U.S. patent application number 13/515240 was filed with the patent office on 2013-08-01 for core-excited nanoparticles and methods of their use in the diagnosis and treatment of disease.
The applicant listed for this patent is Samuel Harry Tersigni. Invention is credited to Samuel Harry Tersigni.
Application Number | 20130195979 13/515240 |
Document ID | / |
Family ID | 46177765 |
Filed Date | 2013-08-01 |
United States Patent
Application |
20130195979 |
Kind Code |
A1 |
Tersigni; Samuel Harry |
August 1, 2013 |
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.
Inventors: |
Tersigni; Samuel Harry;
(Glen Allen, VA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Tersigni; Samuel Harry |
Glen Allen |
VA |
US |
|
|
Family ID: |
46177765 |
Appl. No.: |
13/515240 |
Filed: |
February 14, 2012 |
PCT Filed: |
February 14, 2012 |
PCT NO: |
PCT/US2012/025043 |
371 Date: |
November 27, 2012 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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13052951 |
Mar 21, 2011 |
8197471 |
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13515240 |
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61442615 |
Feb 14, 2011 |
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Current U.S.
Class: |
424/490 ;
604/501 |
Current CPC
Class: |
A61K 51/1244 20130101;
A61N 2005/1098 20130101; A61P 35/00 20180101; A61N 5/10 20130101;
A61B 18/04 20130101; A61N 5/1001 20130101; Y10S 977/904 20130101;
A61K 41/0052 20130101 |
Class at
Publication: |
424/490 ;
604/501 |
International
Class: |
A61K 41/00 20060101
A61K041/00; A61N 5/10 20060101 A61N005/10 |
Claims
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.sub.aAl.sub.bO.sub.c, where a, b and c are integers that may
vary, including Sr.sub.4Al.sub.14O.sub.25, SrAl.sub.2O.sub.4,
SrAl.sub.2O.sub.7, and Sr.sub.3Al.sub.2O.sub.6; forms of strontium
aluminate doped with a rare earth element (RaE),
Sr.sub.aAl.sub.bO.sub.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.sub.4Al.sub.14O.sub.25, SrAl.sub.2O.sub.4, SrAl.sub.2O.sub.7,
and Sr.sub.3Al.sub.2O.sub.6; Dysprosium(III)-doped
Sr.sub.4Al.sub.14O.sub.25, SrAl.sub.2O.sub.4, SrAl.sub.2O.sub.7,
and Sr.sub.3Al.sub.2O.sub.6; and Neodymium(III)-doped
Sr.sub.4Al.sub.14O.sub.25,SrAl.sub.2O.sub.4, SrAl.sub.2O.sub.7, and
Sr.sub.3Al.sub.2O.sub.6; forms of strontium aluminate co-doped with
two or more different rare earth elements (RaEs),
Sr.sub.aAl.sub.bO.sub.c:(RaE).sub.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.sub.4Al.sub.14O.sub.25:Eu.sup.2+:Dy.sup.3+,
SrAl.sub.2O.sub.4:Eu.sup.2+:Dy.sup.3+,
SrAl.sub.2O.sub.7:Eu.sup.2+:Dy.sup.3+, and
Sr.sub.3Al.sub.2O.sub.6:Eu.sup.2+:Dy.sup.3+; and strontium
aluminate co-doped with Europium(II) and Neodymium(III) as in
Sr.sub.4Al.sub.14O.sub.25:Eu.sup.2+:Nd.sup.3+,
SrAl.sub.2O.sub.4:Eu.sup.2+:Nd.sup.3+,
SrAl.sub.2O.sub.7:Eu.sup.2+Nd.sup.3+, and
Sr.sub.3Al.sub.2O.sub.6:Eu.sup.2+: Nd.sup.3+; forms of rare-earth
ion-doped gadolinium oxide or oxysulfide phosphor,
Gd.sub.2O.sub.3:RaE.sup.3+ or Gd.sub.2O.sub.2S:RaE.sup.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.sub.2O.sub.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.sub.3:Ce.sup.3+, LuF.sub.3:Ce.sup.3+,
CaF.sub.2:Mn.sup.2+, CaF.sub.2:Eu.sup.2+, BaFBr:Eu.sup.2+,
BaFBr:Mn.sup.2+, CaPO.sub.4:Mn.sup.2+, LuI.sub.3:Ce, SrI.sub.2:Eu,
CaI.sub.2:Eu, GdI.sub.3:Ce; and other suitable material including
CdS, CdSe, CdTe, CaWO.sub.4, ZnS:Cu, TmO, ZnSe:Te, ZnS, ZnO,
TiO.sub.2, GaN, GaAs, GaP, InAs, InP, Y.sub.2O.sub.3, WO.sub.3,
ZrO.sub.2, YAlO.sub.3:Ce, Y.sub.2O.sub.3:Eu.sup.3+,
CeMgAl.sub.11O.sub.19:Tb, LaPO.sub.4:Ce, Tb,
GdMgB.sub.5O.sub.10:Ce, Tb, BaMgAl.sub.10O.sub.17:Eu.sup.2+, and
Sr.sub.5(PO.sub.4).sub.3O:Eu.sup.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.sub.3:Ce,
Y.sub.2O.sub.3:Eu.sup.3+, CeMgAl.sub.11O.sub.19:Tb, LaPO.sub.4:Ce,
Tb, GdMgB.sub.5O.sub.10:Ce, Tb, BaMgAl.sub.10O.sub.17:Eu.sup.2+,
Sr.sub.4Al.sub.14O.sub.25:Eu.sup.2+:Dy.sup.3+,
SrAl.sub.2O.sub.4:Eu.sup.2+:Dy.sup.3+,
SrAl.sub.2O.sub.7:Eu.sup.2+:Dy.sup.3+, and
Sr.sub.3Al.sub.2O.sub.6:Eu.sup.2+:Dy.sup.3+; and
Sr.sub.5(PO.sub.4).sub.3Cl:Eu.sup.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.
Description
FIELD OF THE INVENTION
[0001] The present invention is generally in the field of
core-shell nanoparticles, especially metal and ceramic core
nanoparticles, for use in diagnosis and treatment of disease.
BACKGROUND OF THE INVENTION
[0002] Generation of heat in the range of temperature from about
40.degree. C. to about 46.degree. C. (hyperthermia) can cause
irreversible damage to diseased cells, whereas normal cells are not
similarly affected. Three widely investigated methods for inducing
hyperthermia, including radio-frequency waves (U.S. Pat. No.
7,510,555 to Kanzius), magnetic fields and near infrared radiation,
have been utilized. As mentioned in U.S. Pat. No. 7,074,175 to
Handy, "Hyperthermia may hold promise as a treatment for cancer
because it induces instantaneous necrosis (typically called
thermo-ablation) and/or a heat-shock response in cells (classical
hyperthermia), leading to cell death via a series of biochemical
changes within the cell. One particularly advantageous property is
that, in some cases, heating of the local cell environment may be
sufficient to kill the targeted cell but not sufficient to raise
the temperature of the bulk medium.
[0003] Several laboratories have investigated cell-specific
nanoparticle-based hyperthermia based on near infrared radiation
(NIR). Research includes using techniques of NIR to excite gold
nanoparticles and nanoshells, as described in U.S. Pat. No.
6,530,944 to West et al. In the '944 patent, after nanoparticles
are delivered to a tumor or nearby cancer cells, an external NIR
laser of about 800 nm in wavelength is used to excite the gold
shell (plasmon mode), to generate the necessary heat. The choice
and design of core material shifts the natural plasmon resonance of
the gold nanoshell from the 500 nm range (of solid gold
nanoparticles) to the 800 nm range. A 800 nm NIR laser is used for
optimal transmission through mammalian tissue due to "water
windows" for NIR. The essentially energetically inert cores of
these nanomaterials in the '944 patent are made of silica and gold
sulfide, neither of which absorb X-rays in any significant amount.
No example in the '944 patent discusses X-rays, except with respect
to the diagnostic embodiments, in which the shell is doped with
scintillator material as a tag. Such technical approaches are most
likely to be effective for cells in a test tube or for surface
tumors of the skin. However, NIR is of limited practical clinical
value for most cancers because of the inability of safe amounts of
NIR to penetrate more than a few centimeters into the human body.
The '944 patent also discusses the use of scintillation probes that
emit IR and NIR for imaging purposes, but there is no discussion of
attempts at therapeutic heat treatment with such an approach.
[0004] Other researchers have designed core-shell nanoparticles
with phosphors in the core of a gold shell for the purpose of
creating a sensitive diagnostic tag, enhanced by the volume of
atoms that can fit inside the shell. In these cases, the shell is
made to let light from the phosphor out of the shell (not to absorb
it or turn it into heat), such as in the work of Kennedy and
Lakshmana (International Publication No. WO 2011/084641).
Specifically, these authors note that a core-shell nanoparticle
"with a metal shell that does not inhibit phosphorescence from the
phosphor core would further be an advancement as it would also
improve the sensitivity of the application." These inventors design
particles for medical diagnostic purposes with the view that the
generation of heat is an inefficiency, stating "phosphors . . .
used for the purpose of light emission, for example, produce heat
and therefore the light emission efficiency is limited."
[0005] Other researchers have designed core-shell nanoparticles to
serve as diagnostic devices or to deliver focused radiation
treatment. For example, Rondinone et al. (U.S. Patent Application
Publication No. US 2007/0009436) uses a radioactive core inside an
inorganic shell; the shell serves the purposes of i) delivering a
large volume of concentrated radioactive atoms, ii) supplying a
"continuous coating" so that the " . . . radionuclide core remains
undissolved when the encased radionuclide is under physiological
conditions . . . ," iii) allowing radiation to escape from the
particle and iv) allowing targeting moieties to be easily attached
to the particle. These particles do not generate a significant
amount of heat, nor do they use shell materials that facilitate
heating, as heating would suggest inefficiency in emitting
radiation from these radioimmunotherapy nanoparticles.
[0006] Delivering the nanoparticle to the vicinity of the targeted
cell ("targeting") can improve therapeutic efficacy. Beyond simply
injecting the nanoparticles into a region of interest, there are a
wide range of targeting methodologies involving tumor cell surface
molecules, including the conjugation of antibodies to various
therapeutic agents and drugs. The U.S. Food & Drug
Administration (FDA) has approved a number of antibody-based cancer
therapeutics. In summary, there are several methods of targeting,
including monoclonal antibodies (mABs) which are a practical way to
carry a lethal agent specifically to the cancer cell and not to
normal tissue.
[0007] While methodologies for selectively delivering nanoparticles
to target cells are known, existing nanoparticles cannot be
sufficiently heated to kill cells. In order to practically and
effectively treat diseases and disorders using cell-specific
hyperthermia, nanoparticles are needed that are capable of being
selectively targeted to cells and efficiently producing thermal
energy when excitation energy is applied.
[0008] It is therefore an object of the present invention to
provide nanoparticles which are effective and efficient for use in
hyperthermia treatment of diseases and disorders such as cancers,
and which can be targeted for even greater specificity.
[0009] It is a further object of the invention to provide improved
methods of treating diseases and disorders, such as cancer, using
nanoparticles that are both targeted to cells and efficient at
producing thermal energy when an excitation energy is applied to
the particles.
SUMMARY OF THE INVENTION
[0010] Core-excited nanoparticle thermotherapy (CENT) represents a
new paradigm in thermotherapy. The CENT method uses both
core-excitation energy such as ionizing radiation (including
X-rays) and core-shell nanoparticles, preferably formed of metal or
ceramic, specifically designed to absorb such radiation in their
core structure, then transfer energy from the core to the shell, to
heat the shell of the nanoparticle. The heated nanoparticle then
heats the surrounding region to a temperature sufficient to detect,
affect, damage and/or destroy the targeted cell or material. CENT
nanoparticles can be bound to targeting agents that deliver them to
the region of the diseased cell.
[0011] The nanoparticles are core-shell nanoparticles formed from a
core designed to absorb core-exciting energy from an energy source,
and transfer the absorbed energy from the core to the shell to heat
the shell of the nanoparticle. In some cases, the nanoparticles are
designed to absorb core-exciting energy from an external energy
source. In other embodiments, the nanoparticles further contain one
or more materials within the nanoparticle which provides
core-exciting energy.
[0012] Core-shell nanoparticles are formed from a core containing
one or more core-exciting, energy absorbing materials. The
core-exciting, energy absorbing materials absorb core-exciting
energy from an energy source, and subsequently reemit energy. The
energy source may be outside of the nanoparticle, such as X-ray or
gamma ray radiation with an electromagnetic radiation wavelength
ranging from 10.0 nm to 0.0001 nm, 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. Alternatively, the energy say source may be one
or more radionuclides within the nanoparticle, most preferably
within the nanoparticle core.
[0013] Examples of suitable core-exciting, energy absorbing
materials include scintillators, long-lived phosphors, persistent
luminescent materials, and combinations thereof. In certain
embodiments, the core-exciting, energy absorbing materials are any
form of strontium aluminate, such as Sr.sub.aAl.sub.bO.sub.c, where
a, b and c are integers that may vary (e.g.,
Sr.sub.4Al.sub.14O.sub.25, SrAl.sub.2O.sub.4, SrAl.sub.2O.sub.7,
and Sr.sub.3Al.sub.2O.sub.6); any form of strontium aluminate doped
with a rare earth element (RaE), Sr.sub.aAl.sub.bO.sub.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, such as Europium(II)-, Dysprosium(III)-, and
Neodymium(III)-doped Sr.sub.4Al.sub.14O.sub.25, SrAl.sub.2O.sub.4,
SrAl.sub.2O.sub.7, and Sr.sub.3Al.sub.2O.sub.6; any form of
strontium aluminate co-doped with two or more different rare earth
elements (RaEs), Sr.sub.aAl.sub.bO.sub.c:(RaE).sub.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, such
as strontium aluminate co-doped with Europium(II) and
Dysprosium(III) as in
Sr.sub.4Al.sub.14O.sub.25:Eu.sup.2+:Dy.sup.3+,
SrAl.sub.2O.sub.4:Eu.sup.2+:Dy.sup.3+,
SrAl.sub.2O.sub.7:Eu.sup.2+:Dy.sup.3+, and
Sr.sub.3Al.sub.2O.sub.6:Eu.sup.2+:Dy.sup.3+; and strontium
aluminate co-doped with Europium(II) and Neodymium(III) as in
Sr.sub.4Al.sub.14O.sub.25:Eu.sup.2+:Nd.sup.3+,
SrAl.sub.2O.sub.4:Eu.sup.2+:Nd.sup.3+,
SrAl.sub.2O.sub.7:Eu.sup.2+Nd.sup.3+, and
Sr.sub.3Al.sub.2O.sub.6:Eu.sup.2+: Nd.sup.3+; any form of
rare-earth ion-doped gadolinium oxide or oxysulfide phosphor,
Gd.sub.2O.sub.3:RaE.sup.3+ or Gd.sub.2O.sub.2S:RaE.sup.3+, wherein
RaE=La, Lu, Ce, Pr, Nd, Sm, Eu, Tb, Dy, Ho, Er, Tm, or Yb; any
rare-earth (RaE) ion co-doped alkaline earth aluminate,
xMO+yAl.sub.2O.sub.2:RaE' RaE, where x and y are integers, and
M=Ca, Sr, or Ba, and RaE=La, Lu, Ce, Pr, Nd, Sm, Eu, Tb, Dy, Ho,
Er, Tm, or Yb; any rare-earth- or transition-metal-doped metal
halide, including, but not limited to, LaF.sub.3:Ce.sup.3+,
LuF.sub.3:Ce.sup.3+, CaF.sub.2:Mn.sup.2+, CaF.sub.2:Eu.sup.2+,
BaFBr:Eu.sup.2+, BaFBr:Mn.sup.2+, CaPO.sub.4:Mn.sup.2+,
LuI.sub.3:Ce, SrI.sub.2:Eu, CaI.sub.2:Eu, GdI.sub.3:Ce; or any
other suitable material, such as CdS, CdSe, CdTe, CaWO.sub.4,
ZnS:Cu, TmO, ZnSe:Te, ZnS, ZnO, TiO.sub.2,GaN, GaAs, GaP, InAs,
InP, Y.sub.2O.sub.3, WO.sub.3, ZrO.sub.2, YAlO.sub.3:Ce,
Y.sub.2O.sub.3:Eu.sup.3+, CeMgAl.sub.11O.sub.19:Tb, LaPO.sub.4:Ce,
Tb, GdMgB.sub.5O.sub.10:Ce, Tb, BaMgAl.sub.10O.sub.17:Eu.sup.2+,
and Sr.sub.5(PO.sub.4).sub.3Cl:Eu.sup.2+; and combinations
thereof.
[0014] In some cases, the nanoparticles are designed to absorb
core-exciting energy from an external energy source. In these
cases, ionizing radiation, predominantly X-ray radiation, is
applied to the nanoparticles containing a core-exciting energy
absorbing material and an energy conducting shell. However, the
core must be designed to both absorb the excitation energy and then
transfer the energy to heat the shell.
[0015] In certain embodiments, 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 60 eV, more preferably greater than about 120
eV. In preferred embodiments, the one or more core-exciting, energy
absorbing materials is an X-ray absorbing species. In certain
embodiments, the one or more core-exciting, energy absorbing
materials absorbs photons or mass particles of individual energy of
between about 30 keV and 120 keV.
[0016] In the case of nanoparticles designed to absorb core
exciting energy from an external energy source, the one or more
core-exciting energy absorbing species preferably possess an
excited state lifetime which allows them to continue to transfer
energy to the shell of the nanoparticles for some period of time
after the discontinuation of excitation using an external energy
source. In certain embodiments, the one or more core-exciting,
energy absorbing species continue to reemit energy for more than
one minute after the discontinuation of excitation by the external
energy source. In this way, the shell of the nanoparticle continues
to be heated for a period of time, preferably at least one minute,
following the discontinuation of excitation by the external energy
source.
[0017] In some embodiments, the nanoparticles further contain one
or more materials which provide core-exciting energy. For example,
the nanoparticle may further contain one or more radionuclides. In
such cases, the primary source of energy for heating may come from
the one or more radionuclides that are incorporated into the
nanoparticle.
[0018] When one or more radionuclides are incorporated into the
nanoparticles, the radionuclides emit decay products which excite
the one or more core-exciting energy absorbing materials (e.g.,
scintillators). The one or more core-exciting energy absorbing
materials subsequently reemit energy, preferably in the form of
light in the range of 200 nm to 6000 nm.
[0019] One or more radionuclides can be incorporated into the
core-shell nanoparticles in various ways. In certain embodiments,
one or more radionuclides are present within the core of the
core-shell nanoparticle. In these cases, the one or more
radionuclides may be present as a solid mass forming an inner
sphere within the core, as a layer surrounding an inner core
composed of one or more core-exciting energy absorbing materials,
or mixed with one or more core-exciting energy absorbing materials
to form a single core structure within the nanoparticle. One or
more radionuclides can also be incorporated into the shell of the
core shell nanoparticles.
[0020] The one or more radionuclides may emit X-rays, gamma-rays,
electrons (such as Auger electrons or Coster-Kroenig electrons),
alpha particles, beta particles and other typical products of
nuclear transitions. As the one or more radionuclides decay, one or
more core-exciting energy absorbing materials absorb the particles
emitted by the decay of the radionuclides, and emit light at a
frequency that is significantly absorbed by the shell. In this way,
energy is transferred from the nanoparticle core to heat the shell
of the nanoparticle. For example, a cerium- and terbium-doped
lanthanum phosphate (LAP) layer may absorb the decay particles of a
solid inner core of Pd-103 and emit green light into a gold shell,
so as to excite the surface plasmons and generate heat.
[0021] Any suitable radionuclide or radionuclides may be
incorporated into the particle core. Generally, the radionuclides
have a half-life, decay mode, decay energy, and combinations
thereof suitable for incorporation into the core-shell
nanoparticles described herein. In certain embodiments, 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 ten 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.
[0022] Examples of suitable radionuclides which may be incorporated
into the nanoparticles described herein include, but are not
limited to, 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, Sri-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.
[0023] The nanoparticle shell is preferably formed from one or more
metals. Examples of suitable metals include gold, silver, platinum,
palladium, ruthenium, rhodium, and combinations thereof, which
serve as effective nanoshells for heating via plasmon absorption.
The physical and optical parameters of the shell are matched to the
design capabilities of the core material, as discussed below.
[0024] The core and the shell are designed to simultaneously
optimize the internal molecular energy flow such that core-exciting
energy absorbed in the nanoparticle core is converted to heat
emission from the shell. In the case where the energy transfer
between core and shell is via electromagnetic radiation, the one or
more core-exciting energy absorbing materials are selected such
that the emission spectrum of the one or more core-exciting energy
absorbing species overlaps the absorption spectrum of the shell. In
certain embodiments, one or more core-exciting energy absorbing
materials which emit blue light may be combined with a silver shell
which absorbs blue light. In other embodiments, one or more
core-exciting energy absorbing materials which emit green light may
be combined with a gold shell which absorbs green light. In other
cases, an appropriately designed gold shell may be heated by red
light from a scintillator such as Y.sub.2O.sub.3:Eu.sup.3+. Some
materials absorb high frequency ultraviolet radiation and reemit
light in the visible spectrum.
[0025] In certain embodiments, the one or more core-exciting,
energy absorbing materials is selected such that the energy
reemitted by the one or more core-exciting energy absorbing
materials following excitation by the core-exciting energy is
electromagnetic radiation between about 100 nanometers and about
6000 nanometers, more preferably between about 200 nanometers and
about 3000 nanometers, more preferably between 300 nanometers and
2000 nanometers.
[0026] The nanoparticles may employ chemical targeting agents to
deliver them to the target cell or tissue, either in vivo or in
vitro. In the preferred embodiment, the nanoparticles are bound to
a targeting antibody which can further participate, either in vivo
or in vitro, in antigen-antibody binding or binding to the targeted
cell.
[0027] In another embodiment, heat-catalyzed functional agents
(HCFAs) are bound to or associated with the nanoparticle shell or a
targeting support film. HCFAs can be any therapeutic, prophylactic,
or diagnostic agent which is bound to the shell or targeting
support film of the nanoparticle and is released (or reacted) upon
heating of the shell. In a preferred embodiment, the HCFA is an
antineoplastic agent.
[0028] This technology provides practical, cost-effective methods
and nanomaterial compositions for diagnosis and hyperthermia
treatment of disease or disorders. The technology should be
effective to treat disease that has spread throughout the body,
such as metastatic cancers (known as stage IV, in the case of
cancer), even when the disease is in such small amounts or
locations in the body that it is not detectable. The materials and
methods can also be used for imaging, with detection resulting from
either the X-ray absorption or the generation of heat. The
technology is practical, effective, and non-invasive, with minimal
side-effects, and should be usable with existing medical hardware
now widely deployed in hospitals around the world.
BRIEF DESCRIPTION OF THE DRAWINGS
[0029] FIG. 1 is a schematic cross-section (not drawn to scale)
illustrating the design of nanoparticles designed to absorb
external radiation in their core structure, and transfer the
absorbed energy from the core to the shell to heat the outer shell
of the nanoparticle.
[0030] FIG. 2 is a schematic cross-section (not drawn to scale)
illustrating the design of nanoparticles containing one or more
radionuclides and one or more core-exciting energy absorbing
materials.
[0031] FIG. 3 is a plot of the absorbance (in arbitrary units) as a
function of wavelength (in nanometers) of gold nanoparticles of
different diameters (9 nm, dashed black line; 22 nm, dotted line;
48 nm, gray line, and 99 nm, black line). The maximum absorbance
for the gold nanoparticles varies in a range between approximately
500 nm and 600 nm (Taken from Link and EI-Sayed, J. Phys. Chem. B,
103(21):4212, 1999).
[0032] FIG. 4 is a plot of the absorbance (in arbitrary units) of
metal nanoparticles (silver nanoparticles, solid black line; gold
nanoparticles, dotted line; and nanoparticles formed from a 1:1
gold:silver alloy; dashed line) as a function of wavelength (in
nanometers, taken from Pal et al., African Phys. Rev, 1 (Special
Issue--Micrafluidics) (2007)).
[0033] FIG. 5 is a schematic, not drawn to scale, describing
methods of using the particles described herein for the treatment
of a disease or disorder. The nanoparticles (2) contain at least a
core material (3) and a shell material (4). The first step (5)
involves positioning the nanoparticle(s) into the region of the
targeted material (1), which may be, for example, a tissue or cell.
In the case of nanoparticles designed to absorb external radiation,
the next step (6) is exposing the targeted region to a source of
external ionizing radiation, such as an X-ray, which the core,
containing one or more core-exciting, energy absorbing materials,
absorbs. In the case of nanoparticles containing one or more
radionuclides, this step is not required. In these embodiments, the
nanoparticle core contains one or more radionuclides which decay,
emitting particles that are absorbed by one or more core-exciting,
energy absorbing materials located within the nanoparticle. The
next step (7) involves energy transfer from the nanoparticle core
material (the core-exciting, energy absorbing materials) to the
nanoparticle shell for the purpose of heating the shell, through
any of several mechanisms, one being overlap of the core emission
spectrum with the shell absorption spectra (fluorescence resonance
energy transfer, FRET). As the shell is heated, it gives off heat
(8). The heat (8) is transferred from the nanoparticle shell to the
nearby region that includes the targeted material (9). Optionally,
in a further step not illustrated in FIG. 5, the nanoparticles may
be removed from the targeted material. For example, in the case of
nanoparticles administered to a patient, the nanoparticle may be
removed from the patient through magnetic separation from the
blood, whereby blood is taken from one arm of the patient,
filtered, then returned through the other arm, in a procedure
similar in clinical practice to conventional kidney dialysis.
[0034] FIGS. 6A-6B are plots of the X-ray luminescence intensity
(in arbitrary units) of two nano-scintillator materials as a
function of wavelength (in nanometers; taken from Chen and Zhang,
J. Nanoscience and Nanotechnology 6, 1159-1166, 2006). FIG. 6A is a
plot of the X-ray luminescence intensity of BaFBr:Eu.sup.2+,
Mn.sup.2+ nanoparticles (20 nm in diameter). FIG. 6B is a plot of
the X-ray luminescence intensity of LaF.sub.3:Ce.sup.3+
nanoparticles (15 nm in diameter).
[0035] FIG. 7 is a plot of the X-ray emission spectrum (in
arbitrary units) of Europium-activated strontium aluminate as a
function of wavelength (nm). The Europium-activated strontium
aluminate is 0.9 parts Strontium (Sr), 1.0 part Al.sub.2O.sub.3,
and 0.03 parts EuO (Taken from U.S. Pat. No. 3,294,699 to
Lange).
DETAILED DESCRIPTION OF THE INVENTION
[0036] The thermotherapy discussed here is for the imaging and
treatment of diseases, including cancer. Hyperthermia is a
long-established method of treating some diseases, but is most
effective when it can be focused at the cellular or molecular
level. Nanoparticles have been used to generate localized heat near
a target cell, but existing methods have limitations in efficacy,
cost and availability.
[0037] CENT employs core-shell nanoparticles. The core of the CENT
nanoparticles is formed from a material which absorbs core-exciting
energy from an energy source (e.g., one or more core-exciting,
energy absorbing materials), and subsequently reemits energy. The
nanoparticles are designed to absorb core-exciting energy from an
external energy source, or the nanoparticles may further contain
one or more materials within the nanoparticle which provides
core-exciting energy. The shell, which surrounds the particle core,
absorbs the energy reemitted from the one or more core-exciting
energy absorbing materials, emitting heat.
[0038] In this way, the energy absorbed or generated by the core is
transferred from the nanoparticle core to nanoparticle the 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.
[0039] CENT nanoparticles can be bound to targeting agents that
deliver them to the region of the diseased cell. The method also
may include the removal of nanoparticles from the body. The method
also enables the imaging of targeted cells or material.
[0040] These nanoparticles provide several advantages over
previously described technologies. In the case of nanoparticles
designed to absorb external energy, the nanoparticles can be used
in medical treatments in which the core-shell nanoparticles are
exposed to X-rays for the purpose of producing therapeutic amounts
of heat. In these embodiments, the nanoparticles have a core-shell
configuration with a core that absorbs X-rays for the purpose of
heating the shell. In many other methods of cell-specific
hyperthermia, such as near infrared ("NIR"), the nanoparticle core
is inert and functions primarily to shift the maximum of the
(plasmon resonance) absorption spectrum of the gold shell to higher
wavelength, so as to overlap with an externally applied laser, at a
frequency chosen in consideration of the "water window."
[0041] In CENT, energy flows from the nanoparticle core, where
core-exciting energy is absorbed, to the nanoparticle shell, which
heats the targeted cells or tissue. This is in contrast to many
other nanomaterials used for hyperthermia, where the plasmon
resonance of the shell, which is typically gold, is directly
excited by external fields, whether electric, magnetic,
radiofrequency ("RF") radiation or NIR. In these instances, energy
flows, if at all, from the shell to the core.
[0042] The nanoparticles can be removed from the blood if desired.
CENT can be conducted using diagnostic and treatment equipment
commonly found in hospitals. CENT can combine therapy and
diagnostics, in that X-ray (or gamma-ray) absorption is the basis
for both diagnostic tools, such as CT scans, and for treatment.
CENT can be coupled with diagnostic tools, such as PET-CT scanners,
to measure the efficacy of the method "in real time" and to
determine the duration of the treatment session. In addition, the
nanoparticle design, irradiation regime, and combinations thereof
can be customized for a given disease and patient.
I. DEFINITIONS
[0043] "Core-Excited Nanoparticle Thermotherapy" (CENT), as used
herein refers to a method of thermotherapy which involves the use
of core-excitation energy, such as ionizing radiation, and
core-shell nanoparticles, preferably formed of metal or ceramic,
specifically designed to absorb such radiation in their core
structure, then transfer energy from the core to the shell, to heat
the shell of the nanoparticle. When core-exciting energy is applied
to the nanoparticles, the nanoparticle heat the surrounding region
to a temperature sufficient to detect, affect, damage and/or
destroy a targeted cell or material.
[0044] "Nanoparticle," as used herein, generally refers to a
particle of any shape having a diameter from about 1 nm up to, but
not including, about 1 micron, more preferably from about 5 nm to
about 500 nm, most preferably from about 10 nm to about 200 nm.
Nanoparticles can be of any shape, such as a sphere ("nanosphere"),
rod ("nanorod"), cube ("nanocube"), or ovoid ("nanoovoid").
[0045] "Core," as used herein, refers to all layers or structures
forming a core-shell nanoparticle which are surrounded by or
encapsulated within a shell.
[0046] "Shell," as used herein, refers to a metal or ceramic layer
which surrounds the core of a core-shell nanoparticle, and is
designed to be heated.
[0047] "Core-Shell Nanoparticle," as used herein, refers to a
nanoparticle formed from at least two different structures (a core
and a shell) formed from at least two different materials, as well
as any external attachments to the shell (such as one or more
targeting agents, one or more heat-catalyzed functional agents, a
targeting support film, or combinations thereof.
[0048] "Core-Exciting, Energy Absorbing Material," as used herein,
refers to a material present in the core of a core-shell
nanoparticle which absorbs core-exciting energy from an energy
source.
[0049] "Radionuclide," as used herein, refers to an atom with an
unstable nucleus, which is a nucleus characterized by excess energy
available to be imparted either to a newly created radiation
particle within the nucleus or to an atomic electron. The
radionuclide, in this process, undergoes radioactive decay, and
emits gamma ray(s), subatomic particles, X-rays, atomic electrons,
or combinations thereof. Some of these particles constitute
ionizing radiation. Radionuclides can be naturally occurring or
artificially produced.
[0050] "Scintillator," as used herein, refers to a material which
luminesces when excited by radiation or particles of energy greater
than 100 eV. Examples of scintillators include
Y.sub.2O.sub.3:Eu.sup.3+, CeMgAl.sub.11O.sub.19:Tb,
La.sub.2PO.sub.4:Ce, Tb, GdMgB.sub.5O.sub.10:Ce, Tb.sup.+,
BaMgAl.sub.10O.sub.17:Eu.sup.2+, and
Sr.sub.5(PO.sub.4).sub.3Cl:Eu.sup.2+.
[0051] "Energy Source," as used herein, refers to any form of
excitation, whether from within a nanoparticle or from an external
source. Examples of energy sources include radionuclides,
high-energy particles and radiation from all regions of the
electromagnetic spectrum; ultrasound, electric fields and magnetic
fields.
[0052] "Electromagnetic Radiation," as used herein, refers to
radiation having propagating perpendicular electric and magnetic
fields, and is limited to the range of radiofrequency waves through
cosmic rays.
II. NANOPARTICLES AND ENERGY SOURCES FOR USE IN THERAPEUTIC
METHODS
[0053] The CENT method employs core-shell nanoparticles which can
be designed to either absorb energy from an external energy source
or generate energy within the particle core. This energy is then
transferred from the nanoparticle core to the nanoparticle shell,
where heat is generated.
[0054] As described below, the mechanisms by which heat is
generated between these materials determines the composition and
relative amounts of the shell and core materials.
[0055] A. Core-Shell Nanoparticles
[0056] The nanoparticles described herein are formed from a core
containing one or more core-exciting energy absorbing materials
which absorbs core-exciting energy, and then reemits energy, and a
shell surrounding, which is formed from one or more materials which
absorbs the energy reemitted from the nanoparticle core, and then
emits heat in sufficient quantity to kill or damage cells or
tissue.
[0057] In some embodiments, the nanoparticle is a core-shell
nanoparticle designed to absorb energy from an external energy
source in their core structure, and transfer the absorbed energy
from the core to the shell to heat the outer shell of the
nanoparticle. Nanoparticles of this type are schematically
illustrated in FIG. 1. The nanoparticles contain a core material
(20) formed from one or more core-exciting, energy absorbing
materials. The nanoparticles also contain a shell (23) formed from
a material to which the energy absorbed by the one or more
core-exciting, energy absorbing materials is transferred. In some
embodiments, the nanoparticle can optionally contain one or more
additional layers, including a core stabilizing layer (21) to
improve and/or ensure particle stability, a core-shell binding
layer (22) to improve the binding between the core and the inner
shell layer, and combinations thereof. Such layers are typically
small, normally being less than 10 nm in thickness. The outer shell
surface may need a supporting film (24), such as a polyethylene
glycol (PEG) film, to allow one or more different types of
targeting agents (25) to be bound to the particle surface.
Heat-catalyzed functional agents (26), such as chemotherapy
compounds, may also be bound to the shell or targeting support film
and released (or reacted) upon heating of the shell.
[0058] In other embodiments, the nanoparticle further contains one
or more materials which generate core-exciting energy within the
particle core. Nanoparticles of this type are schematically
illustrated in FIG. 2. The nanoparticles contain a core material
(40) formed from one or more radionuclides in combination with one
or more core-exciting energy absorbing materials. In some cases,
the one or more radionuclides and the one or more core-exciting
energy absorbing materials are mixed together, forming a single
core. In these cases, the surrounding core layer (41) is not
required. In preferred embodiments, the core (40) is formed from
one or more radionuclides, and the core is surrounded by a layer
(41) formed from one or more core-exciting energy absorbing
materials (i.e., a core-exciting energy absorbing layer). In other
cases, the core (40) is formed from one or more core-exciting
energy absorbing materials, and the core is surrounded by a layer
(41) formed from one or more radionuclides (i.e., a radionuclide
layer). The nanoparticles also contain a shell (43) formed from a
material to which the energy generated in the nanoparticle core is
transferred. In some is embodiments, the nanoparticle can
optionally contain one or more additional layers (42), including
stabilizing layers to improve and/or ensure particle stability,
interface binding layers to improve the binding between two
adjacent layers in the nanoparticle, and combinations thereof. Such
layers are typically small, normally being less than 10 nm in
thickness. The outer shell surface may need a supporting film (44),
such as PEG, to allow one or more different types of targeting
agents (45) to be bound to the particle surface. Heat-catalyzed
functional agents (46), such as chemotherapy compounds, may also be
bound to the shell or targeting support film and released (or
reacted) upon heating of the shell.
[0059] The nanoparticles typically have an average length or
average diameter less than 1000 nm, preferably less than 500 nm,
and most preferably less than 300 nm. The core material can be any
diameter but is preferably less than 1000 nanometers, more
preferably less than 500 nanometers. The thickness of the shell
material is preferably less than 1000 nanometers, and most
preferably less than 200 nanometers. In the most preferred
embodiment, the nanoparticles are less than 200 nanometers, which
allows them to avoid being metabolized by the liver or kidneys.
[0060] The main criteria for matching the core material to the
shell material is that the radiation emission (wavelength
distribution bell curve) from the core material(s) should overlap
the absorption spectrum (wavelength distribution bell curve) of the
shell materials, as described in more detail below.
[0061] There are several potential mechanisms of energy flow within
these core-shell nanomaterials. One approach to facilitate transfer
of X-ray energy within the core-shell structure is to induce core
emission of radiation into the shell (FRET). There are several
mechanisms of emissions from material that absorb X-rays, commonly
referred to as scintillator materials. These mechanisms of
scintillator emission of radiation include emissions from
luminescent activator ions (e.g., Ce.sup.3+, Eu.sup.2+), from
self-trapped excitons, from excitons bound to an isoelectronic hole
trap (e.g., CdS:Te), from charge-transfer emissions (e.g.,
CaWO.sub.4), and from core-valence transitions (e.g., BaF.sub.2).
In scintillator materials that do not contain a luminescent ion and
where a specific emission mechanism is unknown, the event is
considered to be self-activated. In short, emission is just one
form of energy transfer by which energy in the core material can be
transferred to (absorbed by) the shell.
[0062] There are several considerations in the design of the
nanoparticle shell. Along with safety, the shell may be selected to
be i) transparent to X-ray or gamma-rays, ii) have a plasmon
absorption spectrum that overlays the core emission (FRET), iii) be
a good conductor of heat, and iv) allow attachment (if needed) of a
targeting moiety and other species as needed. In the preferred
embodiment, the shell comprises a significant amount of gold,
silver, platinum, palladium, rhodium, ruthenium, or mixtures
thereof. The plasmon absorbance spectrum of solid gold particles of
about 10 nm in diameter have a maximum at around 520 nm, as
indicated in FIG. 3. Silver has an absorption peak near 350-400 nm
(FIG. 4). Zhou et al. have shown that modification in design of
core material within a gold shell, such as adjusting the ratio of
the core radius to the shell thickness (as well as the material
composition of the core), can push the maximum absorbance of the
gold shell into the range of 600 nm to 900 nm (Zhou, et al. Phys.
Rev. B. 50:12052-12056 (1994)). In general, metal nanoshells have
the property of having a tunable optical resonance (movable
absorbance peak), which provides the opportunity to match core and
shell energy to each other.
[0063] The shell and core structures must be designed as a single
system. The geometric design of the core-shell structure improves
energy flow from core to shell in the form of emitted radiation
from the core because it minimizes energy loss due to emitted
photons "missing" the shell. Almost 100% of the energy emitted is
transmitted to the shell. However, if the X-ray absorbing material
is placed on the shell, only a portion of the radiation emitted
from this material would be emitted in the direction of the shell.
Since the core-shell energy flow is within a particle, in the case
of energy redistribution via intraparticle emission as discussed
here (FRET), there is no need for fitting the excitation and
absorbance into a "water window" (800-1300 nm and 1600-1850 nm)
constraint that forces a preference for NIR over higher frequency
(lower wavelength, higher energy) portions of the electromagnetic
spectrum. For example, cores that emit in the visible or UV, and
shells that absorb in the UV or visible, may be more preferred than
NIR resonances for several reasons.
[0064] 1. Core-Exciting Energy Absorbing Materials
[0065] Core-shell nanoparticles are formed from a core containing
one or more core-exciting, energy absorbing materials. The
core-exciting, energy absorbing materials absorb core-exciting
energy from an energy source, and subsequently reemit energy. The
energy source may be outside of the nanoparticle, such as X-ray or
gamma ray radiation with an electromagnetic radiation wavelength
ranging from 10 nm to 0.0001 nm, 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. Alternatively, the energy say source may be one
or more radionuclides within the nanoparticle.
[0066] Core-exciting energy absorbing materials may either generate
intrinsic luminescence upon excitation by incident radiation or do
so as a consequence of doping with ions, such as Europium, that
serve the role of activators of luminescence. The incident
radiation generates electron-hole pairs in the material. The
relaxation of these electron-hole pairs results from a range of
possible multistep mechanisms in the emission of photons in the
ultraviolet, visible or near-infrared range of the spectrum. The
mechanism of relaxation of ions excited by energy transfer from
electron-hole pairs may involve either allowed or forbidden
radiative transitions between quantized ionic or atomic energy
levels. In the case of intrinsically luminescent core materials,
the mechanism may involve the recombination of electron-hole pairs,
radiative decay of free or trapped excitons, or core-valence
transitions.
[0067] In some embodiments, the core-exciting energy absorbing
materials are capable of undergoing scintillation luminescence,
defined here as the reemission of electromagnetic radiation when
excited by an energy source such as X-rays or gamma-rays. The
nanoparticle core material can absorb energy then emits
electromagnetic radiation as a result of a dopant ion, present at a
minimum level to serve as an activator of luminescence. In certain
embodiments, the nanoparticle core contains a material doped with
at least one rare-earth- or lanthanide-series (La, Ce, Pr, Nd, Pm,
Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu) element of the periodic
table, in an amount greater than about 0.05 mass percent of the
nanoparticle, more preferably greater than about 0.1 mass percent
of the nanoparticle, more preferably greater than about 0.15 mass
percent of the nanoparticle.
[0068] Examples of suitable core-exciting, energy absorbing
materials include scintillators, long-lived phosphors, persistent
luminescent materials, and combinations thereof. In certain
embodiments, the core-exciting, energy absorbing materials are any
form of strontium aluminate, such as Sr.sub.aAl.sub.bO.sub.c, where
a, b and c are integers that may vary (e.g.,
Sr.sub.4Al.sub.14O.sub.25, SrAl.sub.2O.sub.4, SrAl.sub.2O.sub.7,
and Sr.sub.3Al.sub.2O.sub.6); any form of strontium aluminate doped
with a rare earth element (RaE), Sr.sub.aAl.sub.bO.sub.c:RaE,
wherein a, b and c are integers that may vary and RaE=Lu, La, Ce,
Pr, Nd, Sm, Eu, Tb, Dy, Ho, Er, Tm, or Yb in one or more oxidation
states, such as Europium(II)-, Dysprosium(III)-, and
Neodymium(III)-doped Sr.sub.4Al.sub.14O.sub.25, SrAl.sub.2O.sub.4,
SrAl.sub.2O.sub.7, and Sr.sub.3Al.sub.2O.sub.6; any form of
strontium aluminate co-doped with two or more different rare earth
elements (RaEs), Sr.sub.aAl.sub.bO.sub.c:(RaE).sub.2, wherein a, b
and c are integers that may vary and RaE=Lu, La, Ce, Pr, Nd, Sm,
Eu, Tb, Dy, Ho, Er, Tm, or Yb in one or more oxidation states, such
as strontium aluminate co-doped with Europium(II) and
Dysprosium(III) as in
Sr.sub.4Al.sub.14O.sub.25:Eu.sup.2+:Dy.sup.3+,
SrAl.sub.2O.sub.4:Eu.sup.2+:Dy.sup.3+,
SrAl.sub.2O.sub.7:Eu.sup.2/:Dy.sup.3+, and
Sr.sub.3Al.sub.2O.sub.6:Eu.sup.2+:Dy.sup.3+; and strontium
aluminate co-doped with Europium(II) and Neodymium(III) as in
Sr.sub.4Al.sub.14O.sub.25:Eu.sup.2+:Nd.sup.3+,
SrAl.sub.2O.sub.4:Eu.sup.2+:Nd.sup.3+,
SrAl.sub.2O.sub.7:Eu.sup.2+Nd.sup.3+, and
Sr.sub.3Al.sub.2O.sub.6:Eu.sup.2+: Nd.sup.3+; any form of
rare-earth ion-doped gadolinium oxide or oxysulfide phosphor,
Gd.sub.2O.sub.3:RaE.sup.3+ or Gd.sub.2O.sub.2S:RaE.sup.3+, wherein
RaE=Lu, La, Ce, Pr, Nd, Sm, Eu, Tb, Dy, Ho, Er, Tm, or Yb; any
rare-earth (RaE) ion co-doped alkaline earth aluminate,
xMO+yAl.sub.2O.sub.2: RaE.RaE, where x and y are integers, and
M=Ca, Sr, or Ba, and RaE=Lu, La, Ce, Pr, Nd, Sm, Eu, Tb, Dy, Ho,
Er, Tm, or Yb; any rare-earth- or transition-metal-doped metal
halide, including, but not limited to, LaF.sub.3:Ce.sup.3+,
LuF.sub.3:Ce.sup.3+, CaF.sub.2:Mn.sup.2+, CaF.sub.2:Eu.sup.2+,
BaFBrEu.sup.2+, BaFBr:Mn.sup.2/, CaPO.sub.4:Mn.sup.2+,
LuI.sub.3:Ce, SrI.sub.2:Eu, CaI.sub.2:Eu, GdI.sub.3:Ce; or any
other suitable material, such as CdS, CdSe, CdTe,
CaWO.sub.4,ZnS:Cu, TmO, ZnSe:Te, ZnS, ZnO, TiO.sub.2, GaN, GaAs,
GaP, InAs, InP, Y.sub.2O.sub.3, WO.sub.3, ZrO.sub.2, YAlO.sub.3:Ce,
Y.sub.2O.sub.3:Eu.sup.3+, CeMgAl.sub.11O.sub.19:Tb, LaPO.sub.4:Ce,
Tb, GdMgB.sub.5O.sub.10:Ce, Tb, BaMgAl.sub.10O.sub.17:Eu.sup.2+,
and Sr.sub.5(PO.sub.4).sub.3Cl:Eu.sup.2+; and combinations
thereof.
[0069] These materials can be made by chemical synthesis, solid
state reaction, other methods, or any combination thereof. In some
embodiments, the core is any form of strontium aluminate doped with
Europium(II), such as Sr.sub.4Al.sub.14O.sub.25:Eu.sup.2+,
SrAl.sub.2O.sub.4:Eu.sup.2+, SrAl.sub.2O.sub.7:Eu.sup.2+, or
Sr.sub.3Al.sub.2O.sub.6:Eu.sup.2+. In some embodiments, the core is
any of strontium aluminate co-doped with Europium(II) and
Dysprosium(III), such as
Sr.sub.4Al.sub.14O.sub.25:Eu.sup.2+:Dy.sup.3+,
SrAl.sub.2O.sub.4:Eu.sup.2+:Dy.sup.3+,
SrAl.sub.2O.sub.7:Eu.sup.2+:Dy.sup.3+, or
Sr.sub.3Al.sub.2O.sub.6:Eu.sup.2+:Dy.sup.3+. In some embodiments,
the core material is a semiconductor nanomaterial such as ZnS, ZnO,
or TiO.sub.2. In preferred embodiments, the core is any form of
strontium aluminate Sr.sub.wAl.sub.xO.sub.y doped with Eu.sup.2+,
Dy.sup.3+, Nd.sup.3+, or combinations thereof, wherein the ratio of
"y/x" is from 1 to 10 and/or the ratio "w/x" is from 1 to 10 (e.g.,
Sr.sub.4Al.sub.14O.sub.25,SrAl.sub.2O.sub.4, SrAl.sub.2O.sub.7, and
Sr.sub.3Al.sub.2O.sub.6 doped with Eu.sup.2+, Dy.sup.3+, Nd.sup.3+,
or combinations thereof.
[0070] In certain preferred embodiments, the one or more
core-exciting energy absorbing materials are AlO.sub.3:Ce,
Y.sub.2O.sub.3:Eu.sup.3+, CeMgAl.sub.11O.sub.19:Tb, LaPO.sub.4:Ce,
Tb, GdMgB.sub.5O.sub.10:Ce, Tb, BaMgAl.sub.10O.sub.17:Eu.sup.2+,
Sr.sub.5(PO.sub.4).sub.3Cl:Eu.sup.2+, or combinations thereof.
[0071] In certain embodiments, the one or more core-exciting,
energy absorbing materials absorbs a significant amount of photons
or mass particles of individual energy of greater than about 1 eV,
more preferably greater than about 6 eV, more preferably greater
than about 60 eV, more preferably greater than about 120 eV, more
preferably greater than about 500 eV, more preferably greater than
about 1 keV, more preferably greater than about 30 keV. In
preferred embodiments, the one or more core-exciting, energy
absorbing materials is an X-ray absorbing species. In certain
embodiments, the one or more core-exciting, energy absorbing
materials absorbs photons or mass particles of individual energy of
between about 30 keV and 120 keV.
[0072] In the case of nanoparticles designed to absorb core
exciting energy from an external energy source, the one or more
core-exciting energy absorbing species preferably possess an
excited state lifetime which allows them to continue to transfer
energy to the shell of the nanoparticles for some period of time
after the discontinuation of excitation using an external energy
source. In certain embodiments, the one or more core-exciting,
energy absorbing species continue to reemit energy for more than
one minute after the discontinuation of excitation by the external
energy source. In this way, the shell of the nanoparticle continues
to be heated for a period of time, preferably at least one minute,
following the discontinuation of excitation by the external energy
source.
[0073] In certain embodiments, the one or more core-exciting,
energy absorbing materials is selected such that the energy
reemitted by the one or more core-exciting energy absorbing
materials following excitation by the core-exciting energy is
electromagnetic radiation between about 100 nanometers and about
6000 nanometers, more preferably between about 200 nanometers and
about 3000 nanometers, more preferably between about 250 nanometers
and about 3000 nanometers, more preferably between 300 nanometers
and 2000 nanometers, more preferably between 300 nanometers and
1000 nanometers.
[0074] 2. Radionuclides
[0075] In some embodiments, the nanoparticles further contain one
or more materials within the nanoparticle which provides
core-exciting energy. In certain embodiments, the nanoparticle may
further contain one or more radionuclides. In such cases, the
primary source of energy for heating may come from the one or more
radionuclides that are incorporated into the nanoparticle.
[0076] One or more radionuclides can be incorporated into the
core-shell nanoparticles in various ways. In certain embodiments,
one or more radionuclides are present within the core of the
core-shell nanoparticle. In these cases, the one or more
radionuclides may be present as a solid mass forming an inner
sphere within the core, as a layer surrounding an inner core
composed of one or more core-exciting energy absorbing materials,
or mixed with one or more core-exciting energy absorbing materials
to form a single core structure within the nanoparticle. One or
more radionuclides can also be incorporated into the shell of the
core shell nanoparticles. In these embodiments, the one or more
radionuclides in the nanoparticle shell may both excite the one or
more core-exciting energy absorbing materials and affect the target
cells or tissue.
[0077] In the case of nanoparticles containing both a radionuclide
and a core-exciting energy absorbing material, it is important to
realize that both these components and the shell material must all
be designed together. In these systems, energy flows 1) from the
radionuclide to the core-exciting energy absorbing material, in the
form of radionuclide decay particles which are absorbed by the
core-exciting energy absorbing material (e.g., a scintillator), 2)
from the core-exciting energy absorbing material to the shell, in
the form of electromagnetic radiation emitted by the core-exciting
energy absorbing material and absorbed by the shell to produce heat
(from surface plasmon modes excited by visible light), and 3) heat
from the shell to the nearby targeted elements. For example, a
cerium- and terbium-doped lanthanum phosphate (LAP) layer may
absorb the decay particles of a solid inner core of Pd-103 and emit
green light into a gold shell, so as to excite the surface plasmons
and generate heat.
[0078] The one or more radionuclides may emit particles, such as
alpha particles, beta particles, X-rays, gamma-rays, atomic
electrons, Coster-Kronig electrons, Auger electrons, neutrons, and
combinations thereof. One or more of the core-exciting energy
absorbing materials described above, absorb the particles emitted
by the decay of the radionuclide, and emit light at a frequency
that is significantly absorbed by the shell. In this way, energy is
transferred from the nanoparticle core to heat the shell of the
nanoparticle.
[0079] Any suitable radionuclide or radionuclides may be
incorporated into the nanoparticle. Generally, the radionuclides
have a half-life, decay mode, decay energy, and combinations
thereof suitable for incorporation into the core-shell
nanoparticles described herein. In certain embodiments, 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
one hour and less than about ten 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.
[0080] Examples of suitable radionuclides which may be incorporated
into the nanoparticles described herein include 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.
[0081] 3. Shell Materials
[0082] The nanoparticle shell is preferably formed from one or more
metals; however, ceramics which possess surface plasmon modes can
also be used. Examples of suitable metals include gold, silver,
platinum, palladium, rhodium, ruthenium, and combinations thereof,
which serve as effective nanoshells for heating via plasmon
absorption. Ceramic semi-conductors materials, such as ZnO and
TiO.sub.2, are also potentially useful because of their plasmonic
modes. The physical and optical parameters of the shell are matched
to the design capabilities of the core material, as discussed
below.
[0083] The core and the shell are designed to simultaneously
optimize the internal molecular energy flow such that core-exciting
energy absorbed in the nanoparticle core is converted to heat
emission from the shell. In the case where the energy transfer
between core and shell is via electromagnetic radiation, the one or
more core-exciting energy absorbing materials are selected such
that the emission spectrum of the one or more core-exciting energy
absorbing species overlaps the absorption spectrum of the shell. In
certain embodiments, one or more core-exciting energy absorbing
materials which emit blue light may be combined with a silver shell
which absorbs blue light. In other embodiments, one or more
core-exciting energy absorbing materials which emit green light may
be combined with a gold shell which absorbs green light.
[0084] 4. Additional Layers within the Nanoparticles
[0085] In addition to the core and shell, the nanoparticle
described above can optionally contain one or more additional
layers. In some embodiments, the nanoparticle core is surrounded by
or has integrated into a core stabilizer (e.g., a film or covering
layer to ensure the hydrolytic stability of the core). In some
embodiments, the nanoparticle contains a core-shell binder (e.g., a
film or layer between the nanoparticle core and shell or between
layers of the core that facilitates binding of the core layers
and/or the core to the inner layer of the nanoparticle shell).
Non-limiting examples of such films include phosphates and amines.
In some embodiments, the shell of the nanoparticle is coated with a
targeting support film (e.g., polyethylene glycol) which serves as
a point of attachment for targeting ligands and/or HCFAs.
Additional particle layers are typically small, normally less than
10 nm in thickness, and are introduced into the particle without
causing significant detriment to energy flow between the core and
shell.
[0086] B. Energy Sources and Particle Design
[0087] The nanoparticles can be excited by any suitable energy
source, including radionuclides, high-energy particles and
radiation from all regions of the electromagnetic spectrum;
ultrasound, electric fields and magnetic fields. Such sources can
be used in exciting atoms, molecules, chemical complexes, composite
particles or nanomaterials. The term "exposure" herein means an
irradiation regime, for either diagnostic or therapeutic purposes,
that may include i) single events or multiple events, ii) in one
session or many sessions over many years, or iii) involve a single
particle or photon or a wide spectral range of photons.
[0088] In certain embodiments, the energy source is an X-ray. A
suitable X-ray is any electromagnetic radiation that is sufficient
to pierce the human body; preferable X-rays are those with
wavelengths less than 10 nanometers, more preferably those with
wavelengths between 10.0 and 0.001 nanometers. The power and
pulsing of the X-ray must be sufficient to bring about the desired
heating of the target cell, which may vary among diseases and
patients. X-ray devices that may be used in the methods herein
include conventional commercial X-ray units commonly used for
diagnostic or therapeutic purposes, computed-tomography (CT)
scanners, full-body scanners or even X-ray lasers. X-rays may be
products of radionuclide decay.
[0089] X-rays are advantageous because of both their ability to
penetrate through the entire body and the amount of energy
contained within the X-ray photon. But other high-energy sources,
such as gamma rays, and high-energy particles can also be used. The
core material of the nanoparticle should be chosen to both absorb
the energy and then direct the energy flow into exciting a heating
mode of the shell so as to generate heat.
[0090] In certain embodiments, the energy source is a gamma ray. A
suitable range of gamma-ray radiation is an amount sufficient to
pierce the human body and excite the nanoparticle core material, to
begin step 2 of the process, as outlined in FIG. 5. Electromagnetic
radiation in the wavelength range of 0.01 to 0.00001 nm is
typically considered gamma radiation.
[0091] In some cases, the energy source is a high energy particle.
High-energy particles include positrons, such as those used in
positron emission tomography (PET) scans, and high-energy protons
and electrons and are useful as sources of energy.
[0092] As described above, the energy source for particle heating
can also be one or more radionuclides incorporated within the
nanoparticles. Radionuclides are atoms with unstable nuclei, which
are nuclei characterized by excess energy available to be imparted
either to a newly created radiation particle within the nucleus or
to an atomic electron. Radionuclides undergo radioactive decay,
emitting gamma ray(s), X-rays, subatomic particles, or combinations
thereof. Some of these particles constitute ionizing radiation.
Radionuclides occur naturally, and can also be artificially
produced. Many types of high-energy particles can be emitted from
radionuclides, including those discussed below. Alpha particles are
charged particles with mass and charge equal to a helium nucleus,
which consists of two protons and two neutrons but no electrons. A
beta particle is a negatively or positively charged electron
(negatron or positron) that is emitted from the nucleus,
simultaneously with a neutrino. Coster-Kroenig and Auger electrons
are atomic electrons that are emitted from the atom as a result of
a transitions occurring within the K- and L-shells of the atom.
Neutrons are located in the nucleus and have mass similar to that
of a proton but carry no charge.
[0093] Ionizing radiation consists of particles or electromagnetic
waves that are energetic enough to detach electrons from atoms or
molecules, thereby ionizing them. Direct ionization from the
effects of single particles or single photons produces free
radicals, which are atoms or molecules containing unpaired
electrons, that tend to be especially chemically reactive due to
their electronic structure. The degree and nature of such
ionization depends on the energy of the individual particles
(including photons), not on their number (intensity). In the
absence of heating or multiple absorption of photons, an intense
flood of particles or particle-waves will not cause ionization if
each particle or particle-wave does not carry enough individual
energy to be ionizing (e.g., a high-powered radio beam).
Conversely, even very low-intensity radiation will ionize, if the
individual particles carry enough energy (e.g., a low-powered X-ray
beam). Roughly speaking, particles or photons with energies above a
few electron volts (eV) are ionizing, no matter what their
intensity. Examples of ionizing particles are alpha particles, beta
particles, neutrons, and cosmic rays. The ability of an
electromagnetic wave (photons) to ionize an atom or molecule
depends on its frequency, which determines the energy of its
associated particle, the photon. Radiation from the
short-wavelength end of the electromagnetic spectrum,
high-frequency ultraviolet, X-rays, and gamma rays, is ionizing,
due to their composition of high-energy photons. Lower-energy
radiation, such as visible light, infrared, microwaves, and radio
waves, are not ionizing.
[0094] A scintillator is a material which exhibits the property of
luminescence when excited by ionizing radiation. Luminescent
materials, when struck by an incoming particle, absorb its energy
and scintillate, i.e., reemit the absorbed energy in the form of a
small flash of light, typically in the visible range. If the
reemission occurs promptly, i.e., within the approximately
10.sup.-8s required for an atomic transition, the process is called
fluorescence. Sometimes, the excited state is metastable, so the
relaxation back out of the excited state is delayed, necessitating
anywhere from a few microseconds to hours depending on the
material. The process then corresponds to either one of two
phenomena, depending on the type of transition and hence the
wavelength of the emitted optical photon: delayed fluorescence or
phosphorescence (also called after-glow). In order to supply a
source of continuous heating of the targeted material to induce
hyperthermia, delayed fluorescence and phosphorescence offer the
ability for continued heating of the nanoparticle shell from the
inside. A third approach is to use a sequence of high luminosity
X-ray scintillations.
[0095] In embodiments that employ external X-rays, there are two
basic approaches to the design of the core-shell nanoparticle if
FRET is the method of intraparticle energy flow from the core to
the shell. The first approach is to use high luminosity materials
that emit large amounts of energy, but only for a short time after
the excitation pulse (here the X-ray) is terminated. Repeated
pulses of X-ray excitation are required for shell heating. The
second approach is to use materials that emit for much longer
periods of time but at a lower intensity. More than one excitation
dose of (X-ray) radiation may be necessary and applied. Within the
core material, the energy depth of electron traps, and the number
of electron traps, in the nanomaterial are the main factors in
designing a nanomaterial with long and intense afterglow
performance. (Chang et al. J. of Alloys and Compounds; 415:220-224
(2006)).
[0096] For some diseases, a less rapid elevation in temperature,
along with a less elevated temperature level that is sustained over
longer time periods, offers more selective destruction of targeted
cells, than does rapid high-powered heating. Therefore, the CENT
treatment paradigm includes nanoparticle designs and irradiation
schemes that cover the extremes of treatment approaches, from rapid
heating and destruction of targeted species (seconds) to much
longer periods (days) of continuous therapeutic heating by CENT
nanoparticles.
[0097] In the first approach above, the nanoparticle core is made
from high luminosity scintillation material, which is then
subjected to a series of X-ray pulses over time to heat the
nanoshell. X-ray excited scintillation luminescence is the common
term given to this excitation. Moses et al., IEEE Trans. Nucl Sci.,
NS-45, 462, 1998, discuss dense infrared emitting scintillators.
The infrared (and NIR) radiation band is just one portion of the
electromagnetic spectrum that can be used, but is useful as an
example because of the data summarized in Table 1. More
specifically, in Tables 1 and 2 of the Moses et al. publication,
the authors note that rare earth elements and other specific ions,
when used as dopants into the proper host material, can have
intense room temperature luminescent emissions in the 200-1100 nm
range. The website http://scintillator.lbl.gov lists scintillator
properties, from which Table 1 below was constructed. The first
entry in Table 2 is of LuI.sub.3, doped with Ce. The mechanism of
scintillation is based on the Ce.sup.3+ ion. This material has high
luminosity in that 98,000 photons at 540 nm (visible) are emitted
for every MeV of X-ray energy that is absorbed; but the emission is
relatively long for scintillation (a duration of 10 microseconds).
The binding of this material within a gold or silver shell is
guided by the reported synthesis of a hybrid nanoparticle of AgI
and gold (Au), (J. Phys. Chem. 104, 4031 (2000)), offering evidence
of metal iodides binding with gold.
TABLE-US-00001 TABLE 1 X-ray Excitation of High Luminosity
Scintillation Materials Emission Photons/ duration Emission MeV
(nanoseconds, Peak Formula Mechanism Luminosity ns) (nanometers)
LuI.sub.3:Ce Ce3+ 98,000 10 microseconds 540 nm SrI.sub.2:Eu Eu2+
120,000 1200 ns 435 nm CaI.sub.2:Eu Eu2+ 86,000 790 ns 470 nm
GdI.sub.3:Ce Ce3+ 89,000 33 ns 563 nm
[0098] U.S. Pat. No. 4,499,005 to McColl et al. discloses the use
of thulium (Tm), along with silver coactivated zinc sulfide in an
infrared-emitting phosphor that emits at 800 nm. This finding is in
agreement with that reported in Moses et al., where the Tm.sup.+3
ion transitions of .sup.3H.sub.4.fwdarw..sup.3H.sub.6 and
.sup.1G.sub.4.fwdarw..sup.3H.sub.5 correspond to 800 nm when the
Tm.sup.+3 powders of YPO.sub.4:2% Tm and LuPO.sub.4:2% Tm, were
excited with X-rays in the 20-30 KeV range. The YPO.sub.4:2% Tm
material was reported to yield 9242 photons/MeV (this value may be
high due to the nature of the powdered sample). Importantly,
rare-earth-based materials can be used to form nanorods, as
demonstrated by Das et al., Langmuir, 26(11):8959 (2010), and
references therein. As shown in FIG. 5 of the Das et al.
publication, significant luminescence in the 500-700 nm range
occurs upon excitation of nanorods of Yb/Er-co-doped
Gd.sub.2O.sub.3.
[0099] In the above second approach to designing the desired CENT
nanoparticles, the nanoparticle core is made from long-lived
luminescence material, employing X-ray (or gamma ray) excited
persistent luminescence, the basic mechanisms of which are either
delayed fluorescence or phosphorescence (also known as long-lived
phosphors or after glow). Select members of these classes of
materials absorb high energy X-rays and then emit radiation in a
spectral range that overlaps the absorption spectrum of important
metal nanoshells, including gold. As an example, FIG. 6A shows the
X-ray luminescence spectrum of BaFBr:Eu.sup.2+, Mn.sup.2+
nanoparticles, while FIG. 6B shows the similar spectrum of
LaF.sub.3:Ce.sup.3+. These emission spectra overlap the absorption
spectra of gold nanoshells (FIG. 3). BaFBr:Eu.sup.2+ and Mn.sup.2+
and LaF.sub.3:Ce.sup.3+ nanoparticles, designed with a "trap
system" to sustain luminescence, can emit light with an intensity
exceeding 25 mW/cm.sup.2 (Chen and Zhang, J. Nanoscience and
Nanatechnalogy 6, 1159-1166, 2006). Strontium aluminate
(SrAl.sub.2O.sub.4) has also been recognized as a long-lived
phosphor. Europium (Eu.sup.2+) doped versions of SrAl.sub.2O.sub.4
are also well known as a further enhancement. More recent
enhancements include co-doping with Eu.sup.2+ and Dy.sup.3+ for
long "afterglow" duration, which are available commercially (see
Table 2 below).
TABLE-US-00002 TABLE 2 Select Commercial Long-lived (afterglow)
Phosphors Emission Supplier nm Product Composition Time Emission
Peak MolTECH Gmbh SrAlO4:Eu, Dy 15-18 hours 530 nm MolTech Gmbh
CaAlO4:EuDy 8-10 hours 440 nm Boston ATI SrAl.sub.2O.sub.4:Eu 10
hours 525 nm Boston ATI Sr.sub.4Al.sub.14O.sub.25:Eu 10 hours 490
nm
[0100] Therefore, persistent luminescence from a nanoparticle core
can supply the total energy needed to supply a lethal level of heat
to tumor cells. In comparison to the total energy deposited into
the gold nanoshells proven effective for NIR ablation of human
colorectal tumors in mice, as suggested by the entries in Table 1,
a core emission of 25 mW/cm.sup.2 for a period of 7 hours is
necessary. The implicit assumption in this calculation is that the
skin of the nude mice is transparent to the 800 nm NIR, just as one
assumes that the transfer from the CENT core to the shell is 100%
efficient.
[0101] Photodynamic therapy (PDT) is a therapeutic approach to
disease, including cancer, whereby singlet oxygen is generated in
vivo (or in vitro) by light. Singlet oxygen then plays a central
role in the attack on the cancer cell. Scintillation and persistent
luminescent materials are two classes of materials of research
interest in PDT, that have X-ray excited emission in the 350 nm to
750 nm range with long lifetimes. Researchers in PDT have worked
with long-lived luminescence, but their application is not related
to thermotherapy, nor do they consider coating their nanoparticles
with a metal shell. As expected by their need for visible light,
the nanomaterials discussed in PDT research literature employ an
emission spectrum that could be made to overlap the absorption
spectrum needed to heat gold (or silver) nanoshells. Also
importantly, these scintillation and persistent luminescent
materials have been shown to be useful for fabrication into
nanoparticles for use in the generation of singlet oxygen for PDT.
(Chen and Zhang, J. Nanoscience and Nanotechnology 6, 1159-1166,
2006).
[0102] C. Targeting Molecules
[0103] Systemically administered nanoparticles may be targeted so
that they travel to a desired location where they are retained
until activated by an energy source. They may also be sized so that
they are administered to an area and then retained as the
nanoparticles are trapped within smaller blood or lymph vessels
into the tissue. A targeting molecule is a substance which will
direct the particle to a receptor site on a selected cell or tissue
type, can serve as an attachment molecule, or serve to couple or
attach another molecule. As used herein, "direct" refers to causing
a molecule to preferentially attach to a selected cell or tissue
type. This can be used to direct cellular materials, molecules, or
drugs, as discussed below.
[0104] Targeting ligands include any molecule that recognizes and
binds to target antigen or receptors over-expressed or selectively
expressed by particular cells or tissue components. These may
include antibodies or their fragments, peptides, glycoproteins,
carbohydrates or synthetic polymers. Specificity is determined
through the selection of the targeting molecules. The effect can
also be modulated through the density and means of attachment,
whether covalent or ionic, direct or via the means of linkers.
Targeted particles which have therapeutic compounds such as drugs,
cellular materials or components, and antigens, and have targeting
ligands directly bound to the particle surface can be used to
induce cellular immunologic responses or as therapeutics. Targeting
greatly increases specificity, while not decreasing therapeutic
load, such as DNA vaccines, drugs, peptides proteins or antigens.
Another advantage is that more than one material can be
encapsulated and/or coupled to the surface of the particle. This
may be a therapeutic and/or targeting material.
[0105] Targeting molecules can be proteins, peptides, nucleic acid
molecules, saccharides or polysaccharides that bind to a receptor
or other molecule on the surface of a targeted cell. The degree of
specificity can be modulated through the selection of the targeting
molecule. For example, antibodies are very specific. These can be
polyclonal, monoclonal, fragments, recombinant, or single chain,
many of which are commercially available or readily obtained using
standard techniques. Antibodies, peptides and aptamers are just a
few ways of identifying and selectively binding to both
nanoparticles and tumor cells. For example, the cell-surface
differentiation antigen A33 is a glycoprotein that is expressed in
greater than 95% of primary and metastatic colon cancer cells, but
absent in normal cells. (US 2009/0263394 A1 by Scanlan et al.)
Antibodies developed against the A33 antigen bind to tumor cells
and exhibit prolonged retention in tumor tissue. A mouse monoclonal
antibody (mAb), and a humanized version (huA33), have been
developed and radio-labeled for studies. These antibodies can be
attached to a gold metal surface through use of a polyethylene
glycol (PEG) derivative. An excellent review of targeting molecules
and nanoparticles to tumors is by Ruoslahti, Nat. Rev. Cancer,
2:83-90, 2002. For breast cancer, the recombinant humanized
monoclonal antibody trastuzumab (mAb-trz) has seen most use as an
imaging agent, when labeled with the radioisotope zirconium Zr 89,
with radioisotopic activity. The trastuzumab moiety of zirconium Zr
89 trastuzumab binds with high affinity to the extracellular domain
of human epidermal growth factor receptor 2 (HER2). Upon binding,
the radioisotope moiety can be used in positron emission tomography
(PET), allowing the imaging and quantification of HER2-expressing
tumor cells. HER2, a tyrosine kinase client protein of heat shock
protein 90 (Hsp90), may be over expressed on the cell surfaces of
various tumor cell types; most current research on mAb-trz involves
breast cancer.
[0106] Examples of molecules targeting extracellular matrix ("ECM")
include glycosaminoglycan ("GAG") and collagen.
[0107] Nanoparticles may be treated using a mannose amine. This
treatment may cause the nanoparticles to bind to the target cell or
tissue at a mannose receptor on the antigen presenting cell
surface. Alternatively, surface conjugation with an immunoglobulin
molecule containing an Fc portion (targeting Fc receptor), heat
shock protein moiety (HSP receptor), phosphatidylserine (scavenger
receptors), and lipopolysaccharide (LPS) are additional receptor
targets on cells or tissue.
[0108] The attachment of any positively charged ligand, such as
polyethyleneimine or polylysine, to any particle may improve
bioadhesion due to the electrostatic attraction of the cationic
groups coating the beads to the net negative charge of the mucus.
The mucopolysaccharides and mucoproteins of the mucin layer,
especially the sialic acid residues, are responsible for the
negative charge coating. Polyclonal antibodies raised against
components of mucin or else intact mucin, when covalently coupled
to particles, provide for increased bioadhesion. Similarly,
antibodies directed against specific cell surface receptors exposed
on the lumenal surface of the intestinal tract would increase the
residence time of beads, when coupled to particles using the
appropriate chemistry. The ligand affinity need not be based only
on electrostatic charge, but other useful physical parameters such
as solubility in mucin or else specific affinity to carbohydrate
groups.
[0109] Methods are known for attachment of the targeting ligands to
the nanoparticles. For example, WO 2007/02493 to Semprus describes
grafting sulfobetaine and carboxybetaine from self-assembled
monolayers on gold substrates or from silyl groups on glass
substrates using atom transfer radical polymerization (ATRP). For
metallic and ceramic substrates, increased surface area can be
created through surface roughening, for example by a random process
such as plasma etching. Alternatively, the surface can be modified
by controlled nano-patterning using photolithography. For the
development of surface-functionalized gold nanoparticles as
cellular probes and delivery agents, hetero-bifunctional
poly(ethylene glycol) (PEG, MW 1500) having a thiol group on one
terminus and a reactive functional group on the other can be
synthesized for use as a flexible spacer. Using the PEG spacer, the
gold nano-platform can be conjugated with a variety of biologically
relevant ligands. See also El-Sayed, et al., Nanoletters,
5(5):829-834 (2005) describing methods for conjugating antibodies
to gold nanoparticles.
[0110] D. Heat-Catalyzed Functional Agents
[0111] The nanoparticles can also be functionalized with, or
administered with, one or more heat-catalyzed functional agents
(HCFAs). HCFAs can be any therapeutic, prophylactic, or diagnostic
agent which is bound to or associated with the shell or targeting
support film of the nanoparticle, and is released (or reacted) when
the particle is activated by an energy source. For example, HCFAs
can be bound to the nanoparticle shell or targeting support film by
a chemical bond which is cleaved as the nanoparticle is heated,
releasing the HCFA. Alternatively, the HCFAs can be encapsulated in
a thermally sensitive liposome or polymer microcapsule, and
released upon initiation of thermotherapy at the specific site
where the nanoparticles have been targeted or delivered. In some
embodiments, the HCFA is an anti-neoplastic agent. In such cases,
the anti-neoplastic agent is released or reacted when and where the
particle is activated by an energy source. Accordingly, the
anti-neoplastic agent can be selectively administered in the
vicinity of cancer cells. Administration of the anti-neoplastic
agent locally and in combination with thermotherapy lowers the
effective dose of anti-neoplastic agent required to treat cancer.
In some embodiments, multiple HCFAs are bound to the nanoparticle
and administered concomitantly.
[0112] Examples of suitable anti-neoplastic agents include, but are
not limited to alkylating agents (such as cisplatin, carboplatin,
oxaliplatin, mechlorethamine, cyclophosphamide, chlorambucil,
dacarbazine, lomustine, carmustine, procarbazine, chlorambucil and
ifosfamide), antimetabolites (such as fluorouracil (5-FU),
gemcitabine, methotrexate, cytosine arabinoside, fludarabine, and
floxuridine), antimitotics (including taxanes such as paclitaxel
and decetaxel and vinca alkaloids such as vincristine, vinblastine,
vinorelbine, and vindesine), anthracyclines (including doxorubicin,
daunorubicin, valrubicin, idarubicin, and epirubicin, as well as
actinomycins such as actinomycin D), cytotoxic antibiotics
(including mitomycin, plicamycin, and bleomycin), and topoisomerase
inhibitors (including camptothecins such as irinotecan and
topotecan and derivatives of epipodophyllotoxins such as amsacrine,
etoposide, etoposide phosphate, and teniposide).
[0113] Cancer immunotherapy can be effective in the treatment of
select cancer patients with disease poorly amenable to conventional
therapy. In preferred embodiments, the HCFA is an immunomodulator.
In some embodiments, the HCFA is monoclonal antibody, for example,
an epidermal growth factor receptor (EGFR) inhibitor (for example,
Erbitux) or an angiogenesis inhibitor (for example, Bevacizumab).
In further embodiments, the HCFA is a cytokine. Cytokines are
cell-signaling proteins that are important in enhancing both innate
(e.g., inflammation, macrophages) and adaptive (B- and T-cell)
immune responses. Cytokines can be therapeutically administered to
strengthen immune response and overcome tumor suppressive
mechanisms. However, there are significant limitations to
administering cytokines via traditional methods, foremost being
their toxicity and poor drug half-life in circulation. Cytokines
(including interferon-alpha (INF-.alpha.), interferon-beta
(INF-.beta.), interferon-gamma (INF-.gamma.), interleukin-2 (IL-2),
interleukin-12 (IL-12), and granulocyte-macrophage
colony-stimulating factor (GM-CSF) can be incorporated as HCFAs and
released locally when and where the particle is activated by an
energy source. Accordingly, the toxicity associated with the
systemic administration of cytokines can be mitigated.
III. METHOD OF TREATMENT
[0114] A. Diseases and Disorders to be Treated
[0115] The nanoparticles can be administered to an individual to
kill endogenous tissue or cells. The tissue can be undesirable
tissue that has arisen due to transformation, such as a tumor,
cancer, or endometriosis; adipose tissue; plaques present in
vascular tissue and over-proliferation such as those formed in
restenosis; birthmarks and other vascular lesions of the skin;
scars and adhesions; and irregularities in connective tissue or
bone, such as bone spurs. As used herein, the term "cancer"
includes a wide variety of malignant solid neoplasms. These may be
caused by viral infection, naturally occurring transformation, or
exposure to environmental agents. Parasitic infections and
infections with organisms, especially fungal, that lead to disease
may also be targeted.
[0116] The nanoparticles are used to diagnose or treat diseases by
inducing hyperthermia in or near targeted entities. Targeted
entities may include organs, cells, clusters of cells, molecules
within cells or other molecular species. The diseases of interest
include those where an increase in temperature of the target
species brings about a desired result, and where a modest amount of
localized heat may catalyze beneficial reactions, whereas a large
amount of heat may be intentionally destructive. For example, heat
that is sufficient and selective enough to bring about death of a
targeted a cancer cell, and result in overall improvement of the
patient, is preferred.
[0117] B. Pharmaceutical Formulation
[0118] Preferably, the nanoparticles are combined with one or more
pharmaceutically acceptable excipients to form a pharmaceutical
formulation suitable for administration to an animal or human in
need thereof. Representative excipients include solvents, diluents,
pH modifying agents, preservatives, antioxidants, suspending
agents, wetting agents, viscosity modifiers, tonicity agents,
stabilizing agents, and combinations thereof. Suitable
pharmaceutically acceptable excipients are preferably selected from
materials which are generally recognized as safe (GRAS), and may be
administered to an individual without causing undesirable
biological side effects or unwanted interactions.
[0119] The nanoparticles can be formulated for a variety of routes
of administration and/or applications. In preferred embodiments,
nanoparticles are administered by intravenous injection, although,
depending on the application, the nanoparticles may also be
administered into and/or around the target tissue, such as a
tumor.
[0120] Suitable dosage forms for parenteral administration include
solutions, suspensions, and emulsions. Typically, nanoparticles
will be suspended in the form of a sterile aqueous solution.
Acceptable solvents include, for example, water, Ringer's solution,
phosphate buffered saline (PBS), and isotonic sodium chloride
solution. The formulation may also be a sterile solution,
suspension, or emulsion in a nontoxic, parenterally acceptable
diluent or solvent such as 1,3-butanediol.
[0121] In some instances, the formulation is distributed or
packaged in a liquid form. Alternatively, formulations containing
nanoparticles can be packed as a solid, obtained, for example by
lyophilization of a suitable liquid formulation. The solid can be
reconstituted with an appropriate carrier or diluent prior to
administration.
[0122] In some embodiments, the formulation is buffered with an
effective amount of buffer necessary to maintain a pH suitable for
administration. Suitable buffers are well known by those skilled in
the art, and include acetate, borate, carbonate, citrate, and
phosphate buffers.
[0123] In some embodiments, the formulation contains one or more
tonicity agents to adjust the isotonic range of the formulation.
Suitable tonicity agents are well known in the art and some
examples include glycerin, mannitol, sorbitol, sodium chloride, and
other electrolytes.
[0124] In some embodiments, the formulation contains one or more
preservatives to prevent bacterial contamination. Suitable
preservatives are known in the art, and include
polyhexamethylenebiguanidine (PHMB), benzalkonium chloride (BAK),
stabilized oxychloro complexes (otherwise known as Purite.RTM.),
phenylmercuric acetate, chlorobutanol, sorbic acid, chiorhexidine,
benzyl alcohol, parabens, thimerosal, and mixtures thereof.
[0125] 1. Additional Active Agents
[0126] Pharmaceutical compositions can also include one or more
additional active agents. In some embodiments, the one or more
additional active agents are HCFAs. In other embodiments, the one
or more additional active agents do not require the addition of
heat to perform a therapeutic, prophylactic, or diagnostic function
when administered to a patient.
[0127] In some cases, the formulation also includes one or more
small molecule anti-neoplastic agents, including any of those
agents described above in Section II.D.
[0128] In some cases, the formulation also includes one or more
anti-angiogenesis agents known in the art.
[0129] In cases where it is desirable to render aberrantly
proliferative cells quiescent in conjunction with the
administration of one or more anti-neoplastic agents, hormones and
steroids (including synthetic analogs) can also be included in the
formulation.
[0130] In some embodiments, one or more diagnostic agents are
present in the formulation. In these embodiments, the diagnostic
agent can be selected in view of the methods used to monitor
treatment. Exemplary diagnostic agents include paramagnetic
molecules, fluorescent compounds, magnetic molecules, and
radionuclides, X-ray imaging agents, and contrast agents. In
certain embodiments, such as when a PET scan is used to monitor
treatment, the formulation contains a glucose analog labeled with a
positron-emitting isotope such as F-18. In certain embodiments, the
formulation includes 2-Deoxy-2-[18F]fluoroglucose, also known as
Fluorodeoxyglucose (.sup.18F) (10E-FDG or FDG).
[0131] B. Therapy
[0132] Therapeutic methods involving the core-shell nanoparticles
described above are summarized in FIG. 5. The nanoparticles (2)
contain at least a core material (3) and a shell material (4). The
first step (5) involves positioning the nanoparticle(s) into the
region of the targeted material (1), which may be, for example, a
tissue or cell. In the case of nanoparticles designed to absorb
external radiation, the next step (6) is exposing the targeted
region to a source of external ionizing radiation, such as an
X-ray, which the core, containing one or more core-exciting, energy
absorbing materials, absorbs. In the case of nanoparticles
containing one or more radionuclides, this step is not required. In
these embodiments, the nanoparticle core contains one or more
radionuclides which decay, emitting particles that are absorbed by
one or more scintillator materials located within the nanoparticle.
The next step (7) involves energy transfer from the nanoparticle
core material (either the core-exciting, energy absorbing materials
or the scintillators) to the nanoparticle shell for the purpose of
heating the shell, through any of several mechanisms, one being
overlap of the core emission spectrum with the shell absorption
spectra (fluorescence resonance energy transfer, FRET). As the
shell is heated, it gives off heat (8). The heat (8) is transferred
from the nanoparticle shell to the surrounding fluid region, which
includes the targeted material or cell, to bring about the desired
change, damage or cell death (9). Optionally, in a further step not
illustrated in FIG. 5, the nanoparticles may be removed from the
targeted material. For example, in the case of nanoparticles
administered to a patient, the nanoparticle may be removed from the
patient through magnetic separation from the blood, whereby blood
is taken from one arm of the patient, filtered, then returned
through the other arm, in a procedure similar in clinical practice
to conventional kidney dialysis.
[0133] 1. Administration
[0134] The nanoparticles can be administered systemically or
locally, by injection into the bloodstream, the tissue to be
killed, or other lumens or cavities or vessels into the tissue or
region of cells to be killed. The nanoparticles may be administered
by direct injection through a syringe or catheter, preferably
before the X-ray radiation is applied in the case of nanoparticles
designed to absorb external core-exciting energy. In certain
embodiments, the nanoparticles are directly administered to a
tumor, tissue surrounding a tumor, or combinations thereof prior to
or after resection.
[0135] In other scenarios, the nanoparticles are intravenously
administered, thereby employing targeting schemes that depend on
chemical interaction, nanoparticle size (e.g., based upon the
enhanced permeability and retention (EPR) effect), or combinations
thereof. Subsequently, either specific organs, parts of organs, or
regions of the body are treated with the necessary dose of
core-exciting energy (such as X-ray radiation), in the case of
nanoparticles designed to absorb external core-exciting energy.
[0136] 2. Nanoparticie Excitation
[0137] In the ease of nanoparticles containing a core-exciting
energy source, such as a radionuclide, within the nanoparticle,
external core-exciting energy does not have to be applied. In these
cases, the appropriate amount of core-exciting energy can be
controlled by selection of the appropriate isotope, as well as the
amount of isotope incorporated in the nanoparticles.
[0138] In the case of nanoparticles designed to absorb
core-exciting energy from an external energy source, core-exciting
energy is applied following nanoparticle administration.
Preferably, the core-exciting energy is applied to the particles
more than 12 hours following nanoparticle administration, more
preferably more than 24 hours following nanoparticle
administration, so as to allow the nanoparticles (if targeted) to
localize in the vicinity of the target cells or tissues.
[0139] For a given treatment session or diagnostic test, the
irradiation regime to which the nanoparticles are exposed is
dependent upon several factors. The compositions and design of the
nanoparticle core and shell determine the amount of heat that can
be emitted from the nanoparticle. Another consideration is the
ability of the targeting method to deliver nanoparticles into the
desired region of the cell or tissue. Another consideration is
whether the objective of the procedure is diagnostic or
therapeutic. Another consideration, in the case of a therapeutic
method, is the maximum safe dose of radiation that can be tolerated
by the patient. Another consideration, which depends upon the
targeted cell or material, is the amount of heat required to bring
about the desired effect.
[0140] As used herein the term "dose" represents a concentration of
absorbed energy, such as electron volt (eV) per gram (gm) or Grey
(Gy). The quantity termed "dose length product," DLP, represents
total energy imparted to the body and is the product of the dose
and the volume of tissue exposed.
[0141] Research over the last decade involving in vivo heating of
human cancers using gold nanoparticles, allows one skilled in the
art to estimate the necessary energy input into gold nanoshell
plasmon modes, to destroy significantly sized tumors of human
cancers or other tissues. Tumors in nude mice can be killed when
lasers in the 808-820 nm (NIR) wavelength range are used to
irradiate skin covering a tumor of volume of less than 1 cubic
centimeter (cm), for durations ranging from 2 to 5 minutes, with
surface power densities ranging from 2 to 4 Watts/cm.sup.2. These
literature studies are summarized in Table 3.
TABLE-US-00003 TABLE 3 Select Studies of NIR Heating of Gold
Nanoparticles in Tumors in Mice Exposure Cancer Type of NIR time,
Lit. Type Particle (.lamda., nm) energy Reference Mice mda-
nanorods 810 nm 5 min, von Maltzahn 09 mb-435 2 W/cm.sup.2 Mice
ct26.wt peg-ns 808 nm 3 min, O'neal et al. '04 130 nm 4 W/cm.sup.2
Mice canine tuned-ns 820 nm <6 min, Hirsch et al ''03 tvt 4
W/cm2, 5 mm
[0142] Nanoparticles embedded throughout the tumor volume are
responsible for the conversion of NIR into heat which causes cell
death, as either NIR exposure or nanoparticle presence alone are
shown to not be cytotoxic. In these studies, total laser energy
deposited into the tumor is on the order of 2000 MeV. Additionally,
tumors of this size are composed of, at least, billions of
cancerous cells. Therefore, on a per cancer cell basis, rough
estimates of 1 eV delivered into the gold shell plasmon resonance
is sufficient to generate the heat necessary to bring about cancer
cell death in these studies.
[0143] As a reference point for the therapeutic dosages of X-ray
radiation needed, a patient of 180 cm in height and 80 Kg in
weight, undergoing a state-of-the-art commercial CT scan of the
chest, abdomen and pelvis (a body region approximately representing
half his weight and height) may typically receive X-ray pulses with
a range of energies usually 20 to 120 KeV, with an 80 KeV peak,
with a total CT radiation dose (dose length product, DLP) of 1300
mGy-cm. The entire scan may represent 200 to 300 individual X-rays,
separate "slices" through the examined region at a spacing of
approximately two images per cm (typically about 1010 photons per
cm.sup.2). State-of-the-art CT scanners submit the patient to a
"cork screw" of continuous radiation, as the X-ray source rotates
around the patient, from which the "slices" or images are computed.
Therefore, the exposed region of the body (40 Kg and 90 cm) has
received a dose of approximately 10.sup.8 MeV/gm. If the patient
has a tumor volume of 1 cm.sup.3, of approximate density of about 1
g/cm.sup.3, that volume has received approximately 10.sup.8 MeV/gm
of X-ray radiation. The biological response to the radiation is not
considered in the DLP calculation.
[0144] In comparison to the approximate 2000 MeV of laser energy
deposited into the gold plasmons, which was converted into heat to
destroy nearby tumors, in the mice studies of Table 1, conventional
X-ray treatments supply an ample source of energy within the body
to bring about the death of cancer cells, if the energy is
converted to thermal energy and targeted properly. The
nanoparticles described herein are characterized by the efficient
conversion of ionizing (primarily X-ray) radiation into focused
thermal energy. The efficacy of treatment can be monitored in
real-time, for example, if a CT-scan is used to provide the
core-exciting energy. In certain embodiments, the nanoparticles are
co-administered with a glucose analog labeled with a
positron-emitting isotope such as F-18 (e.g., FDG). In these
embodiments, a PET scan can be used to monitor therapeutic efficacy
in real-time, and adjust treatment parameters as required.
[0145] 3. Nanoparticle Removal
[0146] Most of the elements used in the particles are safe to
administer and leave in patients. Colloidal gold particles
(aurothiomalate, auranofin) have been used in the treatment of
patients with rheumatoid arthritis (Jessop et al., Br J Rheumatol
37:992-1002, 1998; Bassett et al., Liver Int 23:89-9, 2003).
Nanoparticle-based contrast agents for MRI, CT and PET imaging have
drawn much interest. The rare-earth element gadolinium (metal
chelate ion Gd.sup.3+) is used in one such contrast agent,
indicating the relative utility and safety of this material.
[0147] However, if desired, the nanoparticles may be designed to be
removed from the patients following treatment. For example, in the
case of nanoparticles administered to a patient, the nanoparticle
may be removed from the patient through magnetic separation from
the blood, whereby blood is taken from one arm of the patient,
filtered, then returned through the other arm, in a procedure
similar in clinical practice to conventional kidney dialysis.
[0148] In these embodiments, the nanoparticle core or shell
material, or portion thereof, may be removed from the body. In such
cases, the nanoparticle may be decorated or doped with magnetic
material, typically on the shell surface, to allow magnetic removal
of the particle from the blood by established cell-separation
techniques.
[0149] The present invention will be further understood by
reference to the following non-limiting hypothetical examples.
EXAMPLES
Example 1
Targeting Breast Cancer
[0150] The following CENT treatment approach is based on a
core-shell nanoparticle designed on the basis of X-ray excited
persistent luminescence and the maximum safe dose of X-ray
radiation the patient may tolerate. As a reference point for the
therapeutic dosages of X-ray radiation needed, the patient is 180
cm in height and 80 Kg in weight.
[0151] First, nanoparticles of SrAl.sub.2O.sub.4:Eu:Dy of
approximately 60 nm in diameter, prepared by solid state reaction
methods, are used as the core in a core-shell nanoparticle material
design. The X-ray luminescence spectrum of this material has a
maximum at approximately 510 nm, similar to the non-doped
SrAl.sub.2O.sub.4 material, as shown in FIG. 7. A nanoshell of gold
is grown over the nanocore material. Gold nanoparticles have the
absorbance spectrum typical of that shown in FIGS. 3 and 4;
additional Mie theory calculations allow design for maximum
spectral overlap (FRET) between core and shell. The nanoparticle is
then coated with polyethylene glycol (PEG), to which the
trastuzumab antibody is attached. The nanomaterial is further
processed for preparation of intravenous administration into a
patient with early stage breast cancer.
[0152] After administration of the nanoparticles, sufficient to
allow targeting to the diseased cells, the patient is prepared for
a CT (X-ray) irradiation regime. The therapeutic portion of the CT
irradiation scheme is optimized based on several factors, including
1) the nanoparticle being used, 2) the organ or body region being
treated (here, the breast), 3) the disease being treated (here
breast cancer), 4) the goal of the treatment and 5) the size of the
patient (patient safety). If several exposures of X-ray radiation
are to be necessary to generate the required therapeutic heating,
the maximum safe dose to the patient determines the appropriate
regimen.
Example 2
Treatment of Colon Cancer
[0153] The following CENT treatment approach is based on a
core-shell nanoparticle designed on the basis of X-ray excited
persistent luminescence and the maximum safe dose of computed
tomography (CT) radiation the patient may tolerate. As a reference
point for the therapeutic dosages of X-ray radiation needed, the
patient is 180 cm in height and 80 Kg in weight.
[0154] First, nanoparticles of BaFBr:Eu.sup.2+, Mn.sup.2+ of 20 nm
in diameter are prepared as the core material as outlined in Chen
and Zhang, J. Nanoscience and Nanotechnology 6, 1159-1166, 2006.
The X-ray luminescence spectrum of this material has a maximum at
approximately 400 nm, as shown in FIG. 6A. A nanoshell of silver
then is grown over the nanocore material. Silver nanoparticles have
the absorbance spectrum typical of that shown in FIG. 4; additional
Mie theory calculations allow design for maximum spectral overlap
(FRET) between core and shell. The nanoparticle is then coated with
polyethylene glycol (PEG), to which the A33 antibody is attached.
The nanomaterial is further processed for intravenous
administration into a patient with colorectal adenocarcinoma and/or
inoperable liver metastases.
[0155] After administration of the nanoparticles, sufficient to
allow targeting to the diseased cells, the patient is prepared for
a PET-CT X-ray scan. PET is used initially and at the completion of
treatment to identify active cancer cells (or lack thereof). The CT
irradiation scheme is optimized based on several factors, including
1) the nanoparticles being used, 2) the organ or body region being
treated (here, the liver), 3) the disease being treated (here colon
cancer) and 4) the size and physical condition of the patient and
extent of disease. Large numbers of cancer cells (for example,
either large tumors or many tumors in the liver), if killed
rapidly, may overload the body's ability to eliminate dead tissue,
creating toxic health-threatening conditions. In such cases, the
overall CENT treatment plan, and the accompanying specific
irradiation regime, must be optimized for the patient, requiring a
series of treatments of lower dosage CENT particles and less
intense (and more regionally limited in the body) ionizing
radiation.
[0156] In a related example, one inoperable but small tumor (sphere
less than 1 cm in diameter), may not require a patient optimized
treatment protocol; if the tumor is heat-responsive, only the
irradiation protocol of a conventional CT scan of the liver
(.about.1010 80 KeV--photons per cm.sup.2) and a dose of CENT
particles sufficient for such tumor size, may constitute the first
CT treatment. Regionally-focused diagnostic PET scans, before and
after treatment, determine the efficacy of the first CENT-CT
treatment. If several exposures of X-ray radiation are to be
necessary to generate the required therapeutic heating, the maximum
safe dose to the patient determines the appropriate regimen.
[0157] In the case of extensive metastatic liver disease and a
weakened patient (for example, having abnormal function of liver or
kidney), the patient may undergo a set of calibration treatments to
determine the optimized therapeutic treatment. The first
calibration treatment involves only a limited dose of
CENT-particles and radiation to kill the tumor mass that medical
experts believe the weakened patient may safely tolerate, even
though active tumor will still remain. The frequency and
optimization of all aspects of additional treatment are
patient-dependent in such cases.
[0158] Cancer cells from a tumor biopsy may be subjected to in
vitro testing to determine both the likely response to a CENT
treatment and help the design and optimization of the irradiation
regime for efficacy in the specific patient. Thermotherapy may be
considered either as the primary treatment or as an adjuvant
therapy in combination with surgery, chemotherapy or radiation.
Example 3
Treatment of Colon Cancer Using Nanoparticles Containing a
Radionucleotide in the Nanoparticle Core
[0159] The following CENT treatment approach is based on a
core-shell nanoparticle designed to a typical geometry of a 100-nm
diameter core of Pd-103 and a 20-nm thick encasing layer of
LaPO.sub.4:Ce, Tb and a 20-nm thick shell of gold. The radionuclide
Pd-103 is an Auger electron emitter, with a 17-day half-life, that
excites the Ce- and Tb-doped LaPO.sub.4 encasing layer to emit
543-nm green light, with a quantum yield of approximately 80%. The
green light is absorbed by the gold shell (See FIG. 3) and heats
the nanoparticle region that contains the targeted elements of the
treatment, which are colon cancer cells in blood, lymph and tissue
(tumors). The maximum dose of these nanoparticles that can be
safely infused is administered to the patient. As a reference point
for the therapeutic dosages, the patient is 180 cm in height and 80
Kg in weight.
[0160] First, nanoparticles of Pd-103 of 100-nm in diameter are
prepared as the center region of the core, by a synthesis method as
outlined in Langmuir, 25, 7116-7128 (2009). Including chloride
salts of Ce and Tb, an encasing layer of LaPO.sub.4 is added
through the methods outlined in J. Am. Ceram. Soc. 84:2783-92
(2001) and Chem. Mater. 18:4442-4446 (2006). Using standard
techniques, a shell of gold is then grown over the doped lanthanum
phosphate (LAP) core and coated with polyethylene glycol (PEG), to
which the A33 antibody is attached using standard techniques. The
nanoparticle is further processed for intravenous administration
into a patient with colorectal adenocarcinoma and two inoperable
liver metastases both of approximately 1 cm.sup.3 which represents
about 1 billion cancer cells. The typical colorectal cancer cell
has approximately 100,000 binding sites to which the A33 antibody
will bind when the A33 concentration in the blood exceeds 20
nanomolar (nM).
[0161] After administration of the nanoparticles, sufficient time
(one week) is allowed for targeting to the diseased cells and
treatment. Then the patient undergoes a diagnostic scan, from a
MRI, CT or PET-CT device, which are used to identify active cancer
cells or tumor growth. If the patient shows evidence of remaining
active disease, and no significant side effects of treatment, the
patient is treated again. Once the treatment protocol has ended,
the patient undergoes removal of the metal-shell nanoparticles from
the blood through dialysis-type technique based on magnetic
separation.
* * * * *
References