# US 8,770,203 B2 · Advanced methods and systems for treating cell proliferation disorders > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 8,770,203 B2 - Document ID: US8770203B2 - Status: Granted - Kind: B2 - Application number: 13/054,279 - Filed: 2009-07-14 - Published: 2011-10-27 - Granted: 2014-07-08 - Earliest claimed: 2008-07-14 - Assignees: Immunolight, LLC; Duke University - Applicants: Frederic A. Bourke, Jr.; Tuan Vo Dinh - Inventors: Frederic A. Bourke, Jr.; Tuan Vo Dinh - Web page: https://patentgrep.com/patent/US8770203B2 ## CPC - A61N 5/062: {Photodynamic therapy, i.e. excitation of an agent} - A61K 31/4427: containing further heterocyclic ring systems - A61K 31/7056: containing five-membered rings with nitrogen as a ring hetero atom - A61K 41/008: {Two-Photon or Multi-Photon PDT, e.g. with upconverting dyes or photosensitisers} - A61K 47/55: the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug - A61K 47/551: {one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid} - A61P 35/00: Antineoplastic agents - A61K 31/7052: having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides - 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) - 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) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract The present invention relates to methods for treating cell proliferation disorders comprising (1) administering to the subject at least one activatable pharmaceutical agent that is capable of activation by a simultaneous two photon absorption event and of effecting a predetermined cellular change when activated, (2) administering at least one plasmonics-active agent to the subject, and (3) applying an initiation energy from an initiation energy source to the subject, wherein the plasmonics-active agent enhances or modifies the applied initiation energy, such that the enhanced or modified initiation energy activates the activatable pharmaceutical agent by the simultaneous two photon absorption event in situ, thus causing the predetermined cellular change to occur, wherein said predetermined cellular change treats the cell proliferation related disorder, and the use of plasmonics enhanced photospectral therapy (PEPST) and exiton-plasmon enhanced phototherapy (EPEP) in the treatment of various cell proliferation disorders, and the PEPST and EPEP agents and probes. ## Claims ### Claim 1 A method for treating a cell proliferation disorder in a subject, comprising: (1) administering to the subject at least one activatable pharmaceutical agent that is capable of activation by a simultaneous two photon absorption event and of effecting a predetermined cellular change when activated; (2) administering at least one plasmonics-active agent to the subject, (3) applying an initiation energy from an initiation energy source to the subject, wherein the applied initiation energy is enhanced or modified by the plasmonics-active agent, and (4) activating the activatable pharmaceutical agent by the simultaneous two photon absorption event in situ, wherein the enhanced or modified energy acts on the activatable pharmaceutical, thus causing the predetermined cellular change to occur, wherein said predetermined cellular change treats the cell proliferation disorder. ### Claim 2 (depends on 1) The method of claim 1, wherein the initiation energy source is selected from UV radiation, visible light, infrared radiation, x-rays, gamma rays, electron beams, phosphorescent compounds, chemiluminescent compounds, bioluminescent compounds, and light emitting enzymes. ### Claim 3 (depends on 1) The method of claim 1, wherein the initiation energy source is x-rays, gamma rays, an electron beam, microwaves or radio waves. ### Claim 4 (depends on 1) The method of claim 1, wherein the initiation energy is capable of penetrating completely through the subject. ### Claim 5 (depends on 1) The method of claim 1, wherein the cell proliferation disorder is at least one member selected from the group consisting of cancer, bacterial infection, viral infection, immune rejection response, autoimmune disorders, aplastic conditions, and combinations thereof. ### Claim 6 (depends on 1) The method of claim 1, wherein the at least one activatable pharmaceutical agent is a photoactivatable agent. ### Claim 7 (depends on 1) The method of claim 1, wherein the at least one activatable pharmaceutical agent is selected from psoralens, pyrene cholesteryloleate, acridine, porphyrin, fluorescein, rhodamine, 16-diazorcortisone, ethidium, transition metal complexes of bleomycin, transition metal complexes of deglycobleomycin organoplatinum complexes, alloxazines, vitamin Ks, vitamin L, vitamin metabolites, vitamin precursors, naphthoquinones, naphthalenes, naphthols and derivatives thereof having planar molecular conformations, porphorinporphyrins, dyes and phenothiazine derivatives, coumarins, quinolones, quinones, and anthroquinones. ### Claim 8 (depends on 6) The method of claim 6, wherein the at least one activatable pharmaceutical agent is a psoralen, a coumarin, a porphyrin or a derivative thereof. ### Claim 9 (depends on 6) The method of claim 6, wherein the at least one activatable pharmaceutical agent is 8-MOP or AMT. ### Claim 10 (depends on 1) The method of claim 1, wherein the at least one activatable pharmaceutical agent is one selected from 7,8-dimethyl-10-ribityl, isoalloxazine, 7,8,10-trimethylisoalloxazine, 7,8-dimethylalloxazine, isoalloxazine-adenine dinucleotide, alloxazine mononucleotide, aluminum (III) phthalocyanine tetrasulonate, hematophorphyrin, and phthadocyanine. ### Claim 11 (depends on 1) The method of claim 1, wherein the at least one activatable pharmaceutical agent is coupled to a carrier that is capable of binding to a receptor site. ### Claim 12 (depends on 11) The method of claim 11, wherein the carrier is one selected from insulin, interleukin, thymopoietin or transferrin. ### Claim 13 (depends on 11) The method of claim 11, wherein the at least one activatable pharmaceutical agent is coupled to the carrier by a covalent bond. ### Claim 14 (depends on 11) The method of claim 11, wherein the at least one activatable pharmaceutical agent is coupled to the carrier by non-covalent bond. ### Claim 15 (depends on 11) The method of claim 11, wherein the receptor site is one selected from nucleic acids of nucleated cells, antigenic sites on nucleated cells, or epitopes. ### Claim 16 (depends on 1) The method of claim 1, wherein the at least one activatable pharmaceutical agent has affinity for a target cell. ### Claim 17 (depends on 1) The method of claim 1, wherein the at least one activatable pharmaceutical agent is capable of being preferentially absorbed by a target cell. ### Claim 18 (depends on 1) The method of claim 1, wherein the predetermined cellular change is apoptosis in a target cell. ### Claim 19 (depends on 1) The method of claim 1, wherein the at least one activated pharmaceutical agent causes an auto-vaccine effect in the subject that reacts with a target cell. ### Claim 20 (depends on 19) The method of claim 19, wherein the auto-vaccine effect is generated in a joint or lymph node. ### Claim 21 (depends on 1) The method of claim 1, wherein the at least one activatable pharmaceutical agent is a DNA intercalator or a halogenated derivative thereof. ### Claim 22 (depends on 1) The method of claim 1, further comprising, prior to said applying the initiation energy, administering to the subject at least one energy modulation agent capable of converting an energy exciting the modulation agent to an energy that activates the at least one activatable pharmaceutical agent. ### Claim 23 (depends on 22) The method of claim 22, wherein the plasmonic-active agent enhances or modifies the initiation energy to the energy exciting the energy modulation agent that converts the excitation energy into the energy that activates the at least one activatable pharmaceutical agent. ### Claim 24 (depends on 22) The method of claim 22, wherein the plasmonic-active agent enhances or modifies an energy emitted by the modulation agent, to the energy that activates the at least one activatable pharmaceutical agent. ### Claim 25 (depends on 22) The method of claim 22, wherein the plasmonic-active agent enhances or modifies (a) the initiation energy to the energy exciting the energy modulation agent that converts the excitation energy into the energy that activates the at least one activatable pharmaceutical agent, and (b) an energy emitted by the modulation agent, to the energy that activates the at least one activatable pharmaceutical agent. ### Claim 26 (depends on 22) The method of claim 22, wherein said at least one energy modulation agent is a single energy modulation agent, and is coupled to said at least one activatable pharmaceutical agent. ### Claim 27 (depends on 22) The method of claim 22, wherein a plurality of the energy modulation agents is administered, and wherein the initiation energy, or the plasmonics-enhanced or modified energy, is converted, through a cascade energy transfer between the plurality of the energy modulation agents, to the energy that activates the at least one activatable pharmaceutical agent. ### Claim 28 (depends on 22) The method of claim 22, wherein the at least one activatable pharmaceutical agent is activated by the two photon absorption event. ### Claim 29 (depends on 23) The method of claim 23, wherein the at least one activatable pharmaceutical agent is activated by the two photon absorption event. ### Claim 30 (depends on 24) The method of claim 24, wherein the at least one activatable pharmaceutical agent is activated by the two photon absorption event. ### Claim 31 (depends on 1) The method of claim 1, wherein the at least one activatable pharmaceutical agent comprises an active agent contained within a photocage, wherein upon exposure to the plasmonics-enhanced or modified energy, the photocage disassociates from the active agent, rendering the active agent available. ### Claim 32 (depends on 22) The method of claim 22, wherein the at least one activatable pharmaceutical agent comprises an active agent contained within a photocage, wherein upon exposure to a reemitted energy by the modulation agent as the activation energy of the at least one activatable pharmaceutical agent, the photocage disassociates from the active agent, rendering the active agent available. ### Claim 33 (depends on 24) The method of claim 24, wherein the at least one activatable pharmaceutical agent comprises an active agent contained within a photocage, wherein upon exposure to the plasmonics-enhanced or modified energy emitted by the modulation agent as the activation energy of the at least one activatable pharmaceutical agent, the photocage disassociates from the active agent, rendering the active agent available. ### Claim 34 (depends on 1) The method of claim 1, wherein said predetermined cellular change treats the cell proliferation disorder by causing an increase or decrease in cell proliferation rate of a target cell. ### Claim 35 (depends on 1) The method of claim 1, wherein the plasmonic-active agent enhances the applied initiation energy from 106 to 1015 fold. ### Claim 36 (depends on 1) The method of claim 1, wherein the plasmonics-active agent is a plasmonics enhanced photospectral therapy (PEPST) probe comprising: a) at least one metal nanoparticle, b) at least one activatable pharmaceutical agent, and c) optionally, at least one energy modulation agent. ### Claim 37 (depends on 36) The method of claim 36, wherein at least two of components a)-c) are coupled one to another. ### Claim 38 (depends on 36) The method of claim 36, wherein the plasmonics-active agent comprises a) and b). ### Claim 39 (depends on 36) The method of claim 36, wherein the plasmonics-active agent comprises a), b), and c). ### Claim 40 (depends on 36) The method of claim 36, wherein the at least one metal nanoparticle is bound to the at least one energy modulation agent via a linker. ### Claim 41 (depends on 36) The method of claim 36, wherein the energy modulation agent is at least one selected from the group consisting of metals, quantum dots, semiconductor materials, scintillation and phosphor materials, materials that exhibit X-ray excited luminescence (XEOL), organic solids, metal complexes, inorganic solids, crystals, rare earth materials (lanthanides), polymers, scintillators, phosphor materials, and materials that exhibit excitonic properties. ### Claim 42 (depends on 1) The method of claim 1, wherein the plasmonics-active agent is a PEPST probe having a multi plasmonics resonance mode. ### Claim 43 (depends on 1) The method of claim 1, wherein the plasmonics-active agent is a PEPST probe comprising plasmonics-active metal nanostructures. ### Claim 44 (depends on 43) The method of claim 43, wherein the metal nanostructure is at least one selected from the group consisting of a nanosphere, nanorod, nanocube, nanopyramid, nanoshell, nanoshell cylinder, and multi-layer nanoshells. ### Claim 45 (depends on 1) The method of claim 1, wherein the plasmonics-active agent is a PEPST probe comprising multiple structures for different plasmonics activation regimes. ### Claim 46 (depends on 45) The method of claim 45, wherein said regime is at least one selected from the group consisting of NIR and X ray. ### Claim 47 (depends on 1) The method of claim 1, wherein the plasmonics-active agent is a PEPST probe comprising at least one metal nanosystem coupled with the activatable pharmaceutical agent, or with an energy modulation agent coupled with the activatable pharmaceutical agent. ### Claim 48 (depends on 47) The method of claim 47, wherein the nanosystem is bound to the activatable pharmaceutical agent or the energy modulation agent by a bond selected from the group consisting of a chemical bond, a biochemical bond, a DNA bond, and an antigen-antibody bond. ### Claim 49 (depends on 47) The method of claim 47, wherein the bond is a photo-liable bond. ### Claim 50 (depends on 47) The method of claim 47, wherein the activatable pharmaceutical agent is released from the nanosystem inside a cell by photon radiation or ultrasound. ### Claim 51 (depends on 1) The method of claim 1, wherein the plasmonics-active agent is a PEPST probe comprising at least one metal nanostructure selected from the group consisting of a metal nanoparticle, a dielectric nanoparticle core covered with a metal nanocap, a spherical metal nanoshell covering a dielectric spheroid core, a oblate metal nanoshell covering a dielectric spheroid core, a metal nanoparticle core covered with a dielectric nanoshell, a metal nanoshell with a protective coating layer, multilayer metal nanoshells covering a dielectric spheroid core, multi-nanoparticle structures, a metal nanocube and a nanotriangle/nanoprism, and a metal cylinder. ### Claim 52 (depends on 1) The method of claim 1, wherein the plasmonics-active agent is a PEPST probe comprising a combination of metal nanoparticles, covered by a layer of a dielectric material comprising the activatable pharmaceutical agent, with an energy modulation agent which is bound to the activatable pharmaceutical agent. ### Claim 53 (depends on 1) The method of claim 1, wherein the plasmonics-active agent is a PEPST probe, which enhances a XEOL light emitted by a modulation agent irradiated by an X ray, wherein the enhanced XEOL light activates the activatable pharmaceutical agent. ### Claim 54 (depends on 1) The method of claim 1, wherein the plasmonics-active agent is a PEPST probe and which is irradiated by X ray to excite the activatable pharmaceutical agent or an energy modulation agent coupled with the activatable pharmaceutical agent. ### Claim 55 (depends on 1) The method of claim 1, wherein the plasmonics-active agent is a PEPST probe comprising plasmonics-active metal nanostructures, said PEPST probe is irradiated by X ray to excite a surface plasmon in nanoparticles or subnanoparticle of a metal. ### Claim 56 (depends on 55) The method of claim 55, wherein the nanoparticles or subnanoparticle of the metal are gold or silver nanoparticles or subnanoparticle. ### Claim 57 (depends on 55) The method of claim 55, wherein the metal nanostructure is at least one selected from the group consisting of a nanosphere, nanorod, nanocube, nanopyramid, nanoshell, and multi-layer nanoshells. ### Claim 58 (depends on 1) The method of claim 1, wherein the plasmonics-active agent is a PEPST probe comprising the activatable pharmaceutical agent or an energy modulation agent coupled with the activatable pharmaceutical agent and further comprising at least one bioreceptor. ### Claim 59 (depends on 58) The method of claim 58, wherein the bioreceptor is at least one selected from the group consisting an antibody/antigen, an enzyme, a nucleic acid/DNA, a cellular structure/cell, and a biomimetic. ### Claim 60 (depends on 1) The method of claim 1, comprising delivering to a target the activatable pharmaceutical agent using a target delivery system comprising the plasmonics-active agent comprising the activatable pharmaceutical agent and, optionally, an energy modulation agent, wherein the plasmonics-active agent is a PEPST probe. ### Claim 61 (depends on 1) The method of claim 1, wherein the plasmonics-active agent is a PEPST probe possessing plasmonics photospectral properties, biocompatibility, an improved drug payload delivery and passive targeting of metal nanoparticles. ### Claim 62 (depends on 36) The method of claim 36, wherein at least one biomolecule is immobilized on the metal nanoparticles. ### Claim 63 (depends on 62) The method of claim 62, wherein the biomolecule is the activatable pharmaceutical agent, the modulation agent, a drug, a protein, an enzyme, an antibody, DNA, or RNA. ### Claim 64 (depends on 36) The method of claim 36, wherein the metal nanoparticles are gold or silver nanoparticles. ### Claim 65 (depends on 36) The method of claim 36, wherein the metal nanoparticles enhance or modify an X ray energy applied to the subject to excite the energy modulation agent which converts the enhanced or modified X ray energy to an energy that activates the at least one activatable pharmaceutical agent directly or via a cascade energy transfer between a plurality of the energy modulation agents. ### Claim 66 (depends on 36) The method of claim 36, wherein the metal nanoparticles enhance or modify an energy emitted by the modulation agent which converts the initiation energy to the emitted energy, said enhanced or modified emitted energy activates the at least one activatable pharmaceutical agent. ### Claim 67 (depends on 36) The method of claim 36, wherein the plasmonics-active agent is a PEPST probe comprising a chain of metal particles having the same or different size and coupled to one another, wherein the chain of the metal particles exhibits dual or multi plasmonics resonance modes. ### Claim 68 (depends on 67) The method of claim 67, wherein the chain of particles is used for providing a plasmonics enhancement of the initiation energy and/or an energy emitted by the modulation agent. ### Claim 69 (depends on 1) The method of claim 1, wherein the activatable pharmaceutical agent is delivered to a target and is released from the plasmonics-active agent by photon radiation or ultrasound, and wherein the plasmonics-active agent is a PEPST probe. ### Claim 70 (depends on 22) The method of claim 22, wherein the activatable pharmaceutical agent is delivered to a cell and is released from the energy modulation agent coupled with the plasmonics-active agent by photon radiation or ultrasound, and wherein the plasmonics-active agent is a PEPST probe. ### Claim 71 (depends on 69) The method of claim 69, wherein the activatable pharmaceutical agent is released from the plasmonics-active agent comprising an antibody or antigen system coupled with the activatable pharmaceutical agent. ### Claim 72 (depends on 1) The method of claim 1, comprising delivering the activatable pharmaceutical agent to a target using liposomes. ### Claim 73 (depends on 1) The method of claim 1, wherein the plasmonics-active agent is a PEPST probe comprising an energy modulation agent and the activatable pharmaceutical agent. ### Claim 74 (depends on 1) The method of claim 1, wherein the plasmonics-active agent is a PEPST probe comprising the activatable pharmaceutical agent which is encapsulated. ### Claim 75 (depends on 73) The method of claim 73, the activatable pharmaceutical agent or the activatable pharmaceutical agent and a modulation agent are encapsulated in a capsule comprising an ferritin and/or apoferritin compound. ### Claim 76 (depends on 1) The method of claim 1, which uses ultrasound for a release of the activatable pharmaceutical agent and photonic excitation of the activatable pharmaceutical agent or an energy modulation agent coupled with the activatable pharmaceutical agent, wherein the plasmonics-active agent is a PEPST probe, and the activatable pharmaceutical agent is released from the PEPST. ### Claim 77 (depends on 1) The method of claim 1, wherein the plasmonics-active agent is a PEPST probe which can be excited by two-photon or multi-photon excitation. ### Claim 78 (depends on 1) The method of claim 1, the method further comprising using a drug delivery, tumor targeting, and/or drug releasing system for delivering and releasing the plasmonics-active agent and/or the activatable pharmaceutical agent, wherein the plasmonics-active agent is a PEPST probe. ### Claim 79 (depends on 1) The method of claim 1, wherein the plasmonics-active agent is a PEPST probe, wherein components of the PEPST probe are bound using conjugates, metals binding to organic and inorganic compounds, and biomolecules. ### Claim 80 (depends on 1) The method of claim 1, wherein the plasmonics-active agent comprises a plasmonic-active metal nanoparticle bound to an excitation energy converter (EEC) material which is bound to the activatable pharmaceutical agent, wherein the EEC material for exciton induced phototherapy (EIP) probes is optimized based on exciton properties. ### Claim 81 (depends on 1) The method of claim 1, wherein the plasmonics-active agent comprises an excitation energy converter (EEC) material, said method tunes an emission of the EEC material in exciton induced phototherapy (EIP) probes to a wavelength capable of exciting the activatable pharmaceutical agent using specific materials with specific exciton properties, wherein said EEC material can produce excitons under a radiative excitation. ### Claim 82 (depends on 80) The method of claim 80, wherein the EEC material is a modulation agent, said EEC material is bound via a linker to the activatable pharmaceutical agent. ### Claim 83 (depends on 80) The method of claim 80, wherein the EEC material is a modulation agent, and the activatable pharmaceutical agent is embedded in a shell around said EEC material. ### Claim 84 (depends on 80) The method of claim 80, wherein the EEC material has structural defects that serve as traps for the excitation. ### Claim 85 (depends on 80) The method of claim 80, wherein the EEC material comprises impurities or dopant molecules that serve as traps for the excitation. ### Claim 86 (depends on 80) The method of claim 80, wherein the initiation energy is X ray which is transformed to UV or visible photons by the EEC material. ### Claim 87 (depends on 1) The method of claim 1, wherein the plasmonics-active agent is an exciton-plasmon enhanced phototherapy (EPEP) probe which comprises at least one plasmonics-active metal nanostructure, at least one exciton-generating energy modulation agent material, and the at least one activatable pharmaceutical agent, wherein said metal nanostructure and said material produce exciton-plasmon (EPC) coupling. ### Claim 88 (depends on 87) The method of claim 87, wherein the plasmonics-active metal nanostructure and the exciton-generating energy modulation agent material are coupled via a spacer. ### Claim 89 (depends on 87) The method of claim 87, wherein exciton-generating energy modulation agent material is coupled with the activatable pharmaceutical agent via a linker. ### Claim 90 (depends on 87) The method of claim 87, wherein the activatable pharmaceutical agent and the plasmonics-active metal nanostructure are coupled via a linker. ### Claim 91 (depends on 87) The method of claim 87, wherein the EPEP probe comprises a bioreceptor. ### Claim 92 (depends on 91) The method of claim 91, wherein the bioreceptor is bound to the plasmonics-active metal nanostructure or to the plasmonics-active metal nanostructure covered with a nanoshell or a nanoshell cylinder made of a dielectric material. ### Claim 93 (depends on 87) The method of claim 87, wherein the plasmonics-active metal nanostructure is covered with a nanoshell made of a dielectric material. ### Claim 94 (depends on 87) The method of claim 87, wherein the plasmonics-active metal nanostructure is a metal nanosphere, a nanowire or a nanorod covered with a nanoshell or a nanoshell cylinder of a dielectric material. ### Claim 95 (depends on 87) The method of claim 87, wherein the EPEP probe comprises multiple metal nanowires coupled with the exciton-generating energy modulation agent material with or without spacers which can be the same or different, said exciton-generating energy modulation agent material is bound to the activatable pharmaceutical agent via a linker. ### Claim 96 (depends on 87) The method of claim 87, wherein the exciton-generating energy modulation agent material is a microresonator. ### Claim 97 (depends on 87) The method of claim 87, wherein the exciton-generating energy modulation agent material is at least one selected from the group consisting of metals, quantum dots, semiconductor materials, scintillation and phosphor materials, materials that exhibit X-ray excited luminescence (XEOL), organic solids, metal complexes, inorganic solids, crystals, rare earth materials (lanthanides), polymers, scintillators, phosphor materials, and materials that exhibit excitonic properties. ### Claim 98 (depends on 87) The method of claim 87, wherein the metal nanostructure is at least one selected from the group consisting of a nanosphere, nanorod, nanocube, nanopyramid, nanoshell, nanoshell cylinder, and multi-layer nanoshells. ### Claim 99 (depends on 87) The method of claim 87, wherein the EPEP probe comprises multiple structures for different plasmonics activation regimes. ### Claim 100 (depends on 99) The method of claim 99, wherein said regime is at least one selected from the group consisting of NIR and X ray. ### Claim 101 (depends on 87) The method of claim 87, wherein the EPEP probe comprises at least one metal nanosystem coupled with the activatable pharmaceutical agent, or with an energy modulation agent coupled with the activatable pharmaceutical agent. ### Claim 102 (depends on 101) The method of claim 101, wherein the nanosystem is bound to the activatable pharmaceutical agent or the energy modulation agent by a bond selected from the group consisting of a chemical bond, a biochemical bond, a DNA bond, and an antigen-antibody bond. ### Claim 103 (depends on 102) The method of claim 102, wherein the bond is a photo-liable bond. ### Claim 104 (depends on 102) The method of claim 102, wherein the activatable pharmaceutical agent is released from the nanosystem inside a cell by photon radiation or ultrasound. ### Claim 105 (depends on 87) The method of claim 87, wherein the EPEP probe comprises at least one metal nanostructure selected from the group consisting of a metal nanoparticle, a dielectric nanoparticle core covered with a metal nanocap, a spherical metal nanoshell covering a dielectric spheroid core, a oblate metal nanoshell covering a dielectric spheroid core, a metal nanoparticle core covered with a dielectric nanoshell, a metal nanoshell with a protective coating layer, multilayer metal nanoshells covering a dielectric spheroid core, multi-nanoparticle structures, a metal nanocube and a nanotriangle/nanoprism, and a metal cylinder. ### Claim 106 (depends on 87) The method of claim 87, wherein the EPEP probe comprises a combination of metal nanoparticles with an energy modulation agent which is bound to the activatable pharmaceutical agent, wherein the metal nanoparticles are covered by a layer of a dielectric material comprising the activatable pharmaceutical agent. ### Claim 107 (depends on 87) The method of claim 87, wherein the EPEP probe enhances a XEOL light emitted by the exciton-generating energy modulation agent material irradiated by an X ray, wherein the enhanced XEOL light activates the activatable pharmaceutical agent. ### Claim 108 (depends on 87) The method of claim 87, wherein the EPEP probe is irradiated by an X ray to excite the activatable pharmaceutical agent or an energy modulation agent coupled with the activatable pharmaceutical agent. ### Claim 109 (depends on 87) The method of claim 87, wherein the EPEP probe comprising the plasmonics-active metal nanostructures is irradiated by an X ray to excite a surface plasmon in nanoparticles or subnanoparticle of a metal. ### Claim 110 (depends on 109) The method of claim 109, wherein the nanoparticles or subnanoparticle of the metal are gold or silver nanoparticles or subnanoparticle. ### Claim 111 (depends on 109) The method of claim 109, wherein the metal nanostructure is at least one selected from the group consisting of a nanosphere, nanorod, nanocube, nanopyramid, nanoshell, and multi-layer nanoshells. ### Claim 112 (depends on 91) The method of claim 91, wherein the bioreceptor is at least one selected from the group consisting an antibody/antigen, an enzyme, a nucleic acid/DNA, a cellular structure/cell, and a biomimetic. ### Claim 113 (depends on 87) The method of claim 87, comprising delivering to a target the activatable pharmaceutical agent using a target delivery system comprising the plasmonics-active metal nanostructure comprising the activatable pharmaceutical agent. ### Claim 114 (depends on 87) The method of claim 87, wherein the EPEP probe possesses plasmonics photospectral properties, biocompatibility, an improved drug payload delivery and passive targeting of metal nanoparticles. ### Claim 115 (depends on 87) The method of claim 87, wherein at least one biomolecule is immobilized on the metal nanostructure. ### Claim 116 (depends on 115) The method of claim 115, wherein the biomolecule is at least one selected from the group consisting of the activatable pharmaceutical agent, the modulation agent, a drug, a protein, an enzyme, an antibody, and a nucleic acid. ### Claim 117 (depends on 87) The method of claim 87, wherein the metal nanostructure is a gold or silver nanoparticle. ### Claim 118 (depends on 87) The method of claim 87, wherein the metal nanostructure enhances or modifies an X ray energy applied to the subject to excite the exciton-generating energy modulation agent which converts the enhanced or modified X ray energy to an energy that activates the at least one activatable pharmaceutical agent directly or via a cascade energy transfer between a plurality of the energy modulation agents. ### Claim 119 (depends on 87) The method of claim 87, wherein the metal nanoparticle enhances or modifies an energy emitted by the exciton-generating energy modulation agent which converts the initiation energy to the emitted energy, said enhanced or modified emitted energy activates the at least one activatable pharmaceutical agent. ### Claim 120 (depends on 87) The method of claim 87, wherein the metal nanostructure enhances or modulates (i) an X ray energy applied to the subject to excite the exciton-generating energy modulation agent material which converts the enhanced or modulated X ray energy to an energy that activates the at least one activatable pharmaceutical agent directly or via a cascade energy transfer between a plurality of the energy modulation agents, and (ii) an energy emitted by the exciton-generating energy modulation agent material which converts the enhanced or modulated energy (i) to an energy that activates the at least one activatable pharmaceutical agent. ### Claim 121 (depends on 87) The method of claim 87, wherein (a) the exciton-generating energy modulation agent, (b) the activatable pharmaceutical agent, or (c) the exciton-generating energy modulation agent and the activatable pharmaceutical agent, are covered with a layer comprising the plasmonics-active metal nanostructure. ### Claim 122 (depends on 87) The method of claim 87, wherein the EPEP probe comprises a chain of metal particles having the same of different size and coupled to one another, wherein the chain of the metal particles exhibit dual or multi plasmonics resonance modes. ### Claim 123 (depends on 122) The method of claim 122, wherein the chain of the particles is used for providing a plasmonics enhancement of the initiation energy and/or an energy emitted by the exciton-generating energy modulation agent material. ### Claim 124 (depends on 87) The method of claim 87, wherein the activatable pharmaceutical agent is delivered to a target and is released from the plasmonics-active metal nanostructure by photon radiation or ultrasound. ### Claim 125 (depends on 124) The method of claim 124, wherein the activatable pharmaceutical agent is released from the plasmonics-active metal nanostructure comprising an antibody or antigen system coupled with the activatable pharmaceutical agent. ### Claim 126 (depends on 87) The method of claim 87, comprising delivering the activatable pharmaceutical agent to a target using liposomes. ### Claim 127 (depends on 87) The method of claim 87, wherein the EPEP probe comprises the activatable pharmaceutical agent which is encapsulated. ### Claim 128 (depends on 127) The method of claim 127, wherein the activatable pharmaceutical agent or the activatable pharmaceutical agent and the exciton-generating energy modulation agent material are encapsulated in a capsule comprising an ferritin and/or apoferritin compound. ### Claim 129 (depends on 87) The method of claim 87, which uses ultrasound for a release of the activatable pharmaceutical agent and photonic excitation of the activatable pharmaceutical agent or the exciton-generating energy modulation agent material coupled with the activatable pharmaceutical agent for the activation of the activatable pharmaceutical agent. ### Claim 130 (depends on 87) The method of claim 87, wherein the EPEP probe can be excited by two-photon or multi-photon excitation. ### Claim 131 (depends on 1) The method of claim 1, the method further comprising using a drug delivery, tumor targeting, and/or drug releasing system for delivering and releasing the plasmonics-active agent and the activatable pharmaceutical agent, wherein the plasmonics-active agent is a EPEP probe. ### Claim 132 (depends on 1) The method of claim 1, wherein the plasmonics-active agent is a EPEP probe, and components of the EPEP probe are bound using conjugates, metals binding to organic and inorganic compounds, and biomolecules. ### Claim 133 (depends on 1) The method of claim 1, wherein the plasmonics agent is a EPEP probe possessing EPIP properties, biocompatibility, an improved drug payload delivery and passive targeting of metal nanoparticles. ### Claim 134 (depends on 1) The method of claim 1, wherein said, disorder is mediated by abnormal cellular proliferation and said predetermined change ameliorates the abnormal cellular proliferation. ### Claim 135 (depends on 134) The method of claim 134, wherein said abnormal cellular proliferation is higher than that of cells from a subject not having said, disorder. ### Claim 136 (depends on 134) The method of claim 134, wherein said abnormal cellular proliferation is lower than that of cells from a subject not having said, disorder. ### Claim 137 (depends on 1) The method of claim 1, wherein said, disorder is not significantly mediated by abnormal cellular proliferation and said predetermined change does not substantially affect cellular proliferation. ### Claim 138 A method for treating a cell proliferation disorder in a subject, comprising: (1) administering to the subject at least one energy modulation agent and at least one activatable pharmaceutical agent that is capable of activation by a simultaneous two photon absorption event and of effecting a predetermined cellular change when activated; (2) administering at least one plasmonics-active agent to the subject, and (3) applying an initiation energy from an initiation energy source to the subject, wherein the applied initiation energy is upgraded or downgraded by the energy modulation agent such that the upgraded or downgraded energy is further enhanced or modified by the plasmonics-active agent, and (4) activating the activatable pharmaceutical agent by the simultaneous two photon absorption event in situ, wherein the enhanced or modified upgraded or downgraded energy acts on the activatable pharmaceutical agent, (3′) applying an initiation energy from an initiation energy source to the subject, wherein the applied initiation energy is enhanced or modified by the plasmonics-active agent such that the enhanced or modified energy acts on the modulation agent which further upgrades or downgrades the enhanced or modified energy to an energy that activates the activatable pharmaceutical agent by the simultaneous two photon absorption event in situ, and (4′) activating the activatable pharmaceutical agent by the simultaneous two photon absorption event in situ, wherein the upgraded or downgraded enhanced or modified energy acts on the activatable pharmaceutical agent, thus causing the predetermined cellular change to occur, wherein said predetermined cellular change treats the cell proliferation related disorder. ### Claim 139 A method for treating a cell proliferation disorder in a subject, comprising: (1) administering to the subject at least one activatable pharmaceutical agent that is capable of activation by a simultaneous two photon absorption event and of effecting a predetermined cellular change when activated; (2) administering at least one plasmonics-active agent to the subject, and (3) applying an initiation energy from an initiation energy source to the subject, wherein the applied initiation energy and the activatable pharmaceutical agent upon activation produce insufficient singlet oxygen in a target cell or tissue in the subject to produce cell lysis, and wherein the plasmonics-active agent enhances or modifies the applied initiation energy, such that the enhanced or modified initiation energy activates the activatable pharmaceutical agent by the simultaneous two photon absorption event in situ, thus causing the predetermined cellular change to occur in the target cell or tissue, wherein said predetermined cellular change treats the cell proliferation disorder. ### Claim 140 A method for generating an autovaccine for a subject, comprising: (1) providing a population of target cells; (2) treating the target cells ex vivo in an environment separate and isolated from the subject with an activatable pharmaceutical agent capable of activation by a simultaneous two photon absorption event and with a plasmonics-active agent; (3) exposing the treated target cells to an energy source; (4) exciting the plasmonics-active agent and the activatable pharmaceutical agent with an initiation energy, wherein the plasmonics-active agent enhances or modifies the initiation energy and the enhanced or modified energy activates the activatable pharmaceutical agent by the simultaneous two photon absorption event, thereby inducing a predetermined cellular change in the target cells; and (5) returning the thus changed cells back to the subject to induce in the subject an autovaccine effect against the target cell, wherein the changed cells act as an autovaccine and the energy source is selected from UV radiation, visible light, infrared radiation, x-rays, gamma rays, an electron beam, microwaves and radio waves.