WO2017173089A1 - Systèmes et méthodes pour améliorer l'administration de compositions diagnostiques et/ou thérapeutiques in vivo au moyen d'impulsions électriques - Google Patents

Systèmes et méthodes pour améliorer l'administration de compositions diagnostiques et/ou thérapeutiques in vivo au moyen d'impulsions électriques Download PDF

Info

Publication number
WO2017173089A1
WO2017173089A1 PCT/US2017/025035 US2017025035W WO2017173089A1 WO 2017173089 A1 WO2017173089 A1 WO 2017173089A1 US 2017025035 W US2017025035 W US 2017025035W WO 2017173089 A1 WO2017173089 A1 WO 2017173089A1
Authority
WO
WIPO (PCT)
Prior art keywords
tissue
certain embodiments
pulses
tumors
expandable element
Prior art date
Application number
PCT/US2017/025035
Other languages
English (en)
Inventor
Govindarajan Srimathveeravalli
Thomas Reiner
Stephen Solomon
Original Assignee
Memorial Sloan Kettering Cancer Center
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Memorial Sloan Kettering Cancer Center filed Critical Memorial Sloan Kettering Cancer Center
Publication of WO2017173089A1 publication Critical patent/WO2017173089A1/fr

Links

Classifications

    • 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
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/04—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating
    • A61B18/12—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating by passing a current through the tissue to be heated, e.g. high-frequency current
    • A61B18/14—Probes or electrodes therefor
    • A61B18/1492—Probes or electrodes therefor having a flexible, catheter-like structure, e.g. for heart ablation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
    • A61K41/0047—Sonopheresis, i.e. ultrasonically-enhanced transdermal delivery, electroporation of a pharmacologically active agent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/12—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by a special physical form, e.g. emulsion, microcapsules, liposomes, characterized by a special physical form, e.g. emulsions, dispersions, microcapsules
    • A61K51/1217—Dispersions, suspensions, colloids, emulsions, e.g. perfluorinated emulsion, sols
    • A61K51/1234—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00053—Mechanical features of the instrument of device
    • A61B2018/00214—Expandable means emitting energy, e.g. by elements carried thereon
    • A61B2018/0022—Balloons
    • A61B2018/00226—Balloons extending from a surface, i.e. Blisters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00053—Mechanical features of the instrument of device
    • A61B2018/00214—Expandable means emitting energy, e.g. by elements carried thereon
    • A61B2018/0022—Balloons
    • A61B2018/00244—Balloons adapted to separate target tissue from other tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00053—Mechanical features of the instrument of device
    • A61B2018/00214—Expandable means emitting energy, e.g. by elements carried thereon
    • A61B2018/00267—Expandable means emitting energy, e.g. by elements carried thereon having a basket shaped structure
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00315—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for treatment of particular body parts
    • A61B2018/00321—Head or parts thereof
    • A61B2018/00327—Ear, nose or throat
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00315—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for treatment of particular body parts
    • A61B2018/00333—Breast
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00315—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for treatment of particular body parts
    • A61B2018/00345—Vascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00315—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for treatment of particular body parts
    • A61B2018/00345—Vascular system
    • A61B2018/00404—Blood vessels other than those in or around the heart
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00315—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for treatment of particular body parts
    • A61B2018/00434—Neural system
    • A61B2018/00446—Brain
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00315—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for treatment of particular body parts
    • A61B2018/00482—Digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00315—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for treatment of particular body parts
    • A61B2018/00505—Urinary tract
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00315—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for treatment of particular body parts
    • A61B2018/00529—Liver
    • A61B2018/00535—Biliary tract
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00315—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for treatment of particular body parts
    • A61B2018/00541—Lung or bronchi
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00315—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for treatment of particular body parts
    • A61B2018/00559—Female reproductive organs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00571—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for achieving a particular surgical effect
    • A61B2018/00577—Ablation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00571—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for achieving a particular surgical effect
    • A61B2018/00589—Coagulation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B2018/00571—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body for achieving a particular surgical effect
    • A61B2018/00613—Irreversible electroporation
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/04—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating
    • A61B18/12—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating by passing a current through the tissue to be heated, e.g. high-frequency current
    • A61B18/14—Probes or electrodes therefor
    • A61B2018/1405—Electrodes having a specific shape
    • A61B2018/1407—Loop
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B18/00—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body
    • A61B18/04—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating
    • A61B18/12—Surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body by heating by passing a current through the tissue to be heated, e.g. high-frequency current
    • A61B18/14—Probes or electrodes therefor
    • A61B2018/1405—Electrodes having a specific shape
    • A61B2018/1425—Needle
    • A61B2018/143—Needle multiple needles

Definitions

  • This invention relates generally to enhanced drug delivery to tumor tissue.
  • the invention relates to combination of liposomes with electric pulses for drug delivery to dense tumors (e.g., pancreatic, colorectal, breast cancer).
  • dense tumors e.g., pancreatic, colorectal, breast cancer.
  • the invention relates to tissue ablation using electric pulses.
  • Solid tumors especially those from ovarian, colorectal, pancreatic cancers, certain forms of breast cancers, sub-types of sarcoma, and melanoma are characterized by high interstitial fluid pressure (IFP).
  • IFP interstitial fluid pressure
  • High IFP negatively impacts the penetration and distribution of therapeutic agents within these tumors, leading to poor or low bioavailability of these agents.
  • Unsurpri singly, high IFP in a tumor is correlated strongly with poor treatment response and high mortality rate in patients.
  • High IFP in tumors is driven by three key factors: (i) leaky and immature tumor vasculature; (ii) fibrosis and high density of collagen fibers; and (iii) dense cellular growth.
  • EPR Enhanced Permeability and Retention
  • nanoparticles can provide the added benefit of longer half-life and remain in circulation for hours or days, which led to the development of multiple nanoparticle formulation of drugs (e.g., Doxil (doxirubicin), Caelyx (doxirubicin), Abraxane (paclitaxel ) etc.) and the use of nanoparticles as imaging agents (e.g., silica nanoparticles, liposomes, iron oxide nanoparticles).
  • the vasculature may not be homogenous throughout the tumor and therefore affect the uniform deposition of such nanoparticle agents.
  • Zr labeled liposomes are an example of a non-invasive quantitative positron emission tomography (PET) nanoreporter technology that allows personalized therapeutic outcome prediction.
  • PET quantitative positron emission tomography
  • Zr labeled liposomes can serve as dual-labeled liposomes and provide use as diagnostic tools, e.g., to screen individual subjects for nanotherapy amenability and biodistribution.
  • a stable liposome platform can be efficiently labeled with the radioisotope 89 Zr and a fluorophore, such as a Cy5 analog or a Cy7 analog.
  • Zr labeled liposomes accumulate in vascularized tumor areas via the EPR effect and can be used as companion imaging agents to stratify patients into their appropriate treatment groups. For example, use of 89 Zr-NRep PET imaging revealed remarkable Doxil accumulation heterogeneity independent of tumor size. Additional details on Zr labeled liposomes are described in U.S. Publication No.20150343100A1, and International Publication No. WO
  • nanoparticle formulations do not necessarily improve tumor response.
  • nanoparticle formulations of drugs do not demonstrate higher penetration or homogeneous distribution within tumors, negating their potential benefits.
  • imaging modality that can map the uptake pattern of drugs in nanoparticle form and/or prognosticate treatment response from use of such drugs.
  • Table 1 outlines currently used tools for increasing perfusion and permeability of dense tumor tissue, including modalities, outcome, therapeutic window, current status, advantages, and shortcomings.
  • Described herein are systems and methods that combine nanoparticle drugs with electric pulses for enhanced nanoparticle drug delivery to tumors, more particularly to certain “dense” tumors (e.g., pancreatic, colorectal, breast cancers).
  • the systems and methods described herein satisfy the unmet need for a theranostic product for oncology diagnosis and treatment, especially when combined with liposome-delivered drugs.
  • the systems and methods described herein are pertinent to any ductal cancer that has low diffusion coefficient and/or is non responsive to chemotherapy.
  • devices described herein can be used to apply pulsed electric fields to tumors or other tissue types.
  • pulsed electric fields can alter the interstitial fluid pressure of tumors, increase vascular permeability and flow, cause fluid redistribution within the tumor that leads to reduced collagen density, and increase the interstitial space between cells in the tumor.
  • systems, methods, and devices are described herein for the enhanced uptake of administered liposomal or other nanoparticle delivered drugs into tissue of interest/concern, particularly along or in the vicinity of interior lumens of the body.
  • Devices are described herein with an expandable, self-adjusting element that enables
  • the electric pulses delivered to the lumen wall via the electrode(s) of this device increase the total amount of nanoparticle-delivered drugs that enter the tissue of interest, facilitate faster clearance of the nanoparticles from the system, and/or increase homogeneous distribution of the drug throughout the tumor.
  • devices described herein are used for the delivery of square wave pulses to luminal organs in a circumferential or focal fashion.
  • the square wave pulses can be used to either ablate tumors or other undesirable normal tissue within the organ through irreversible electroporation or nanoporation.
  • the square pulses can also facilitate reversible electroporation of the lumen wall allowing transfection of genetic material or drugs to constituent cells.
  • the devices described herein can be used to deliver high frequency electrical energy into the inner walls of luminal organs. This functions similarly to electrocautery and allows the rapid coagulation of any bleeding in the organ. This is valuable, for example, in the control of internal hemorrhaging, the treatment of bleeding ulcers, and the treatment of diseases such as varices.
  • the devices described herein can be used to deliver radiofrequency energy within hollow organs to partially ablate the lumen wall. This finds application in controlling diseases marked by the hypertrophy of smooth muscle or muscularis of luminal organs. Examples include treatment of asthma, esophageal strictures, and debulking of vascular stenosis.
  • the invention is directed to a method of enhancing uptake of an administered composition into a tissue of interest, the method comprising: administering to a subject a therapeutic and/or diagnostic agent; and delivering electric energy (e.g., one or more electric pulses) to an interior surface of a body lumen of the subject (e.g., at one or more points/positions about a circumference of the lumen), thereby enhancing uptake of the administered therapeutic and/or diagnostic agent into the tissue of interest.
  • electric energy e.g., one or more electric pulses
  • the tissue of interest is within, on, and/or in the vicinity of the interior surface of the body lumen of the subject.
  • the body lumen is the interior of a vessel (e.g., an artery, vein, gastrointestinal tract, esophagus, alimentary canal, respiratory tract, nasal passage, bronchi in the lungs, renal tubule, urinary collecting duct, female genital tract, pathway of the vagina, uterus, fallopian tube, the stomach, sinus tract, biliary duct, pancreatic duct, breast duct, and/or the abdominal cavity).
  • a vessel e.g., an artery, vein, gastrointestinal tract, esophagus, alimentary canal, respiratory tract, nasal passage, bronchi in the lungs, renal tubule, urinary collecting duct, female genital tract, pathway of the vagina, uterus, fallopian tube, the stomach, sinus tract, biliary duct, pancreatic duct, breast duct, and/or the abdominal cavity.
  • the tissue is a manifestation of neoplastic disease.
  • the neoplastic disease is cancer.
  • the tissue of interest is a dense tumor.
  • Tumor density can be ascertained by pathology (excess collagen or extracellular matrix), imaging (diffusion coefficient across the tumor with MRI), or IFP measurements.
  • the therapeutic and/or diagnostic agent comprises a nanoparticle.
  • the therapeutic and/or diagnostic agent comprises a liposome.
  • the electric energy is delivered before administration of the therapeutic agent.
  • the electric energy is delivered after administration of the therapeutic agent. [0027] In certain embodiments, the electric energy is delivered using a device as described herein.
  • the electric energy is delivered by one or more electrodes in the form of one or more electric pulses, wherein the electric pulses are wave pulses (e.g., square waves, sine waves, step waves, triangle waves, or sawtooth waveforms).
  • wave pulses e.g., square waves, sine waves, step waves, triangle waves, or sawtooth waveforms.
  • the electric pulses are square wave pulses.
  • the number of pulses applied at a given position along the lumen is between 1 and 1000, between 5 and 500, between 10 and 100, or between 10 and 50.
  • the pulse frequency is between 0.1 Hz and 20 Hz (e.g., between any two of the following values: 0.1 Hz, 0.2 Hz, 0.5 Hz, 1 Hz, 2 Hz, 3 Hz, 4 Hz, 5 Hz, 10 Hz, and 20 Hz).
  • the pulse width is between 0.001 ⁇ s and 1 s, between 0.01 ⁇ s and 100 ms, between 0.1 ⁇ s and 10 ms, between 1 ⁇ s and 1 ms, or between 10 ⁇ s and 0.1 ms.
  • the pulses have sufficient voltage to induce an electric field between the electrodes, wherein the electric field has a strength of at least 100 V/cm, at least 200 V/cm, at least 300 V/cm, at least 400 V/cm, at least 500 V/cm, at least 600 V/cm, at least 700 V/cm, at least 800 V/cm, at least 900 V/cm, or at least 1000 V/cm.
  • the voltage applied is between 1 and 1000 V, between 5 and 500 V, between 10 and 100 V, or between 10 and 50 V.
  • the electrodes are needle electrodes.
  • the electrodes are in direct contact with tumor tissue.
  • the method comprises delivering the electric pulses using a device as described herein.
  • the invention is directed to a method for treating a condition comprising delivering electric square wave pulses to tissue of a luminal organ (e.g., an artery, vein, gastrointestinal tract, esophagus, alimentary canal, respiratory tract, nasal passage, bronchi in the lungs, renal tubule, urinary collecting duct, female genital tract, pathway of the vagina, uterus, fallopian tube, the stomach, and/or the abdominal cavity) or other vessel of a subject in a circumferential or focal fashion.
  • a luminal organ e.g., an artery, vein, gastrointestinal tract, esophagus, alimentary canal, respiratory tract, nasal passage, bronchi in the lungs, renal tubule, urinary collecting duct, female genital tract, pathway of the vagina, uterus, fallopian tube, the stomach, and/or the abdominal cavity
  • a luminal organ e.g., an artery, vein, gastrointestinal tract, esophagus, alimentary canal, respiratory
  • the square wave pulses ablate tumors or other undesirable tissue within the organ or other vessel.
  • the method comprises performing irreversible electroporation and/or nanoporation of the tissue.
  • the method comprises performing reversible
  • the tissue is an interior wall of a lumen.
  • the method comprises transfecting the tissue with genetic material and/or one or more drugs.
  • the electric square wave pulses are delivered using a device as described herein.
  • the invention is directed to a method for treating a condition comprising delivering high frequency electrical energy into the inner walls of a luminal organ.
  • the method comprises performing coagulation of bleeding in the luminal organ.
  • the condition is a varix (or varices), internal hemorrhage, or a bleeding ulcer.
  • the high frequency electrical energy is delivered using a device as described herein.
  • the invention is directed to a method for treating a condition comprising delivering radiofrequency energy to a lumen wall of a hollow organ.
  • the method comprises partial ablation of the lumen wall.
  • the condition is hypertrophy of smooth muscle or muscularis of luminal organs.
  • the condition is asthma, esophageal strictures, or vascular stenosis.
  • the radiofrequency energy is delivered using a device as described herein.
  • the invention is directed to a device for treating and/or diagnosing a condition in a subject, the device comprising a catheter comprising an expandable element at a distal end that maintains contact with the interior surface of a body lumen at at least two points about a circumference of the body lumen, the expandable element capable of delivering electric energy (e.g., one or more electric pulses) at the at least two points.
  • a catheter comprising an expandable element at a distal end that maintains contact with the interior surface of a body lumen at at least two points about a circumference of the body lumen, the expandable element capable of delivering electric energy (e.g., one or more electric pulses) at the at least two points.
  • electric energy e.g., one or more electric pulses
  • the expandable element has an adjustable diameter such that the expandable element is capable of changing diameter (increasing and/or decreasing diameter) as the catheter is drawn along a length of the body lumen, so as to maintain contact between the body lumen at at least two points as the catheter is drawn along the length of the body lumen.
  • the expandable element comprises an electrically conducting material.
  • the expandable element is disposed concentrically around substantially the (e.g., entire) outer circumference of the catheter.
  • the expandable element is disposed around a fraction of the circumference of the catheter.
  • the expandable element is a basket.
  • the device comprises a second expandable element.
  • the device comprises a handle, wherein the handle can be manipulated to cause the expandable element to expand from a first, compressed state to a second, expanded state.
  • the expandable element has a fully expanded
  • the expandable element has a fully expanded
  • circumference at its widest of between 1 cm and 100 cm, of between 3 cm and 75 cm, of between 5 cm and 50 cm, of between, 7 cm and 30 cm, or between 10 cm and 20 cm.
  • the expandable element has an adjustable diameter or an adjustable shape after expansion within the body lumen (e.g., in certain embodiments, the expandable element is capable of decreasing its diameter by at least approximately 2%, 5%, 8%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 99% of its maximum diameter while still maintaining contact with the interior surface of a lumen of varying diameter, e.g., as the element is drawn through the lumen).
  • the expandable element is capable of decreasing its diameter by at least approximately 2%, 5%, 8%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 99% of its maximum diameter while still maintaining contact with the interior surface of a lumen of varying diameter, e.g., as the element is drawn through the lumen).
  • the invention is directed to a composition comprising a nanoparticle for use in a method for treating a neoplastic disease in a subject, wherein the method comprises: administering to a subject having a tissue of interest the nanoparticle; and delivering one or more electric pulses to an interior surface of a body lumen of the subject, thereby enhancing uptake of the administered therapeutic and/or diagnostic agent into the tissue of interest.
  • the invention is directed to a composition comprising a nanoparticle comprising a radiolabel for use in a method of in vivo diagnosis of a neoplastic disease in a subject, wherein the method comprises: administering to a subject having a tissue of interest the nanoparticle; and delivering one or more electric pulses to an interior surface of a body lumen of the subject, thereby enhancing uptake of the administered therapeutic and/or diagnostic agent into the tissue of interest.
  • the nanoparticle is a liposome.
  • the electric pulses are delivered before administration of the nanoparticle.
  • the electric pulses are delivered after administration of the nanoparticle.
  • the term "approximately” or “about” refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).
  • administering refers to introducing a substance into a subject.
  • any route of administration may be utilized including, for example, parenteral (e.g., intravenous), oral, topical, subcutaneous, peritoneal, intraarterial, inhalation, vaginal, rectal, nasal, introduction into the cerebrospinal fluid, or instillation into body compartments.
  • administration is oral. Additionally or alternatively, in some embodiments, administration is parenteral. In some embodiments, administration is intravenous.
  • associated typically refers to two or more entities in physical proximity with one another, either directly or indirectly (e.g., via one or more additional entities that serve as a linking agent), to form a structure that is sufficiently stable so that the entities remain in physical proximity under relevant conditions, e.g., physiological conditions.
  • associated moieties are covalently linked to one another.
  • associated entities are non-covalently linked.
  • associated entities are linked to one another by specific non-covalent interactions (e.g., by interactions between interacting ligands that discriminate between their interaction partner and other entities present in the context of use, such as, for example.
  • non-covalent interactions include, but are not limited to, electrostatic interactions, hydrogen bonding, affinity, metal coordination, physical adsorption, host-guest interactions, hydrophobic interactions, pi stacking interactions, van der Waals interactions, magnetic interactions, electrostatic interactions, dipole-dipole interactions, etc.
  • substantially refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest.
  • biological and chemical phenomena rarely, if ever, go to completion and/or proceed to completeness or achieve or avoid an absolute result.
  • Subject includes humans and mammals (e.g., mice, rats, pigs, cats, dogs, and horses). In many embodiments, subjects are be mammals, particularly primates, especially humans. In some embodiments, subjects are livestock such as cattle, sheep, goats, cows, swine, and the like; poultry such as chickens, ducks, geese, turkeys, and the like; and domesticated animals particularly pets such as dogs and cats. In some embodiments (e.g., particularly in research contexts) subject mammals will be , for example, rodents (e.g., mice, rats, hamsters), rabbits, primates, or swine such as inbred pigs and the like.
  • rodents e.g., mice, rats, hamsters
  • rabbits, primates, or swine such as inbred pigs and the like.
  • Therapeutic agent refers to any agent that has a therapeutic effect and/or elicits a desired biological and/or pharmacological effect, when administered to a subject.
  • Treatment refers to any administration of a substance that partially or completely alleviates, ameliorates, relives, inhibits, delays onset of, reduces severity of, and/or reduces incidence of one or more symptoms, features, and/or causes of a particular disease, disorder, and/or condition.
  • Such treatment may be of a subject who does not exhibit signs of the relevant disease, disorder and/or condition and/or of a subject who exhibits only early signs of the disease, disorder, and/or condition.
  • such treatment may be of a subject who exhibits one or more established signs of the relevant disease, disorder and/or condition.
  • treatment may be of a subject who has been diagnosed as suffering from the relevant disease, disorder, and/or condition. In some embodiments, treatment may be of a subject known to have one or more susceptibility factors that are statistically correlated with increased risk of development of the relevant disease, disorder, and/or condition.
  • FIG.1 shows a catheter according to one embodiment with a basket extended to maximum size.
  • FIG.2A-D shows a catheter according to one embodiment with a handle that can control the diameter to which the basket unfurls.
  • FIG.3 shows a catheter according to one embodiment with a basket that is unfurled to make contact within the right main bronchus in swine.
  • FIG.4 shows exemplary results with CT images post-energy delivery (B) and after withdrawal of the catheter (A).
  • the arrow points to the unfurled electrode making contact with the bronchial wall.
  • the electrodes can be seen as small white dots. After energy delivery there is congestion, and an inflammation region surrounding the bronchus with a hyperintense appearance. There is no evidence of air leak (perforation) which is a common serious complication after energy delivery in the lung.
  • FIG.5 shows a cross-sectional view of the lung (cut perpendicular to the bronchus) with an exemplary location of the basket placement within the bronchus matching hyperemic regions (arrow, B). There is a region of hemorrhage and congestion surrounding the bronchus, extending 3-4 cm into parnechyma on each side. A cross section of the bronchus (cut along the bronchus) shows red lines on the internal surface and uniform effects similar to those seen in the perpendicular view (arrow, A).
  • FIG.6A shows a catheter according to one embodiment wherein a first expandable element is a basket arranged in a planar fashion.
  • FIG.6B shows a catheter according to one embodiment, further comprising a balloon configured such that inflating the balloon would cause the basket to encapsulate a tumor infiltrating the lumen.
  • FIG.7 shows a schematic of bilateral MiaPaCa2 tumors in a rodent model.
  • the right flank tumor was treated with electric pulses, the left flank tumor was not treated.
  • FIG.8A-F shows autoradiography results of Cohort 1, which was first injected with a drug and then treated with pulsed electric fields described herein, compared to controls that were not treated with pulsed electric fields.
  • FIG.9 shows relative radiation from the autoradiography results from Cohort 1, where tumors were injected with drug and then treated with pulses of electric field, compared to controls (i.e., tumors not receiving any drug). Results suggest that pulsed electric fields increase uptake by tumors.
  • FIG.10 shows relative radiation from the autoradiography results from Cohort 2, where the tumors treated with pulses of electric field and then injected with a drug, compared to controls (i.e., tumors not receiving any drug). Results suggest that pulsed electric fields increase uptake by tumors.
  • FIG.11 shows PET imaging of Cohort 1 (e.g., mouse 1 (M1), mouse 2 (M2)), and control.
  • the top row shows animals 2 hours post pulse delivery, and the bottom row shows animals at 24 hours post pulse delivery.
  • the PET images display differences between the tumors injected with drug and then treated with pulses of electric field compared to controls (i.e., tumors not receiving any drug).
  • FIG.12 shows PET imaging of Cohort 2 (e.g., mouse 3 (M3), mouse 4 (M4)), and control.
  • the top row shows animals 2 hours post pulse delivery, and the bottom row shows animals at 24 hours post pulse delivery.
  • the PET images display differences between the tumors treated with pulses of electric field and then injected with a drug compared to controls (i.e., tumors not receiving any drug).
  • FIGS.13A-13C show PET imaging of Cohorts 1 and 2 imaged after 24 hours.
  • FIG.14 shows a schematic describing the secondary effects of electric pulses on tumor microvasculature and connective tissue (B), compared to untreated tumors (A). These effects are expected to increase the extravasation and retention of liposomal nanoparticles in treated tumors.
  • FIG.15A-F shows the uptake of radiotracer and drug in treated and untreated tumors in mice bearing unilateral tumors, measured at different time points.
  • Asterisk indicates data points which were more than 3 quartiles from the mean (outliers).
  • FIG.16 shows a comparison of rate of uptake (compared to maximum uptake at 48 hours when nanoparticles clear completely from blood circulation) of tracer (A) and drug (B) in treated and untreated tumors in mice bearing unilateral tumors. Correlation is shown of tracer and drug uptake in treated (C) and untreated (D) tumors combining data from all time points at which measurements were performed.
  • FIG.17 shows a comparison of tracer and drug with tumor weight in treated (A- C) and untreated (D-F) tumors.
  • FIG.18 shows injection of radiotracer before pulse delivery demonstrating uptake at the 2 hour time point (A). Similar uptake cannot be seen when the tracer was injected one hour following pulse delivery (B). However, 24 hours following treatment, there was no appreciable impact of injection/treatment on order and uptake (C and D). Solid arrows indicate tumors receiving treatment, and dashed arrows indicate contralateral untreated tumors.
  • FIG.19 shows (A) an isosurface representing tracer uptake in a treated tumor (solid arrow).
  • the untreated tumor (dashed arrow) cannot be adequately visualized.
  • Liver (arrowhead) and spleen (diamond) can also be seen in the image.
  • Autoradiography of tumors treated with electric pulses (B) demonstrates even distribution of tracer everywhere in the tumor, while similar measurements performed on untreated tumors (C) suggest pockets of tracer deposition.
  • FIG.20 shows (A) autoradiography of tumors treated with electric pulses demonstrating distribution of tracer throughout the tumor.
  • Graph (B) depicts radiation counts comparing treated tumors with contralateral control.
  • the box insert in (A) is shown in higher magnification in (B), displaying a region of necrosis (dashed boundary) closely bounded by the defect in the tumor from needle placement (arrow).
  • Scale bar 0.5 mm.
  • FIG.22 shows an embodiment of the device: (a) Two looped electrodes (arrows) are buried in a 9Fr catheter. Electrodes are placed at a right angle. (b) The electrode can be expanded and contact the bronchial wall by pushing it through the catheter.
  • FIG.23 shows radio images of a sample procedure.
  • An expandable catheter electrode black arrow
  • CT shows that electrodes are in contact with the bronchial wall (white arrows).
  • Dense consolidation (white arrowheads) appeared after ablation.
  • FIG.24 shows specimen of untreated and treated bronci.
  • (a) Depicted here is the internal surface of the untreated bronchus opened along the way of the main duct.
  • (b) Depicted here is the internal surface of the treated bronchus.
  • FIG.25 shows H&E stained tissue specimens.
  • sloughing of bronchial epithelium black arrows
  • hemorrhage black arrowheads
  • hyperemic congestion white arrowheads
  • necrosis of submucosal glands (white arrows)
  • FIG.26 shows Simulation images. Simulation of catheter directed endoluminal IRE: Simulation of IRE with placing 2 electrodes along the bronchus (B: Bronchus, V: Vessel). In both treatments, temperature increases around the electrodes (white arrows). The lesion of preferential passage of electric field into the parenchyma (black arrows) is slightly larger in endoluminal IRE (a) than IRE with 2 electrodes placed around the bronchus (b).
  • compositions are described as having, including, or comprising specific components, or where methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are
  • compositions of the present invention that consist essentially of, or consist of, the recited components, and that there are methods according to the present invention that consist essentially of, or consist of, the recited processing steps.
  • Electroporation is commonly used for the transfection of cells with drugs and genetic material that normally cannot permeate an intact cell membrane.
  • Electroporation has also been used for the image-guided ablation of colorectal metastases, pancreatic cancer and renal tumors in patients (See Narayanan et. al., Cardiovasc Intervent Radiol.2014 Dec;37(6):1523-9.; Dollinger M J et. al., Vasc Interv Radiol.2014
  • Described herein are systems and methods for manipulation of tumors with pulsed electric fields. Without wishing to be bound by theory, techniques and treatment parameters were identified for the application of pulsed electric fields to alter the interstitial fluid pressure of tumors. In certain embodiments, devices such as those described herein can be used to apply pulsed electric fields to tumors. Without wishing to be bound by theory, in certain embodiments, pulsed electric fields can increase vascular permeability and flow, causing fluid redistribution within the tumor that leads to reduced collagen density, and can increase the interstitial space between cells in the tumor.
  • Pulsed electric fields can be applied as a series of low voltage wave pulses.
  • the wave pulses can be square waves, sine waves, step waves, triangle waves, or have sawtooth waveforms.
  • the number of wave pulses delivered at a given position can be 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more pulses, for example.
  • Electric pulses can be applied in quantities of between 1 and 1000, between 5 and 500, between 10 and 100, or between 10 and 50, for example.
  • the pulses can have a frequency of 0.1 Hz, 0.2 Hz, 0.5 Hz, 1 Hz, 2 Hz, 3 Hz, 4 Hz, 5 Hz, 10 Hz, or 20 Hz.
  • the pulse width can be between 0.001 ⁇ s and 1 s, between 0.01 ⁇ s and 100 ms, between 0.1 ⁇ s and 10 ms, between 1 ⁇ s and 1 ms, or between 10 ⁇ s and 0.1 ms.
  • the pulses can have sufficient voltage to induce an electric field between the electrodes, wherein the electric field has a strength of at least 100 V/cm, 200 V/cm, 300 V/cm, 400 V/cm, 500 V/cm, 600 V/cm, 700 V/cm, 800 V/cm, 900 V/cm, or 1000 V/cm.
  • the voltages applied can be between 1 and 1000 V, between 5 and 500 V, between 10 and 100 V, or between 10 and 50 V.
  • the method described herein is a treatment that applies a series (10-50) of low voltage (less than 1000 V) square wave DC pulses of 1 ⁇ s to 1 ms pulse width.
  • a series (10-50) of low voltage (less than 1000 V) square wave DC pulses of 1 ⁇ s to 1 ms pulse width can be rapid, lasting less than a minute, and the effects on the tumor can start manifesting a few hours (4 - 8 hours) following treatment.
  • the effects can persist for a period of up to about 57 days.
  • tumors are treated with pulses with sufficient voltage to induce an electric field with strength of 700V/cm between the needle electrodes, with 10 pulses delivered at 1 Hz with a pulse length of 90 microseconds.
  • the pulses can be applied to tissues, such as tumors, using either pairs of needle electrodes or pairs of plate electrodes for transcutaneous noninvasive treatment. Electrodes may be configured as required by tissue type or application. In certain embodiments, pulses may be applied using 2, 3, 4, 5, 6, 7, 8, or more electrodes.
  • the devices and methods include electroporation mediated vascular changes and edema, passively modifying the tumor microenvironment, resulting in changes to its permeability and retention properties.
  • the devices and methods include causing an Enhanced Permeability and Retention (EPR) effect in the tissue.
  • the devices and methods include causing selective uptake of nanoparticles in tumors.
  • the devices and methods include treating tumors with electric pulses.
  • the devices and methods can cause the uptake of nanoparticles.
  • the devices and methods can cause an uptake of nanoparticles by a tumor, wherein the uptake by the tumor treated with electric pulses is increased compared to the uptake by a tumor not treated with electric pulses.
  • uptake is independent of electropermeabilization of the cell membrane.
  • the uptake of nanoparticles by the tumor treated with electric pulses is increased compared to the uptake by a tumor not treated with electric pulses, and this increase in uptake is independent of electropermeabilization of the cell membrane.
  • compositions described herein include (i) imaging agents that are, or are associated with, the therapeutic agent, and/or (ii) imaging agents that are associated with, or are a part of, liposomes or other nanoparticle-based delivery platform, e.g., Zr labeled liposomes.
  • imaging agents that are, or are associated with, the therapeutic agent
  • imaging agents that are associated with, or are a part of, liposomes or other nanoparticle-based delivery platform, e.g., Zr labeled liposomes.
  • Zr labeled liposomes that can be used with the methods and devices described herein are described in U.S. Publication No.20150343100A1, and International Publication No. WO 2015/183876, the disclosures of which are incorporated by reference herein in their entireties.
  • the imaging agents can include radiolabels, radionuclides, radioisotopes, fluorophores, fluorochromes, dyes, metal lanthanides, paramagnetic metal ions, superparamagnetic metal oxides, ultrasound reporters, x-ray reporters, and/or fluorescent proteins.
  • radiolabels comprise 99m Tc, 111 In, 64 Cu, 67 Ga, 186 Re, 188 Re, 153 Sm, 177 Lu, 67 Cu, 123 I, 124 I, 125 I, 11 C, 1 3N, 15 O, 18 F, 186 Re, 188 Re, 153 Sm, 166 Ho, 177 Lu, 149 Pm, 90 Y, 212 Bi, 103 Pd, 109 Pd, 159 Gd, 140 La, 198 Au, 199 Au, 169 Yb, 175 Yb, 165 Dy, 166 Dy, 67 Cu, 105 Rh, 111 Ag, 89 Zr, and 192 Ir.
  • paramagnetic metal ions comprise Gd(III), Dy(III), Fe(III), and Mn(II).
  • Gadolinium (III) contrast agents comprise Dotarem, Gadavist, Magnevist, Omniscan, OptiMARK, and Prohance.
  • x-ray reporters comprise iodinated organic molecules or chelates of heavy metal ions of atomic numbers 57 to 83.
  • PET (Positron Emission Tomography) tracers are used as imaging agents.
  • PET tracers comprise 89 Zr, 64 Cu, [ 18 F]
  • fluorophores comprise fluorochromes, fluorochrome quencher molecules, any organic or inorganic dyes, metal chelates, or any fluorescent enzyme substrates, including protease activatable enzyme substrates.
  • fluorophores comprise fluorochromes, fluorochrome quencher molecules, any organic or inorganic dyes, metal chelates, or any fluorescent enzyme substrates, including protease activatable enzyme substrates.
  • fluorophores comprise long chain carbophilic cyanines.
  • fluorophores comprise DiI, DiR, DiD, and the like.
  • Fluorochromes comprise far red, and near infrared fluorochromes (NIRF). Fluorochromes include but are not limited to a carbocyanine and indocyanine fluorochromes.
  • imaging agents comprise commercially available fluorochromes including, but not limited to Cy5.5, Cy5 and Cy7 (GE Healthcare); AlexaFlour660, AlexaFlour680, AlexaFluor750, and AlexaFluor790 (Invitrogen); VivoTag680, VivoTag-S680, and VivoTag-S750 (VisEn Medical); Dy677, Dy682, Dy752 and Dy780
  • Dyomics DyLight547, DyLight647 (Pierce); HiLyte Fluor 647, HiLyte Fluor 680, and HiLyte Fluor 750 (AnaSpec); IRDye 800CW, IRDye 800RS, and IRDye 700DX (Li-Cor); and
  • ADS780WS, ADS830WS, and ADS832WS (American Dye Source) and Kodak X-SIGHT 650, Kodak X-SIGHT 691, Kodak X-SIGHT 751 (Carestream Health).
  • compositions described herein include a therapeutic agent.
  • the therapeutic agent is associated with a liposome or other nanoparticle-based delivery platform, e.g., Zr labeled liposome, which is administered to the subject.
  • the therapeutic agent is an anti-cancer agent.
  • the anti-cancer agent is a chemotherapeutic agent.
  • the therapeutic agent is an alkylating agent, an antimetabolite, an anthracycline, an antibiotic, and camptothecin, a vince alkaloid, a taxane, a platinum compound, a hormonal agent, a cytotoxic agent, an enzyme, a microtubule damaging agent, a topoisomerase-1 inhibitor, a topoisomerase-2 inhibitor, a tyrosine proteinkinase inhibitor, an EGF receptor inhibitor, an angiogenesis inhibitor, a protease inhibitor, a glucocorticoid, an estrogen, an aromatase inhibitor, an antiandrogen, a 5-alpha inhibitor, a GnRH analog, or a progestin.
  • compositions incorporating the nanoparticle described herein may be administered according to any appropriate route and regimen.
  • a route or regimen is one that has been correlated with a positive therapeutic benefit.
  • the exact amount administered may vary from subject to subject, depending on one or more factors as is well known in the medical arts. Such factors may include, for example, one or more of species, age, general condition of the subject, the particular composition to be administered, its mode of administration, its mode of activity, the severity of disease; the activity of the specific nanoparticle employed; the specific
  • compositions described herein may be administered by any route, as will be appreciated by those skilled in the art. In certain embodiments, compositions described herein are administered by oral (PO), intravenous (IV), intramuscular (IM), intra-arterial,
  • compositions are administered directly to a tissue via a catheter.
  • the pharmaceutical compositions and/or Zr labeled liposomes thereof may be administered intravenously (e.g., by intravenous infusion), by intramuscular injection, by intratumoural injection, and/or via portal vein catheter, for example.
  • intravenously e.g., by intravenous infusion
  • intramuscular injection by intratumoural injection
  • portal vein catheter for example.
  • the subject matter described herein encompasses the delivery of pharmaceutical compositions and/or Zr labeled liposomes thereof in accordance with embodiments described herein by any appropriate route taking into consideration likely advances in the sciences of drug delivery.
  • devices and methods described herein can be used to diagnose and/or treat the diseases and conditions situated within, on, and/or in the vicinity of the interior surface of a body lumen.
  • the body lumen is the interior of a vessel, such as the central space in an artery or vein; the interior of the gastrointestinal tract; the interior of the respiratory tract; the pathways of the bronchi in the lungs; the interior of renal tubules and urinary collecting ducts; the pathways of the female genital tract, starting with a single pathway of the vagina, splitting up in two lumina in the uterus, both of which continue through the fallopian tubes; the interior of the stomach; sinus tract; biliary duct; pancreatic duct; breast duct; or the abdominal cavity.
  • the diseases and conditions that can be diagnosed and/or treated with the devices and methods described herein include neoplastic disease.
  • the neoplastic disease is cancer.
  • the cancer is Stage I cancer, Stage II cancer, Stage III cancer, Stage IV cancer, carcinoma, lymphoma, sarcoma, myeloma, blastoma, and
  • adenocarcinoma bone cancer, breast cancer, colon/rectum cancer, lung cancer, nasopharyngeal cancer, oral cavity and oropharyngeal cancer, small intestine cancer, stomach cancer, uterine sarcoma, or vaginal cancer.
  • Described herein are devices to administer to a tissue a voltage or an agent, or both, wherein the agent is an imaging agent or a therapeutic agent, or both.
  • the agent is an imaging agent or a therapeutic agent, or both.
  • the voltage, the imaging agent or therapeutic agent, alone or in combination are administered systemically. In certain embodiments, the voltage, the imaging agent or therapeutic agent, alone or in combination, are administered locally directly to the tissue to be treated.
  • the device comprises a catheter.
  • the catheter is an electrode catheter.
  • the catheter is an electrode catheter, wherein the catheter comprises a needle end, wherein the needle end is an electrode.
  • the electrode catheter further comprises one or more additional elements capable of conducting an electric current.
  • the device comprises one or more electrodes.
  • the electrodes can be linear, flat, round, spherical, cylindrical, square, cubic, triangular, pyramidic, hexagonal, or any combination thereof.
  • the electrodes can be in the form of a needle, a wire, a tine, a hollow tube, a coil, a loop, a sling, a blade, a fork, a spoon, a surface, or a cage.
  • the device comprises a needle.
  • the needle is an electrode.
  • the needle is a 7 G, 8 G, 9 G, 10 G, 11 G, 12 G, 13 G, 14 G, 15 G, 16 G, 17 G, 18 G, 19 G, 20 G, 21 G, 22 G, 22s G, 23 G, 24 G, 25 G, 26 G, 26s G, 27 G, 27 G, 28 G, 29 G, 30 G, 31 G, 32 G, 33 G, or 34 G needle.
  • the device comprises one or more expandable elements, e.g., a basket, a stent, or a balloon.
  • the expandable element is capable of conducting an electric current.
  • the expandable element comprises an electrically conducting material.
  • the expandable element is a wire element.
  • the catheter comprises a needle end and an expandable element, wherein the needle end and the expandable element are moveable independently from each other.
  • the expandable element when in its constrained or un- expanded state, has a sharp or pointed end that may be inserted into the tissue.
  • the expandable element when in its constrained or un-expanded state, causes the catheter to have a total length greater than its length with an expandable element in the expanded state.
  • the expandable element may maintain a collapsed configuration during insertion and/or positioning within the lumen, and then expand when the distal end of the device is positioned where desired within the lumen, thereby achieving contact between electrodes of the expandable element (or electrodes otherwise coupled to the expandable element) and the interior surface of the lumen.
  • the expandable element is also capable of automatical adjustment (e.g., via its shape, flexibility, configuration, and the like) to vary its circumference during use.
  • a basket configuration comprising multiple tines is capable of maintaining contact with the interior surface of a lumen as the device is drawn along the length of the lumen, where the lumen has varying internal diameter.
  • the device comprises a basket (See FIG.1).
  • the basket is comprised of 4 tines.
  • the basket is comprised of 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 tines, or about 25 tines, about 30 tines, about 35 tines, about 40 tines, about 45 tines, or about 50 or more tines.
  • the expandable element is configured to deliver electrical energy into the walls of hollow organs. Hollow organs include the bronchus, esophagus, urinary tract, intestine, stomach, abdominal cavity, bladder, blood vessel, heart, and lung.
  • the expandable element is configured to deliver electrical energy into a cavity or lumen of any size or shape without loss of contact.
  • the expandable element has the basic shape of a sphere, a cylinder, a cone, a truncated cones, a cube, a prisms, or a pyramid, or a combination thereof.
  • the expandable element has a fully expanded circumference at its widest of approximately 1 cm, 2 cm, 3 cm, 4 cm, 5 cm, 6 cm, 7 cm, 8 cm, 9 cm, 10 cm, 11 cm, 12 cm, 13 cm, 14 cm, 15 cm, 16 cm, 17 cm, 18 cm, 19 cm, 20 cm, 22 cm, 24 cm, 26 cm, 28 cm, 30 cm or more.
  • the expandable element has a fully expanded circumference at its widest of between 1 cm and 100 cm, of between 3 cm and 75 cm, of between 5 cm and 50 cm, of between, 7 cm and 30 cm, or between 10 cm and 20 cm.
  • the expandable element has an adjustable diameter or an adjustable shape when fully expanded.
  • the expandable element is capable of decreasing its diameter by approximately 2%, 5%, 8%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 99% of its maximum diameter while still maintaining contact with the interior surface of a lumen of varying diameter, e.g., as the element is drawn through the lumen).
  • the expandable element has a length when fully expanded of about 1 cm, 2 cm, 3 cm, 4 cm, 5 cm, 6 cm, 7 cm, 8 cm, 9 cm, 10 cm, 11 cm, 12 cm, 13 cm, 14 cm, 15 cm, 16 cm, 17 cm, 18 cm, 19 cm, 20 cm, 22 cm, 24 cm, 26 cm, 28 cm, 30 cm or more.
  • the expandable element is constructed to be compliant, therefore adjusting to the size or shape, or both, of the lumen or other cavity within it is placed.
  • the electrode catheter comprises an inflatable element.
  • the inflatable element is a balloon.
  • the inflatable element comprises one or more electrically conducting elements.
  • the balloon comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 electrically conducting elements, or about 25 electrically conducting elements, about 30 electrically conducting elements, about 35 electrically conducting elements, about 40 electrically conducting elements, about 45 electrically conducting elements, or about 50 or more electrically conducting elements.
  • the electrically conducting elements can be arranged in various patterns on the surface of the inflatable element, for example in rows, columns, circles, on a rectangular grid, on a triangular grid, on hexagonal grid, or in random configuration.
  • the inflatable element is configured to deliver electrical energy into the walls of hollow organs.
  • Hollow organs include the bronchus, esophagus, urinary tract, intestine, stomach, abdominal cavity, bladder, blood vessel, heart, and lung.
  • the inflatable element is configured to deliver electrical energy into a cavity or lumen of any size or shape without loss of contact.
  • the inflatable element has the basic shape of a sphere, a cylinder, a cone, a truncated cones, a cube, a prisms, or a pyramid, or a combination thereof.
  • the inflatable element has a fully expanded circumference at its widest of approximately 1 cm, 2 cm, 3 cm, 4 cm, 5 cm, 6 cm, 7 cm, 8 cm, 9 cm, 10 cm, 11 cm, 12 cm, 13 cm, 14 cm, 15 cm, 16 cm, 17 cm, 18 cm, 19 cm, 20 cm, 22 cm, 24 cm, 26 cm, 28 cm, 30 cm or more.
  • the inflatable element has a fully expanded circumference at its widest of between 1 cm and 100 cm, of between 3 cm and 75 cm, of between 5 cm and 50 cm, of between, 7 cm and 30 cm, or between 10 cm and 20 cm.
  • the inflatable element has an adjustable diameter or an adjustable shape when fully expanded.
  • the inflatable element is capable of decreasing its diameter by approximately 2%, 5%, 8%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, or 99% of its maximum diameter while still maintaining contact with the interior surface of a lumen of varying diameter, e.g., as the element is drawn through the lumen).
  • the inflatable element has a length when fully expanded of about 1 cm, 2 cm, 3 cm, 4 cm, 5 cm, 6 cm, 7 cm, 8 cm, 9 cm, 10 cm, 11 cm, 12 cm, 13 cm, 14 cm, 15 cm, 16 cm, 17 cm, 18 cm, 19 cm, 20 cm, 22 cm, 24 cm, 26 cm, 28 cm, 30 cm or more.
  • the catheter further comprises a handle.
  • the handle can move, or can cause other elements of the catheter to move, along the length of the catheter.
  • the handle is disposed such that manipulation of the handle causes change in the size (e.g., the diameter) of the expandable element.
  • Manipulation includes sliding, twisting, squeezing, folding, pushing, pulling, pressing, or splitting the handle or any component or part thereof.
  • the catheter has a distal end, the distal end comprising a needle end, and a proximal end comprising the moveable handle.
  • moving the handle, or a part or component thereof, in a proximal direction causes the size of the expandable element (e.g., a basket) to increase, and moving the handle in a distal direction causes the size of the basket to decrease.
  • moving the handle, or a part or component thereof proximally causes the size of the expandable element (e.g., a basket) to decrease, and moving the handle distally causes the size of the basket to increase.
  • FIG.2A-D shows how moving the handle can control the diameter to which the basket unfurls.
  • FIG.3 shows an embodiment wherein the basket is unfurled to make contact within the right main bronchus in swine.
  • FIG.4 shows exemplary results with CT images post-energy delivery (B) and after withdrawal of the catheter (A).
  • FIG.5B shows a cross-sectional view of the lung (cut perpendicular to the bronchus) with an exemplary location of the basket placement within the bronchus matching hyperemic regions (arrow). There is a region of hemorrhage and congestion surrounding the bronchus, extending 3- 4 cm into parenchyma on each side.
  • a cross section of the bronchus shows red lines on the internal surface and similar uniform effects similar to those seen in the perpendicular view (arrow, FIG.5A).
  • the expandable element (e.g., a basket) is disposed concentrically around substantially the entire outer circumference of the catheter. In certain embodiments, the expandable element is disposed around a fraction of the circumference of the catheter. In certain embodiments, the catheter comprises a first and a second expandable element, e.g., a basket, a stent, or a balloon. In certain embodiments, the first expandable element is disposed around a fraction of the circumference of the catheter, and the second expandable element is disposed around another fraction of the circumference of the catheter.
  • the first expandable element is a basket arranged in a planar fashion as shown in FIG.6A
  • the second expandable element is a balloon, configured such that inflating said balloon would cause said basket to encapsulate a tumor infiltrating the lumen (FIG.6B).
  • the device is configured such that it is suitable for use with tumors that may be infiltrating a lumen of a hollow organ.
  • the catheter can be used to deliver electrical energy to perform ablation using radiofrequency, irreversible electroporation, electrochemical therapy, EStress or other techniques.
  • the energy delivered by the devices described herein can facilitate drug delivery through hyperthermia, electroporation, or the use of electric pulses to modulate tissue vasculature and stroma.
  • the devices deliver pulses to increase or expand space, loosening tumor stroma, which (i) increases total amount of nanoparticles that can be absorbed by the tumor, (ii) facilitate faster clearance of nanoparticles from the system, and (iii) causes homogeneous distribution of nanoparticle throughout the tumor.
  • the devices can be used in Oncology, wherein ablation or drug delivery can be performed to nonsurgically destroy tumors that cannot be removed with surgery.
  • the devices can be used to treat or control nonmalignant disease conditions, including drug or gene delivery for acute lung injury, infections in the lung, and conditions like Asthma or COPD.
  • the devices can be used to opening the blood-brain barrier for the improved deliver of drugs to the brain. [0144] Described herein is a device that can be used for the delivery of square wave pulses to luminal organs in a circumferential or focal fashion.
  • the square wave pulses can be used to ablate either tumors or other undesirable normal tissue within the organ through irreversible electroporation or nanoporation. In certain embodiments, the square pulses can also facilitate reversible electroporation of the lumen wall allowing transfection of genetic material or drugs to constituent cells.
  • Described herein is a device that can be used to delivered high frequency electrical energy into the inner walls of luminal organs.
  • the device is configured to function similar to electrocautery to allow the rapid coagulation of any bleeding in the organ.
  • the device can be used to treat certain conditions such as varices, internal hemorrhage, and/or bleeding ulcers.
  • Described herein is a device that can be used to deliver radiofrequency energy within hollow organs.
  • the device is configured such that its use pursuant to the methods described herein would cause partial ablation of the lumen wall.
  • the device can be used to treat certain conditions marked by the hypertrophy of smooth muscle or muscularis of luminal organs, such as asthma, esophageal strictures, and/or debulking of vascular stenosis.
  • Radiolabeled nanoparticles allow imaging and quantification of the change or difference in distribution and retention of particles in treated tumors (See International Publication No. WO 2015/183876, attached hereto).
  • Radiolabeled liposomal nanoparticles show a linear correlation in tumor uptake when compared with simultaneously administered liposomal drugs. Therefore, co-administration of a nanoparticle drug formulation with a small dose of radiolabeled liposome can serve as method to map the uptake and relative distribution of therapeutic agents in tumors treated with pulsed electric fields. Subsequently, the uptake value of the radiotracer can be used to establish the concentration of the therapeutic agent at different locations in the tumor, and therefore serve as a tool to prognosticate treatment response at a very early stage.
  • Pulsed electric fields were applied to tumors in mice to determine if an increase in drug uptake via EPR effect occurred. Timing of the injection of drug and electric pulse treatment was also investigated to determine effect on uptake by a tumor. As depicted in the schematic of FIG.7, bilateral MiaPaCa2 tumors in two cohorts were treated with electric pulses (e.g., right flank) or not treated (e.g., left flank). Cohort 1 was first injected with the drug, treated with pulsed electric fields, imaged, and sacrificed to determine level of drug uptake by the tumor. Cohort 2 was first treated with pulsed electric fields, injection of drug, imaged and sacrificed to determine level of drug uptake by the tumor.
  • electric pulses e.g., right flank
  • Cohort 2 was first treated with pulsed electric fields, injection of drug, imaged and sacrificed to determine level of drug uptake by the tumor.
  • FIG.8A-F shows autoradiography results of Cohort 1, which was first injected with a drug and the treated with pulsed electric fields described above (A-C) compared to controls that were not treated with pulsed electric fields (D-F).
  • FIG.9 shows relative radiation from the autoradiography results from Cohort 1 between the tumors injected with drug and then treated with pulses of electric field compared to controls (e.g., tumors not receiving any drug). Results suggest that pulse electric fields increase uptake by tumors.
  • FIG.10 shows relative radiation from the autoradiography results from Cohort 2 between the tumors treated with pulses of electric field and then injected with a drug compared to controls (e.g., tumors not receiving any drug). Results suggest that pulse electric fields increase uptake by tumors.
  • FIG.11 shows PET imaging of Cohort 1 (e.g., mouse 1 (M1), mouse 2 (M2)), and control.
  • the top row shows animals 2 hours post pulse delivery, and the bottom row shows animals at 24 hours post pulse delivery.
  • the PET images display differences between the tumors injected with drug and then treated with pulses of electric field compared to controls (e.g., tumors not receiving any drug).
  • FIG.12 shows PET imaging of Cohort 2 (e.g., mouse 3 (M4), mouse 4 (M4)), and control.
  • the top row shows animals 2 hours post pulse delivery, and the bottom row shows animals at 24 hours post pulse delivery.
  • the PET images display differences between the tumors treated with pulses of electric field and then injected with a drug compared to controls (e.g., tumors not receiving any drug).
  • a drug compared to controls (e.g., tumors not receiving any drug).
  • the present technique is agnostic as to when the nanoparticle agent is injected.
  • FIGS.13A-13C show Cohorts 1 and 2 imaged after 24 hours.
  • the PET/CT images were processed with a software to extract iso-surfaces corresponding to bone window (white) and the locations positive for radioactivity (gold).
  • the results of using the systems and methods herein showed increased drug uptake in electrically treated tissue (about 2 or more times) compared to controls. These changes were achieved by applying a series (10-50) of low voltage (less than 1000 V) square wave DC pulses of 1 ⁇ s to 1 ms pulse width. The treatment can last less than a minute and the effects on the tumor start manifesting a few hours (48 hours) following treatment and can persist up till a period of 57 days.
  • MiaPaca-2 cells were cultured using DME modified to contain 1 mM sodium pyruvate, 1.5 g/L sodium bicarbonate and 4.5 g/L glucose, supplemented with 10% (vol/vol) heat-inactivated FCS and 100 IU penicillin and 100 ⁇ g/mL streptomycin.5 ⁇ 106 cells were then injected in athymic nude mice, strain NU(NCr)-Foxn1 nu (Charles River Laboratories,
  • the needles were placed parallel to each other at a distance of 5-7mm contingent on the size of the tumor.
  • the length of the needle was insulated except for 5mm at the tip that was left uncovered to allow passage of electricity.
  • Tumors were treated with pulses with sufficient voltage to induce an electric field with strength of 700V/cm between the needle electrodes.
  • Each animal was treated with 10 pulses delivered at 1 Hz with a pulse length of 90 microseconds.
  • ECM835 generator (BTX, Harvard Apparatus, Holliston, MA) was used to deliver the square wave pulses. The pulse parameters were chosen for their ability to induce reversible electroporation of the tumor with limited cytotoxic effects.
  • lysis buffer (10:1 v/w ratio) and were processed for drug extraction.
  • Samples 200 ⁇ L were added to a 96 well plate and drug measurements were performed using a microplate reader (Safire, Tecan, Mannedorf, Switzerland).
  • a calibration curve was generated by adding increasing known quantities of doxorubicin to tumor sample lysates from untreated animals (no drug or pulse delivery).
  • Animals with bilateral tumors underwent PET imaging at 2 hours and 24 hours following injection of 89 Zr-NRep. Imaging was performed using an Inveon MicroPET/CT (Siemens Healthcare Global). Whole body PET static scans recording a minimum of 50 million coincident events were performed, with duration of 10-20 min.
  • the image data was normalized to correct for nonuniformity of response, dead-time count losses, positron branching ratio, and physical decay to the time of injection, but attenuation, scatter, or partial-volume averaging correction was not performed.
  • the counting rates in the PET images were converted to equivalent activity concentration (percentage injected dose per gram of tissue) through use of a system calibration factor. Images were analyzed using ASIPro VMTM software (Concorde Microsystems). Quantification of activity concentration was done by averaging the maximum values in at least 5 ROIs drawn on adjacent slices of the treated and untreated tumors. Tumors were excised and embedded in OCT (Sakura Finetek, Torrance, CA), frozen and sectioned in 10 ⁇ m thick sections at five different levels throughout the tumor.
  • Sections were imaged against a phosphor imaging plate (BASMS-2325, Fujifilm, Valhalla, NY) and the plates were read on a Typhoon 7000IP plate reader (GE Healthcare, Pittsburgh, PA) at a pixel resolution of 25 ⁇ m.
  • Tissue sections from animals bearing bilateral tumors underwent histology analysis. OCT embedded and sectioned frozen tumor samples were then stained with IBA1, Cleaved Caspase-3, and Hematoxilin and Eosin. An experienced staff veterinary pathologist evaluated the samples for evidence of necrosis or injury, and to ascertain differences in macrophage population between treated and untreated tumor samples.
  • treated tumors When compared to untreated control tumors, treated tumors demonstrated significantly increased tracer / drug uptake at the 6 hour time point. The changes were not statistically significant at the 24-hour and 48 hour time points, suggesting that the post-treatment increase in uptake did not persist at later time points (FIG.15A-F and Table 3). Treatment accelerated the uptake of exemplary tracer 89 Zr-NRep (FIG.16A). Measurements performed at the 6 hour time point indicated that treated tumors had 78.8 ⁇ 24% of their maximum 89 Zr-NRep uptake seen at 48 hours. In comparison, untreated tumors had just 41 ⁇ 15.6% of the maximum uptake seen at 48 hours.
  • drug e.g., doxorubicin
  • Presence of exemplary tracer 89 Zr-NRep in the blood pool during pulse delivery resulted in immediate uptake of nanoparticles on PET imaging (FIG.18 A, solid arrow; 10.57 ⁇ 0.95 %ID/g). Uptake was limited in contralateral untreated tumors (FIG.18 A and B, dashed arrow; 3.59 ⁇ 0.45 %ID/g) and in tumors where 89 Zr-NRep was injected one hour after pulse delivery (FIG.18 B, solid arrow; 6.61 ⁇ 0.85 %ID/g).
  • PET imaging 24 hours following injection suggested uptake to be similar in tumors undergoing electroporation treatment after or before injection of tracer 89 Zr-NRep (FIG.18 C and D, solid arrows), while contralateral untreated tumors (FIG.18 C and D, dashed arrows) demonstrated markedly lesser concentration of 89 Zr-NRep (Inject/RE: 13.16 ⁇ 0.69 %ID/g vs. RE/Inject: 12.84 ⁇ 7.18 %ID/g vs. Contralateral Control: 3.9 ⁇ 1.3 %ID/g; p ⁇ 0.01).
  • mice receiving treatment with electric pulses freely available nanoparticles may be clearing from the blood pool earlier than in untreated mice, which may explain the absence of increased uptake in treated mice at 24 and 48 hour time points.
  • autoradiography analysis and PET imaging performed on a subset of animals indicated that distribution of the tracer was more uniform and widespread than in untreated tumors.
  • the tumor microenvironment can be heterogeneous, demonstrating non-uniform deposition of nanoparticle agents in different regions.
  • application of electric pulses may normalize the microenvironment by creating a baseline level of permeability and retention in regions experiencing the effect of the electric pulses.
  • the cells are in a permeabilized state for a short time window (few minutes) within which drug delivery has to be completed and/or during which drug delivery is enhanced.
  • a short time window for a short time window (few minutes) within which drug delivery has to be completed and/or during which drug delivery is enhanced.
  • electroporation such as membrane permeabilization and vascular changes
  • superparamagnetic and radiolabeled nanoparticles have been evaluated as contrast agents for imaging electroporation mediated nanoparticle delivery with MRI and PET imaging techniques.
  • the clinical utility of these agents were limited as they were either integrated with the therapeutic or were not completely validated for their ability to act as a reporter for therapeutics used with patients.
  • treatment with electric pulses opens a simple and rapid way of altering the tumor microenvironment for enhancing the delivery of nanoparticle therapeutics.
  • the technique does not substantially increase the overall uptake of nanoparticles, it seems that it alters the rate and dynamics of uptake.
  • such a treatment could therefore help to reach drug tissue levels in a tumor necessary to achieve better treatment outcomes, and could become standard of treatment during interventional ablation procedures.
  • IRE bronchopleural fistula, stenosis or stricture formation.
  • the heat sink effect of large airways can also impact treatment outcomes.
  • IRE is unaffected by the heat sink effect and has good safety profile when used adjacent to hollow organs in patients. The purpose of this study was to evaluate feasibility and intra-procedural safety of our new catheter electrode device for endobronchial IRE.
  • An expandable catheter electrode was designed to allow circumferential contact with airways of any diameter (See FIG.22). Endobronchial pulse delivery (treatment settings) was performed in the left or right main bronchi at 9 locations in 7 swine. Catheter placement was performed under fluoroscopy guidance and post-treatment CT was performed in all animals (See FIG.23). Animals were sacrificed 4 hours after ablation; airway and surrounding parenchyma was extracted for immunohistochemistry. CT images were used to create numerical simulations to estimate treatment zone and thermal effects.
  • Catheter directed endobronchial IRE may provide an alternate to thermal ablation for treatment of tumors adjacent to large airways. As the endobronchial approach directs electrical energy into the tissue it may reduce distortive effects associated with IRE during percutaneous treatment delivery in the lung. Further examination should be done to confirm the exact ablated area or late onset complication.

Abstract

L'invention concerne des systèmes et des méthodes pour manipuler de tumeurs avec des champs électriques pulsés. Les systèmes et les procédés décrits peuvent avoir des applications théragnostiques pour le diagnostic et le traitement oncologiques, notamment lorsqu'ils sont combinés avec des médicaments administrés par liposomes.
PCT/US2017/025035 2016-03-31 2017-03-30 Systèmes et méthodes pour améliorer l'administration de compositions diagnostiques et/ou thérapeutiques in vivo au moyen d'impulsions électriques WO2017173089A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201662316454P 2016-03-31 2016-03-31
US62/316,454 2016-03-31

Publications (1)

Publication Number Publication Date
WO2017173089A1 true WO2017173089A1 (fr) 2017-10-05

Family

ID=58639042

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2017/025035 WO2017173089A1 (fr) 2016-03-31 2017-03-30 Systèmes et méthodes pour améliorer l'administration de compositions diagnostiques et/ou thérapeutiques in vivo au moyen d'impulsions électriques

Country Status (1)

Country Link
WO (1) WO2017173089A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111743617A (zh) * 2019-03-27 2020-10-09 捷锐士阿希迈公司(以奥林巴斯美国外科技术名义) 用于月经过多的治疗的具有环形电极的设备
US20220047686A1 (en) * 2020-08-14 2022-02-17 Mayo Foundation For Medical Education And Research Methods for treating infectious diseases
WO2022260723A1 (fr) * 2021-06-10 2022-12-15 Galvanize Therapeutics, Inc. Extravasation induite par apport d'énergie à un tissu
EP4225425A4 (fr) * 2020-10-07 2024-03-20 Univ Northwestern Intégration de systèmes de cartographie électrophysiologique avec électroporation synchronisée avec stimulation
US11938317B2 (en) 2017-12-26 2024-03-26 Galvanize Therapeutics, Inc. Optimization of energy delivery for various applications

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070129760A1 (en) * 2002-04-08 2007-06-07 Ardian, Inc. Methods and apparatus for intravasculary-induced neuromodulation or denervation
US20080300571A1 (en) * 2007-05-30 2008-12-04 Lepivert Patrick Process and device for selectively treating interstitial tissue
EP2495012A1 (fr) * 2004-10-05 2012-09-05 Medtronic Ardian Luxembourg S.à.r.l. Appareil pour une neuromodulation rénale
WO2015183876A1 (fr) 2014-05-28 2015-12-03 Memorial Sloan Kettering Cancer Center Liposomes marqués au fluorophore bimodal et procédés et systèmes associés

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070129760A1 (en) * 2002-04-08 2007-06-07 Ardian, Inc. Methods and apparatus for intravasculary-induced neuromodulation or denervation
EP2495012A1 (fr) * 2004-10-05 2012-09-05 Medtronic Ardian Luxembourg S.à.r.l. Appareil pour une neuromodulation rénale
US20080300571A1 (en) * 2007-05-30 2008-12-04 Lepivert Patrick Process and device for selectively treating interstitial tissue
WO2015183876A1 (fr) 2014-05-28 2015-12-03 Memorial Sloan Kettering Cancer Center Liposomes marqués au fluorophore bimodal et procédés et systèmes associés
US20150343100A1 (en) 2014-05-28 2015-12-03 Memorial Sloan Kettering Cancer Center Bimodal fluorophore-labeled liposomes and associated methods and systems

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
BELLARD E ET AL., J CONTROL RELEASE, vol. 163, no. 3, 10 November 2012 (2012-11-10), pages 396 - 403
BELLARD E, J CONTROL RELEASE, vol. 163, no. 3, 10 November 2012 (2012-11-10), pages 396 - 403
DOLLINGER M J, VASC INTERV RADIOL., vol. 25, no. 10, October 2014 (2014-10-01), pages 1589 - 1594
LAGINHA KM ET AL., CLIN CANCER RES., vol. 11, no. 19, 1 October 2005 (2005-10-01), pages 6944 - 6949
MARKELC B ET AL., J MEMBR BIOL., vol. 245, no. 9, September 2012 (2012-09-01), pages 545 - 554
NARAYANAN, CARDIOVASC INTERVENT RADIOL., vol. 37, no. 6, December 2014 (2014-12-01), pages 1523 - 1529
PEREZ-MEDINA C ET AL., J NUCL MED., vol. 55, no. 10, October 2014 (2014-10-01), pages 1706 - 1711
SCHEFFER HJ, J VASC INTERV RADIOL., vol. 25, no. 7, July 2014 (2014-07-01), pages 997 - 1011
SERSA G, EUR J CANCER, vol. 35, no. 4, April 1999 (1999-04-01), pages 672 - 677
ZHANG ZI; LI W ET AL., NANOMEDICINE, vol. 9, no. 8, 2014, pages 1181 - 1192

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11938317B2 (en) 2017-12-26 2024-03-26 Galvanize Therapeutics, Inc. Optimization of energy delivery for various applications
CN111743617A (zh) * 2019-03-27 2020-10-09 捷锐士阿希迈公司(以奥林巴斯美国外科技术名义) 用于月经过多的治疗的具有环形电极的设备
US11547471B2 (en) * 2019-03-27 2023-01-10 Gyrus Acmi, Inc. Device with loop electrodes for treatment of menorrhagia
US20220047686A1 (en) * 2020-08-14 2022-02-17 Mayo Foundation For Medical Education And Research Methods for treating infectious diseases
EP4225425A4 (fr) * 2020-10-07 2024-03-20 Univ Northwestern Intégration de systèmes de cartographie électrophysiologique avec électroporation synchronisée avec stimulation
WO2022260723A1 (fr) * 2021-06-10 2022-12-15 Galvanize Therapeutics, Inc. Extravasation induite par apport d'énergie à un tissu

Similar Documents

Publication Publication Date Title
WO2017173089A1 (fr) Systèmes et méthodes pour améliorer l'administration de compositions diagnostiques et/ou thérapeutiques in vivo au moyen d'impulsions électriques
Missaoui et al. Toxicological status of nanoparticles: what we know and what we don't know
US20200398049A1 (en) Interventional drug delivery system and associated methods
Lu et al. Effects of photoacoustic imaging and photothermal ablation therapy mediated by targeted hollow gold nanospheres in an orthotopic mouse xenograft model of glioma
Muhanna et al. Multimodal image-guided surgical and photodynamic interventions in head and neck cancer: from primary tumor to metastatic drainage
US11819548B2 (en) Inorganic nanoparticles compositions in combination with ionizing radiations for treating cancer
Thorsen et al. Multimodal imaging enables early detection and characterization of changes in tumor permeability of brain metastases
Saadatpour et al. Molecular imaging and cancer gene therapy
Wang et al. An electric-field-responsive paramagnetic contrast agent enhances the visualization of epileptic foci in mouse models of drug-resistant epilepsy
Saito et al. Regression of recurrent glioblastoma infiltrating the brainstem after convection-enhanced delivery of nimustine hydrochloride: case report
Chanda et al. Gold nanoparticle based X-ray contrast agent for tumor imaging in mice and dog: a potential nanoplatform for computer tomography theranostics
Liu et al. The combined therapeutic effects of 131iodine-labeled multifunctional copper sulfide-loaded microspheres in treating breast cancer
CN108430520A (zh) 长效钆基肿瘤靶向成像与治疗剂
CN108136217A (zh) 用于治疗膀胱癌的制剂
Tam et al. Imaging intratumoral nanoparticle uptake after combining nanoembolization with various ablative therapies in hepatic VX2 rabbit tumors
Zhao et al. Specific diagnosis of lymph node micrometastasis in breast cancer by targeting activatable near-infrared fluorescence imaging
ES2395436T3 (es) Diagnóstico por formación de imágenes mediante la combinación de agentes de contraste
Kodama et al. Catheter-based endobronchial electroporation is feasible for the focal treatment of peribronchial tumors
Zhang et al. Highly stable near-infrared dye conjugated cerasomes for fluorescence imaging-guided synergistic chemo-photothermal therapy of colorectal cancer
Chen et al. Manganese (iii)-chelated porphyrin microbubbles for enhanced ultrasound/MR bimodal tumor imaging through ultrasound-mediated micro-to-nano conversion
Braun et al. Imaging in sinonasal sarcoidosis: CT, MRI, 67Gallium scintigraphy and 18F-FDG PET/CT features
Wang et al. Gadolinium-loaded solid lipid nanoparticles for colorectal tumor in MR colonography
Chavda et al. Interventional nanotheranostics in hepatocellular carcinoma
Liu et al. Nanotechnology for cancer imaging: advances, challenges, and clinical opportunities
Yao et al. A folate-conjugated dual-modal fluorescent magnetic resonance imaging contrast agent that targets activated macrophages in vitro and in vivo

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17719956

Country of ref document: EP

Kind code of ref document: A1

122 Ep: pct application non-entry in european phase

Ref document number: 17719956

Country of ref document: EP

Kind code of ref document: A1