# US 8,784,846 B2 · Systems and methods for particle radiation enhanced delivery of therapy > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 8,784,846 B2 - Document ID: US8784846B2 - Status: Granted - Kind: B2 - Application number: 12/694,642 - Filed: 2010-01-27 - Published: 2011-07-28 - Granted: 2014-07-22 - Earliest claimed: 2007-07-30 - Assignees: Loma Linda University Medical Center - Applicants: Reinhard Schulte; Gilmer Valdes-Diaz - Inventors: Reinhard Schulte; Gilmer Valdes-Diaz - Web page: https://patentgrep.com/patent/US8784846B2 ## CPC - A61K 9/14: Particulate form, e.g. powders, {Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles (microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51)} - A61K 47/02: Inorganic compounds - A61N 5/1042: {with spatial modulation of the radiation beam within the treatment head} - C07K 16/18: against material from animals or humans - A61N 2005/1052: {using positron emission tomography [PET] single photon emission computer tomography [SPECT] imaging} - A61N 2005/1061: {using an x-ray imaging system having a separate imaging source} - A61N 2005/1087: {Ions; Protons} - A61N 2005/1098: {Enhancing the effect of the particle by an injected agent or implanted device} - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61N: ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY (measurement of bioelectric currents A61B; surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body A61B18/00; anaesthetic apparatus in general A61M; incandescent lamps H01K; infrared radiators for heating H05B) - C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00) ## Abstract Systems and methods for enhancing the selective targeting of agents for preferential action at a target with reduced action with healthy tissue distal the target tissue. One or more agents can be combined with nano scale structures/particles for delivery to the target tissue. Appropriate bombardment with accelerated particle radiation, such as proton radiation, induces the release of the agents at the target site. Nano carriers can be combined with therapeutic and/or imaging enhancement agents. Imaging of the target tissue can provide a verification of the delivered dose of particle radiation. Nanocarriers can be provided with an outer shell selected for biocompatibility and durability in the in vivo environment and further selected to provide a feedback mechanism in the treatment environment to accelerate the release of the agent and reduce a total radiation dose needed for that release. ## Claims ### Claim 1 A method of delivering therapy, the method comprising: introducing a quantity of therapeutic agent into a patient, the therapeutic agent configured to provide a beneficial effect to the patient when allowed to appropriately interact with a target tissue; introducing a quantity of protective agent into the patient, the protective agent configured to prevent the therapeutic agent from interacting with surrounding tissue; introducing a quantity of activating agent into the patient, the activating agent having a high molecular weight and configured to be irradiated by particle radiation, thereby facilitating release of the therapeutic agent from the protective agent into the target tissue; wherein the therapeutic agent, the protective agent, and the activating agent are associated with each other in the patient; and directing a dose of particle radiation comprising accelerated protons or accelerated heavier positive ions having a Bragg peak at the target tissue of the patient so that the dose interacts with the activating agent proximal to the target tissue, thereby releasing the therapeutic agent from its association with the protective agent; wherein the patient is oriented and the dose of particle radiation is directed into the patient at a specified vector so that the Bragg peak of the dose of particle radiation at least partially overlaps the activating agent proximal to the target tissue, thereby reducing undesired radiation to, and interaction of therapeutic agent with, non-target tissue. ### Claim 2 (depends on 1) The method of claim 1, wherein introducing the quantity of therapeutic agent comprises introducing a quantity of nanoparticle carriers combined with the therapeutic agent and wherein the nanoparticle carriers convey the therapeutic agent to the target tissue. ### Claim 3 (depends on 2) The method of claim 2, wherein irradiation with the particle radiation induces release of the therapeutic agent from the nanoparticle carriers. ### Claim 4 (depends on 3) The method of claim 3, wherein the nanoparticle carriers comprise at least one outer coating and wherein the irradiation with the particle radiation induces decomposition of the outer coating so as induce the release of the therapeutic agent from the nanoparticle carriers. ### Claim 5 (depends on 4) The method of claim 4, wherein the decomposition of the outer coating via the irradiation with the particle radiation induces a localized change in physical characteristics of the target tissue and wherein the changed physical characteristics of the target tissue accelerate the decomposition of the outer coating and the release of the therapeutic agent. ### Claim 6 (depends on 5) The method of claim 5, wherein the change in physical characteristics comprises a localized change in pH. ### Claim 7 (depends on 1) The method of claim 1, wherein the directing the dose of particle radiation comprises directing a dose of accelerated protons. ### Claim 8 (depends on 1) The method of claim 1, further comprising configuring the dose of particle radiation such that energy of the dose of particle radiation is preferentially deposited within the target tissue with respect to upstream and downstream of the target tissue such that the particle radiation provides therapy independently of the action of the therapeutic agent. ### Claim 9 (depends on 1) The method of claim 1, further comprising registering the patient such that the dose of particle radiation is directed along one or more desired treatment vectors to the target tissue. ### Claim 10 (depends on 1) The method of claim 1, further comprising: introducing a quantity of imaging enhancement agent into the patient, the imaging enhancement agent configured to enhance the imaging of the patient after introduction; and imaging the patient during and/or following the directing of particle radiation at the patient, wherein the imaging enhancement agent is configured such that an image of the target tissue is responsive to the irradiation with particle radiation as a function of the delivered dose of the particle radiation such that the delivered dose can be verified via analyzing the imaging of the patient. ### Claim 11 (depends on 10) The method of claim 10, comprising forming the imaging enhancement agent by combining contrast nanoparticles with a nanocarrier such that the contrast nanoparticles are released from the nanocarrier upon bombardment with the particle radiation. ### Claim 12 (depends on 10) The method of claim 10, comprising forming the imaging enhancement agent by combining one or more positron emitting radionuclides with a nanocarrier such that the one or more positron emitting radionuclides are released from the nanocarrier upon bombardment with the particle radiation such that the one or more positron emitting radionuclides can be imaged. ### Claim 13 (depends on 12) The method of claim 12, further comprising forming the imaging enhancement agent by combining the one or more positron emitting radionuclides with antibodies selected for tumor antigens such that the antibodies preferentially select cancer foci within the target tissue and such that one or more positron emitting radionuclides enhance the image of the cancer foci with respect to non-cancerous tissue within the target tissue. ### Claim 14 (depends on 2) The method of claim 2, further comprising: providing an in vivo agent delivery vehicle comprising the nanoparticle carriers; and engaging the therapeutic agent with the nanoparticle carriers such that the therapeutic agent can be durably entrained within living tissue and wherein bombardment with a selected dose of particle radiation releases the therapeutic agent from the nanoparticle carriers. ### Claim 15 (depends on 14) The method of claim 14, wherein the therapeutic agent comprises a layer arranged about an exterior of the nanoparticle carriers. ### Claim 16 (depends on 15) The method of claim 15, further comprising an outer coating such that the therapeutic agent layer is interposed between the nanoparticle carriers and the outer coating. ### Claim 17 (depends on 14) The method of claim 14, wherein the nanoparticle carriers comprise one or more internal voids and wherein the therapeutic agent is contained at least partially within the one or more voids. ### Claim 18 (depends on 14) The method of claim 14, wherein the therapeutic agent comprises an in vivo agent that comprises antibodies selected for tumor antigens. ### Claim 19 (depends on 10) The method of claim 10, wherein the quantity of imaging enhancement agent is selected such that the degree of enhancement of the target tissue image is a generally linear function of the delivered dose of particle radiation. ### Claim 20 (depends on 10) The method of claim 10, further comprising selecting the image enhancement agent such that the imaging enhancement agent preferentially concentrates at the target tissue. ### Claim 21 (depends on 11) The method of claim 11, wherein releasing the nanoparticles increases the density of the target tissue. ### Claim 22 (depends on 3) The method of claim 3, wherein the activating agent comprises the nanoparticle carriers. ### Claim 23 A method of delivering therapy, the method comprising: introducing a quantity of therapeutic agent into a patient, the therapeutic agent configured to provide a beneficial effect to the patient when allowed to appropriately interact with a target tissue; introducing a quantity of protective agent into the patient, the protective agent configured to prevent the therapeutic agent from interacting with surrounding tissue; wherein the therapeutic agent and the protective agent are associated with each other in the patient; and directing a dose of particle radiation comprising accelerated protons or accelerated heavier positive ions having a Bragg peak at the target tissue of the patient so that the dose interacts with the protective agent proximal to the target tissue, thereby releasing the therapeutic agent from its association with the protective agent; wherein the patient is oriented and the dose of particle radiation is directed into the patient at a specified vector so that the Bragg peak of the dose of particle radiation at least partially overlaps the protective agent proximal to the target tissue, thereby reducing undesired radiation to, and interaction of therapeutic agent with, non-target tissue.