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WO2010029496A1 - Système de commande à contre-réaction pour une administration de composés induite par les ultrasons - Google Patents

Système de commande à contre-réaction pour une administration de composés induite par les ultrasons Download PDF

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Publication number
WO2010029496A1
WO2010029496A1 PCT/IB2009/053908 IB2009053908W WO2010029496A1 WO 2010029496 A1 WO2010029496 A1 WO 2010029496A1 IB 2009053908 W IB2009053908 W IB 2009053908W WO 2010029496 A1 WO2010029496 A1 WO 2010029496A1
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Prior art keywords
ultrasound
compound
spect
pet
distribution
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English (en)
Inventor
Christopher S. Hall
Balasundara I. Raju
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Koninklijke Philips NV
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Koninklijke Philips Electronics NV
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N7/00—Ultrasound therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/48—Other medical applications
    • A61B5/4836—Diagnosis combined with treatment in closed-loop systems or methods
    • A61B5/4839—Diagnosis combined with treatment in closed-loop systems or methods combined with drug delivery

Definitions

  • the invention relates to the field of ultrasound-mediated compound delivery. More particularly, the invention relates to a system for ultrasound-mediated compound delivery and to a method for controlling ultrasound- mediated compound delivery.
  • Molecular medicine includes molecular therapy where ultrasound active compounds and/or molecules such as drugs, genes or proteins are locally delivered to specific sites in the body.
  • Molecular therapy may involve molecular imaging with site-specific contrast agents to determine the location for the therapy.
  • Therapeutic ultrasound is a powerful way to induce local physiological effects, possibly by causing the release of pharmaceutically active molecules locally.
  • Ultrasound contrast agents such as microbubbles can be carrying entities that can be activated using high pressure or high intensity acoustic pulses to provide local physiological effects or deliver pharmaceutically active molecules locally.
  • Other agents such as liposomes or nanoparticles can also be used as for example carrying entities that can be activated through ultrasound mediated mechanisms such as radiation force and heat- activation mechanisms.
  • Ultrasound active indicates any change or reaction of a compound when exposed to ultrasound.
  • the amount of ultrasound active compound accumulating at a specific site depends on several factors that are beyond the control of the user including the topology of the blood vessels, blood flow velocity, binding efficiency when targeting systems are used, the amount of binding proteins that are expressed, and the rate of clearance from the blood through natural excretion mechanisms among many other possible factors.
  • Patent US7141234B1 describes imaging methods (e.g. using positron emission tomography (PET)) to visualize the accumulation of a radio-labeled compound in the body.
  • PET positron emission tomography
  • SPECT single photon emission computed tomography
  • PET positron emission tomography
  • the present invention provides a system for ultrasound-mediated compound delivery that combines the potential of nuclear medicine methods with ultrasonic therapy methods.
  • the use of ultrasound is desirable because it allows the non- invasive treatment of deep tissues with little or no effect on overlying organs.
  • the SPECT or PET imaging modality provides quantification of ultrasound active compounds. Ultrasound is used to activate the compound, possibly leading to rupture or leakage.
  • a controller is arranged for controlling the ultrasound system based on the distribution of the compound monitored by the SPECT or PET system.
  • the incorporation of such a controller that can use e.g. spatial distribution and/or quantification of the PET/SPECT agent in the treated tissue volume as an input to modify the compound delivery/activation planning and execution via ultrasound is a key element of this invention. It facilitates the execution of tailored protocols and quantitative compound delivery highly demanded by the current developments in molecular medicine.
  • the compound is an ultrasound active particle comprising a pharmaceutically active molecule.
  • ultrasound active compound SPECT or PET scanner is combined with a CT or
  • the system comprises an interface to visualize co -registration of the SPECT or PET system and ultrasound system. This facilitates visualization of the dosage being delivered, a visual inspection of the therapy and positioning of the ultrasound beam. It is understood that such a co-registration system could make use of co-registration of other integrated imaging modalities such as CT-SPECT and PET-MR to better align the therapy transducer to the imaging volume.
  • the controller further controls a dispensing system arranged for administering the compound. Such a dispensing unit couples the information from the controller, via a predetermined therapy protocol, to amount of agent delivered to the patient. In this way a tailored therapy plan can be made for every patient such that an optimal dose of a compound is delivered.
  • the ultrasound system is arranged for delivering pulses with an adjustable intensity or pressure. If the system is able to deliver different pulses with more than one acoustic pressure, it provides the possibility to control compound release through the use of (a plurality of) acoustically active compounds that have different thresholds and different radioisotopes attached to them. It is facilitated that multiple radioisotopes on separate populations of compounds can be used in the therapy protocol.
  • the controller is configured to use pharmacokinetic and or pharmacodynamic modeling.
  • pharmakinetic modeling In addition to the detection of SPECT and/or PET labeled tracers during the therapy session, it will be possible to employ pharmakinetic modeling to determine the amount of ultrasonically activated, labeled compound or labeled pharmaceutically active molecule that is in the vasculature versus that which is in the extra- cellular and intra-cellular spaces.
  • the controller is configured to use pharmacokinetic and or pharmacodynamic modeling
  • the invention also relates to a method for controlling ultrasound-mediated compound delivery, comprising the following steps: a) providing an ultrasound active compound comprising a single photon emission computed tomography (SPECT) or positron emission tomography (PET) label, the ultrasound active compound comprised within a subject b) monitoring the compound distribution with a SPECT or PET system, c) controlling an ultrasound system based on the distribution of the compound monitored by the SPECT or PET system.
  • SPECT single photon emission computed tomography
  • PET positron emission tomography
  • distribution of the compound is determined by using pharmacokinetic and or pharmacodynamic modeling.
  • the ultrasound active compound comprises a targeting modality.
  • a targeting modality By targeting the compound to a specific region, tissue or other defined volume, the side effects of potentially harmful compounds is further reduced.
  • the ultrasound active compound is an ultrasound active particle comprising a pharmaceutically active molecule.
  • the SPECT or PET system is combined with a CT or MR system. This will allow better alignment of the therapy transducer to the imaging volume.
  • a first ultrasound pulse of a certain pressure is applied to activate a first compound at a target site, followed by a second pulse with a different pressure to activate a second compound at the target site.
  • steps b and c are repeated until a threshold compound concentration is reached at a target site.
  • the object is further realized by a computer program product comprising instructions which, when carried out by a computer, cause the computer to carry out step b) and c) of the method according to the invention.
  • Fig. 1 Schematic representation of a system according to the invention
  • Fig. 2 Volumetric representation of a rabbit leg with SPECT/CT
  • Fig. 3 Hind leg of a rabbit in CT for positioning the ultrasound therapy zone.
  • Fig. 4 Accuracy of the position of the therapy zone after correction
  • Fig. 5 The total dose and relative effective doses locally versus nearby structures
  • Compound delivery to a site locally in the body provides a way to specifically target diseased areas and in this way reduces side effects.
  • Different patients and different tumors require a different therapeutic strategy.
  • the amount of drug to be released or compound to be activated depends for example on the pathology (e.g. size of tumor), the age of the patient, and the need to minimize side effects.
  • the need for tailored protocols to locally modify physiological parameters is not restricted to therapy or cancer therapy in particular.
  • Ultrasound activatable agents in combination with ultrasound waves provide an elegant way to locally modify physiological parameters, possibly via or by locally distributing drugs in the body. It is however hard to obtain quantitative data on the amount of ultrasound active compound or the amount of pharmaceutically active molecules that are locally present or released. Therefore currently in molecular therapy methods, the local concentration that can be achieved is not known.
  • the present invention overcomes these limitations by ingeniously combining the potential of nuclear medicine methods with ultrasonic therapy methods.
  • the SPECT or PET imaging modality provides quantification of acoustically active compounds and or drugs attached to or incorporated in these acoustically active compounds. Ultrasound is then used to activate/control the compound and/or drug delivery.
  • a compound/agent is needed that is responsive to ultrasound (ultrasound active) and comprises a PET or SPECT radioisotope.
  • the ultrasound active compound is a particle comprising a core and a shell.
  • the acoustically active particle could be fully or partially gas filled bubbles having a size between 0.1 to 10 ⁇ m, liposomes with or without gaseous component inside or perfluorocarbon particles with size ranging from 5 nm to 5 ⁇ m in diameter.
  • SPECT agents include radio-isotopes or tracer compounds that contain the isotope (e.g. 99m Tc-Sestamibi). The radiolabel can be attached to the shell or be incorporated in the core of the particle.
  • a targeting moiety in accordance with the invention may be used to enhance the localization of the binding of the compound.
  • Such moieties may consist of any of a variety of targeting approaches including the use of monoclonal antibodies, polyclonal antibodies, antibody fragments, aptamers, peptides, pepto-mimetics, biotin/streptavidin linkers, chemical orthogonal coupling moieties such as phosphine and azide groups for Staudinger reactions and other approaches.
  • the ultrasound active compound comprises a pharmaceutically active molecule.
  • This pharmaceutically active molecule can comprise a PET or SPECT label to directly monitor the distribution of the molecule.
  • Pharmaceutically actice molecule refers to any bioactive agent that is useful to be administered through ultrasound mediation. This includes truly therapeutic agents, that serve the treatment of a disease or disorder, as well as agents for prophylaxis that serve to prevent the occurrence, or worsening, of a disease or disorder. It also includes genetic material such as plasmid DNA or siRNA.
  • compounds envisaged for use as bioactive agents in the context of the present invention include any compound with physiological, therapeutic or prophylactic effects. It can be a compound that affects or participates in tissue growth, cell growth, cell differentiation, a compound that is able to invoke a biological action such as an immune response, or a compound that can play any other role in one or more biological processes.
  • a non- limiting list of examples includes antimicrobial agents (including antibacterial, antiviral agents and anti-fungal agents), anti-viral agents, anti-tumor agents, thrombin inhibitors, antithrombogenic agents, thrombolytic agents, fibrinolytic agents, vasospasm inhibitors, calcium channel blockers, vasodilators, antihypertensive agents, antimicrobial agents, antibiotics, inhibitors of surface glycoprotein receptors, antiplatelet agents, antimitotics, microtubule inhibitors, anti secretory agents, actin inhibitors, remodeling inhibitors, anti metabolites, antiproliferatives (including antiangiogenesis agents), anticancer chemotherapeutic agents, anti- inflammatory steroid or non-steroidal anti- inflammatory agents, immunosuppressive agents, growth hormone antagonists, growth factors, dopamine agonists, radiotherapeutic agents, extracellular matrix components, ACE inhibitors, free radical scavengers, chelators, antioxidants, anti polymerases, and photodynamic therapy
  • Anti-tumor agents such as altretamin, fluorouracil, amsacrin, hydroxycarbamide, asparaginase, ifosfamid, bleomycin, lomustin, busulfan, melphalan, chlorambucil, mercaptopurin, chlormethin, methotrexate, cisplatin, mitomycin, cyclophosphamide, procarbazin, cytarabin, teniposid, dacarbazin, thiotepa, dactinomycin, tioguanin, daunorubicin, treosulphan, doxorubicin, tiophosphamide, estramucin, vinblastine, etoglucide, vincristine, etoposid, vindesin and paclitaxel.
  • bioactive agents which are water soluble
  • other water-soluble compounds can be incorporated such as anti-oxidants, ions, chelating agents, dyes, imaging compounds.
  • Preferred therapeutic agents are in the area of cancer (e.g. antitumor) and cardiovascular disease (e.g. thrombus treatment or prevention). These constitute the best candidates among Therapeutic Agents that allow benefit from ultrasound-mediated delivery.
  • Ultrasound active means that the compound is able to locally respond to ultrasound inducing any change or reaction of the compound. Examples of such a reaction include change of the compound permeability, resonance, rupture or leakage. Rupture or leakage potentially leads to release of the pharmaceutically active molecule it is carrying upon the application of ultrasound. However, physiological effects can also be obtained by the application of ultrasound to ultrasound active particles that do not carry a specific pharmaceutical molecule. In addition, the ultrasound may induce temporary or permanent alteration of the permeability of the vessel walls and surrounding tissue, for example to allow better penetration of a pharmaceutically active molecule once released.
  • the radioisotopes are attached to the acoustically active compound in such a way that the number of particles can be calculated by direct observation of radioactive decay of the isotopes.
  • the amount of radioactive decay within a specific region can be calculated.
  • the amount of ultrasound active compound is then determined.
  • the acoustically active particles contain molecules with radioisotopes directly attached. This allows a direct measurement of the pharmaceutically active molecule concentration via the PET/SPECT scanner. This approach also allows the tracking of the molecules once released by employing sophisticated but state-of-the-art methods for modeling compartment retention / expulsion of the tracers to ascertain amount of compound in the intra-vessel, extra-vessel, and intra-cellular compartments.
  • acoustically active particles In a third scenario multiple radioisotopes on separate populations of acoustically active particles are envisioned. These particles have been designed in such a way to allow for selective acoustic activation at specific pressures, temperatures, or other acoustically controlled parameters. By measuring the relative concentrations of these particles, it would be possible to release molecules that are inherently inactive until they meet. With knowledge of the ratio of concentrations, one would then be able to calculate the overall dosage.
  • ultrasound is used to activate compounds at a specific site in the body.
  • a subject is provided with the ultrasound responsive agent in the circulation.
  • PET/SPECT the distribution and local concentration of the compound can be calculated.
  • Ultrasound is then applied to locally activate the ultrasound responsive compound controlled by information from the PET/SPECT system.
  • the application of ultrasound can be continued until a certain (predetermined) concentration or activation threshold is met.
  • the Ultrasound pulse can be continued or intensified based on the concentration information obtained by the PET/SPECT scanner via the controller.
  • the ultrasound system is arranged for delivering pulses with an adjustable intensity or pressure. More than one pulse frequency opens the possibility to design compound targeting protocols using different compounds potentially carrying different pharmaceutically active molecules.
  • An example can be pro-compounds or molecules that only become active when both components meet.
  • a two step delivery strategy can be envisioned whereby a first a compound is activated to modify the local environment, and then a second compound is activated leading to release of a pharmaceutically active molecule that will have a better effect due to the first pre-treatment.
  • a two step delivery strategy can be envisioned whereby a first a compound is activated to modify the local environment, and then a second compound is activated leading to release of a pharmaceutically active molecule that will have a better effect due to the first pre-treatment.
  • by combining the different compounds it is possible to gradually increase the dosage delivery one step at a time by successively emitting ultrasound pulses with increasing pressures that selectively destroy each class of compound. In this manner it is possible to better achieve a target compound or pharmaceutically active molecule dose to the subject.
  • pharmacokinetic and or pharmacodynamic modeling e.g. a multicompartment model is used to track the distribution of compound in the vascular system and extra-vascular / cellular space.
  • site-targeting of acoustically active compounds is a preferred embodiment of the invention, the invention also includes the case where the compounds are not targeted but are rather in circulation. The compound activation is then targeted through careful placement of the acoustic beam.
  • the feedback control system requires user permission or input to execute the modified protocol.
  • the feedback control system preferably uses one or more the following parameters to determine the delivery protocol: quantification of SPECT/PET agents; spatial location of the SPECT/PET agents; time variation or modification thereto of the SPECT/PET agent concentration; use of CT to correct for breathing motion or organ shift to place the therapeutic zone accurately.
  • quantification of SPECT/PET agents quantification of SPECT/PET agents
  • spatial location of the SPECT/PET agents spatial location of the SPECT/PET agents
  • time variation or modification thereto of the SPECT/PET agent concentration use of CT to correct for breathing motion or organ shift to place the therapeutic zone accurately.
  • CT to correct for breathing motion or organ shift to place the therapeutic zone accurately.
  • an abnormal distribution of radioisotopes injected into the body is determined using the gamma rays that are emitted from the isotopes. Both these methods provide a high degree of sensitivity for pathology detection. Also, the absence of inherent background radiation provides a high signal-to-noise ratio
  • a specific advantage of SPECT is that multi-isotope procedures using tracers that emit gamma rays of different energy are possible. PET procedures use gamma emissions due to positron annihilation and therefore use the same energy of 511 keV.
  • An ultrasound system in accordance with the invention comprises an ultrasound transducer constructed out of piezo-electric material in any of a variety of approaches including but not limited to piezo-ceramics, piezo-composites, PZT, CMUT, PMUT and other technologies.
  • the therapy transducer will typically have the capability of focusing ultrasound energy with high enough geometric gain to increase the pressure sufficiently for acoustic activation of injected compounds/particles.
  • the therapy transducer will typically have one or more acoustic elements that are excited by a pulse or continuous wave electrical signal.
  • the ultrasound therapy device also contains the necessary electronics to generate the excitation signals to each of the transducer elements as well as electrical matching networks in order to allow for efficient power transmission to the transducer.
  • the system will then be controlled by a controller capable of reacting to the PET/SPECT information to alter the therapeutic protocol.
  • the ultrasound system preferably comprises an image acquisition part that facilitates visualization of the ultrasound application.
  • a PET/ SPECT system in accordance with the invention will utilize the state- of-the-art detectors for gamma-ray emissions.
  • the detectors can be rotated around the patient so that a full tomographic image can be re-constructed. Images may be enhanced through such innovations as solid-state detectors, time-of- flight imaging, and correction for breathing or patient motion.
  • Such systems may be integrated with other imaging modalities such as CT or MRI to provide anatomic information and to allow for corrections due to attenuation of the photons before they reach the detector.
  • An ultrasound transducer having one or more elements is seated in a tissue- coupling medium.
  • the transducer is registered in the coordinate system of the SPECT or PET imaging system and can be placed beneath the table the patient is lying on, although other locations are not excluded.
  • a composition consisting of acoustically active compound with a SPECT or PET tracer, possibly carrying a pharmaceutically active molecule is injected into the patient.
  • the number of atoms of the radio-isotopes per acoustically active particle could be measured a priori precisely. See for example Hu et al. where in a certain number (e.g.
  • Indium- 111 atoms can be conjugated to perfluorocarbon nanoparticles via a methoxy- benyl DOTA chelator (G. Hu, et al, "Imaging of Vx-2 rabbit tumors with 0C v ⁇ 3 - integrin targeted 111 In nanoparticles", Int. J. Cancer: 120, 1951-1957 (2007)).
  • a methoxy- benyl DOTA chelator G. Hu, et al, "Imaging of Vx-2 rabbit tumors with 0C v ⁇ 3 - integrin targeted 111 In nanoparticles", Int. J. Cancer: 120, 1951-1957 (2007).
  • the SPECT/PET imaging system captures a volumetric image of the pathological tissue.
  • the output data contains readings of the activity in counts/min. Since the measured activity directly relates to the number of nuclear disintegrations, the total number of radioactive atoms (including decayed ones) that must be present can be calculated by extrapolating to time zero using the exponential decay equation. Since the number of atoms to the acoustically active particle is also known, this then means that the quantity of acoustically active particles is also known precisely. Also, if present, the quantity of pharmaceutically active molecules in the acoustically active particles is also known a priori from the composition preparation, from which means that the quantity of compounds/molecules in the region of interest can be calculated.
  • the information from the PET/SPECT scanner is computed with a controller. Based on a signal from the controller, the ultrasound therapy apparatus is then turned on to activate compound delivery.
  • the therapeutic ultrasound can be delivered to the specific diseased tissue.
  • Ultrasound mediated therapy can occur to alter pathological tissue through the use of compound bearing pharmaceutically active molecules, thermally activated compounds, thermal sensitization of tissue for concomitant radiotherapy treatments.
  • Fig. 1 shows an example of a system according to the invention.
  • a single photon emission computed tomography (SPECT) or positron emission tomography (PET) scanner (11) is shown, in combination with an ultrasound system (12).
  • Information from the PET/SPECT scanner is preferably received by a means (13) for computing a concentration of a compound based on this information obtained from the SPECT or PET scanner.
  • the information is then send to a control system (14) that is arranged for modulating the ultrasound system to execute a compound delivery protocol based on information from the controller.
  • the SPECT/PET system is combined with CT or MR.
  • CT or MR additional imaging components will provide morphology that will allow for treatment planning such as acoustic windows, absorbing material in the path, etc. with ultrasound therapy.
  • a volumetric representation of a rabbit leg imaged with SPECT/CT is visualized.
  • a VX-2 rabbit was injected with a nanoparticle compound conjugated to a Tc99 SPECT tracer.
  • the nanoparticle consists of a perfluorocarbon core (perfluoro-octyl bromide) with a lipid shell.
  • the nanoparticle has an average diameter of 250 nm.
  • the surface of the nanoparticle has been modified by conjugation of a pepto-mimetic molecule that is targeted towards the avb3 integrin associated with neo -vasculature.
  • the enhancement in the image is due to retention of the agent in the areas of neo vasculature.
  • the animal has been implanted intra-muscularly with tumor cells and is imaged at a time point 10 to 16 days post injection of tumor cells. The highlighting of the tumor is indicative of the amount of nanoparticles bound to the tumor vasculature.
  • the feedback and planning console utilizes the images gathered from a combined CT/SPECT machine to show the morphology of a rabbit hind leg (Fig. 3).
  • Fig. 3 rabbit hind leg
  • the images are then used to plan the therapy by overlaying a grid on the picture and showing the ultrasound beam location.
  • PET/SPECT and ultrasound therapy systems is that the two systems are co-registered with one another so that the spatial SPECT information can be accurately translated into a modified ultrasound therapy protocol.
  • Fig. 4 we show the accuracy of co-registration between the ultrasound therapy system and the CT/SPECT imaging volume. This co- registration is evaluated by the positioning of a therapy zone on the tip of an implanted thermocouple. If the registration is perfect, then the temperature rise of the thermocouple will be largest without additional movement of the therapy zone. If the registration is less than optimal, then slight movements in the therapy zone from the volumes chosen on the CT/SPECT images will result in increased temperature measurements in the thermocouple.
  • the registration in this case is performed by taking a three-dimensional image of the therapeutic transducer using CT and correlating using mutual information of this image with a prior image gathered with perfect alignment between the ultrasound and CT/SPECT imaging coordinate frames. This co-registration yields a translation and rotation matrix to bring the two coordinate frames into alignment.
  • One of the important elements of this invention is the capability of SPECT imaging to quantify the amount of the bound compound at the site of therapy.
  • Fig. 5 we show the SPECT tracer Tc-99m binding to a tumor in a VX-2 rabbit model. The tracer is attached to nanoparticles and injected into the animal. The SPECT measurement is made every 30 minutes post injection starting at 20 minutes.

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  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Radiology & Medical Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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Abstract

La présente invention concerne un système d’administration contrôlée de composés induite par les ultrasons, un système de tomographie d’émission monophotonique (SPECT) ou un système de tomographie par émission de positons (PET) destiné à contrôler la distribution d’un composé compris à l’intérieur d’un sujet, un système à ultrasons destiné à activer le composé compris à l’intérieur du sujet et un dispositif de commande qui est conçu pour commander le système à ultrasons sur la bae de la distribution du composé contrôlé par le système SPECT ou PET. L’invention concerne en outre un procédé pour contrôler l’administration de composés induite par les ultrasons et un produit-programme informatique.
PCT/IB2009/053908 2008-09-11 2009-09-08 Système de commande à contre-réaction pour une administration de composés induite par les ultrasons Ceased WO2010029496A1 (fr)

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US61/096,010 2008-09-11

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105854186A (zh) * 2016-03-15 2016-08-17 西安邮电大学 基于量子超弦引擎的中晚期癌症治疗设备
WO2021097224A1 (fr) * 2019-11-15 2021-05-20 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Complexes de médicaments liposome-microbulle cardioprotecteurs

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6740039B1 (en) * 1999-08-20 2004-05-25 Koninklijke Philips Electronics N.V. Methods and apparatus for displaying information relating to delivery and activation of a therapeutic agent using ultrasound energy
WO2006129099A1 (fr) * 2005-06-02 2006-12-07 Cancercure Technology As Systeme de traitement a ultrasons
WO2008075304A1 (fr) * 2006-12-21 2008-06-26 Koninklijke Philips Electronics N.V. Système intégré d'imagerie tem et de thérapie par ultrasons

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6740039B1 (en) * 1999-08-20 2004-05-25 Koninklijke Philips Electronics N.V. Methods and apparatus for displaying information relating to delivery and activation of a therapeutic agent using ultrasound energy
WO2006129099A1 (fr) * 2005-06-02 2006-12-07 Cancercure Technology As Systeme de traitement a ultrasons
WO2008075304A1 (fr) * 2006-12-21 2008-06-26 Koninklijke Philips Electronics N.V. Système intégré d'imagerie tem et de thérapie par ultrasons

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105854186A (zh) * 2016-03-15 2016-08-17 西安邮电大学 基于量子超弦引擎的中晚期癌症治疗设备
WO2021097224A1 (fr) * 2019-11-15 2021-05-20 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Complexes de médicaments liposome-microbulle cardioprotecteurs

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