US20020198567A1 - Electro-endocytotic therapy as a treatment modality of cancer - Google Patents

Electro-endocytotic therapy as a treatment modality of cancer Download PDF

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Publication number
US20020198567A1
US20020198567A1 US09/876,624 US87662401A US2002198567A1 US 20020198567 A1 US20020198567 A1 US 20020198567A1 US 87662401 A US87662401 A US 87662401A US 2002198567 A1 US2002198567 A1 US 2002198567A1
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Prior art keywords
cells
low electric
cell
electric field
exposing
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Abandoned
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US09/876,624
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Yona Keisari
Rafi Korenstein
Igor Entin
Yosef Rosemberg
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Ramot at Tel Aviv University Ltd
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Ramot at Tel Aviv University Ltd
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Priority to US09/876,624 priority Critical patent/US20020198567A1/en
Assigned to RAMOT-UNIVERSITY AUTHORITY FOR APPLIED RESEARCH AND INDUSTRIAL DEVELOPMENT, INC. reassignment RAMOT-UNIVERSITY AUTHORITY FOR APPLIED RESEARCH AND INDUSTRIAL DEVELOPMENT, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ENTIN, IGOR, KEISARI, YONA, KORENSTEIN, RAFI, ROSEMBERG, YOSEF
Priority to EP02735958A priority patent/EP1409076A4/fr
Priority to US10/478,207 priority patent/US7395112B2/en
Priority to CA002450009A priority patent/CA2450009A1/fr
Priority to PCT/IL2002/000445 priority patent/WO2002098501A2/fr
Priority to JP2003501537A priority patent/JP2004534784A/ja
Priority to AU2002309240A priority patent/AU2002309240A1/en
Priority to IL15909302A priority patent/IL159093A0/xx
Publication of US20020198567A1 publication Critical patent/US20020198567A1/en
Priority to US12/068,099 priority patent/US20080132963A1/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N1/00—Electrotherapy; Circuits therefor
    • A61N1/18—Applying electric currents by contact electrodes
    • A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
    • A61N1/327—Applying electric currents by contact electrodes alternating or intermittent currents for enhancing the absorption properties of tissue, e.g. by electroporation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a system for exposing cells to low electric fields in the presence or absence of therapeutic agents. More specifically, the present invention relates to a pulsed low voltage system capable of stimulation of endocytosis and of macromolecular transfer.
  • low molecular weight molecules are incorporated into cells based either of two methods, one method uses the employment of lipophilic molecules which are modified into hydrophilic molecules following their penetration into the cytosol by intracellular enzymes, such as esterases.
  • the esterases act on, for example, the pH indicator 2′, 7′′-bis (2-carboxyethyl)-5(6)-carboxyfluorescein, an acetoxy methyl ester.
  • Permeability change can be induced by adenosine tri-phosphate via formation of small pores in the membrane.
  • the second method relates to the incorporation of high molecular weight molecules and is based on several approaches.
  • One approach is the use of chemicals such as detergents, polyethyleneglycol, and lipofectin.
  • Additional approaches include liposome-cell fusion, electroporation, and cell bombardment by particles coated with molecules.
  • Fusing liposomes is another approach.
  • the liposomes are loaded with the appropriate genes and are fused with the target cells.
  • Electroporation is generally defined as the formation of hydrophilic pores through an electrical process wherein larger pores allow higher permeability. Electroporation utilizes short, high voltage electrical pulses to produce a transient high permeability state (reversible electrical breakdown, REB) which occurs at the beginning of the high permeability state. REB is a decrease in the electrical resistance of a tissue which is caused by brief exposure to an abnormally high transtissue potential.
  • U.S. Pat. No. 5,019,034 to Weaver discloses the use of a high voltage, short duration electrical pulse on the tissue surface to produce electroporation of molecules into cells of the tissue.
  • this and other existing methods suffer from at least one of the following problems:
  • the present invention provides an alternative method to the above, which not only enables the incorporation into cells of macromolecules without destruction of the cells, but also provides an efficient introduction of the molecules.
  • the method can be accomplished in vivo or in vitro.
  • cancer is second only to heart disease as a cause of death.
  • the leading cause of cancer death is the growth of metastases, and in the majority of patients, by the time of diagnosis of primary malignant neoplasms, metastases have spread to regional or distant sites, but only in the minority of these patients metastases can be clinically detected (for review see Fidler and Balch, 1987) or effectively treated. It would therefore be useful to develop a method and therapy for the efficient removal of the primary tumor mass and prevention of secondary tumor growth, eradication of metastatic cells, and reconstitution of the immune response.
  • a method for treating cancer by one of the two methods includes introducing a chemotherapeutic agent into a membrane vesicle, cell or tissue by exposing the membrane vesicle, cell, or tissue to a low electric field in the presence of the chemotherapeutic agent in an extracellular compartment of the membrane vesicle, cell, or tissue. Also provided is therapy utilizing a low electric field and a chemotherapeutic agent or the tumor can be exposed to a low electric field in the absence of externally added therapeutic agent.
  • a method for treating tumors and increasing inflammatory and immunologic responses by exposing cells to a low electric field in the presence and absence of a therapeutic agent and in the presence or absence of immunomodulatory agent in an extracellular compartment of the cell is also provided.
  • a method for treating tumors and increasing inflammatory response including the step of exposing cells to a low electric field is also provided.
  • FIG. 1 is a graph showing the cumulative proportion of surviving C57BL/6 mice bearing B16-F10.9 melanoma following EECT with cisplatin;
  • FIG. 2 is a graph showing the cumulative proportion of surviving C57BL/6 mice bearing B16-F10.9 melanoma following EECT with taxol;
  • FIG. 3 is a graph showing the survival percentages of mice utilizing various treatments
  • FIG. 4 is a graph showing the tumor volume of C57BL/6 mice, bearing B16-F10.9 melanoma at seventh day following EECT (20 days following tumor inoculation);
  • FIG. 5 is a graph showing the cumulative proportion of surviving Balb/c mice bearing DA-3 mammary adenocarcinoma following EECT with taxol.
  • FIG. 6 is a graph showing the cumulative proportion of surviving C57BL/6 mice cured by EECT challenged with 2 ⁇ 10 5 B16-F10.9 cells.
  • the present invention provides a method and apparatus for the introduction of a therapeutic agent into a cell while maintaining the function of the therapeutic agent.
  • the method is accomplished by the general steps of preparing either a suspension or an adherent growth of cells, introducing a therapeutic agent into the cells, and applying a train of unipolar or alternating low voltage pulses to the suspension or adherent layer to incorporate the molecules into the cell.
  • the exposure to unipolar or alternating train or series of trains of voltage pulses leads to electrophoretic movement of the charged proteins into the cell membrane, thereby leading to membrane destabilization resulting in endocytosis. This induces uptake of therapeutic molecules/macromolecules into the cell.
  • extracellular compartment as used herein it is meant any of the space located outside of the cell membrane.
  • a method for treating cancer cells by applying a low electric field to the cancer cells.
  • This electric field induces endocytosis in the cancer cells thereby leading to cell death.
  • the treatment can also include applying the low electric field in the absence of a therapeutic agent. This treatment functions because the endocytosis incorporates cell surface receptors into the cytosol. Once these receptors are incorporated into the cell, this down regulates the cell's response, eventually leading to cell death.
  • Cell membrane destabilization causes penetration of therapeutic molecules and macromolecules into the cytosolic compartment of the cell via an endocytic process. The process leads to increased vesicle formation with the therapeutic molecules and macromolecules trapped inside the vesicle. Alternatively or additionally the therapeutic macromolecules penetrate the cells via diffusion through the induced structural defects in the lipid bilayer.
  • a series of pulses such as a single train or multiple trains of unipolar low-voltage direct current (D.C.) or alternating current (A.C.) pulses, is applied to an environment containing the cells and therapeutic agents.
  • the term “series” is used to designate a single train of voltage pulses or a number of continuous repetitions of the train of voltage pulses.
  • These low voltage pulses can be unipolar, bipolar or alternating bipolar. This step of the process is a critical difference from other processes, such as electroporation.
  • the cells are suspended in a medium of low conductance in order to limit electric heating effects and/or electrolytic reactions at the electrode—medium interface.
  • a medium of low conductance in order to limit electric heating effects and/or electrolytic reactions at the electrode—medium interface.
  • Such medium can consist of 300 mM sucrose or mannitol in the presence of a small amount of a buffer (e.g. 1 to 3 mM Hepes) of a pK in the pH range of 7.0 to 8.0.
  • 5% glycerol can be added to the medium in order to enhance incorporation.
  • the cells are washed with PBS or growth medium and finally, the medium is replaced with fresh growth medium in the presence of 5%-10% FCS (fetal calf serum) or bovine calf serum.
  • FCS fetal calf serum
  • the train or series of trains of unipolar voltage pulses is applied by the application of two electrodes to the suspension.
  • the electrodes can be made from different metal with the preference of using inert and non-polarizable electrodes (e.g., platinum or Ag/AgCl electrodes, correspondingly).
  • the cells are adhered to a surface by growth in a suitable growth medium.
  • the growth medium is then removed and replaced with a suitable incubation medium such as BGJ media supplemented with 10% FCS.
  • An alternating current field 60 V/cm at 30 kHz is then applied to the cells.
  • the cells are washed with PBS or medium and finally replaced with fresh grown medium.
  • the incorporation of therapeutic macromolecules is carried out in the presence of a very conductive medium. That is, therapeutic macromolecules are incorporated into cells in the presence of a highly conductive medium.
  • the present invention can also be applied to enhance incorporation of therapeutic molecules into adherent cells by utilizing both the method and apparatus of the present invention.
  • adherent cells For use with adherent cells, there is no need to change the growth medium of the cells to a low conductivity medium. That is, the same medium used for cell growth can be utilized for incorporating the therapeutic macromolecule.
  • the present invention can also be utilized in vivo by application of the molecules to be introduced at the site or area containing the cells which are the target of the introduction.
  • Sites such as skin and internal tissues can be targets either non-invasively or invasively, respectively.
  • Therapeutic agents include any molecules capable of incorporation by the present invention, which can be defined over a wide range. This range includes agents known in the art, whether electrically charged or neutral. This can include, but is not limited to, DNA, antisense, enzymes, taxol etc. The endocytotic event is independent of any electrical charge of the agent. Further, the present invention induces increased incorporation of the agent into the cell. Accordingly, the process increases drug uptake and thereby, increases drug potency at a desired cell site. That is, the present invention enables an efficient introduction of therapeutic molecules and macromolecules into living cells in vitro and in vivo. These therapeutic molecules are within an extremely wide range of molecular weight and size.
  • transfection with different DNA vectors is possible by use of the present inventive method either by itself or in combination with other methods of transfection, thereby enhancing the effectiveness of those methods.
  • Other existing methods of incorporation include incorporation of therapeutic macromolecules based on the use of chemical compounds e.g., DNA transfections based on the use of calcium phosphate precipitation.
  • the therapeutic agents can also include antisense oligonucleotides.
  • the present invention is based on an electric field induced relative movement of charged or neutral therapeutic molecules, charged therapeutic macromolecules, or charged liposomes toward cells (or the converse) using appropriate electric field parameters which yield an accumulation of the charged entities near the cell membrane.
  • These charged therapeutic agents can either be charged initially or can be neutral agents to which a charge is added.
  • the present invention does not use either high voltages, such as those used with electroporation, or frequencies which create summation of voltage pulses in a way where the effective pulse is the summation of several pulses, resulting in equilibrating molecules between the extracellular and intracellular compartments.
  • This method differs from electroporation (or the equivalent terms) by the following features:
  • Electroporation and consequent uptake under specific electric field parameters, were shown to be proportional to the volume of the biological object (e.g. cell, bacteria etc.) which is exposed to the electric field.
  • the uptake by the method of the present invention is independent of the volume of the exposed biological object and can be proportional to the surface area of the object.
  • Uptake is not limited by the electrochemical potential difference across the membrane. Under conditions of electroporation, at most, the same concentration of therapeutic molecules/macromolecules in the cytosol and in the external medium can be achieved. Under the experimental conditions, applications have demonstrated up to two orders of magnitude increase of therapeutic molecules/macromolecules concentration in the cytosol as compared with the concentration in the external medium.
  • the cell suspension or the cells adhered to a surface in the presence of the chemotherapeutic molecular entity to be incorporated are exposed to an electric field produced by several trains of electrical pulses.
  • the amplitude of the voltage in each train or series of trains of pulses is in the amplitude range of 1 V/cm to 150 V/cm.
  • the frequency range of the pulses of different shapes is from 1 Hz to 50 MHz processing pulse with widths of 20 ns to 20 ms, in the case of unipolar pulses (D.C.), and 5-500 kHz for bipolar pulses of and different shapes.
  • the exact field characteristics to be applied depend upon the charge and the molecular weight of the specific therapeutic molecules to be incorporated.
  • the present invention has possible applications in various fields.
  • the present invention can be used to load drugs into cells for slow drug release.
  • the drugs are the molecules being transferred into the cells via the present invention.
  • Other molecules, such as dyes and tracers, can be loaded into cells for imaging-based diagnosis.
  • In-situ enzymology loading agents for diagnostics
  • Loading of antibodies for therapy or diagnostics can be carried out.
  • the present invention can be used for incorporating therapeutic drugs into specific cell or tissue types, for example loading of drugs into tumor tissue for cancer therapy.
  • enzymes can be loaded into cells for specific purposes.
  • the present invention enables therapeutic agents to be endocytotically incorporated into the intracellular space without losing any therapeutic functions. This increases the effectiveness of therapeutic agents without necessitating an increase in the amount of the agent being administered. Additionally, multiple therapeutic agents can be administered in a single treatment.
  • the present invention can be used as a means of transfection, as well as tissue gene therapy.
  • the gene therapy can be used to make a cell more susceptible to treatments including, but not limited to, radiation and chemotherapy.
  • an antisense oligonucleotide can be incorporated into a cell, whereby upon incorporation the cell is made luminescent and thus more easily recognized for surgery.
  • the antisense oligonucleotide can be programmed to induce cell death.
  • the immunologic response can be augmented by the application of immunostimulatory agents.
  • agents can be selected from the group including agents such as cytokines, thymic factors, bacteria derived immunostimulants, and other agents known in the art. These can be combined with other therapeutic agents to effect a combinatorial treatment. That is, the immunostimulator can be induced and is induced during the application of other therapeutics. Hence, augmentation by the application of immunostimulants can be combined with treatment of therapeutic agents.
  • Various combination therapies can also be augmented by increased cellular uptake pursuant to the present invention.
  • the field of gene therapy can also use the methods of the present invention to activate an immunological or inflammatory response. This occurs, for example, by incorporating genetic material into the target cell. The genetic material through translation, creates an inflammatory or immunological response by causing an antigen or other signal to be displayed on the cells surface.
  • Electroendocytotic Chemotherapy As Treatment Modality of Primary and Secondary Tumors
  • Endocytosis-like process is a mechanism of internalization of macromolecules. Endocytosis includes a complex sequence of membrane-linked processes that results in the uptake of extrinsic substances by binding to the cell surface, or incapsulation in the endocytotic formed vesicles, maturation of endocytotic vesicles, and partial transfer to lysosomes (Mellman, 1996).
  • Exposure of membrane vesicles and cells to low electric fields can generate, among others, electrophoretic lateral mobility of charged proteins and lipids in the plane of the cell membrane (Poo, 1981; Brumfield et al., 1989). Also generated is an induction of a cross membrane potential difference across the membrane (Farkas et al., 1984).
  • EECT electroendocytotic-like chemotherapy
  • C57BL/6 mice were injected subcutaneously with 2 ⁇ 10 5 B16-F10.9 tumor cells.
  • BALB/c mice were inoculated subcutaneously (4 ⁇ 10 5 ) with the metastatic Mammary Adenocarcinoma DA-3 tumor cell line.
  • C57BL/6 and BALB/c mice were treated by a single EECT treatment when the tumor reached the size of four to five mm in diameter.
  • EECT was performed with a unipolar pulsed field strength of 40 V/cm having a repetition frequency of 500 Hz; a pulse width of 180 ⁇ s; and a distance between electrodes of 5 mm. The electric pulse was applied for 10-15 minutes.
  • the doses for intra-tumoral chemotherapy treatment were as follows: for 5-FU, a dose of 75 mg/kg; for taxol, a dose of 20 mg/kg.; and for cisplatin, a dose of 4 mg/kg.
  • mice bearing subcutaneous B16-F10.9 tumors were treated with chemotherapy intratumorally (i.t.) and/or with electric stimulation (ES).
  • the exposure to electric field was carried out three to four minutes after i.t. injection of the cytotoxic drug for a ten minute duration.
  • the mortality of B16-F10.9 melanoma bearing mice (n—number of animals in group) after electroendocytotic-like chemotherapy (EECT) is displayed in FIGS. 1 - 3 .
  • Cisplatin was the first anti-cancer drug tested as a candidate for EECT.
  • the results presented in FIG. 1 clearly show a significant difference in life expectancy of the experimental groups.
  • Mean survival time ⁇ standard error (MST ⁇ SE) of EECT treated mice was 50.5 ⁇ 5.2 days, while non treated tumor bearing mice had a mean survival time of 27.4 ⁇ 1.5 days.
  • Chemotherapy with cisplatin alone and electrostimulation alone posed a survival time of 30.5 ⁇ 1.7 and 33 ⁇ 1.7 days, respectively.
  • 14% of the animals were cured of the tumor.
  • mice that were tumor free after electroendocytotic chemotherapy, were rendered resistant to a tumorigenic dose of B16-F10.9 melanoma cells.
  • mice cured by EECT were injected with 2 ⁇ 10 5 .
  • B16-F10.9 cells subcutaneously 120-180 days after initial tumor inoculation.
  • Challenge of these mice with B16-F10.9 cells shows significant survival extension as compared to the first-time inoculated normal mice. Also, there is significant survival difference, following the challenge, between the groups of the animals treated by EECT with cisplatin and by EECT with taxol.
  • FIG. 6 shows the resistance of mice, previously bearing B16-F10.9 melanoma and cured by electroendocytotic chemotherapy with cisplatin and taxol, to subsequent inoculation of B16-F10.9 melanoma cells.
  • Mice cured by EECT were challenged with 2 ⁇ 10 5 B16-F10.9 cells subcutaneously 120-180 days after initial tumor inoculation. The data were plotted using Kaplan-Meir technique.
  • Haskell C M Principles of cancer chemotherapy. In: Cancer Treatment, Haskell C M, (ed.) 4th ed. Pp. 31, W.B. Saunders Co. Philadelphia, 1995.

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US09/876,624 US20020198567A1 (en) 2001-06-07 2001-06-07 Electro-endocytotic therapy as a treatment modality of cancer
IL15909302A IL159093A0 (en) 2001-06-07 2002-06-09 Method and apparatus for treating tumors using low strength electric fields
PCT/IL2002/000445 WO2002098501A2 (fr) 2001-06-07 2002-06-09 Procede et appareil pour traiter les tumeurs a l'aide de champs electriques a faible intensite
US10/478,207 US7395112B2 (en) 2001-06-07 2002-06-09 Method and apparatus for treating tumors using low strength electric fields
CA002450009A CA2450009A1 (fr) 2001-06-07 2002-06-09 Procede et appareil pour traiter les tumeurs a l'aide de champs electriques a faible intensite
EP02735958A EP1409076A4 (fr) 2001-06-07 2002-06-09 Procede et appareil pour traiter les tumeurs a l'aide de champs electriques a faible intensite
JP2003501537A JP2004534784A (ja) 2001-06-07 2002-06-09 低強度電界を用いる腫瘍の治療方法および装置
AU2002309240A AU2002309240A1 (en) 2001-06-07 2002-06-09 Method and apparatus for treating tumors using low strength electric fields
US12/068,099 US20080132963A1 (en) 2001-06-07 2008-02-01 Method and apparatus for treating tumors using low strength electric fields

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US10/478,207 Continuation-In-Part US7395112B2 (en) 2001-06-07 2002-06-09 Method and apparatus for treating tumors using low strength electric fields
PCT/IL2002/000445 Continuation-In-Part WO2002098501A2 (fr) 2001-06-07 2002-06-09 Procede et appareil pour traiter les tumeurs a l'aide de champs electriques a faible intensite

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US10/478,207 Expired - Fee Related US7395112B2 (en) 2001-06-07 2002-06-09 Method and apparatus for treating tumors using low strength electric fields
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* Cited by examiner, † Cited by third party
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US20080132963A1 (en) * 2001-06-07 2008-06-05 Ramot At Tel Aviv University Ltd. Method and apparatus for treating tumors using low strength electric fields
US20090264809A1 (en) * 2006-04-10 2009-10-22 The Regents Of The University Of California Method and apparatus of low strengh electric field network-mediated delnery of drug, gene, sirna, shrn, protein, peptide, antibody or other biomedical and therapeutic molecules and reagents in skin, soft tissue, joints and bone
US20090288953A1 (en) * 2008-05-20 2009-11-26 Honeywell International Inc. Apparatus and method of using porous material for antigen separation, identification, and quantification with electrophoresis techniques
US9526911B1 (en) * 2010-04-27 2016-12-27 Lazure Scientific, Inc. Immune mediated cancer cell destruction, systems and methods
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US11071875B2 (en) 2018-02-20 2021-07-27 University Of Iowa Research Foundation Therapeutic systems using magnetic and electric fields
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US11938317B2 (en) 2017-12-26 2024-03-26 Galvanize Therapeutics, Inc. Optimization of energy delivery for various applications

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US7742811B2 (en) 2000-03-13 2010-06-22 Onco Stim Implantable device and method for the electrical treatment of cancer
US8024048B2 (en) 2000-03-13 2011-09-20 Ionix Medical Inc. Method and device for treating cancer with electrical therapy in conjunction with chemotherapeutic agents and radiation therapy
JP4659300B2 (ja) * 2000-09-13 2011-03-30 浜松ホトニクス株式会社 レーザ加工方法及び半導体チップの製造方法
WO2004037341A2 (fr) 2002-05-07 2004-05-06 Schroeppel Edward A Methode et dispositif de traitement du cancer par le biais de la therapie electrique en conjonction avec des agents chimiotherapeutiques et la radiotherapie
JP4750784B2 (ja) * 2004-04-23 2011-08-17 ノヴォキュアー・リミテッド 異なる周波数の電界による腫瘍等の治療
FR2872056B1 (fr) * 2004-06-24 2007-08-10 Yves Scherman Dispositif pour l'administration de principe actif aux cellules et tissus utilisant une ou deux forces physiques
FR2872055B1 (fr) * 2004-06-24 2008-02-08 Yves Leon Scherman Dispositif pour le transfert de molecules aux cellules utilisant une force d'origine physique et combinaison permettant la mise en oeuvre du procede
EP1786514B1 (fr) 2004-06-24 2015-01-07 Sphergen Dispositif our le transfert de molecules aux cellules utilisant une force electrique
WO2006064503A2 (fr) * 2004-12-14 2006-06-22 E-Pill Pharma, Ltd. Prolongation du temps de transit d'une pilule d'elution de medicament avec amelioration de la permeabilite
US20070021803A1 (en) 2005-07-22 2007-01-25 The Foundry Inc. Systems and methods for neuromodulation for treatment of pain and other disorders associated with nerve conduction
US8019414B2 (en) * 2006-04-05 2011-09-13 Novocure Ltd. Treating cancer using electromagnetic fields in combination with other treatment regimens
WO2008112787A2 (fr) * 2007-03-14 2008-09-18 The Regents Of The University Of California Procédé et appareil pour l'administration par l'intermédiaire de réseau de champ électrique de faible puissance de médicament, gène, arnsi, protéine arnsh, peptide, anticorps ou d'autres molécules biomédicales et thérapeutiques et de réactifs dans
US8642306B2 (en) 2007-06-14 2014-02-04 Mitsui Engineering & Shipbuilding Co., Ltd. Flow cytometer having cell-sorting function and method of separating living cells
US8348938B2 (en) 2008-05-06 2013-01-08 Old Dominian University Research Foundation Apparatus, systems and methods for treating a human tissue condition
US9597145B2 (en) 2008-08-20 2017-03-21 Prostacare Pty Ltd Non-thermal ablation system for treating tissue
WO2010106544A1 (fr) 2009-03-16 2010-09-23 Rajah Vijay Kumar Procédé et appareil de nanoperméabilisation par résonance focalisée(forn)
US20100240995A1 (en) * 2009-03-17 2010-09-23 Bioelectromed Corp. System and method for treating tumors
US8414559B2 (en) 2009-05-07 2013-04-09 Rainbow Medical Ltd. Gastroretentive duodenal pill
US20130004581A1 (en) 2010-03-19 2013-01-03 Ramot At Tel-Aviv University Ltd. Controlling uptake by cells
US20140296948A1 (en) * 2013-03-27 2014-10-02 Hitops Gmbh New therapy of cancer with pulsed radio frequency
US10363416B2 (en) 2016-11-23 2019-07-30 Hill-Rom Services, Inc. Electrostimulation to increase perfusion
CN108339195B (zh) * 2017-01-22 2020-06-26 北京市神经外科研究所 一种用于电血栓形成的装置和方法
US11590345B2 (en) 2017-08-08 2023-02-28 Pulse Biosciences, Inc. Treatment of tissue by the application of energy
US10850095B2 (en) 2017-08-08 2020-12-01 Pulse Biosciences, Inc. Treatment of tissue by the application of energy
US10857347B2 (en) 2017-09-19 2020-12-08 Pulse Biosciences, Inc. Treatment instrument and high-voltage connectors for robotic surgical system
US11338135B2 (en) 2017-10-23 2022-05-24 Cardiac Pacemakers, Inc. Medical devices for cancer therapy with electric field shaping elements
WO2019104326A1 (fr) 2017-11-27 2019-05-31 Prostacare Pty Ltd Appareil et procédé pour le traitement d'une maladie prostatique
WO2019168949A1 (fr) 2018-02-28 2019-09-06 Prostacare Pty Ltd Système de gestion des grandes variations d'impédance dans un système d'ablation non thermique pour hbp
US11571569B2 (en) 2019-02-15 2023-02-07 Pulse Biosciences, Inc. High-voltage catheters for sub-microsecond pulsing
WO2020170164A1 (fr) * 2019-02-22 2020-08-27 Moshe Giladi Traitement du cancer gastrique en utilisant des champs de traitement de tumeur combinés à xelox ou folfox
US12109412B2 (en) 2019-04-22 2024-10-08 Boston Scientific Scimed, Inc. Combination electrical and chemotherapeutic treatment of cancer
WO2020219336A1 (fr) 2019-04-22 2020-10-29 Boston Scientific Scimed, Inc. Dispositifs de stimulation électrique pour le traitement du cancer
WO2020219337A1 (fr) 2019-04-22 2020-10-29 Boston Scientific Scimed, Inc. Systèmes d'administration de stimulation électrique pour traiter le cancer
CN113747936B (zh) 2019-04-23 2024-06-18 波士顿科学国际有限公司 用于电刺激来治疗癌症的电极
US11607542B2 (en) 2019-04-23 2023-03-21 Boston Scientific Scimed, Inc. Electrical stimulation for cancer treatment with internal and external electrodes
CN113766950A (zh) 2019-04-23 2021-12-07 波士顿科学国际有限公司 带有热治疗或热监测的电刺激
CN115515674A (zh) 2020-02-24 2022-12-23 波士顿科学国际有限公司 用于治疗胰腺癌的系统和方法
WO2022133360A1 (fr) * 2020-12-18 2022-06-23 Humanity Neurotech, Inc. Système et procédés pour le traitement au moyen de rafales d'impulsions inductives
WO2022147212A1 (fr) * 2020-12-30 2022-07-07 Ohio State Innovation Foundation Implant électromagnétique destiné au traitement de cancers solides

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL108775A (en) * 1994-02-25 2003-09-17 Univ Ramot Method for efficient incorporation of molecules into cells
US6505078B1 (en) * 1996-04-04 2003-01-07 Medtronic, Inc. Technique for adjusting the locus of excitation of electrically excitable tissue
BR9810500A (pt) * 1997-06-30 2000-09-05 Rhone Poulenc Rorer Sa Sistema e aparelho para a transferência de ácido nucléico in vivo para o interior de células de organismos eucarióticos pluricelulares
US6241701B1 (en) * 1997-08-01 2001-06-05 Genetronics, Inc. Apparatus for electroporation mediated delivery of drugs and genes
US6366808B1 (en) * 2000-03-13 2002-04-02 Edward A. Schroeppel Implantable device and method for the electrical treatment of cancer
US20020198567A1 (en) * 2001-06-07 2002-12-26 Yona Keisari Electro-endocytotic therapy as a treatment modality of cancer

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080132963A1 (en) * 2001-06-07 2008-06-05 Ramot At Tel Aviv University Ltd. Method and apparatus for treating tumors using low strength electric fields
CN112402798A (zh) * 2005-10-03 2021-02-26 诺沃库勒有限责任公司 优化电场特征以增加电场在增殖细胞上的效果
US20090264809A1 (en) * 2006-04-10 2009-10-22 The Regents Of The University Of California Method and apparatus of low strengh electric field network-mediated delnery of drug, gene, sirna, shrn, protein, peptide, antibody or other biomedical and therapeutic molecules and reagents in skin, soft tissue, joints and bone
US20090288953A1 (en) * 2008-05-20 2009-11-26 Honeywell International Inc. Apparatus and method of using porous material for antigen separation, identification, and quantification with electrophoresis techniques
US8105844B2 (en) * 2008-05-20 2012-01-31 Honeywell International Inc. Apparatus and method of using porous material for antigen separation, identification, and quantification with electrophoresis techniques
US9526911B1 (en) * 2010-04-27 2016-12-27 Lazure Scientific, Inc. Immune mediated cancer cell destruction, systems and methods
US11938317B2 (en) 2017-12-26 2024-03-26 Galvanize Therapeutics, Inc. Optimization of energy delivery for various applications
US11071875B2 (en) 2018-02-20 2021-07-27 University Of Iowa Research Foundation Therapeutic systems using magnetic and electric fields
US11980768B2 (en) 2018-02-20 2024-05-14 University Of Iowa Research Foundation Therapeutic systems using magnetic and electric fields
US11623085B2 (en) 2018-08-29 2023-04-11 Regents Of The University Of Minnesota Devices and methods for treatment of tumors using electromagnetic signal
US11850440B2 (en) 2019-08-22 2023-12-26 University Of Iowa Research Foundation Therapeutic systems using magnetic fields
WO2021050093A1 (fr) 2019-09-10 2021-03-18 Novocure Gmbh Procédé de réduction de la viabilité de cellules cancéreuses par l'application de champs électriques alternatifs et l'administration d'inhibiteurs de points de contrôle aux cellules cancéreuses

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AU2002309240A1 (en) 2002-12-16
EP1409076A2 (fr) 2004-04-21
US20040158288A1 (en) 2004-08-12
US7395112B2 (en) 2008-07-01
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WO2002098501A2 (fr) 2002-12-12
WO2002098501A3 (fr) 2004-02-26

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