Core-Excited Nanoparticles and Methods of Their Use in the Diagnosis and Treatment of Disease

Abstract

Core-excited nanoparticle thermotherapy (CENT) represents a new paradigm in thermotherapy. The CENT method employs core-shell nanoparticles. The core of the nanoparticles is formed from one or more core-exciting, energy absorbing materials which absorbs core-exciting energy, either from an external energy source or from an energy source within the nanoparticle core (e.g., one or more radionuclides which undergo decay). Upon excitation by the core-exciting energy, the one or more core-exciting, energy absorbing materials reemit energy. A shell surrounds the particle nanoparticle core. The energy reemitted by the one or more core-exciting, energy absorbing materials is absorbed by the nanoparticle shell, so as to heat the shell of the nanoparticle. The heated nanoparticle then heats the surrounding region, to a temperature sufficient to detect, affect, damage or destroy the targeted cell or material. These core-shell nanoparticles can be administered to a patient in need thereof to treat diseases or disorders, including cancer. CENT nanoparticles can be optionally be bound to targeting agents that deliver them to the region of the diseased cell.

1 . Nanoparticles comprising:
 a) a core comprising one or more core-exciting energy absorbing materials which i) absorbs core-exciting energy, and ii) subsequently reemits energy, and   b) a shell surrounding the core, which comprises one or more materials which absorbs the energy reemitted from the one or more core-exciting energy absorbing materials, and then emits heat in sufficient quantity to kill or damage cells or tissue.   
     
     
         2 . The nanoparticles of  claim 1 , wherein the nanoparticles are nanospheres or nanorods with an average length or average diameter less than 1000 nm, preferably less than 500 nm, and most preferably less than 300 nm. 
     
     
         3 . The nanoparticles of  claim 1 , wherein the one or more core-exciting energy absorbing materials are scintillators, long-lived phosphors, persistent luminescent materials, or combinations thereof. 
     
     
         4 . The nanoparticles of  claim 1 , wherein the one or more core-exciting, energy absorbing materials are selected from the group consisting of
 forms of strontium aluminate, such as Sr a Al b O c , where a, b and c are integers that may vary, including Sr 4 Al 14 O 25 , SrAl 2 O 4 , SrAl 2 O 7 , and Sr 3 Al 2 O 6 ;   forms of strontium aluminate doped with a rare earth element (RaE), Sr a Al b O c :RaE, wherein a, b and c are integers that may vary and RaE=La, Lu, Ce, Pr, Nd, Sm, Eu, Tb, Dy, Ho, Er, Tm, or Yb in one or more oxidation states, including Europium(II)-doped Sr 4 Al 14 O 25 , SrAl 2 O 4 , SrAl 2 O 7 , and Sr 3 Al 2 O 6 ; Dysprosium(III)-doped Sr 4 Al 14 O 25 , SrAl 2 O 4 , SrAl 2 O 7 , and Sr 3 Al 2 O 6 ; and Neodymium(III)-doped Sr 4 Al 14 O 25 ,SrAl 2 O 4 , SrAl 2 O 7 , and Sr 3 Al 2 O 6 ;   forms of strontium aluminate co-doped with two or more different rare earth elements (RaEs), Sr a Al b O c :(RaE) 2 , wherein a, b and c are integers that may vary and RaE=La, Lu, Ce, Pr, Nd, Sm, Eu, Tb, Dy, Ho, Er, Tm, or Yb in one or more oxidation states, including strontium aluminate co-doped with Europium(II) and Dysprosium(III) as in Sr 4 Al 14 O 25 :Eu 2+ :Dy 3+ , SrAl 2 O 4 :Eu 2+ :Dy 3+ , SrAl 2 O 7 :Eu 2+ :Dy 3+ , and Sr 3 Al 2 O 6 :Eu 2+ :Dy 3+ ; and strontium aluminate co-doped with Europium(II) and Neodymium(III) as in Sr 4 Al 14 O 25 :Eu 2+ :Nd 3+ , SrAl 2 O 4 :Eu 2+ :Nd 3+ , SrAl 2 O 7 :Eu 2+ Nd 3+ , and Sr 3 Al 2 O 6 :Eu 2+ : Nd 3+ ;   forms of rare-earth ion-doped gadolinium oxide or oxysulfide phosphor, Gd 2 O 3 :RaE 3+  or Gd 2 O 2 S:RaE 3+ , wherein RaE=La, Lu, Ce, Pr, Nd, Sm, Eu, Tb, Dy, Ho, Er, Tm, or Yb;   rare-earth (RaE) ion co-doped alkaline earth aluminates, xMO+yAl 2 O 2 : RaE, RaE, where x and y are integers, and M=La, Lu, Ca, Sr, or Ba, and RaE=Ce, Pr, Nd, Sm, Eu, Tb, Dy, Ho, Er, Tm, or Yb;   rare-earth- or transition-metal-doped metal halides, including LaF 3 :Ce 3+ , LuF 3 :Ce 3+ , CaF 2 :Mn 2+ , CaF 2 :Eu 2+ , BaFBr:Eu 2+ , BaFBr:Mn 2+ , CaPO 4 :Mn 2+ , LuI 3 :Ce, SrI 2 :Eu, CaI 2 :Eu, GdI 3 :Ce; and   other suitable material including CdS, CdSe, CdTe, CaWO 4 , ZnS:Cu, TmO, ZnSe:Te, ZnS, ZnO, TiO 2 , GaN, GaAs, GaP, InAs, InP, Y 2 O 3 , WO 3 , ZrO 2 , YAlO 3 :Ce, Y 2 O 3 :Eu 3+ , CeMgAl 11 O 19 :Tb, LaPO 4 :Ce, Tb, GdMgB 5 O 10 :Ce, Tb, BaMgAl 10 O 17 :Eu 2+ , and Sr 5 (PO 4 ) 3 O:Eu 2+ ; and combinations thereof.   
     
     
         5 . The nanoparticles of  claim 1 , wherein the core comprises a material doped with one or more rare-earth- or lanthanide-series elements of the periodic table in an amount greater than 0.05 mass percent of the total mass of the particle. 
     
     
         6 . The nanoparticles of  claim 1 , wherein the one or more core-exciting, energy absorbing materials absorbs photons or mass particles of individual energy of greater than about 1 eV, more preferably greater than about 500 eV, more preferably greater than about 30 keV. 
     
     
         7 . The nanoparticles of  claim 1 , wherein the energy reemitted by the one or more core-exciting energy absorbing materials is electromagnetic radiation between about 100 nanometers and about 6000 nanometers, more preferably between about 250 nanometers and about 3000 nanometers, more preferably between 300 nanometers and 1000 nanometers. 
     
     
         8 . The nanoparticles of  claim 1 , wherein the core, shell, or combinations thereof further comprise one or more radionuclides which emits core-exciting energy. 
     
     
         9 . The nanoparticles of  claim 8 , wherein the one or more radionuclides have half-lives of greater than about one hour and less than about fifty years, more preferably greater than about ten hours and less than about one year, most preferably greater than about one day and less than about two months. 
     
     
         10 . The nanoparticles of  claim 8 , wherein the one or more radionuclides emit one or more particle types selected from the group consisting of alpha particles, beta particles, X-rays, gamma-rays, atomic electrons, Coster-Kronig electrons, Auger electrons, and neutrons. 
     
     
         11 . The nanoparticles of  claim 8 , wherein the one or more radionuclides are selected from the group consisting of Be-7, F-18, Mg-28, P-32, P-33, S-35, Ar-37, S-35, Ca-47, Sc-46, Sc-47, V-48, Cr-51, Mn-52, Mn-54, Fe-59, Fe-55, Co-58, Co-57, Co-56, Co-55, Ni-57, Cu-67, Zn-65, Ga-67, Ge-68, Se-72, Se-75, Kr-79, Rb-83, Rb-84, Rb-86, Sr-82, Sr-83, Sr-85, Sr-89, Y-88, Y-91, Zr-95, Nb-95, Tc-95m, Tc-97m, Tc-99m, Ru-97, Ru-103, Pd-103, Pd-100, Ag-111, Cd-109, Cd-115m, In-111, In-113m, In-114m, In-115m, Sn-113, Sn-117m, Sb-119, Te-118, Te-123m, I-123, I-124, I-125, I-126, I-131, Xe-122, Xe-127, Xe-131m, Xe-133, Cs-129, Cs-131, Cs-132, Ba-128, Ba-131, Ba-140, Ce-134, Ce-139, Ce-141, Pr-143, Nd-140, Pm-149, Pm-145, Sm-145, Eu-145, Eu-147, Gd-147, Gd-147, Gd-149, Gd-153, Tb-157, Dy-157, Dy-159, Er-165, Er-169, Tm-167, Tm-170, Yb-169, Ta-177, Ta-179, W-178, W-181, O-191, Ir-190, Ir-192, Pt-193, Pt-193m, Pt-195m, Au-195, Hg-197, Tl-201, Tl-202, Pb-203, and combinations thereof. 
     
     
         12 . The nanoparticles of  claim 1 , wherein the shell comprises a metal selected from the group consisting of gold, silver, platinum, palladium, rhodium, ruthenium, and combinations thereof. 
     
     
         13 . The nanoparticles of  claim 1 , wherein the nanoparticles further comprise one or more stabilizing materials on or within the nanoparticle core, one or more core-shell binders selected from the group consisting of phosphorus compounds and amines, and combinations thereof. 
     
     
         14 . The nanoparticles of  claim 1 , wherein the nanoparticles further comprise one or more targeting molecules bound thereto. 
     
     
         15 . The nanoparticles of  claim 1 , wherein the nanoparticles further comprise one or more heat-catalyzed functionalized agents bound thereto. 
     
     
         16 . The nanoparticles of  claim 1 , wherein the nanoparticles comprise
 a) a shell comprising a metal selected from the group that consists of gold, silver, palladium, platinum and combinations thereof;   b) a core comprising a material AlO 3 :Ce, Y 2 O 3 :Eu 3+ , CeMgAl 11 O 19 :Tb, LaPO 4 :Ce, Tb, GdMgB 5 O 10 :Ce, Tb, BaMgAl 10 O 17 :Eu 2+ , Sr 4 Al 14 O 25 :Eu 2+ :Dy 3+ , SrAl 2 O 4 :Eu 2+ :Dy 3+ , SrAl 2 O 7 :Eu 2+ :Dy 3+ , and Sr 3 Al 2 O 6 :Eu 2+ :Dy 3+ ; and Sr 5 (PO 4 ) 3 Cl:Eu 2+ , optionally wherein the core further comprises Pd-103; and   c) optionally a layer of polyethylene glycol bound to the surface of the nanoparticle.   
     
     
         17 . A pharmaceutical composition comprising the nanoparticles defined by  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         18 . A method for generating heat to kill or damage target cells or tissue comprising administering the nanoparticles defined by  claim 1 . 
     
     
         19 . The method of  claim 18 , further comprising exciting the nanoparticles with an external energy source in a manner and duration such that the nanoparticles emit heat in sufficient quantity to kill, damage, affect or identify the cells or tissue to be treated. 
     
     
         20 . The method of  claim 19 , wherein the external energy source is X-ray or gamma ray radiation, with an electromagnetic radiation wavelength ranging from 10.0 nm to 0.0001 inn, which may be generated from a conventional computed-tomography (CT) scanner, an X-ray or gamma-ray machine that is used in medicine, dentistry or imaging, or an X-ray laser. 
     
     
         21 . The method of  claim 20 , wherein the radiation is selected from the group consisting of a pulse of radiation that is less than one second in duration, a series of radiation pulses administered over a period of time, or a continuous exposure of radiation for a period of time. 
     
     
         22 . The method of  claim 18 , further comprising removing the nanoparticles from the cells or tissues following treatment. 
     
     
         23 . The method of  claim 18 , wherein total energy reemitted by the one or more core-exciting energy absorbing materials during the course of treatment is at least 100 electron volts (eV) with frequencies that fall within the absorbance band of the shell material. 
     
     
         24 . The method of  claim 18 , wherein the target cells or tissue are undesirable cells or tissue that has arisen due to transformation, cancerous cells or tissue, infected cells or tissue, inflamed cells or tissue, adipose cells or tissue, plaques present in vascular tissue and overproliferation, birthmarks and other vascular lesions of the skin, scars and adhesions, or irregularities in connective tissue or bone. 
     
     
         25 . The method of  claim 18 , wherein the target cells or tissue are from a human, animal, or plant.