Surgery – Instruments – Electrical application
Reexamination Certificate
2002-03-29
2004-11-23
Peffley, Michael (Department: 3739)
Surgery
Instruments
Electrical application
C606S028000, C435S173100
Reexamination Certificate
active
06821274
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the use of a combination of electric field energy and ultrasound energy for the selective ablation of tissues, such as tumor tissues, and preferably cells in an organism.
BACKGROUND TO THE INVENTION
In general therapeutic applications of ultrasound in the clinic may be divided into two major categories; applications that employ low intensity (0.125-3 W/cm
2
) and those that employ higher intensities (≧5 W/cm
2
) (ter Haar, 1999
, Eur. J. Ultrasound
9: 3). Low intensity ultrasound is commonly used in applications such as physiotherapy, for example, to stimulate normal physiological responses to injury or to accelerate processes, such as the transport of drugs across the skin. Treatment with low intensity ultrasound rarely results in collateral tissue damage and usually extreme efforts are employed to minimise such effects. This includes minimising excessive tissue heating which results from exposure to ultrasound, typically by reducing the treatment time and/or delivering the ultrasound in a pulsed manner.
In contrast, the major objective of applications involving the use of high intensity ultrasound is to selectively destroy tissue by hyperthermic processes. High intensity ultrasound-mediated tissue ablation may be categorised according to the way in which ultrasound energy is delivered to tissues. Ultrasound may be delivered directly from a transducer to the treatment area; alternatively, a coupling device which focuses the ultrasound may mediate delivery. When provided through a coupling device, ultrasound passing through intervening tissues is usually low intensity and therefore, relatively non-destructive. However, at the focal point, the energy which has accumulated is raised to a pre-determined higher intensity and tissue destruction occurs at, or around, the focal point. Thus, using a coupling device has the advantage of selectively delivering ablative energy to a tissue being treated without causing major damage to intervening tissues.
In general, therapeutic applications which rely on the use of high intensity focussed ultrasound, or “HIFU,” exploit the heat which is generated at the focal point and a number of methods together with devices for achieving focus and tissue ablation have been suggested (see, e.g., U.S. Pat. Nos. 4,888,746; 5,895,356; 5,938,608 and International Patent Applications WO 97/35518 A1 and WO 99/22652 A1).
In addition to a requirement for relatively sophisticated equipment to achieve focussing of high intensity ultrasound, one major disadvantage associated with the use of HIFU involves the potential for the occurrence of cavitation events which, in turn, leads to the formation of destructive, or possibly mutagenic, free radicals (Miller et al., (1996)
Ultrasound in Med.
&
Biol.
22: 1131). An alternative approach involving a mechanism of sensitising the target tissue to low intensity ultrasound (either focussed or non-focussed) would therefore provide an advantage.
It has been found that the delivery of short, intense electric pulses to cell populations or tissues in vivo results in transient permeabilisation of cell membranes and this has provided the basis for what has become known as electrochemotherapy (Heller et al., (1999)
Advanced Drug Delivery Rev.
35: 119). Electrochemotherapy was originally developed to facilitate the passage of chemotherapeutic drugs into cancer cells which had become impermeable to those drugs. The technique has developed to a stage where delivery of electric pulses in vivo is being exploited in areas such as gene therapy in order to mediate introduction of DNA to target tissues. Devices designed to facilitate delivery of electric pulses in vivo under a variety of conditions (e.g., transdermal, laparoscopic, catheter-mediated delivery, etc.) currently exist (see, e.g., International Patent Applications WO 99/22809 A1, WO 99/06101 A1; WO 99/01157 A1, WO 99/01157 A1, and WO 99/01158).
More recently, it has been found that exposure of human erythrocytes to short and intense electric pulses which facilitates transient permeabilisation also results in a dramatic sensitisation to low intensity ultrasound (WO 01/07011).
SUMMARY OF THE INVENTION
The present invention relies partially on the discovery that sensitisation of nucleated cells by application of an electric field (“electrosensitisation”) renders the cells susceptible to ablation using low intensity ultrasound and thereby provides a means of eliminating unwanted cells and tissues in the body. The invention also relies on the discovery that exposure of a cell to ultrasound followed by exposure to electric fields also results in cell disruption. Thus, exposure of a nucleated cell to ultrasound and an electric field applied in any order, results in cell disruption.
In one aspect, the invention provides a method of rendering a cell sensitive to disruption by ultrasound comprising exposing the cell to an electric field for an amount and time sufficient to render it more susceptible to disruption by ultrasound than an unsensitised cell. The invention also provides a method of disrupting a cell comprising providing a cell which has been exposed to an electric field for an amount and time sufficient to render it more susceptible to disruption by ultrasound than an unsensitised cell; and exposing the cell to ultrasound, thereby disrupting the cell. The invention further provides a method of disrupting a cell comprising exposing the cell to an electric field for an amount and time sufficient to render it more susceptible to disruption by ultrasound than an unsensitised cell; and exposing said cell to ultrasound, thereby disrupting the cell. The cell can be part of a tissue, such as a tumor tissue, and exposure to ultrasound can be performed in vitro, ex vivo, or in vivo. Similarly, the step of exposing the cell to the electric field can occur in vitro, ex vivo, or in vivo. Disruption can be a result of apoptosis of the cell and in a preferred aspect, disruption results in ablation of cells from the body of an organism.
In one aspect, the method further comprises the step of exposing the cell to an agent which facilitates cell death. The cell-death facilitating agent can be selected from the group consisting of an oligonucleotide, a ribozyme, an antibody, an enzyme, a cytotoxic agent, a cytostatic agent, a cytokine, GM-CSF, IL-2, an immunogen, and combinations thereof.
In one aspect, the electric field to which the cell is exposed is from about 1 Volt/cm to 10 kVolts/cm. The electric field is preferably applied for between about 1 &mgr;s and 100 milliseconds. Ultrasound is preferably applied at a power level of from about 0.05 W/cm
2
to 100 W/cm
2
and continuous wave ultrasound or pulsed wave ultrasound can be applied.
In one aspect, the invention provides a method for disrupting a cell which comprises exposing the cell to a sensitising stimulus. The sensitising stimulus makes a cell more susceptible to a disrupting stimulus than a non-sensitised cell. The cell is then exposed the cell to a disrupting stimulus under conditions suited to disrupt the sensitised cell while not substantially disrupting non-sensitised cell.
In another aspect, the invention provides a method for selectively disrupting one or more target cells at a target site comprising a plurality of cells comprising: (a) exposing the one or more cells to an electric field; and (b) exposing the one or more cells to ultrasound; wherein the exposing in steps (a) and (b) disrupts the one or more target cells.
Preferably, the electric field is a low intensity electric field which has an electric field strength of less than 20 V/cm. In one aspect, direct current is applied to expose the one or more cells to the low intensity electric field. In another aspect, the current is between 100 &mgr;A to 200 mA.
In one aspect, the method is performed using an electric field is from 1 Volt/cm to 10 kVolts/cm under in vivo conditions. In another aspect, the electric field is applied for between 1 &mgr;s and 100 milliseconds. In a further aspect, ultrasound is app
Haro Anna Maria Rollan
McHale Anthony Patrick
Frommer & Lawrence & Haug LLP
Gendel Ltd.
Kowalski Thomas J.
Lu Deborah
Peffley Michael
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