposure of healthy tissue to the cargo
materials. In one embodiment, the delivery system 100 may include
inflatable members 402, as schematically shown in FIGS. 10 and 11,
which illustrate the distal end of the catheter device 400 with the
expandable member 402 in its relaxed and inflated/expanded states,
respectively. The catheter device 400 may include a guide wire for
positioning the catheter device 400 near the target site. The term
catheter as used in the present application is intended to broadly
include any medical device designed for insertion into a body
passageway to permit injection or withdrawal of fluids, to keep a
passage open or for any other purpose. In other instances, an area
to be treated may be occluded by blocking or damming an area using
a balloon or a polymer cap or fibers (not shown).
[0072] With reference to FIG. 12, in some embodiments of the
present invention, placement of the cargo, such as the PRINT
nanoparticles, may be achieved by using a hollow tube needle member
500 having an iontophoretic tip to facilitate distribution of the
particles into the surrounding target site (tissue). In such
embodiments, the needle tip may represent the source electrode 200,
while the counter electrode is positioned internally or external to
the body so as to create a voltage potential when a power supply is
energized, as described previously with respect to iontophoretic
techniques. Such a technique may be used for disease states
including cancer (brain, prostate, colon, others), inflammation,
damaged tissue `rescue` situations (e.g. cardio/neuro/peripheral
vascular), ocular diseases, rhinitis, and other applications.
Furthermore, the hollow tube portion of the needle member 500 may
serve as a reservoir for the cargo, wherein the needle member 500
may be connected to a port member (not shown) located externally
such that the reservoir may be filled and/or refilled
externally.
[0073] Referring to FIGS. 13A, 13B, 14, 15, and 16, one or more
counter electrodes 500 may be provided with the delivery system
100, wherein the counter electrode 500 consists of a probe of
opposite polarity to that of the source electrode 200 that
completes the electrical circuit of the system. That is, in using
embodiments of the present invention for iontophoretically enhanced
drug delivery, a separate electrode of opposite polarity to the
source electrode 200 is used in order to generate the potential
gradient across the artery or other body tissue. In some instances,
the counter electrode 500 may be positioned internally or otherwise
external to the body such as on the patient's body (usually the
skin) and may be attached using any known means, such as ECG
conductive jelly. That is, placement of the source electrode 200
and the counter electrode 500 may be altered to fit the tissue
location and disease state to be treated. For example, the source
electrode 200 and the counter electrode 500 may be placed
internally, externally or one internal and one external as long as
appropriate electrical connection can be made. Internally placed
electrodes can be proximal or distal in relation to each other and
the tissue.
[0074] In some instances, as shown in FIGS. 13A and 13B, the
counter electrode 500 may be designed to maximize movement of the
cargo (e.g., the therapeutic agent) towards itself and away from
the source electrode 200 so as to promote distinct and varied
delivery zones 550. That is, the position of the counter electrode
500 may be manipulated to exert control over targeted delivery to
specific in vivo locations. For example, as shown in the
configuration of FIG. 13A, the counter electrode 500 may be
positioned substantially perpendicularly with respect to the source
electrode 200, whereas, as shown in the configuration of FIG. 13B,
the counter electrode 500 may be concentrically positioned about
the source electrode 200. Such configurations of the counter
electrode 500 may lead to highly directional transport or broader
transport bands, as dependent on the configuration and orientation
with respect to the source electrode 200.
[0075] In some instances, the counter electrode 500 can have an ion
selective membrane portion 502 for the movement of ions to and from
the counter electrode 500. In some instances, the counter electrode
500 may have a coolant device 510 for use therewith to maintain the
temperature of the counter electrode 500 and to minimize the
potential for tissue burns, as illustrated in FIGS. 14-16. The
coolant device 510 may be configured to allow a coolant substance
512 to flow at least partially about the counter electrode 500. In
this regard, the membrane portion 502 may be positioned to prevent
ions that may be part of the coolant substance 512 from interfering
with the cargo, drug, or material to be deposited. In some
embodiments, the coolant device 510 may include a perforated
tubular structure 514 defining an aperture 516 to allow for release
of the coolant around the counter electrode 500, as shown in FIG.
16. The coolant substance 512 may be, for example, water, an
electrolyte solution, or gel-like substance that has a high heat
capacitance to maintain cooler temperatures. In addition to
performing a cooling function, the coolant substance 512 may allow
for a continuous flow of electrolytes for maximum ion transfer into
the tissue, and maintain pH levels around the counter electrode
500. A gelatinous membrane around the counter electrode 500 may
also be utilized, to minimize pH changes occurring at the
conducting surface and tissue interface. In one particular
embodiment, the counter electrode 500 may be disposed between the
insulator member 250 and the membrane portion 502 so as to improve
delivery control of the cargo to the target site.
[0076] Embodiments of the present invention further comprise a
reservoir (see, for example, FIGS. 1, 6-9, and 12) configured to
store or otherwise carry the cargo such that the cargo may be at
least partially disposed between the source electrode 200 and the
counter electrode 500. In this manner, the cargo may interact with
the electric field formed between the source electrode 200 and the
counter electrode 500 so as to be delivered to the target site. The
reservoir can be maintained as a solution, dispersion, emulsion or
gelatinous solid, as previously describe with respect to FIGS. 7-9.
The reservoir entraps the cargo (e.g., the therapeutic agent) until
the application of a physical, chemical, or electrical stimulus. In
one embodiment, the cargo reservoir may be located remotely from
the source electrode 200 and may be connected to the source
electrode 200 via a hollow conduit. In another embodiment, the
reservoir and the source electrode 200 may be designed to be a
single assembly. In any instance, it may be possible to refill the
reservoir, either remotely or after every use. Large, medium, and
small reservoirs may be provided to allow for directionality and
concentration of the cargo (e.g., the therapeutic agent) issued to
the tissue of interest.
[0077] In one particular embodiment of the present invention, the
intraperitoneal cavity may serve as the drug reservoir. In this
regard, the peritoneal cavity may be flooded with a cargo or drug
of choice in an appropriate buffer. The source and counter
electrodes 200, 500 may be positioned proximate to the target site
of the pancreas, such as, for example, in a pancreatic duct and at
an appropriate location or locations at the exterior of the
pancreas near the tumor. Various arrangements of the source and
counter electrodes may be implemented so that the cargo is
positioned to interact with the electric field, upon actuation
thereof, to drive the cargo to the target site of the pancreas.
That is one, both, or neither of the electrodes may be positioned
substantially within the pancreas. For example, both electrodes may
be positioned exterior to the pancreas and on opposite sides
thereof. In one particular example, one of the electrodes may be
arranged as a wire mesh arrangement that can be positioned on and
contact an exterior surface of the pancreas. A current may then be
applied to drive the cargo (e.g., drug or therapeutic agent) from
the peritoneal cavity to the pancreas and the site of the tumor. In
another instance, the reservoir may be implanted in the
intraperitoneal cavity such that the reservoir is provided remotely
from the source electrode 200 and the counter electrode 500.
[0078] However, embodiments of the present invention may also be
used in association with other cavities of the body, wherein at
least some of these cavities are internal body cavities, while
others are not. For example, the cargo may be delivered to the
cranial cavity (brain cancers), the oral cavity (head and neck
cancers, thyroid cancers), the thoracic cavity or mediastinum
(thymus cancer, esophageal cancers and heart disease), the pleural
cavity (lung cancers, cystic fibrosis, pulmonary fibrosis,
emphysema, adult respiratory distress syndrome (ARDS), and
sarcoidosis), the abdominopelvic cavity or peritoneal cavity
(pancreatic cancer, liver cancers and metastases, stomach cancer,
small bowel cancer, genital warts, inflammatory bowel diseases
(Crohn's disease and ulcerative colitis), renal cancers and
metastases, splenic cancers, and Hodgkin's disease), and the pelvic
cavity (testicular cancer, prostate cancer, ovarian cancer
fallopian tube, cervical cancer, endometrial cancer, uterine
cancers, Kaposi's sarcoma, colorectal cancers, and urinary bladder
cancer).
[0079] In order to apply a voltage potential across the source
electrode 200 and the counter electrode 500, the source electrode
200 and the counter electrode 500 are in electrical communication.
In this regard, the source electrode 200 and the counter electrode
500 are connected to a power source (not shown). In some instances,
the power source may comprise a programmable power supply and
function generator capable of generating both direct current and
pulsed waveforms at various voltages and for various time
intervals. The power source can generate the potential difference
between the source electrode 200 and the counter electrode 500
necessary to induce electromigration and electroosmosis of the
cargo (e.g., the therapeutic agent). A function generator allows
for manipulation of the wave generated from the power source.
Square, triangular, sawtooth, multi-step wave forms may be used to
drive a direct current through the source and counter electrodes
200, 500.
[0080] As described above, the disclosed iontophoretic techniques
may take either an inside-out or an outside-in approach in driving
the cargo toward the target site of tissue. That is, reverse
iontophoretic techniques may be employed in all of the embodiments
described hereinabove, and as described, for example, in Example 8.
In this regard, the source electrode may be disposed exterior to a
duct, organ, tissue, or target site, while the counter electrode is
positioned within a duct, lumen, organ, etc. such that the cargo is
driven from outside the target site inwardly toward the target
site.
[0081] Many modifications and other embodiments of the invention
will come to mind to one skilled in the art to which this invention
pertains having the benefit of the teachings presented in the
foregoing description; and it will be apparent to those skilled in
the art that variations and modifications of the present invention
can be made without departing from the scope or spirit of the
invention. Therefore, it is to be understood that the invention is
not to be limited to the specific embodiments disclosed and that
modifications and other embodiments are intended to be included
within the scope of the appended claims. Although specific terms
are employed herein, they are used in a generic and descriptive
sense only and not for purposes of limitation.
[0082] The following examples are presented by way of illustration,
not by way of limitation.
EXPERIMENTAL
Example 1: Delivery of Rhodamine 6G Dye into Agarose Phantoms
[0083] A cylindrical tube of 2% (w/v) agarose gel in deionized
(D.I.) water was fabricated as a phantom with an outer diameter
(o.d.)=2.5 cm and length .about.3-4 cm. A concentric reservoir for
holding the dye (o.d=0.8 cm, length .about.2 cm) was cored out from
the top surface along the longitudinal axis of the gel cylinder.
Electrodes were fabricated out of aluminum foil (width 0.5 cm,
length .about.15 cm, thickness .about.0.1 cm). A solution of 0.5%
Rhodamine 6G in D.I. water was used to model the delivery of a
small molecule drug. The dye was filled inside the cored reservoir
in the agarose phantom and the source electrode (anode, in this
case) was inserted into the dye reservoir. The other end of the
anode was hooked to a DC power source with an alligator clip. The
agarose phantom was immersed in a beaker containing 0.25.times.PBS
solution, as shown in FIG. 17A. The cathode, a second piece of
aluminum foil, was placed in the PBS beside the agarose phantom and
hooked up to the DC power source. In the negative control, passive
diffusion of the dye was allowed without any passage of current for
10 minutes. In the experimental condition, a constant current of 5
mA (voltage .about.9.5V) was driven through the electrodes for the
same duration (10 minutes). As shown in FIG. 17B, to characterize
the extent of iontophoretic transport, cross-sections of the
agarose phantom were taken every 0.5 cm along the length. The
radial transport of the dye from the edge of the cored reservoir
was quantified. In the negative control (0 mA) dye was localized to
the inner wall of the reservoir, while in the experimental
condition (5 mA) the dye spread radially to the edge of the agarose
phantom.
Example 2: Unshielded Electrode Configurations for Control Over
Targeted Delivery to Specific In Vivo Locations
[0084] Unshielded electrode configurations were developed for
demonstrating control over delivery to specific in vivo locations.
These include electrodes fabricated out of metal wire (silver,
silver chloride), metal foil (silver, platinum, aluminum) and wire
mesh (aluminum), as shown in FIGS. 18A and 18B. These are
representative examples, and similar designs can be fabricated with
variations in size, material and additional enhancements or
refinements to the basic configuration. The advantages of wire and
foil electrodes shown FIG. 18A are: simplicity and ease of use,
flexibility for insertion into tiny orifices and ducts, precise
control over size and potential for miniaturization. Their primary
limitation is their tendency for hydrolysis of the conducting fluid
medium. Silver electrodes are also susceptible to oxidation, while
silver chloride electrodes can get reduced to metallic. As shown in
FIG. 18B, wire mesh electrodes can be fabricated either in a stent
configuration for intra-luminal placement, or as a patch or net
configuration for placement on the outside surface of an organ or
target tissue. Such a configuration may provide greater control
over the surface area of delivery, as well as better heat flow to
reduce the potential for tissue burns. Additionally, these may be
fabricated from conducting polymers or coated with biodegradable
polymers to create designs that are highly conformable to organ
surface characteristics and geometrical contours.
Example 3: Insulated Electrode Configurations for Control Over
Targeted Delivery to Specific In Vivo Locations
[0085] An insulated electrode was developed to demonstrate control
over targeted delivery to specific in vivo locations. By insulating
a portion of the electrode surface, it is possible to control the
delivery to the tissue or organ systems in a well defined fashion.
For example, the flux of drug or particles will be attenuated
corresponding to the insulated areas of the electrode. Aluminum
foil was folded into a long rectangular shape of appropriate
dimensions (length .about.10 cm, width .about.0.4 cm, thickness
.about.0.1 cm). Insulating tape (width .about.1 cm) was wrapped
around the foil in alternating sections. This insulated electrode
was immersed in the central reservoir of an agarose phantom (2%
agarose w/v in deionized water), as shown in FIG. 19A. A solution
of 0.5% Rhodamine 6G in D.I. water was used to model the delivery
of a small molecule drug. The dye was filled inside the cored
reservoir in the agarose phantom and the insulated source electrode
(anode, in this case) was inserted into the dye reservoir. The
agarose phantom was immersed in a beaker containing 0.25.times.PBS
solution. A bare aluminum foil electrode served as a cathode, and
was placed in the PBS beside the phantom. Both electrodes were
hooked to a DC power source with alligator clips. In the negative
control, passive diffusion of the dye was allowed without any
passage of current for 10 minutes. In the experimental condition, a
constant current of 5 mA (voltage .about.9.5V) was driven through
the electrodes for the same duration (10 minutes). To characterize
the extent of iontophoretic transport, the agarose phantom was
sectioned longitudinally. A difference is seen in the extent of
transport from the sections of the phantom exposed to the
unshielded sections of the electrode, as compared to diffusion from
the passive control, as shown in FIGS. 19B and 19C,
respectively.
Example 4: Electrode Configurations with Built-in Drug
Reservoirs
[0086] Since it may not be possible to confine the drug to be
delivered within a localized cavity or lumen in the target tissue,
electrodes with built-in drug reservoirs were developed. Such
examples were fabricated by encapsulating insulated foil electrodes
described earlier within an agarose gel matrix. The agarose gel
containing the 0.5% Rhodamine 6G solution, serving as a model drug,
was first poured into a glass test-tube of diameter 1.2 cm. The
insulated electrode was then inserted into the gel solution. The
gel was allowed to solidify, and the electrode was extracted by
breaking the test tube. An agarose gel phantom with a central
reservoir of inner diameter .about.1.5 cm was prepared. This
electrode was then inserted into the phantom and tested for
iontophoretic delivery at a constant current of 5 mA for 10
minutes. The results show zones of controlled delivery through the
gel that are visible under short wave UV light, as shown in FIG.
20B. FIG. 20A shows the electrode having the built-in drug
reservoir being at least partially depleted of the model drug after
completion of the experiment. Similar results were also seen in
transport through muscle and fat tissue.
Example 5: Delivery of Dye into Muscle Tissue (Chicken Breast)
[0087] A soft-gel electrode was fabricated from 2% (w/v) agarose
gel containing 5% Rhodamine 6G solution in D.I. water by casting
the gel in a test tube (o.d.=13 mm and length 25 mm) with an
aluminum foil electrode inserted along the central axis. Chicken
breast was chosen as a representative tissue to demonstrate
iontophoretic delivery in accordance with one embodiment of the
present delivery system. A cylindrical core was removed from the
center of the tissue sample to produce a drug reservoir of o.d.=15
mm. The soft-gel electrode was then placed in the reservoir inside
the tissue sample and the source electrode (anode, in this case)
was hooked to a DC power source with an alligator clip. The tissue
sample was immersed in a beaker containing deionized water. The
cathode, a regular aluminum foil electrode without gel, was placed
in the PBS beside the tissue sample and hooked up to the DC power
source. In the negative control, passive diffusion of the dye into
the tissue was allowed without any passage of current for 30
minutes. In the experimental condition, a constant current of 10 mA
(voltage .about.1.4 V) was driven through the electrodes for the
same duration (30 minutes). To characterize the extent of
iontophoretic transport, cross-sections of the tissue sample were
taken every 0.5 cm along the depth of the sample, as shown in FIG.
21. The radial transport of the dye from the edge of the drug
reservoir was quantified. As shown in the top row of FIG. 21, in
the negative control (0 mA), the dye was localized to the inner
wall of the reservoir. As shown in the bottom row of FIG. 21, in
the experimental condition (10 mA), the dye spread in a radial
direction into the tissue to a distance of .about.5 mm from the
edge of the reservoir.
Example 6: Delivery of Dye into Adipose Tissue (Bovine)
[0088] Bovine fat was chosen as another representative tissue to
demonstrate iontophoretic delivery. A cylindrical core was removed
from the center of the tissue sample to produce a drug reservoir of
o.d.=15 mm. A soft-gel electrode similar to the one described
earlier, but with platinum foil (0.5 mm thick) as the source
electrode, was then placed in the reservoir at the center of the
tissue sample and was hooked to a DC power source with an alligator
clip. The tissue sample was immersed in a beaker containing
deionized water (mimicking filling the peritoneal cavity). A silver
chloride electrode directly inserted into the tissue sample served
as the cathode and was hooked up to the DC power source. In the
negative control, passive diffusion of the dye into the fat tissue
was allowed without any passage of current for 30 minutes. In the
experimental condition, a constant voltage of 20 V was applied
between the electrodes for the same duration (30 minutes). The
current was allowed to increase from 5-15 mA to maintain constant
potential difference. To characterize the extent of iontophoretic
diffusion, cross-sections of the tissue sample were taken every 0.5
cm along the depth of the sample. The radial diffusion of the dye
from the edge of the drug reservoir was quantified. In the negative
control (0 V) dye was localized to the inner wall of the reservoir
(not shown). In the experimental condition (20 V), a maximum
penetration depth of .about.8 mm from the edge of the reservoir was
achieved, as shown in FIG. 22.
Example 7: Placement of Counter Electrodes for Control Over
Targeted Delivery to Specific In Vivo Locations
[0089] As described previously, the position of the counter
electrode may be manipulated to exert control over targeted
delivery to specific in vivo locations. In this example, two
possible configurations are illustrated in FIGS. 23A and 23B, which
correspond to the configuration of FIGS. 13A and 13B, respectively.
In the first configuration, the counter electrode was placed in
direct point contact with the outside surface of the agarose gel
phantom. In the second configuration, the counter electrode was
wrapped around the mid-section of the gel, as shown in FIG. 23B.
The agarose phantoms were the same as those used in Example 1, and
a constant current of 5 mA was allowed to flow through the
electrodes for 10 minutes. In the first configuration, highly
directional diffusion was seen on the side of the agarose phantom
with direct counter electrode contact, as shown in FIG. 23A. In the
second configuration, a broader diffusion band is seen around the
midsection, demonstrating greater diffusivity towards the counter
electrode wrapped around the phantom.
Example 8: Delivery of Dye Using Reverse Iontophoresis
[0090] The ability to extract a small molecule from the surrounding
medium (like filling the peritoneal cavity) into a reservoir
located inside an agarose phantom was demonstrated by employing the
principle of reverse iontophoresis. To allow diffusion from the
outside surface of the gel to the central reservoir, the phantom
was placed in a solution of Rhodamine 6G in deionized water. For
this application, the polarity of the electrodes was switched, with
the counter electrode being placed in the central drug reservoir,
while the source electrode was placed in the dye solution outside
the gel, as shown in FIG. 24A. The electrodes were then hooked to a
DC power source with an alligator clip. In the negative control,
the gel was soaked in the dye solution without any passage of
current for 10 minutes. In the experimental condition, a constant
current of 5 mA (voltage .about.9.5V) was driven through the
electrodes for the same duration (10 minutes). To characterize the
extent of reverse iontophoretic diffusion, cross-sections of the
agarose phantom were taken every 0.5 cm along the length. The
radial diffusion of the dye from the outside surface of the gel to
the inside edge of the central reservoir was quantified. In the
negative control (0 mA) dye was localized to the outer wall of the
gel, as shown in the top row of FIG. 24B. In the experimental
condition (5 mA) the dye spread radially toward the central
reservoir and collected there, as shown in the bottom row of FIG.
24B. In the experimental condition, the total volume of dye
accumulated in 10 minutes was sufficient to fill up a 3 mL glass
vial, as shown in the bottom vial of FIG. 24B. This example
demonstrates the potential of the invention for delivering drug
molecules from the outside surface of an organ to the inner core.
It also demonstrates an application requiring the extraction of a
toxin from the target tissue into a central reservoir from which it
can be safely and easily extracted.
Example 9: Variable Delivery of Rhodamine 6G Dye into Agarose
Phantoms Using Independently Controlled Electrodes
[0091] An assembly of two independently-powered, insulated
electrodes was developed to demonstrate variable controlled
delivery, as described previously. By allowing independent control
over parameters for iontophoretic delivery such as current, voltage
and time, we were able to demonstrate variable delivery zones at
two distinct sites within the same lumen. Two insulated aluminum
foil electrodes similar to the one shown in Example 3 above, were
combined into a single assembly according to the schematic shown in
FIG. 5. The insulated double-electrode assembly was immersed in the
central reservoir of an agarose phantom (2% agarose w/v in
deionized water). A solution of 0.5% Rhodamine 6G in D.I. water was
used to model the delivery of a small molecule drug and was filled
inside the cored reservoir in the agarose phantom. The agarose
phantom was immersed in a beaker containing 0.25.times.PBS
solution. A pair of bare aluminum foil electrodes served as
cathodes, and were placed in the PBS beside the phantom. Both sets
of electrodes were hooked to two independent DC power sources with
alligator clips. In the negative control, passive diffusion of the
dye was allowed without any passage of current for 5 minutes. In
the experimental condition, one electrode was set for a constant
current of 5 mA, while the other was operated at a constant voltage
of 20 V. Duration of delivery was held constant at 5 minutes, but
as noted earlier, all of the above parameters can be independently
controlled. To characterize the extent of iontophoretic diffusion,
the agarose phantom was sectioned longitudinally. Under UV light, a
difference is seen in the extent of diffusion from the sections of
the phantom exposed to the uninsulated sections of both electrodes
in the assembly, as shown in FIG. 25. For example, the bottom
electrode shows uniform diffusion at the bottom of the well,
whereas the uninsulated section of the top electrode shows more
diffusion on the bare (anterior) side as opposed to the insulated
(posterior) side. This example demonstrates that a similar
electrode assembly can be used to control the location and extent
of delivery at multiple proximal sites within the same lumen or its
branches. This may be particularly useful in targeted delivery to
metastatic tumors within the same organ that can be accessed
through a common ductal or vascular network.
Example 10: Variable Delivery of Rhodamine 6G Dye into Agarose
Phantoms Using Independently Controlled Electrodes with Built-in
Drug Reservoir
[0092] A variation of the double-electrode assembly previously
described in Example 9 was developed with a built-in drug
reservoir. The insulated double-electrode assembly was immersed in
a test-tube of 2% agarose gel containing a 5 mg aqueous solution of
Rhodamine 6G. The soft-gel electrode assembly was then inserted
into an 2% agarose phantom having a cored out central cavity
(diameter: 1.5 mm). The agarose phantom was immersed in a beaker
containing 0.25.times.PBS solution, as shown in FIG. 26A. Two bare
aluminum foil electrodes served as cathodes, and were placed in the
PBS beside the phantom. Both sets of electrodes were hooked to two
independent DC power sources with alligator clips. In the negative
control, passive diffusion of the dye was allowed without any
passage of current for 7 minutes. To demonstrate independent
control of both electrodes, one electrode was set for a constant
current of 5 mA for 5 minutes, while the other was operated at a
constant current of 15 mA for 7 minutes. To characterize the extent
of iontophoretic diffusion, the agarose phantom was sectioned
longitudinally. Under UV light, a difference is seen in the extent
of diffusion from the sections of the phantom exposed to the
uninsulated sections of both electrodes in the assembly, as shown
in FIG. 26B. Depletion of the dye is seen from the areas of the gel
exposed to uninsulated tips of the electrodes. Furthermore, two
distinct delivery zones can be seen resulting from the two
independently controlled electrodes.
Example 11: Delivery of Doxorubicin into Agarose Phantoms
[0093] A cylindrical tube of 2% (w/v) agarose gel in deionized
(D.I.) water was fabricated as a phantom with an outer diameter
(o.d.)=2.5 cm and length .about.3-4 cm. A concentric reservoir for
holding the dye (o.d=0.8 cm, length .about.2 cm) was cored out from
the top surface along the longitudinal axis of the gel cylinder.
Electrodes were fabricated out of platinum foil (width 0.25 cm,
length .about.3 cm, thickness .about.0.05 cm). A solution of 0.25%
Doxorubicin in 4.875% DMSO and 94.875% DI water was used to model
the delivery of a small molecule drug. The dye was filled inside
the cored reservoir in the agarose phantom and the source electrode
(anode, in this case) was inserted into the dye reservoir. The
other end of the anode was hooked to a DC power source with an
alligator clip. The agarose phantom was immersed in a beaker
containing DI water. The cathode, a second piece of platinum foil,
was placed in the PBS beside the agarose phantom and hooked up to
the DC power source. In the negative control, passive diffusion of
the dye was allowed without any passage of current for 5 minutes.
In the experimental condition, a constant current of 5 mA (voltage
.about.9.5V) was driven through the electrodes for the same
duration (5 minutes). As shown in FIG. 27, to characterize the
extent of iontophoretic diffusion, cross-sections of the agarose
phantom were taken every 0.5 cm along the length. The radial
diffusion of the dye from the edge of the cored reservoir was
quantified. In the negative control (0 mA) dye was localized to the
inner wall of the reservoir (bottom row), while in the experimental
condition (5 mA) the dye spread radially to the edge of the agarose
phantom (top row).
Example 12: Injection of Rhodamine 6G into Pancreatic Duct and
Placement of Electrodes on Outer Surface of Pancreas
[0094] As shown in FIG. 28A, Liquified 2% (w/v) agarose gel
containing 0.5% Rhodamine 6G solution in D.I. water was injected
into the pancreas duct through a 18G IV catheter, where it
solidified upon contact. The source electrode, made of aluminum
foil, was placed on one side of the pancreas, and the counter
electrode, made of aluminum foil, was placed on the opposite side
of the pancreas. The electrodes were hooked to a DC power source
with alligator clips. The tissue sample was immersed in a beaker of
DI water. In the experimental condition, a constant current of 5 mA
(voltage .about.2.4 V) was driven through the electrodes for the
same duration (30 minutes). To characterize the extent of
iontophoretic diffusion, cross-sections of the tissue sample were
taken every 0.5 cm along the depth of the sample, as shown in FIG.
28B. The radial diffusion of the dye from the edge of the drug
reservoir was quantified. In the experimental condition (5 mA), the
dye spread in a radial direction into the tissue to a distance of 3
mm from the edge of the reservoir.
Example 13: Delivery of Dye into Pancreas Using Flat Electrodes
[0095] A soft-gel source electrode was fabricated from Liquified 2%
(w/v) agarose gel containing 0.5% Rhodamine 6G solution in D.I.
water by casting the gel in a Petri dish with an aluminum foil
electrode inserted on top of gel. The source electrode was placed
on one side of the pancreas, and the counter electrode was placed
on the opposite side of the pancreas. The electrodes were hooked to
a DC power source with alligator clips. The tissue sample was
immersed in a beaker of DI water. In the experimental condition, a
constant current of 5 mA (voltage .about.2.4 V) was driven through
the electrodes for the same duration (30 minutes). As shown in FIG.
29, in the experimental condition (5 mA), the dye moved from the
agarose source electrode into the tissue.
Example 14: Delivery of Dye Through Pancreatic Duct Using Probe
Electrode
[0096] A soft-gel source electrode was fabricated from Liquified 2%
(w/v) agarose gel containing 0.5% Rhodamine 6G solution in D.I.
water by casting the gel in a test tube (o.d.=5 mm and length
.about.25 mm) with platinum wire inserted along the central axis.
The soft-gel source electrode was probed into the pancreatic duct,
and the counter electrode, made of platinum foil, was placed on the
outer surface of the pancreas, as shown in FIG. 30A. The electrodes
were hooked to a DC power source with alligator clips. The tissue
sample was immersed in a beaker of DI water. In the negative
control, passive diffusion of the dye into the tissue was allowed
without any passage of current for 30 minutes. In the experimental
condition, a constant current of 20 mA (voltage .about.9.2 V) was
driven through the electrodes for 30 minutes. To characterize the
extent of iontophoretic diffusion, cross-sections of the tissue
sample was taken every 1 cm along the depth of the sample. As shown
in FIG. 30B, in the experimental condition (20 mA), the dye moved
from the agarose source electrode into the tissue. As shown in FIG.
30C, in the negative control (0 mA), the dye was localized to the
inner wall of the pancreatic duct. In the experimental condition
(20 mA), the dye spread in a radial direction into the tissue to a
distance of .about.3 mm from the edge of the reservoir.
Example 15: Delivery of PRINT Nanoparticles into Agarose
Phantoms
[0097] A miniaturized agarose phantom was used to demonstrate the
delivery of PRINT.RTM. nanoparticles using iontophoresis. A 2%
agarose gel was poured into a small test tube (diameter 13 mm) and
a capillary tube (o.d. 1 mm) was used to create a central
reservoir. An aqueous solution of fluorescent polyampholyte
PRINT.RTM. nanoparticles (size: 343 nm, charge: .about.59 mV,
concentration: 9.5 mg/mL) was deposited into the reservoir. A
platinum wire (diameter 0.25 mm) was inserted into the reservoir as
anode and a similar wire served as a cathode outside the phantom.
The phantom was then immersed in a solution of 0.25.times.PBS, and
the electrodes were hooked up to a DC power source using alligator
clips. In the negative control, the particles were allowed to
passively diffuse into the gel without the application of current
for 5 minutes. For iontophoretic delivery, the nanoparticles were
driven into the gel by a constant current of 5 mA for the same
duration. The phantoms were then cut into 1 mm thick transverse
slices that were placed onto glass slides for imaging under a
fluorescent microscope. The difference in the extent of migration
due to the electric field is shown in FIGS. 31A and 31B. FIG. 31A
represents passive diffusion, while FIG. 31B shows results from
migration in the 5 mA current.
[0098] The following examples, which are not meant to be limiting,
generally relate to proof-of-concept studies relating to electric
field assisted delivery (EFAD), engineering of EFAD devices,
exploratory studies in large animals have been performed, and
methods of pharmacokinetic analysis for local delivery mechanisms
have been developed. Proof-of-concept studies for EFAD were
performed in tumor tissue surrogates and pancreatic tumor tissue.
Two EFAD devices were designed and prototyped for different
approaches to the primary pancreatic tumor, including endoductal,
and surgically implantable. Four large animal models were evaluated
for the different device approaches, and the canine model was
chosen as the most amenable to all device approaches. A tissue
sampling system and methods of pharmacokinetic analysis for tissue
and plasma have also been developed. Overall, these devices could
potentially offer an entirely new modality for the treatment of
pancreatic cancer under the emerging field of interventional
oncology. Moreover, the further development of these devices could
translate directly into new treatments for other types of primary
tumors and metastatic diseases.
Example 16: Examination of Gemcitabine Transport in Pancreatic
Tissue and Tumor Tissue
[0099] To assess and optimize the electrical transport parameters
in tissue, a transport testing system was built (see FIG. 32A). The
transport of gemcitabine, the current standard-of-care therapy for
pancreatic cancer, was evaluated in orthotopic xenograft tumors
using this transport testing system (see FIG. 32B). The tumors
chosen for the studies were 1.25 to 1.5 cm in diameter because of
compatibility with the size of the transport cell. The gemcitabine
was used according to the current clinical formulation (Gemzar.RTM.
to Eli Lilly and Company), at a concentration relevant to that
administered in the clinic. For three tumors, a constant current of
20 mA was applied for 20 minutes, and the amount of gemcitabine was
evaluated using a high-performance liquid chromatography (HPLC)
analysis method. For three additional tumors, no current was
applied, which allowed for passive diffusion of the gemcitabine
into the tumor, and the amount of gemcitabine was evaluated using
the same HPLC analysis method. As shown in FIG. 32B, an eight-fold
increase in the amount of gemcitabine was measured within an
orthotopic xenograft tumor when a constant current of 20 mA was
applied for 20 minutes compared to the control (no current
applied).
Example 17: Implantable Device
[0100] The laparoscopic implantable device was developed for
surgical implantation onto the surface of the pancreas in proximity
to the tumor. The device would be sutured or bioadhered to the
pancreas. As seen in FIGS. 33A-D, the laparoscopic implantable
system was designed with a drug reservoir, cellulose membrane,
polyurethane shell, AgCl electrode, conducting wire, and an inlet
and outlet for drug flow into and out of the reservoir. The
reservoir is covered by a semi-permeable membrane through which
drug can be transported. Drug flows through an inlet tube and is
removed from the reservoir through an outlet tube. A metallic
electrode is situated at the back of the reservoir. A conducting
wire is situated through the reservoir to connect to the metallic
electrode. There exist anchor points on the device situated for
attachment to tissue. The reservoir and flow system allow for a
constant drug concentration around the electrode and the removal of
the by-products of the redox reaction. The cellulose membrane will
minimize uncontrolled drug flow out of the system.
Example 18: Studies in Large Animals
[0101] As there are no readily available large animal models of
pancreatic cancer, device development and evaluation will be
performed in healthy large animals. Four large animal models,
including goats, sheep, dogs, and pigs, were evaluated for three
device approaches to the pancreas. Table 1 shows the relative
assessment of each animal model. The dog was determined to be the
most amenable to all device approaches.
TABLE-US-00001 TABLE 1 Assessment of animal model for device
approach. Animal Surgical Endoscopic Intravascular Goat 2 2 5 Sheep
2 2 5 Dog 4 4 4 Pig 2 2 4 Scale: (1) Not feasible-(5) Very
feasible
[0102] The reservoir based system similar to that shown in FIGS.
33A-D was surgically implanted onto the pancreas of a canine. All
animal models were anesthetized and attached to a respirator for
the entirety of the study. The implantable device approach was
assessed via a laparotomy. The pancreas was assessed for ease of
access.
[0103] There were three arms for the large animal experiment: 1.
Device with current; 2. Device without current; and 3. IV Infusion
(see Table 2). The device was sutured onto the right lobe of the
canine pancreas. Gemcitabine formulated at clinically relevant
concentrations was pumped into and out of the device at .about.1.5
mL/min during the application of 10 mA of current applied for 60
minutes. Control experiments were run without current. After
administration of therapy, the pancreas was excised and snap frozen
for analysis. The gemcitabine was measured from the section tissue
using UV-HPLC from established protocols in the literature (see
Olive, K P, et al. Science 324 (2009) 1457-1461 and Kirstein M N,
et al., J Chromatogr B Analyt Technol Biomed Life Sci. 835 (2006)
136-142). Shown in FIG. 34 are the results obtained from the three
experimental arms analyzing the mass of gemcitabine from the entire
pancreas.
TABLE-US-00002 TABLE 2 Experimental arm parameters Device Device
w/o w/Current Current IV Infusion Current 10 mA 0 mA -- Time of 60
minutes 60 minutes 30 minutes Administration Sample Size 5 5 4
[0104] In FIG. 35, the transport distance of the gemcitabine is
shown for the with and without current arms. In particular, FIG. 35
shows the quantification of gemcitabine mass at different distances
away from the electrode. The plasma concentrations determined for
the with and without current arms are given in Table 3. Plasma
concentrations of gemcitabine were detected at 15-minute increments
prior to and during the large animal study. The tissue was
sectioned using a cryostat microtome and gemcitabine was extracted
using an established extraction method (see Olive et al.). The
gemcitabine was detected and quantified using UV-HPLC (see Olive et
al. and Kirstein et al.). Essentially, the gemcitabine levels
detected in the plasma of the dogs was below the detectable
limit.
TABLE-US-00003 TABLE 3 Plasma Concentrations of Gemcitabine. Device
- Current Applied Device - No Current Gem Concentration Gem
Concentration Sample (ug/mL) (ug/mL) -15 min * * 0 min * * 15 min *
* 30 min * * 45 min * * 60 min * * * Below limit of detection
[0105] Pharmacokinetics and Analysis in Tissue and Serum
[0106] The pharmacokinetic analysis for tissue and serum has been
developed according to a method developed by Kirstein et al. A
validated standard curve has been developed and will be used for
future in vivo studies (data not shown).
Example 19: Endoductal Device
[0107] A second device approach developed for the treatment of
pancreatic cancer was an endoductal device. The device was modeled
in a 3D CAD program (SolidWorks.RTM. to Dassault Systemes
SolidWorks Corporation) prior to prototyping. The endoductal
approach was developed according to endoscopic retrograde
cholangiopancreatography (ERCP) devices, which use a duodenoscope
to access the major duodenal papilla. A double balloon catheter was
designed, as seen in FIG. 36. A multi-luminal tube was used for
independent control of balloons, drug expulsion, and electrical
contact with the electrode. The catheter contains two independently
controlled balloons that sandwich an electrode. The balloons and
electrode are UV-cured to the tube. A guide wire is attached to the
front end of the device. Drug can be expelled from the device
around the electrode and would fill the cavity between the two
independently controlled balloons. A conducting wire is in contact
with the silver electrode.
[0108] The tubing of the catheter contained four lumens for saline,
drug, and a conducting wire (see FIG. 37). The two identical lumens
were used to inflate the balloons with saline, the small lumens
were used for the conducting wire, and the larger lumen was used
for the transport of drug. FIG. 37 illustrates exemplary dimensions
for the catheter and lumens according to one experimental
implementation and is not meant to be limiting. A nitinol
conducting wire was connected to a silver electrode located between
two pre-fashioned urethane balloons. The double balloon catheter
system created a reservoir for drug containment, which could limit
drug exposure to the epithelium, allow for good electrical contact
between the electrode and drug, and reduce the effect of extraneous
ions in the system. Ultimately, an endoductal EFAD device could be
designed to slip over a guide wire that has entered the main
pancreatic duct.
* * * * *