Method of treatment using electroporation mediated delivery of drugs and genes

Abstract

A method for in vivo electrotherapy, or electroporation-mediated therapy, using a needle array apparatus is provided. Treatment of tumors with a combination of electroporation using the apparatus of the invention, and a chemotherapeutic agent, caused regression of tumors in vivo.

1 . canceled  
   
   
       2 . A method of electroporating a portion of the body of a patient to introduce molecules into tissues therein, comprising: 
 a. providing an array of multiple opposed pairs of electrodes connected to a generator, wherein at least two pairs of electrodes are activated simultaneously, at least one of said pairs of electrodes having a needle configuration for penetrating tissue;    b. inserting a first pair of said needle electrodes, into selected tissue for introducing molecules into the tissue;    c. positioning a second pair of electrodes of said array of electrodes in conductive relation to said selected tissue so that said tissue is between said first and second opposed pairs of electrodes; and    d. applying electric pulses to at least two different pairs of electrodes to generate an electric field of sufficient strength to cause in vivo electroporation of the tissue.    
   
   
       3 . A method for the delivery of molecules to a predetermined tissue of a subject, comprising: 
 a. providing an array of electrodes comprising at least two pairs of opposed electrodes, wherein at least one of said electrodes has a needle configuration for penetrating said tissue;    b. contacting said tissue with said array such that the electrode(s) penetrate said tissue;    C. administering said molecules to said tissue; and    d. applying at least one electric pulse simultaneously to at least two of the pairs of electrodes sufficient to electroporate cells of said tissue and thereby allow said molecules to be delivered to said tissue.    
   
   
       4 . A method according to  claim 3 , wherein the array comprises at least three pairs of opposed electrodes and at least one of said pairs is not pulsed when at least two of the pairs of electrodes are pulsed simultaneously.  
   
   
       5 . A method according to  claim 3 , wherein the molecules are selected from the group consisting of a chemotherapeutic agent, a polynucleotide, and a polypeptide.  
   
   
       6 . A method according to  claim 5 , wherein the chemotherapeutic agent is bleomycin.  
   
   
       7 . A method according to  claim 2 , wherein the molecules are administered by a method selected from the group consisting of intratumoral, systemic, and local administration.  
   
   
       8 . A method according to  claim 2 , wherein the predetermined tissue is selected from the group consisting of pancreas, lung, heart, kidney, muscle, breast, colon, prostate, thymus, testis, and ovary.  
   
   
       9 . A method for the delivery of molecules to a predetermined tissue of a subject, comprising: 
 a. providing an array of electrodes comprising at least two pairs of opposed electrodes, wherein at least one of said electrodes has a needle configuration for penetrating said tissue;    b. contacting said tissue with said array such that the electrode(s) penetrate said tissue;    c. administering said molecules to said tissue;    d. applying at least one electric pulse simultaneously to at least two of the pairs of opposed electrodes sufficient to electroporate cells of said tissue using an electric field of predefined strength and thereby allow said molecules to be delivered to said tissue.    
   
   
       10 . A method according to  claim 9 , wherein the electric field of predefined strength is created by delivering electric pulse(s) of a voltage suitable to generate said electric field.  
   
   
       11 . A method according to  claim 10 , wherein the voltage is determined based on the distance between the electrodes of the electrode pair to be energized.  
   
   
       12 . A method according to  claim 9 , wherein the array comprises at least three pairs of opposed electrodes and at least one of said pairs is not pulsed when at least two of the pairs of electrodes are pulsed simultaneously.  
   
   
       13 . A method according to  claim 9 , wherein the molecules are selected from the group consisting of a chemotherapeutic agent, a polynucleotide and a polypeptide.  
   
   
       14 . A method according to  claim 9 , wherein the molecules are introduced by a method selected from the group consisting of intratumoral, systemic, and local administration.  
   
   
       15 . A method according to  claim 13 , wherein the chemotherapeutic agent is bleomycin.  
   
   
       16 . A method according to  claim 9 , wherein the tissue is selected from the group consisting of pancreas, lung, heart, kidney, muscle, breast, colon, prostate, thymus, testis, and ovary.  
   
   
       17 . A method according to  claim 8 , wherein the electric field of predefined strength has a field strength of from about 0.2 kV/cm to about 20 kV/cm.  
   
   
       18 . A method according to  claim 8 , wherein the electrode array is in a configuration selected from the group consisting of a substantially square, rectangular, and circular pattern.  
   
   
       19 . A method for the delivery of molecules to a predetermined tissue of a subject, comprising: 
 a. providing an electrode apparatus for the application of at least one electric pulse, wherein said electrode apparatus comprises: 
 i. at least two pairs of needles for penetrating said predetermined tissue, wherein each needle has a lumen for insertion of an electrode;  
 ii. at least two pairs of electrodes, wherein each electrode is configured for insertion into the tissue through the lumen of one of said needles; and  
 iii. a power generator to apply an electric potential of sufficient strength across at least two of the pairs of the electrodes to generate an electric field for electroporation of cells of the tissue; and  
   b. applying at least one electric pulse simultaneously to at least two of the pairs of electrodes sufficient to electroporate cells of said tissue and thereby allow said molecules to be delivered to said tissue.    
   
   
       20 . A method according to  claim 19 , wherein the array comprises at least three pairs of opposed electrodes and at least one of said pairs is not pulsed when at least two of the pairs of electrodes are pulsed simultaneously.  
   
   
       21 . A method according to  claim 19 , wherein said needles are tubular.  
   
   
       22 . A method according to  claim 19 , wherein said needles are removed and the electrodes are left in said tissue.  
   
   
       23 . A method according to  claim 19 , wherein said needles are nonconductive.  
   
   
       24 . A method according to  claim 19 , wherein each of the electrodes comprises an elongated insulated conductor with a conductive tip at its distal end.  
   
   
       25 . A method according to  claim 19 , wherein the needles are connected to a source of molecules and are used to inject a solution comprising said molecules and a carrier into the tissue.  
   
   
       26 . A method according to  claim 19 , wherein the electrode apparatus produces electrical pulses between electrodes according to a set of predetermined electrode configurations.  
   
   
       27 . A method according to  claim 19 , wherein the electrode apparatus further comprises an identification circuit to determine the number of electrodes in the electrode apparatus and desired electrical signal parameters for the application of one or more electric pulses.  
   
   
       28 . A method according to  claim 19 , wherein the power generator includes a control module that controls at least one electrical treatment parameter selected from the group consisting of an electrode voltage set point, pulse length, pulse shape, pulse number, and an electrode switching sequence.  
   
   
       29 . A method according to  claim 28 , wherein the control module directs the power generator to generate at least one electric pulse having a voltage that depends on a spacing of the electrodes in the electrode apparatus.  
   
   
       30 . A method according to  claim 28 , wherein the control module directs the power generator to generate at least one electric pulse according to the number of electrodes in the electrode apparatus.  
   
   
       31 . A method according to  claim 19 , wherein electric field strength produces by the pulse(s) between the electrodes ranges from about 10 V/cm to about 1300 V/cm.  
   
   
       32 . A method according to  claim 19 , wherein each pulse produced by the power generator has a pulse width from about 10 microsecond to about 100 millisecond.  
   
   
       33 . A method according to  claim 19 , wherein at least one needle in the electrode apparatus is configured for transit of a solution.  
   
   
       34 . A method according to  claim 19 , wherein each electrode comprises a base portion that makes electrical contact with the electrode apparatus and a distal tip portion that is exposed to deliver electricity to tissue, wherein the electrode is covered with a layer of electrically insulating material between the base portion and the distal tip portion.  
   
   
       35 . A method for the delivery of molecules to a predetermined tissue of a subject, comprising: 
 a. providing an electrode apparatus for the application of at least one electric pulse, wherein said electrode apparatus comprises: 
 i. at least two pairs of needle electrodes for penetrating said predetermined tissue, wherein at least one of said needle electrodes is used to deliver a solution containing said molecules to said tissue, and wherein at least two pairs of said needle electrodes is used to deliver at least one electric impulse; and  
 ii. a power generator to apply an electric potential of sufficient strength across at least two of the pairs of the electrodes to generate an electric field for electroporation of cells of the tissue; and  
   b. applying at least one electric pulse simultaneously to at least two of the pairs of electrodes sufficient to electroporate cells of said tissue and thereby allow said molecules to be delivered to said tissue.    
   
   
       36 . A method according to  claim 35 , wherein the electrode apparatus comprises at least three pairs of opposed electrodes and at least one of said pairs is not pulsed when at least two of the pairs of electrodes are pulsed simultaneously.