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WO2000043045A1 - Procedes et agents destines a une radiotherapie amelioree - Google Patents

Procedes et agents destines a une radiotherapie amelioree Download PDF

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Publication number
WO2000043045A1
WO2000043045A1 PCT/US2000/001815 US0001815W WO0043045A1 WO 2000043045 A1 WO2000043045 A1 WO 2000043045A1 US 0001815 W US0001815 W US 0001815W WO 0043045 A1 WO0043045 A1 WO 0043045A1
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WO
WIPO (PCT)
Prior art keywords
agent
agents
tissue
radiosensitizer
volume
Prior art date
Application number
PCT/US2000/001815
Other languages
English (en)
Inventor
Eric Wachter
John Smolik
H. Craig Dees
Original Assignee
Photogen, Inc.
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 Photogen, Inc. filed Critical Photogen, Inc.
Priority to EP00908366A priority Critical patent/EP1146912A4/fr
Priority to AU29725/00A priority patent/AU2972500A/en
Priority to KR1020017009307A priority patent/KR20020001723A/ko
Priority to JP2000594498A priority patent/JP2002535291A/ja
Priority to BR0007692-9A priority patent/BR0007692A/pt
Priority to IL14442800A priority patent/IL144428A0/xx
Priority to CA002358989A priority patent/CA2358989A1/fr
Publication of WO2000043045A1 publication Critical patent/WO2000043045A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • 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
    • A61K41/0038—Radiosensitizing, i.e. administration of pharmaceutical agents that enhance the effect of radiotherapy
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to methods and compositions for radiation treatment of a selected volume of tissue, such as the treatment of abnormal cellular proliferation or malignant tissue. More specifically, the present invention relates to a novel method that involves distributing a radiosensitizer and a plurality of ionizing radiation sources substantially within the volume of tissue to produce treatment zones that are generally uniformly distributed throughout the volume of tissue. The present invention also particularly relates to a novel agent for treating such tissue wherein the agent includes a radiosensitizer and an ionizing radiation source in conjunction to define an injectable treatment agent.
  • abnormal cellular proliferation occurring in cancer is often treated using ionizing radiation in a process known as radiation therapy.
  • radiation therapy which typically but not necessarily uses electromagnetic radiation with energies of 1 keV or higher
  • radiation may be applied from an external source or through introduction of a radioactive source inside tissue to be treated.
  • a maj or challenge in radiation therapy is selective delivery of a therapeutic dose of radiation to the desired tissue, such as that in a cancerous tumor.
  • One technique for localizing the effect of the radiation is to use radiodense or radiopaque radiosensitizing agents in conjunction with applied radiation. These agents enhance the effect of the radiation on the tissue treated with the sensitizer and have in the past, yielded dose enhancement (DE) in tumors, when such agents are introduced in the tissue to be treated.
  • DE yielded dose enhancement
  • sensitizers are only an advance, not the complete answer in radiation therapy.
  • the radiosensitizer in the treated tissue closest to the radiation source may tend to shield or block the more distal tissue from the ionizing radiation. As a result, only part of the tissue to be treated receives an effective radiation dose.
  • brachytherapy when a confined radiation source, such as a radioactive needle or the tip of a wire or ribbon, is introduced directly into or into the proximity of the tissue to be treated (commonly called brachytherapy), the radiosensitizer in proximity to the radiation source may act to shield the remainder of the tissue from the desired dose. The result is less than uniform treatment of the tissue volume, such as a tumor, in question.
  • Another object of the present invention is to provide methods and agents for radiation treatment of tissue that help provide more uniform treatment of desired volume of tissue.
  • the present invention is directed to a method for treating a selected volume of tissue.
  • the method comprises the steps of distributing a radiosensitizer within the volume of tissue; and distributing a plurality of ionizing radiation sources within the volume of tissue with each radiation source producing a radiation treatment zone.
  • the radiation sources are distributed within the volume of tissue such that the treatment zones from the plurality of radiation sources are generally distributed throughout the volume of tissue and substantially all of the tissue in the selected volume is within at least one treatment zone.
  • the radiosensitizer and/or the radiation sources are substantially uniformly distributed within the selected volume to afford a more uniform treatment to the tissue within the selected volume.
  • each of the treatment zones may overlap at least one other treatment zone to better assure effective treatment of the tissue in the selected volume.
  • the distributing of a radiosensitizer and the distributing of ionizing radiation sources may be carried out sequentially or simultaneously, by injecting them together, directly into or into proximity to the selected volume of tissue or, in another aspect of the present invention, the distributing of a radiosensitizer and the distributing of ionizing radiation sources may be carried out by sequentially administering the radiosensitizer and the ionizing radiation sources.
  • the treatment zones of the radiation source preferably do not extend substantially beyond the selected volume of tissue.
  • the present invention in accordance with another aspect, is also directed to an agent for treatment of tissue.
  • the agent comprises a radiosensitizer component and an ionizing radiation source component, with the radio sensitizer component and radiation source component being combined to define an injectable treatment agent.
  • the agent may be of any suitable form, but in preferred aspects of the present invention is a liquid or gel.
  • the radio sensitizer and radiation source may be conjugated to define an injectable agent.
  • FIG. 1 a illustrates an example of shielding of the interior and distal portions of a treatment region using prior treatment methods
  • Fig. lb illustrates an example of shielding of the distal portions of a treatment region using an internal source with prior treatment methods
  • Fig. 2a illustrates the effect of a single tumor-dispersible radioactive material in conjunction with a tumor-specific radiosensitizer in a desired treatment volume
  • Fig. 2b illustrates a preferred embodiment of the present invention wherein multiple entities of tumor-dispersible radioactive material are present in the treatment volume of Fig. 2a;
  • Fig. 3a illustrates the linkage of a radiosensitizer moiety and a radioactive moiety to produce a sensitizer-radioconjugate agent, in accordance with an embodiment of the present invention
  • Fig. 3b illustrates a conjugate radiosensitizer moiety attached to a targeting moiety to produce a sensitizer conjugate, and a conjugate radioactive moiety attached to a targeting moiety to produce a radioconjugate agent, in accordance with an embodiment of the present invention
  • Fig. 3c illustrates a radiosensitizer moiety and a radioactive moiety in a delivery vehicle, in accordance with an embodiment of the present invention.
  • Figures 1 a and 1 b illustrate radiation shielding or blocking problems in the prior art.
  • Figure la shows an example of shieldinglO of interior and distal portions of a treatment volume.
  • a radiopaque sensitizer 16 has been distributed throughout the treatment volume 18, such as a cancerous or malignant tumor.
  • the sensitizer closest (20) to the external source 14 substantially absorbs a major portion of the radiation 12 before it can reach sensitizer located distal (22) to the external source.
  • the interior and distal portions of the treatment volume 18 are shielded from the radiation 12, and the efficiency of activation of the distal sensitizer 22, located beyond a certain radiation penetration distance 24, is severely reduced.
  • This self-shielding yields an uneven treatment, where most or all activation occurs in a sub-volume 26 which is primarily confined to that portion of the treatment volume 18 proximal to the source 14 (i.e., at a source-target separation within the radiation penetration distance 24). Even with delivery along multiple paths, such shielding occurs at interior portions of the treatment volume, reducing efficacy of the overall treatment regimen.
  • shielding 30 is shown in Fig. lb, where a contained, internal source is used, such as for example in brachytherapy.
  • a radiopaque sensitizer 16 is distributed in a substantially uniform fashion throughout the treatment volume 18. Shielding of distal portions of a treatment volume 18 occurs when radiation 12 is applied using an internal source 32.
  • the sensitizer present proximal to the internal source 34 substantially absorbs a major portion of the radiation 12 before it can reach sensitizer present distal to the internal source 36, thereby shielding and reducing efficiency of activation of such distal sensitizer 36 located beyond a certain effective radiation penetration distance 24.
  • This self-shielding yields an uneven treatment, where most or all activation occurs in a sub-volume 38 which is primarily confined to that portion of the treatment volume 18 proximal to the source 32 (i.e., at a source-target separation within the radiation effective penetration distance 24).
  • a method for more uniform radiation treatment of a selected volume of tissue such as a malignant mass or tumor.
  • the method of the present invention in general, includes distributing a radiosensitizer 44 within the volume 46 of tissue to be treated, and distributing a plurality of ionizing radiation sources 42 within the volume.
  • Each radiation source 42 emits radiation in all directions which has an effective radius, before being unduly shielded, blocked, or attenuated by the sensitizer 44, tissue or other material in the tissue, to define a treatment zone 56 within which the radiation provides the desired dose enhancement effect acting in conjunction with the radiosensitizer.
  • the radiation sources are distributed throughout the tissue volume so that substantially all of the tissue in the treatment volume lies within one or more treatment zones.
  • the radiosensitizer and radiation sources are distributed substantially uniformly throughout the selected volume of tissue to better provide generally uniform and effective radioactive therapy to the selected tissue volume.
  • multiple entities of tumor- dispersible radioactive material 42 in the form of multiple radioactive particles or nanoparticles are located within the treatment volume, as illustrated in Fig. 2b.
  • the tumor- dispersiable radioactive material serves, once distributed, preferably substantially uniformly, throughout the tumor (where such distribution from one or more the primary administrative sites occur via natural dispersion, dilution, or other substantially physician- passive distribution mechanisms), as a uniformly dispersed source that produces a substantially uniform radiation throughout the tumor volume. Further, use of such distribution mechanisms delivers minimal effective radiation dose to healthy tissues outside the treatment volume. Such uniform radiation results in a more uniform activation of said radiosensitizers throughout the tumor volume (owing between radiation source and target, namely tumor-dispersible radioactive material and radiosensitizer as discussed infra), and thereby yields a more simple and effective means for delivering a therapeutic dose of radiation therapy to the entire tumor.
  • tumor-specific radiosensitizer 44 is substantially present only within the desired treatment volume 46 as explained supra, the existence of a portion 66 of any radiation interaction volume 56 extending beyond the desired treatment volume 46 will not produce significant collateral damage in such irradiated adjacent volumes 68. Also described supra, such delivery of multiple entities of tumor-dispersible radioactive material 42 can be easily effected through intratumorla injection of a solution of such material or other similar administrative techniques, such as proximal venous or lymphatic injection.
  • the treatment volume or selected volume of tissue may be any particular tissue that is selected for treatment.
  • the tissue to be treated will be tissue in which proliferative cell growth is occurring and which can be treated by ionizing radiation.
  • cell proliferation may be benign, it is anticipated that the present invention will find greater application in treating malignant tissue in the form of a tumor, such as for example a cancerous tumor, or other malignancy, or a mass of diseased tissue, such as a cyst, polyp or abscess.
  • the present invention is not limited to the specific radiosensitizer employed.
  • radiosensitizers include the various radiodense halogenated xanthenes and their derivatives, such as Rose Bengal and its various derivatives, Pholixine B and its various derivatives, Erythrosin B and its various derivatives, Eosin Y and its various derivatives, along with various other highly brominated or iodinated halogenated xanthenes and their various derivatives, such as 4,5,6,7-Tetrabromoerythrosin; various x-ray contrast agents, such as OmnipaqueTM (iohexol), OmniscanTM (gadodiamide), WIN 8883 (diatrizoic acid), and iodamide, and lipiodol, along with those agents containing various radiodense elements or moieties, such as iodine, bromine, chlorine, barium, bismuth, boron, gold, silver, platinum, iron, gadolinium, dysprosium, and tantalum;
  • these radiosensitizers can be introduced into the treatment volume by systemic administration, such as intravenous administration, direct injection, or similar conventional techniques. More preferably, such administration includes direct injection or other administrative techniques into or proximal to the desired treatment volume. Use of such administrative techniques with various radiosensitizers, such as those described above can lead to a localized retention of a therapeutically useful level of such radiosensitizers within the desired treatment volume for a period of several hours to several weeks. As a result, the radiosensitizer becomes substantially uniformly distributed throughout the desired treatment volume, through dispersion, dissolution, or other passive equilibration or concentration processes, including preferential uptake.
  • the method of the present invention further includes the step of distributing a plurality of ionizing radiation sources.
  • the present invention is not limited to the number of ionizing radiation sources, but contemplates the use of more than one ionizing or other o high energy radiation sources.
  • An example of such a source, for use in the present invention is a tumor-dispensible radioactive material, as discussed intra.
  • the present invention is not limited to such radioactive material, as tumor dispersiable radioactive material and radioactive moieties mentioned, such as those discussed infra, and other similar materials, can also be used.
  • the one or more sources is located within the treatment volume. Further, as explained below, it is preferred that a plurality of such radiation sources be distributed within the treatment volume.
  • Figure 2a illustrates the effect 40 of a single radiation source, for example a tumor-dispersiable radioactive material 42, located in a treatment volume wherein a quantity of tumor-specific radiosensitizer 44, such as for example that described supra, is substantially uniformly distributed and contained within the treatment volume 46.
  • Tumor-dispersiable means readily dispersiable within a treatment volume, for example a tumor.
  • a tumor dispersiable radioactive material may be a liquid, gel or other dispersiable form or formulation of a radioactive material made up of a fine particulate or colloidal suspension, dissolved or otherwise solubilized or dispersible in form, of a radioactive material that is stable upon injection, or other administrative technique, into a patient's body.
  • the tumor-dispersiable radioactive material is injected, or other administrated by commonly known methods such as intravenous drip or injection, directly into or proximal to a treatment volume, such as a cancerous tumor.
  • tumor-dispersible radioactive materials include radioisotopes that are attached to or encompassed in organic or inorganic microspheres, micelles, or nanoparticles, or are solubilized using chelates or other organic or inorganic agents. It is well known in that art that such materials, when locally administered into or proximal to diseased tissue, such as a cancerous tumor, can exhibit prolonged retention in said tissue, with biological half-lives ranging from several hours to several weeks.
  • Isotropic radiation 48 emitted by the tumor-dispersiable radioactive material 42 activates a portion of the tumor-specific radiosensitizer 50 that is present within a radiation interaction volume 52 (defined by the penetration distance of such radiation 48 within the tumor/radiosensitizer environment) to produce a localized treatment zone 56. Since any radiation 58 that reaches beyond this localized treatment zone 56 is of insufficient intensity to substantially activate radiosensitizer 60 present outside this localized treatment zone 56, the localized treatment zone 56 is surrounded by a non- therapeutic or non-treated volume 62. Thus, in most cases a single entity of tumor- dispersible radioactive material 42, such as a single radioactive particle or nanoparticle, will be insufficient for complete treatment of the entire desired treatment volume 46.
  • the present invention overcomes this apparent short coming through the use of a plurality of sources within the treatment volume.
  • radiation sources are distributed substantially uniform within the volume of tissue such that the treatment zones for each source are contiguous or overlap, and there are sufficient number of radiation sources so that substantially all of the tissue volume to be treated lies within at least one treatment zone.
  • the radioactive sources also may be distributed within the treatment volume so that the areas of tissue to be treated that reside in the outer reaches of a treatment zone, such as for example, the outer third of the zone, lie within two or more zones to better assure sufficient radiation treatment. In other words, the treatment zones overlap, and some of the tissue volume lies within two or more zones.
  • the radiosensitizer and tumor-dispersible radioactive material are administered to the patient (directly into or proximal to the tumor or other diseased tissue) by ( 1 ) simple injection or other similar delivery technique of a mixed solution of each, or (2) by sequential administration of each (by simple injection or other similar delivery technique). It is further preferred that such administration be performed using a concentration and volume of the radiosensitizer material selected so as to deliver a dose of more than about 1 nanogram radiosensitizer per kilogram diseased tissue (i.e. >ng/kg) but not more than about 10 gram radiosensitizer per kilogram diseased tissue (i.e.
  • ⁇ 10 g/kg such does being selected so as to produce sufficient localized cytotoxicity in said diseased tissue upon irradiation while avoiding induction of non-specific or systemic toxicity or cytotoxicity from the material alone.
  • administration be performed using a concentration and volume of said radioactive material selected so as to deliver a dose to the tissue within a selected volume of more than about 1 milliGray (i.e. > 1 mGy) but not more than about 1000 Gray (i.e. ⁇ 1000 Gy), with a preferred does in the range from about 0.1 Gy to 100 Gy.
  • the dose is selected so as to produce sufficient localized activation of the radiosensitizer while avoiding induction of non-specific or systemic damage from the radioactive material alone.
  • Concerted delivery of materials may be facilitated by utilizing radiosensitizer and tumor-dispersible radioactive materials having similar dimensional and chemical or biological properties (such as hydrophilicity or lipophilicity), since dispersion of such agents will tend to occur in a similar fashion, resulting in substantially uniform distribution of both radiosensitizer and tumor-dispersible radioactive material at the treatment site.
  • radiosensitizers and radioactive materials that are capable of quick decay or natural clearance from the body are utilized, the complexity of follow- up procedures are also greatly reduced, since upon destruction of the tumor such agents will either decompose or be otherwise cleared from the tumor site and patient by natural processes. Hence, unlike brachytherapy, no residual material will be left at the site (such as brachytherapy needles that might require surgical removal).
  • the agent includes a radiosensitizer component and an ionizing radiation source component combined to form an injectable treatment agent.
  • Figure 3a illustrates a linkage of one or more radiosensitizer moiety 70. such as for example one of the radiosensitizers discussed supra, and one or more radioactive moiety 72. using for example covalent attachment or other chemical or physical mechanisms 74, to produce a sensitizer-radioconjugate agent 76.
  • Such covalent linkage may consist, for example, of a covalent bond between a ligand-complexed radioactive moiety and an organic radiosensitizer.
  • Such a conjugate agent 76 assures that radiosensitizer and radiation source are delivered together in the proper stoichiometry, in a manner similar to that discussed above.
  • multiple entities of such conjugate agents are administered to the treatment volume or region, as discussed above.
  • radioactive moieties that can be used in the present invention include various radioisotopes and chemical derivatives of such radioisotopes, including those of aluminum, americium, cobalt, copper, gallium, gold, indium, iodine, iridium, manganese, phosphorus, radium, rhenium, rhodium, ruthenium, sulfur, technetium, thallium, yttrium, and of other radioactive elements, compounds, or materials capable of producing ⁇ -, ⁇ -, ⁇ -, x-ray, or other high energy or ionizing radiation.
  • An alternate embodiment, illustrated in Figure 3b, uses (a) a radiosensitizer moiety 70, such as for example those discussed supra, attached to a chemical or biological targeting moiety 78 to produce a sensitizer conjugate 80, and (b) a radioactive moiety 72, such as for example those discussed above, attached to a similar chemical or biological targeting moiety 78 to produce a radioconjugate 82. Delivery of the sensitizer conjugate
  • a further alternate embodiment of the present invention includes one or more radiosensitizer moiety 70 and one or more radioactive moiety 72, such as for example the moieties discussed above, in a delivery vehicle 82.
  • delivery vehicles include a micelle, liposome, or nanoparticle, formed using methods commonly available in the art.
  • Such an encapsulated agent 84 can be designed to deliver its contents 70 and 72 to a specific treatment area or cellular structure, such as cell membranes, so as to further augment the efficacy of dose enhancement, as described in U.S. application no. 09/216,787 which is incorporated herein by reference.
  • chemical or biological targeting moieties include DNA, RNA, amino acids, proteins, antibodies, ligands, haptens, carbohydrate receptors or complexing agents, protein receptors or complexing agents, lipid receptors or complexing agents, chelators, encapsulating vehicles, nanoparticles, short-or-long-chain aliphatic or aromatic hydrocarbons, including those containing aldehydes, ketones, alcohols, esters, amides, amines, nitriles, azides, or other hydrophilic or hydrophobic moieties.
  • an efficient radiosensitizer such as for example Rose Bengal
  • a tumor- dispersible radioactive material such as for example rhenium-188 (' 88 Re)
  • an injectable mixture into diseased tissue, such as a cancerous tumor.
  • l 88 Re is a generator-produced gamma emitter (155 keV) that is readily packaged in nanoparticulate form, with a biological half-life of approximately 1 week.
  • gamma energy is readily absorbed by iodine atoms contained in Rose Bengal, which transform such energy to a therapeutically active form (such as Auger electrons and other lower-energy secondary emissions) that is capable of facile tumor destruction.
  • Radiosensitizer agent present in the cytoplasm will be suitably disposed so as to facilitate damage to cellular genetic material and other cellular structures as a consequence of similar secondary emission mechanisms. Further, because the radiosensitizer and radioisotope is rapidly cleared from the body, the complexity of any necessary follow-up procedure is minimal, since the body will tend to eliminate residual radiosensitizer, radioactive material, and destroyed tumor products via natural means.

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Abstract

L'invention concerne un procédé pour traiter un volume sélectionné de tissu qui consiste à distribuer un agent de sensibilisation aux rayonnements à l'intérieur du volume de tissu pour produire des zones de traitement qui sont généralement réparties de manière uniforme à travers le volume du tissu. L'invention concerne aussi un agent pour traiter ce tissu, l'agent comprenant un agent de sensibilisation aux rayonnements et une source de rayonnement ionisant, utilisés conjointement pour définir un agent de traitement injectable.
PCT/US2000/001815 1999-01-25 2000-01-25 Procedes et agents destines a une radiotherapie amelioree WO2000043045A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
EP00908366A EP1146912A4 (fr) 1999-01-25 2000-01-25 Procedes et agents destines a une radiotherapie amelioree
AU29725/00A AU2972500A (en) 1999-01-25 2000-01-25 Method for improved radiation therapy
KR1020017009307A KR20020001723A (ko) 1999-01-25 2000-01-25 방사선 치료방법
JP2000594498A JP2002535291A (ja) 1999-01-25 2000-01-25 改善された放射線治療のための方法
BR0007692-9A BR0007692A (pt) 1999-01-25 2000-01-25 Processo para tratar um volume selecionado de tecido, e, agente para tratamento de tecido
IL14442800A IL144428A0 (en) 1999-01-25 2000-01-25 Method for improved radiation theraphy
CA002358989A CA2358989A1 (fr) 1999-01-25 2000-01-25 Procedes et agents destines a une radiotherapie amelioree

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US23624799A 1999-01-25 1999-01-25
US09/236,247 1999-01-25

Publications (1)

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WO2000043045A1 true WO2000043045A1 (fr) 2000-07-27

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EP (1) EP1146912A4 (fr)
JP (1) JP2002535291A (fr)
KR (1) KR20020001723A (fr)
CN (1) CN1337886A (fr)
AR (1) AR022404A1 (fr)
AU (1) AU2972500A (fr)
BR (1) BR0007692A (fr)
CA (1) CA2358989A1 (fr)
IL (1) IL144428A0 (fr)
WO (1) WO2000043045A1 (fr)

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WO2001008660A3 (fr) * 1999-08-02 2001-11-22 Univ Michigan Effecteurs radiatifs exempts de fibres cibles
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WO2002068000A3 (fr) * 2000-11-16 2003-10-23 Microspherix Llc Grain de brachytherapie imageable polymere
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WO2011017456A2 (fr) * 2009-08-04 2011-02-10 Northwestern University Délivrance localisée de nanoparticules pour applications thérapeutiques et diagnostiques
WO2011109387A1 (fr) * 2010-03-01 2011-09-09 Intraop Medical Corporation Radiothérapie combinée avec des sensibilisateurs de cellules hypoxiques
US8269197B2 (en) 2009-07-22 2012-09-18 Intraop Medical Corporation Method and system for electron beam applications
US8329141B2 (en) 2004-09-03 2012-12-11 Board Of Regents, The University Of Texas System Locoregional internal radionuclide ablation of abnormal tissues
US8470296B2 (en) 1998-12-21 2013-06-25 Provectus Pharmatech, Inc. Intracorporeal medicaments for high energy phototherapeutic treatment of disease
US8999947B2 (en) 2005-06-14 2015-04-07 Northwestern University Nucleic acid functionalized nanoparticles for therapeutic applications
US9139827B2 (en) 2008-11-24 2015-09-22 Northwestern University Polyvalent RNA-nanoparticle compositions
US9376690B2 (en) 2009-10-30 2016-06-28 Northwestern University Templated nanoconjugates
WO2016148969A1 (fr) * 2015-03-13 2016-09-22 The Board Of Regents Of The University Of Texas System Kub5/hera comme déterminant de la sensibilité à la lésion de l'adn
US9506056B2 (en) 2006-06-08 2016-11-29 Northwestern University Nucleic acid functionalized nanoparticles for therapeutic applications
US9889209B2 (en) 2011-09-14 2018-02-13 Northwestern University Nanoconjugates able to cross the blood-brain barrier
US9890427B2 (en) 2007-02-09 2018-02-13 Northwestern University Particles for detecting intracellular targets
US10098958B2 (en) 2009-01-08 2018-10-16 Northwestern University Delivery of oligonucleotide functionalized nanoparticles
US10837018B2 (en) 2013-07-25 2020-11-17 Exicure, Inc. Spherical nucleic acid-based constructs as immunostimulatory agents for prophylactic and therapeutic use
US11213593B2 (en) 2014-11-21 2022-01-04 Northwestern University Sequence-specific cellular uptake of spherical nucleic acid nanoparticle conjugates
US11433131B2 (en) 2017-05-11 2022-09-06 Northwestern University Adoptive cell therapy using spherical nucleic acids (SNAs)

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BR0007692A (pt) 2001-11-06
AR022404A1 (es) 2002-09-04
CN1337886A (zh) 2002-02-27
AU2972500A (en) 2000-08-07
JP2002535291A (ja) 2002-10-22
EP1146912A1 (fr) 2001-10-24
KR20020001723A (ko) 2002-01-09
CA2358989A1 (fr) 2000-07-27
EP1146912A4 (fr) 2003-05-21
IL144428A0 (en) 2002-05-23

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