WO2009018383A1 - Systèmes et procédés d'accentuation de l'administration d'une thérapie par rayonnement de particules - Google Patents

Systèmes et procédés d'accentuation de l'administration d'une thérapie par rayonnement de particules Download PDF

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Publication number
WO2009018383A1
WO2009018383A1 PCT/US2008/071653 US2008071653W WO2009018383A1 WO 2009018383 A1 WO2009018383 A1 WO 2009018383A1 US 2008071653 W US2008071653 W US 2008071653W WO 2009018383 A1 WO2009018383 A1 WO 2009018383A1
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WIPO (PCT)
Prior art keywords
target tissue
agent
particle radiation
vivo
dose
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PCT/US2008/071653
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English (en)
Inventor
Reinhard Schulte
Gilmer Valdes-Diaz
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Loma Linda University Medical Center
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Publication date
Application filed by Loma Linda University Medical Center filed Critical Loma Linda University Medical Center
Priority to CA2695985A priority Critical patent/CA2695985C/fr
Priority to EP08826721A priority patent/EP2173430A4/fr
Priority to JP2010520162A priority patent/JP5331116B2/ja
Priority to AU2008282215A priority patent/AU2008282215B2/en
Publication of WO2009018383A1 publication Critical patent/WO2009018383A1/fr
Priority to US12/694,642 priority patent/US8784846B2/en
Priority to US14/336,924 priority patent/US20150050349A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
    • A61N2005/1085—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy characterised by the type of particles applied to the patient
    • A61N2005/1087—Ions; Protons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
    • A61N2005/1092—Details
    • A61N2005/1098—Enhancing the effect of the particle by an injected agent or implanted device

Definitions

  • the invention relates to the field of medical therapy and to systems and methods of enhancing delivery of therapeutic agents to targeted tissue via particle radiation bombardment and/or systems and methods for guiding delivery of particle radiation via post treatment imaging of the target tissue.
  • Cancer remains one of the more challenging diseases to develop effective therapies for.
  • One fundamental difficulty is the ability to effectively deliver cancer drug activity to the tumor while avoiding activity of the cancer drug on non-cancerous tissue.
  • the ideal therapeutic drug would selectively reach the desired tumors target without negatively affecting non-cancerous tissue.
  • existing regimens of chemotherapy and other targeted cancer therapies fall short of this ideal. For example, in some instances only between one to ten parts per one hundred thousand of intravenously administered monoclonal antibodies targeting cancer cells reach their intended targets.
  • a first approach is to increase the targeting selectivity of cancer drugs.
  • a second is to attempt to overcome biological barriers that inhibit cancer drugs from effectively reaching their intended targets, e.g. tumors.
  • Targeting mechanisms can be generally divided into two main groups: passive and active mechanisms.
  • passive targeting mechanism is referred to as enhanced permeation and retention (EPR).
  • EPR exploits the physiological phenomenon that capillaries at the site of infection, inflammation and solid tumors often have a compromised barrier function, facilitating extravasation and protracted lodging of drug carriers.
  • therapeutic agents with prolonged circulation times would be expected to be preferentially targeted to the tumor area with respect to non-cancerous tissue.
  • the carriers can be taken up by the reticuloendothelial system (RES) rather than the tumor tissue, resulting in relatively short circulation time.
  • RES reticuloendothelial system
  • hydrophilic compounds such as polyethylene glycol (PEG) can reduce RES sequestration and significantly extend circulatory half life.
  • Active targeting mechanisms can include the molecular targeting of drug carriers by combining or conjugating the active recognition aspects of tumor specific molecules to the surfaces of drug carrier particles.
  • tumor specific antigens have been used to direct nano particles to angiogenic endothelium, for example to target ⁇ v ⁇ 3 integrins perfluorocarbon nano emulsions for MRI imaging of neovasculature and anti- angiogenesis therapy for melanoma and colon adenocarcinoma.
  • Another type of active, site directed drug delivery mechanism uses some form of external energy to direct the delivery of drug carriers.
  • directed energies that have been used experimentally to control the pharmacokinetics and activation of cytotoxic drugs include magnetic fields, photonic radiation, heat, and ultrasound.
  • a suitable magnetic field for example, by applying a suitable magnetic field to specific regions of tissue, capsules loaded with magnetic materials can be driven preferentially to a tissue area.
  • site directed targeting is induction of adhesion proteins in tumor microvasculature by ionizing radiation which is then used as antigenic targets for site specific drug delivery to tumor blood vessels.
  • Other examples include the use of focused ultrasound to burst lipid encapsulated microbubbles and localized thermal ablation of cancer regions with near infrared photonic radiation.
  • Embodiments are based at least in part on a realization of the advantages of accelerated particle radiation to enhance the regional specificity of therapy delivery.
  • Protons and heavier positive ions exhibit the physical characteristics of delivering a significant portion of their initial energy at a predictable depth of penetration in the target tissue. This physical characteristic is referred to as the Bragg peak and differs significantly from the generally exponentially decreasing energy transfer profile exhibited by photonic radiation.
  • the associated Bragg peak can be selected to coincide with a desired depth of penetration at the desired target location, such as a cancerous tumor.
  • a spread out Bragg peak can be provided to substantially coincide with the extent of the target tissue.
  • particle radiation By significantly reducing the amount of energy transfer to patient tissue between the surface and the target location as compared to photonic radiation, particle radiation, such as proton beam therapy, offers the advantage of providing an effective dose at the target site with significantly reduced undesired transfer of energy to presumably healthy tissue upstream of the target tissue. As a significant portion of the initial energy of proton radiation is deposited at the Bragg peak, particle radiation also offers the advantage of a significant reduction in downstream delivery of energy beyond the target tissue. Proton therapy is also well suited for a fractionated delivery regimen where a smaller fraction of a total dose can be delivered along a plurality of different spatial vectors to intersect at the desired target tissue. This aspect further reduces undesired transfer of radiation energy to upstream and downstream healthy tissue as the approach path for each therapy fraction can differ such that any given portion of healthy tissue sees at most a fraction of the total delivered therapeutic energy.
  • Embodiments are also based on a new understanding of the ability of particle radiation, such as accelerated proton and/or other heavy positive ion radiation, to induce the release of various types of treatment agents from carrier vehicles.
  • particle radiation such as accelerated proton and/or other heavy positive ion radiation
  • cancer drugs and/or other therapeutic agents can be combined with a nano scale structure or particle in such a way that they can be durably entrained within living tissue until they arrive at a desired target location.
  • Appropriate bombardment with particle radiation can then induce the release and/or activation of the therapeutic agents in a concentrated manner at the target location.
  • the previously described spread out Bragg peak can be employed to preferentially localize the activation/release of one or more therapeutic agents within the spread out Bragg peak region.
  • An energy required to activate/release the therapeutic agents can be selected to define a threshold such that undesired activation/release of the agents outside the target tissue area is significantly reduced.
  • Embodiments also employ the particle radiation induced release/activation of imaging enhancement agents and subsequent imaging of the target tissue to verify delivered doses of the radiation.
  • One embodiment includes a method of delivering therapy, the method comprising introducing a quantity of therapeutic agent into a patient and directing a dose of particle radiation at target tissue of the patient so as to preferentially induce action of the therapeutic agent proximal the target tissue with respect to distal the target tissue.
  • Another embodiment includes an in vivo agent delivery vehicle comprising a nanostructure and in vivo agent engaged with the nanostructure such that the in vivo agent can be durably entrained within living tissue and wherein bombardment with a selected dose of particle radiation releases the in vivo agent from the nanostructure.
  • a further embodiment includes a method of image guided radiation therapy, the method comprising introducing a quantity of imaging enhancement agent into a patient, directing a dose of particle radiation at target tissue of the patient so as to preferentially induce action of the imaging enhancement agent proximal the target tissue with respect to distal the target tissue, imaging the target tissue, and verifying the dose of particle radiation delivered to the target tissue by analyzing a degree of enhancement of the target tissue image as compared to an image of non-target tissue adjacent the target tissue.
  • Figure 1 is a flowchart of embodiments of a method of enhancing delivery of therapeutic agents with particle radiation.
  • Figure 2 is a schematic section view of embodiments of a delivery carrier/vehicle for conveying an in vivo agent to a target site.
  • Figure 3 is a schematic section view of additional embodiments of a delivery carrier/vehicle for conveying an in vivo agent to a target site.
  • Figure 4 is a flowchart of embodiments of a method of enhancing imaging with particle radiation to facilitate more accurate delivery of therapy.
  • Figures 5 A and 5B are schematic illustrations of embodiments of a particle therapy delivery system.
  • FIG. 1 is a flowchart illustrating methods 100 of enhancing delivery of therapeutic agents with particle radiation.
  • the method 100 begins in a start block 102.
  • the start block 102 can include the preparatory analysis and diagnosis of a patient's condition by an attending clinician and determining an appropriate therapy regimen.
  • the block 102 can include selecting an appropriate cancer drug and an appropriate fractionated proton therapy prescription.
  • the particular appropriate drugs, doses, radiation energies, approach vectors, and the like can vary widely depending on the particular disease state and patient condition, however, the particular prescription for a given patient and condition will be readily determined by one of ordinary skill.
  • a determined quantity of therapeutic agent is introduced to the patient.
  • the particular method of introduction of the therapeutic agent can depend on the particular type of agent to be introduced and the location of the target tissue, however in various implementations can include one or more of intravenous delivery, transdermal delivery, oral administration, a nebulizer, and the like.
  • introduction of the therapeutic agent in block 104 can comprise introduction of an agent delivery vehicle 200 described and illustrated in greater detail below with respect to Figures 2 and 3.
  • an agent delivery vehicle 200 comprises a nano scale structure or particle.
  • a nano scale particle structure in some embodiments comprises structures or particles having a major dimension x less than approximately 100 nm.
  • a nano scale delivery vehicle 200 preferably has a mean major dimension of approximately 50 nm. It will be understood that the particular dimensions of individual delivery vehicles 200 can vary and the preferred mean size can vary, depending on the composition of the delivery vehicle and any therapeutic agent(s) combined therewith. It will thus be understood that the values and ranges described herein are simply exemplary and other sizes and ranges are possible.
  • a block 204 is implemented to register the patient in at least a first treatment pose.
  • Registering the patient refers to a process and system for orienting and maintaining a patient at a given translational and rotational orientation with respect to a particle radiation delivery assembly such that a given treatment fraction arrives at the target tissue along a desired spatial vector.
  • the Bragg peak generally occurs after the particle radiation has passed through a given depth of patient tissue and thus it will generally be indicated that particle radiation be directed not only at a selected target iso center but also along a selected approach vector such that the Bragg peak of the radiation beam coincides with the target tissue rather than upstream or downstream therefrom. Additional detailed description and illustration of the registration process of block 106 will be provided below with a more detailed description of an exemplary suitable radiation therapy system 400 as illustrated and described below in greater detail with respect to Figures 5A and 5B.
  • a block 110 follows wherein one or more particle radiation treatment fractions are directed towards the target tissue.
  • the delivered dose is selected to at least partially activate and/or release the therapeutic agent in and/or adjacent to the target tissue.
  • Therapeutic particle radiation can be characterized according to the amount of energy transferred per unit path length of the particle that does the energy transfer.
  • Heavy ion accelerated particles generally exhibit what is considered a high linear energy transfer (LET) of greater than approximately lOkeV/ ⁇ m to more than 100,000keV/ ⁇ m.
  • Low LET accelerated particles are generally characterized by an LET not exceeding a few keV/ ⁇ m. Accelerated protons are generally between low LET photons and relatively high LET heavy ions.
  • protons exhibit the characteristic that the entrance or plateau region of the beam exhibits a low LET and the LET rises up to about 80keV/ ⁇ m in the Bragg peak.
  • some embodiments employ a spread out Bragg peak such that the LET is a mixture and covers a range from low to high LET values.
  • particles having a higher LET will exhibit a larger effect on nano scale particles and structures due to the more concentrated release of energy over short distances.
  • delivery of particle radiation need not be fractionated and only a single dose of particle radiation can be delivered at a given treatment session.
  • a single non-fractionated treatment dose of approximately 20 to 25 Gray (Gy) would comprise an appropriate radiation dose.
  • a treatment fraction of a smaller dose, such as approximately 2 Gy can be delivered per treatment fraction.
  • the patient can be repositioned and re-registered and a further treatment fraction administered via iterations of blocks 106 and 110.
  • the patient need not be moved with respect to the particle radiation delivery assembly for each fraction and that multiple fractions can be delivered along a given pose.
  • FIGS 2 and 3 illustrate in greater detail a schematic sectional illustration of embodiments of an agent delivery vehicle 200.
  • the delivery vehicle 200 comprises a nano structure 202.
  • the nano structure 202 is generally a nano scale body and can be substantially solid or can exhibit one or more internal pores or voids.
  • the nano structure 202 preferably comprises a biocompatible material.
  • the nano structure 202 also preferably comprises a relatively high Z material. Relatively high Z materials exhibit the desirable characteristic of favorable interaction with the particle radiation bombardment.
  • the nano structure 202 comprises gold. Gold exhibits a useful release of secondary low energy electrons upon bombardment with a proton beam to facilitate release and activation of components engaged with the gold nano structure.
  • the nano structure 202 comprises platinum, however other elemental compositions and compounds for the nano structure 202 are possible.
  • the delivery vehicle 200 also comprises one or more in vivo agents engaged with the nano structure such that they can be entrained to the target tissue.
  • the agent 204 comprises a therapeutic agent, such as one or more cancer drugs.
  • the agent comprises a contrast media to enhance an image of imaged tissue where the contrast media is released/activated.
  • the agent comprises one or more radionuclides. The radionuclides can be selected to emit positrons when activated/released to enhance an image of imaged tissue containing the radionuclides.
  • the agent 204 can comprise one or more antibodies. For example, antibodies can be selected for particular tumor antigens.
  • the delivery vehicle 200 further comprises an outer coating 206.
  • the outer coating 206 is selected to enhance biocompatibility and preferential action of the delivery vehicle 200 at the target tissue location.
  • the outer layer 206 acts as a protective shell for the delivery vehicle 200 and the delivery vehicle 200 exhibits a multi-layer or nested core/shell configuration.
  • the delivery vehicle 200 can be manufactured by the layer by layer apposition of oppositely charged macro molecules on colloidal templates.
  • the delivery vehicles 200 can further comprise additional layered materials to provide a desired thickness, permeability, biostability and biocompatibility including but not limited to synthetic poly electrolytes, natural polymers such as polysaccharides, polypeptides and/or polynucleotides, lipids, and/or multi-valent imaging agents.
  • the delivery vehicle 200 is formed at least in part with covalent bonding.
  • the incident particle radiation is ionizing with sufficient energy to break the covalent bonding either directly or via indirect action of radiation induced radicals.
  • the outer layer 206 is selected of organic and/or inorganic material such that bombardment with particle radiation degrades the outer layer 206 thereby exposing and releasing the agent layer 204.
  • the delivery vehicle 200 can employ biological feedback processes in combination with particle radiation bombardment to facilitate degradation of the outer layer 206 or otherwise release/activate the agent 204 from the nano structure 202.
  • the outer layer 206 comprises a hydrogel and one or more selected enzymes. Upon bombardment with particle radiation, at least a portion of the enzymes are released from the hydrogel in the outer shell 206. The release of enzymes from the outer shell 206 can involve a small number of enzyme molecules, including only a single enzyme molecule.
  • the released enzyme molecules react with target molecules in the in vivo environment, for example glucose.
  • the enzymes can react with the cellular environment to produce a change in one or more characteristics, preferably in a generally localized manner.
  • the enzymes can react with the cellular environment to produce an acidic reaction product, thereby lowering the local pH.
  • lowering the local pH will induce release of further enzyme molecules from the outer layer 206 thereby leading to a feedback or chain reaction facilitating more rapid release/activation of the payload or agent 204 from the delivery vehicle 200.
  • feedback or trigger mechanisms provided by the outer layer 206 in combination with particle radiation bombardment can specifically target tumor tissue.
  • bombardment with particle radiation up regulates production of certain proteins in cancerous tumors and/or tumor vasculature.
  • Enzymes in the outer layer 206 can be selected to be substrate specific for the up regulated proteins and can catalyze a reaction leading to a lower localized pH.
  • Such embodiments are preferred as the effects of the localized release of the agents 204 is more specifically selective for the tumor cells with respect to normal healthy cells adjacent the tumor cells in the target tissue.
  • Figure 3 illustrates a schematic section view of an alternative structure of delivery vehicle 200.
  • Certain structures, compositions, and features of the delivery vehicle as illustrated with respect to Figure 3 share substantial similarities with the embodiments of delivery vehicle 200 previously illustrated and described with respect to Figure 2 and such similarities will not be repeated for brevity and ease of understanding.
  • the primary difference in the embodiments of delivery vehicle 200 in Figure 2 with respect to Figure 3 is that the embodiments of Figure 3 substantially enclose the agent 204 in an interior of the nano structure 202 rather than about an exterior as in Figure 2.
  • the nano structure 202 comprises a porous structure such that the agent 204 resides within one or more pores or voids of the nano structure 202.
  • the nano structure 202 comprises a shell that can be either solid or can comprise a mesh form. Upon bombardment with a selected dose of particle radiation, such a hollow shell or mesh configuration of nano structure opens or ruptures to release the agent 204.
  • delivery vehicle 200 can have an irregular form.
  • the delivery vehicles 200 can be generally spherical, however a wide variety of other regular and irregular shapes are possible. It will further be understood that in many implementations, a large plurality of delivery vehicles 200 will be introduced into the patient and thus will in such embodiments exhibit a range of sizes and shapes. However, as previously noted in some embodiments a major dimension x of approximately 100 nm or less is generally preferred and in some embodiments a mean major dimension of approximately 50 nm is more preferred. A size of approximately 50 nm is, in at least some implementations, a preferred size for uptake into cells but this is not required to achieve significant advantages and benefits of the various embodiments described herein.
  • a plurality of agents 204 can be combined in the delivery vehicles 200.
  • the delivery vehicles 200 can be manufactured to offer combined drug treatment therapies.
  • radiosensitizing drugs such as 5-Fluorouracil and Cisplatin can be combined with biologically active drugs such as EGF and PDGF receptor inhibitors.
  • EGF and PDGF receptor inhibitors such as EGF and PDGF receptor inhibitors.
  • the PDGF receptor kinase inhibitor Imatinib can decrease interstitial fluid pressure in tumors, leading to a tumor specific increase in the uptake of concomitantly delivered drugs.
  • Figure 4 illustrates embodiments that can be implemented in combination with or as an alternative to the embodiments previously described with respect to Figure 1.
  • Figure 4 is a flowchart illustrating embodiments of a method for image guided radiation therapy 300 or method 300 for brevity.
  • the method 300 begins in a start block 302 which generally includes diagnosis and determination of an appropriate treatment regimen for the patient in a similar manner to that previously described with respect to the block 102.
  • a determined quantity of imaging enhancement agent is introduced to the patient, in some embodiments via entrainment with the delivery vehicles 200.
  • the agent 204 can comprise one or more therapeutic agents.
  • the agent 204 can comprise in addition to or as an alternative to therapeutic agents, one or more image enhancement agents adapted to facilitate or enhance an image of selected tissue.
  • the agent 204 comprises contrast media which when released or activated increase the effective imaging density of the associated tissue.
  • contrast media comprising the agent 204 can comprise a plurality of small gold nano particles that are released upon bombardment with particle radiation.
  • the agent 204 can comprise one or more positron emitting radionuclides that can be imaged with a combination of PET and CT.
  • the number of incident protons intercepting them will be generally randomly distributed according to a Poisson distribution. If the dose concentration is selected sufficiently small such that only a fraction of nano scale delivery vehicles 200 are intercepted, the number of delivery vehicles affected will increase generally linearly with delivered dose.
  • the method 300 can be implemented in combination with the method 100 previously described.
  • an optional block 104 can be implemented substantially similarly to that previously described with respect to the method 100.
  • a block 306 the patient is registered in at least a first desired treatment pose in a similar manner to that previously described with respect to block 106.
  • a block 310 at least one particle radiation treatment fraction is delivered to the target tissue, again in a similar manner to that previously described with respect to block 110.
  • a block 312 at least one image is obtained of the target tissue and the image can include adjacent non-target tissue.
  • imaging systems and methodologies are available that can be advantageously implemented with embodiments as described herein and the choice of an appropriate imaging system and methodology will be readily apparent to one of ordinary skill.
  • the delivered dose of particle radiation can be verified via analyzing the image data from block 312.
  • contrast media and/or positron emitting radionuclides comprising the agent 204 will be activated/released by the particle radiation provided in block 310 and will provide an enhanced image in block 312 with respect to adjacent tissue where the image enhancement agent 204 was to a significantly lesser degree activated/released.
  • the relative degree of enhancement determined in block 314 provides an independent verification of the dose of particle radiation actually delivered to the target tissue providing a valuable verification function.
  • a radiation treatment regimen can be fractionated and in some implementations a decision is made in a block 316 whether additional treatment fractions are indicated. If so, the patient can be re-registered in an iteration of block 306 and additional treatment fractions delivered in iterations of block 310. If the final treatment fraction has been delivered or in embodiments including non-fractionated treatment delivery, the method 300 would then end.
  • the delivery vehicles 200 can comprise materials selected for direction specifically against tumors.
  • the delivery vehicles 200 can comprise antibodies selected against tumor antigens. Directed release via bombardment with particle radiation of the antibodies adjacent the tumors rather than relying on tumor finding properties of systemically injected antibodies results in more effective targeting of tumors with the antigen seeking antibodies in these embodiments.
  • the agent 204 comprises antibodies associated with one or more photon and/or positron emitting radionuclides. The agent 204 can thus specifically target tumors and provide an enhanced imaging of tumor nodules within organ tissue affected by the tumor.
  • early stage prostate cancer may exhibit a single or small number of microscopic cancer foci within an organ volume that is otherwise generally free of cancer.
  • SPECT imaging with Capromab Pentetide, and In-labeled antibody against prostate specific membrane antigen (PSMA), a glycoprotein that is up regulated and prostate adenocarcinoma can provide highly specific enhanced imaging of the cancer foci and facilitate even more specific targeting of the particle radiation to the cancer foci while reducing targeting as much as possible healthy non-cancerous tissue within the organ volume.
  • PSMA prostate specific membrane antigen
  • FIGS 5A and 5B illustrate schematically first and second orientations of one embodiment of a particle radiation therapy system 400, such as based on the proton therapy system currently in use at Loma Linda University Medical Center in Loma Linda, California and as described in U.S. Patent 4,870,287 of Sept. 26, 1989 which is incorporated herein in its entirety by reference.
  • the radiation therapy system 400 is designed to deliver therapeutic radiation doses to a target region within a patient for treatment of malignancies or other conditions from one or more angles or orientations with respect to the patient.
  • the system 400 includes a gantry 402 which includes a generally hemispherical or frustoconical support frame for attachment and support of other components of the radiation therapy system 400. Additional details on the structure and operation of embodiments of the gantry 402 may be found in U.S. Patent No. 4,917,344 and U.S. Patent No. 5,039,057, both of which are incorporated herein in their entirety by reference.
  • the system 400 also comprises a nozzle 404 which is attached and supported by the gantry 402 such that the gantry 402 and nozzle 404 may revolve relatively precisely about a gantry isocenter 420.
  • the system 400 also comprises a radiation source 406 delivering a radiation beam along a radiation beam axis 440, such as a beam of accelerated protons.
  • the radiation beam passes through and is shaped by an aperture 410 to define a therapeutic beam delivered along a delivery axis 442.
  • the aperture 410 is positioned on the distal end of the nozzle 404 and the aperture 410 may preferably be specifically configured for a patient's particular prescription of therapeutic radiation therapy. In certain applications, multiple apertures 410 are provided for different treatment fractions.
  • the system 400 also comprises one or more imagers 412 which, in this embodiment, are retractable with respect to the gantry 402 between an extended position and a retracted position.
  • the imager 412 in one implementation comprises a commercially available solid-state amorphous silicon x-ray imager which can develop image information such as from incident x-ray radiation that has passed through a patient's body.
  • the retractable aspect of the imager 412 provides the advantage of withdrawing the imager screen from the delivery axis 442 of the radiation source 406 when the imager 412 is not needed thereby providing additional clearance within the gantry 402 enclosure as well as placing the imager 412 out of the path of potentially harmful emissions from the radiation source 406 thereby reducing the need for shielding to be provided to the imager 412.
  • the system 400 also comprises corresponding one or more x-ray sources 430 which selectively emit appropriate x-ray radiation along one or more x-ray source axes 444 so as to pass through interposed patient tissue to generate a radiographic image of the interposed materials via the imager 412.
  • x-ray sources 430 which selectively emit appropriate x-ray radiation along one or more x-ray source axes 444 so as to pass through interposed patient tissue to generate a radiographic image of the interposed materials via the imager 412.
  • the particular energy, dose, duration, and other exposure parameters preferably employed by the x-ray source(s) 430 for imaging and the radiation source 406 for therapy will vary in different applications and will be readily understood and determined by one of ordinary skill in the art.
  • At least one of the x-ray sources 430 is positionable such that the x-ray source axis 444 can be positioned so as to be nominally coincident with the delivery axis 442.
  • This embodiment provides the advantage of developing a patient image for registration from a perspective which is nominally identical to a treatment perspective.
  • This embodiment also includes the aspect that a first imager 412 and x-ray source 430 pair and a second imager 412 and x-ray source 430 pair are arranged substantially orthogonal to each other.
  • This embodiment provides the advantage of being able to obtain patient images in two orthogonal perspectives to increase registration accuracy as will be described in greater detail below.
  • the imaging system can be similar to the systems described in U.S. Patent Nos. 5,825,845 and 5,117,829 which are hereby incorporated by reference.
  • the system 400 also comprises a patient positioner 414 and a patient pod 416 which is attached to a distal or working end of the patient positioner 414.
  • the patient positioner 414 is adapted to, upon receipt of appropriate movement commands, position the patient pod 416 in multiple translational and rotational axes and preferably is capable of positioning the patient pod 416 in three orthogonal translational axes as well as three orthogonal rotational axes so as to provide a full six degree freedom of motion to placement of the patient pod 416.
  • the patient pod 416 is configured to hold a patient securely in place in the patient pod 416 so to as substantially inhibit any relative movement of the patient with respect to the patient pod 416.
  • the patient pod 416 comprises expandable foam, bite blocks, and/or fitted facemasks as immobilizing devices and/or materials.
  • the patient pod 416 is also preferably configured to reduce difficulties encountered when a treatment fraction indicates delivery at an edge or transition region of the patient pod 416.

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Abstract

L'invention concerne des systèmes et des procédés permettant d'accentuer le ciblage sélectif d'agents (204) en procurant une action préférentielle sur une cible et une action réduite sur les tissus en bonne santé voisins du tissu cible. Un ou plusieurs agents (204) peuvent être combinés avec des structures/particules de nanoéchelle (202) pour être administrés au tissu cible. Un bombardement approprié avec un rayonnement de particules accéléré, tel qu'un rayonnement de protons, induit la libération des agents (204) du site cible. Des nanoporteurs peuvent être combinés à des agents thérapeutiques et/ou d'accentuation d'imagerie (204). L'imagerie du tissu cible peut assurer la vérification de la dose de rayonnement de particules administrée. Les nanoporteurs peuvent être pourvus d'une coque externe choisie pour sa biocompatibilité et sa durabilité dans l'environnement in vivo ainsi que pour fournir un mécanisme de rétroaction dans l'environnement de traitement en vue d'accélérer la libération de l'agent (204) et de réduire la dose de rayon totale nécessaire à leur libération.
PCT/US2008/071653 2007-07-30 2008-07-30 Systèmes et procédés d'accentuation de l'administration d'une thérapie par rayonnement de particules WO2009018383A1 (fr)

Priority Applications (6)

Application Number Priority Date Filing Date Title
CA2695985A CA2695985C (fr) 2007-07-30 2008-07-30 Systemes et procedes d'accentuation de l'administration d'une therapie par rayonnement de particules
EP08826721A EP2173430A4 (fr) 2007-07-30 2008-07-30 Systèmes et procédés d'accentuation de l'administration d'une thérapie par rayonnement de particules
JP2010520162A JP5331116B2 (ja) 2007-07-30 2008-07-30 粒子放射線で増強された治療を供給するシステム及び方法
AU2008282215A AU2008282215B2 (en) 2007-07-30 2008-07-30 Systems and methods for particle radiation enhanced delivery of therapy
US12/694,642 US8784846B2 (en) 2007-07-30 2010-01-27 Systems and methods for particle radiation enhanced delivery of therapy
US14/336,924 US20150050349A1 (en) 2007-07-30 2014-07-21 Systems and methods for particle radiation enhanced delivery of therapy

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EP2173430A4 (fr) 2012-11-21
EP2173430A1 (fr) 2010-04-14
JP5331116B2 (ja) 2013-10-30
CA2695985C (fr) 2016-06-28
JP2010535084A (ja) 2010-11-18
AU2008282215B2 (en) 2014-05-29
CA2695985A1 (fr) 2009-02-05
AU2008282215A1 (en) 2009-02-05

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