U.S. patent application number 17/094599 was filed with the patent office on 2021-03-11 for iodine-based particles.
The applicant listed for this patent is Nanoprobes, Inc.. Invention is credited to James F. HAINFELD.
Application Number | 20210069352 17/094599 |
Document ID | / |
Family ID | 1000005234811 |
Filed Date | 2021-03-11 |
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United States Patent
Application |
20210069352 |
Kind Code |
A1 |
HAINFELD; James F. |
March 11, 2021 |
IODINE-BASED PARTICLES
Abstract
Described herein are iodine-based particles which can be used as
contrast agents for x-ray radiology. Also described herein are
methods, software modules and hardware modules for imaging
iodine-based particles.
Inventors: |
HAINFELD; James F.;
(Shoreham, NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Nanoprobes, Inc. |
Yaphank |
NY |
US |
|
|
Family ID: |
1000005234811 |
Appl. No.: |
17/094599 |
Filed: |
November 10, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15469283 |
Mar 24, 2017 |
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17094599 |
|
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62313364 |
Mar 25, 2016 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 49/0442 20130101;
A61K 9/5146 20130101; A61K 49/0438 20130101; A61K 49/0485
20130101 |
International
Class: |
A61K 49/04 20060101
A61K049/04; A61K 9/51 20060101 A61K009/51 |
Claims
1. An iodine nanoparticle which is a reaction product of
functionalized triiodobenzene, linking monomers, and biocompatible
polymers; wherein said functionalized triiodobenzene, said linking
monomers, and said biocompatible polymers are covalently
cross-linked resulting in the structure of said nanoparticle being
non-dendritic, non-uniform, and non-linear; wherein said
nanoparticle has a polydispersity index of about 0.5 or less;
wherein said nanoparticle has sufficient iodine density to be
imaged by an imaging device following administration to a subject;
and wherein said nanoparticle provides for an extended blood
half-life.
2. The nanoparticle according to claim 1 wherein said
functionalized triiodobenzene is functionalized
1,3,5-triiodobenzene or functionalized 2,4,6-triiodobenzene.
3. The nanoparticle according to claim 1 wherein said
functionalized triiodobenzene has the structure: ##STR00008##
wherein R.sup.1, R.sup.2, and R.sup.3 are each independently
selected from a group consisting of optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted cycloalkyl, optionally substituted aryl,
optionally substituted heteroaryl, optionally substituted alkoxy,
optionally substituted aryloxy, optionally substituted amino,
optionally substituted thiol, and optionally substituted
phosphonate.
4. The iodine nanoparticle according to claim 1 wherein said
functionalized triiodobenzene is 2,4,6-triiodophenol,
2-(2,4,6-triiodophenoxy)ethanol,
2-(2-bromoethoxy)1,3,5-triiodobenzene,
(2,4,6-triiodophenoxy)acetamide,
2-(2,4,6-triiodophenoxy)ethanesulfonic acid,
3-hydroxy-2,4,6-triiodobenzoic acid, 3-amino-2,4,6-triiodobenzoic
acid, methyl 2-(2,4,6-triiodophenoxy)butyrate,
(2-(2,4,6-triiodophenoxy)-ethyl)trimethylammonium methanesulfonate,
5-amino-2,4,6-triiodoisophthalic acid,
.alpha.-ethyl-3-hydroxy-2,4,6-triiodohydrocinnamic acid, iopanoic
acid, 7-(3-amino-2,4,6-triiodophenyl)heptanoic acid,
7-(3-amino-2,4,6-triiodophenyl)heptanoic acid ethyl ester,
2-phenyl-2-(2,4,6-triiodophenoxy)acetic acid,
(2-(3-hydroxy-2,4,6-triiodobenzyl)butyrylamino)acetic acid,
N-(2-dimethylaminoethyl)-2-(3-hydroxy-2,4,6-triiodobenzyl)butyramide,
(2-(3-hydroxy-2,4,6-triiodobenzyl)butyrylamino)acetic acid ethyl
ester, 3-(acetylamino)-5-[acetyl(methyl)amino]-2,4,6-triiodobenzoic
acid, amidotrizoic acid, 3-acetamido-2,4,6-triiodobenzoic acid,
bis(2-hydroxyethyl)-ammonium salt, 3-acetamido-2,4,6-triiodobenzoic
acid, sodium salt dihydrate,
2-(3-hydroxy-2,4,6-triiodobenzyl)-N-(1-phenylethyl)butyramide,
sodium diatrizoate hydrate,
3-(4-HO-Ph)-2-(2-(3-hydroxy-2,4,6-triiodobenzyl)-butyrylamino)propionic
acid,
3-(acetylamino)-5-{[(2-hydroxyethyl)amino]carbonyl}-2,4,6-triiodobe-
nzoic acid,
2-(3-hydroxy-2,4,6-triiodobenzyl)-N-(2-trifluoromethylphenyl)butyramide,
meglumine diatrizoate, 3-acetamido-2,4,6-triiodobenzoic acid with
1-deoxy-1-(Me-amino)-glucit, 5-(N-2,3-dihydroxypropyl
acetamido)-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)isophthalamide,
(2-(2-(3-hydroxy-2,4,6-triiodobenzyl)butyrylamino)thiazol-4-yl)acetic
acid,
5-(N-2,3-dihydroxypropylacetamido)-2,4,6-triiodo-N,N'-bis(2,3-dihyd-
roxypropyl)isophthalamide,
5-[N-(propylacetamido]-2,4,6-triiodo-N,N'-bis(propyl)isophthalamide,
or any combination thereof.
5. The iodine nanoparticle according to claim 1 wherein said
linking monomers are diaminoethane, diaminopropane, triamine,
ethereal tetraamine, diisopropyl ethylamine, polyethyleneimine,
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, dicarboxyethane,
suberic acid, tricarboxylic acid, citrate, carboxycellulose,
alginic acid, acrylic acid, carboxydextran,
diethylenetriaminepentaacetic dianhydride, carbohydrazide, succinic
dihydrazide, adipic acid dihydrazide, diglycidyl ether,
1,4-butadioldiglycidylether, polyethylene glycol diglycidyl,
ethylene diamine, polyethylene amine, 1,1'-carbonyldiimidazole, or
any combination thereof.
6. The iodine nanoparticle according to claim 1 wherein said
biocompatible polymers are amine functionalized
poly-N-vinylpyrrolidinone, polyvinyl alcohol, polysulfone,
polyethylene terephthalate, polyether-urethanes,
methoxy-polyethylene glycol, polyethyleneglycol-amine,
polydimethylsiloxane, ethylene-co-vinylacetate,
polymethylmethacrylate, polytetrafluoroethylene, polypropylene,
polyethylene, alginic acid, polylysine, polyglycolide, polylactide,
polylactide-co-glycolide, polycaprolactone, polybutylene succinate
and its copolymers, poly-p-dioxanone, polycarbonate, aromatic
copolyesters, polyamides, polyester-amides, polyurethane,
polyphosphazenes, polyphosphoesters, collagen, albumin, gluten,
chitosan, hyaluronate, cellulose, alginate, gelatin, starch or any
combination thereof.
7. The iodine nanoparticle according to claim 1, wherein said
nanoparticle has a diameter from about 1 mm to about 100 mm.
8. The iodine nanoparticle according to claim 1, wherein said
nanoparticle has a diameter from about 0.25 .mu.m to about 100
.mu.m.
9. The iodine nanoparticle according to claim 1, wherein said
nanoparticle has a diameter from about 1 nm to about 500 nm.
10. An encapsulated iodine particle comprising a hydrophobic core
and an amphipathic encapsulating layer wherein said hydrophobic
core consists of a hydrophobic iodine nanoparticle, a hydrophobic
triiodobenzene monomer or a hydrophobic triiodobenzene dimer;
wherein said iodine nanoparticle is a reaction product of
functionalized triiodobenzene and linking monomers; wherein said
functionalized triiodobenzene and said linking monomers are
covalently cross-linked resulting in the structure of said iodine
nanoparticle being non-dendritic, non-uniform, and non-linear;
wherein said iodine nanoparticle has a polydispersity index of
about 0.5 or less; wherein said iodine nanoparticle has sufficient
iodine density to be imaged by an imaging device following
administration to a subject; and wherein said iodine nanoparticle
provides for an extended blood half-life.
11. The encapsulated iodine particle according to claim 10 wherein
said functionalized triiodobenzene is functionalized
1,3,5-triiodobenzene or functionalized 2,4,6-triiodobenzene.
12. The encapsulated iodine particle according to claim 10 wherein
said functionalized triiodobenzene has the structure: ##STR00009##
wherein R.sup.1, R.sup.2, and R.sup.3 are each independently
selected from a group consisting of optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted cycloalkyl, optionally substituted aryl,
optionally substituted heteroaryl, optionally substituted alkoxy,
optionally substituted aryloxy, optionally substituted amino,
optionally substituted thiol, and optionally substituted
phosphonate.
13. The encapsulated iodine particle according to claim 10 wherein
said functionalized triiodobenzene is 2,4,6-triiodophenol,
2-(2,4,6-triiodophenoxy)ethanol,
2-(2-bromoethoxy)1,3,5-triiodobenzene,
(2,4,6-triiodophenoxy)acetamide,
2-(2,4,6-triiodophenoxy)ethanesulfonic acid,
3-hydroxy-2,4,6-triiodobenzoic acid, 3-amino-2,4,6-triiodobenzoic
acid, methyl 2-(2,4,6-triiodophenoxy)butyrate,
(2-(2,4,6-triiodophenoxy)-ethyl)trimethylammonium methanesulfonate,
5-amino-2,4,6-triiodoisophthalic acid,
.alpha.-ethyl-3-hydroxy-2,4,6-triiodohydrocinnamic acid, iopanoic
acid, 7-(3-amino-2,4,6-triiodophenyl)heptanoic acid,
7-(3-amino-2,4,6-triiodophenyl)heptanoic acid ethyl ester,
2-phenyl-2-(2,4,6-triiodophenoxy)acetic acid,
(2-(3-hydroxy-2,4,6-triiodobenzyl)butyrylamino)acetic acid,
N-(2-dimethylaminoethyl)-2-(3-hydroxy-2,4,6-triiodobenzyl)butyramide,
(2-(3-hydroxy-2,4,6-triiodobenzyl)butyrylamino)acetic acid ethyl
ester, 3-(acetylamino)-5-[acetyl(methyl)amino]-2,4,6-triiodobenzoic
acid, amidotrizoic acid, 3-acetamido-2,4,6-triiodobenzoic acid,
bis(2-hydroxyethyl)-ammonium salt, 3-acetamido-2,4,6-triiodobenzoic
acid, sodium salt dihydrate,
2-(3-hydroxy-2,4,6-triiodobenzyl)-N-(1-phenylethyl)butyramide,
sodium diatrizoate hydrate,
3-(4-HO-Ph)-2-(2-(3-hydroxy-2,4,6-triiodobenzyl)-butyrylamino)propionic
acid,
3-(acetylamino)-5-{[(2-hydroxyethyl)amino]carbonyl}-2,4,6-triiodobe-
nzoic acid,
2-(3-hydroxy-2,4,6-triiodobenzyl)-N-(2-trifluoromethylphenyl)butyramide,
meglumine diatrizoate, 3-acetamido-2,4,6-triiodobenzoic acid with
1-deoxy-1-(Me-amino)-glucit, 5-(N-2,3-dihydroxypropyl
acetamido)-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)isophthalamide,
(2-(2-(3-hydroxy-2,4,6-triiodobenzyl)butyrylamino)thiazol-4-yl)acetic
acid,
5-(N-2,3-dihydroxypropylacetamido)-2,4,6-triiodo-N,N'-bis(2,3-dihyd-
roxypropyl)isophthalamide,
5-[N-(propylacetamido]-2,4,6-triiodo-N,N'-bis(propyl)isophthalamide,
or any combination thereof.
14. The encapsulated iodine particle according to claim 10 wherein
said linking monomers comprises diaminoethane, diaminopropane,
triamine, ethereal tetraamine, diisopropyl ethylamine,
polyethyleneimine, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,
dicarboxyethane, suberic acid, tricarboxylic acid, citrate,
carboxycellulose, alginic acid, acrylic acid, carboxydextran,
diethylenetriaminepentaacetic dianhydride, carbohydrazide, succinic
dihydrazide, adipic acid dihydrazide, diglycidyl ether,
1,4-butadioldiglycidylether, polyethylene glycol diglycidyl,
ethylene diamine, polyethylene amine, 1,1'-carbonyldiimidazole,
alkylamines, dodecylamine, oleylamine, octaoic hydrazide, or any
combination thereof.
15. The encapsulated iodine particle according to claim 10 wherein
said amphipathic polymer comprises polyethylene glycol,
poly-D,L-lactic-coglycolic acid, polyethylene glycol-poly lactic
acid, polyethylene glycol-polyepsilon-caprolactone, polysorbates,
polyvinyl alcohol, polyvinyl pyrrolidone, dextran, chitosan,
alginic acid, or carboxycellulose.
16. The encapsulated iodine particle according to claim 10, wherein
said particle has a diameter from about 1 mm to about 100 mm.
17. The encapsulated iodine particle according to claim 10, wherein
said particle has a diameter from about 0.25 .mu.m to about 100
.mu.m.
18. The encapsulated iodine particle according to claim 10, wherein
said particle has a diameter from about 1 nm to about 500 nm.
19. A method of producing enhanced imaging by exposing the iodine
nanoparticle according to claim 1 to radiation.
20. A method of producing enhanced imaging by exposing the
encapsulated iodine particle according to claim 10 to radiation.
Description
CROSS-REFERENCE
[0001] This application is a continuation of U.S. application Ser.
No. 15/469,283, filed on Mar. 24, 2017, which claims the benefit of
U.S. Provisional Application No. 62/313,364, filed 25 Mar. 2016,
both applications are incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] Presently, commercially available iodine-based x-ray
contrast agents are cleared rapidly from the body through the
kidneys. To be effective, high concentrations of these contrast
agents are administered to patients to obtain adequate contrast.
Unfortunately, all of these agents are nephrotoxic. Patients with
poor kidney function can have their kidneys permanently damaged due
to these commercially available iodine-based x-ray contrast agents.
In fact, radiocontrast-induced nephropathy is a common cause of
hospital acquired acute renal failure.
SUMMARY OF THE INVENTION
[0003] A need for contrast agents that do not present a danger to
patients with poor kidney function has been recognized. An extended
blood half-life contrast agent would be beneficial for improved
medical imaging and diagnosis, particularly for abnormal vascular
conditions such as cardiovascular disease and cancer detection. An
extended blood half-life contrast agent that absorbs X-rays and is
targeted to tumors would be beneficial in enhancing the effects of
radiotherapy.
[0004] Described herein are iodine-based particles which can be
used as contrast agents for x-ray radiology. Also described herein
are methods, software modules and hardware modules for imaging
iodine-based particles.
[0005] One aspect described herein is an iodine nanoparticle which
is a reaction product of functionalized triiodobenzene, linking
monomers, and biocompatible polymers; wherein said functionalized
triiodobenzene, said linking monomers, and said biocompatible
polymers are covalently cross-linked resulting in the structure of
said nanoparticle being non-dendritic, non-uniform, and non-linear;
wherein said nanoparticle has a polydispersity index of about 0.5
or less; wherein said nanoparticle has sufficient iodine density to
be imaged by an imaging device following administration to a
subject; and wherein said nanoparticle provides for an extended
blood half-life.
[0006] In one embodiment, the functionalized triiodobenzene is
functionalized 1,3,5-triiodobenzene or functionalized
2,4,6-triiodobenzene. In one embodiment, the functionalized
triiodobenzene has the structure:
##STR00001##
[0007] wherein R.sup.1, R.sup.2, and R.sup.3 are each independently
selected from a group consisting of optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted cycloalkyl, optionally substituted aryl,
optionally substituted heteroaryl, optionally substituted alkoxy,
optionally substituted aryloxy, optionally substituted amino,
optionally substituted thiol, and optionally substituted
phosphonate.
[0008] In one embodiment, the functionalized triiodobenzene is
2,4,6-triiodophenol, 2-(2,4,6-triiodophenoxy)ethanol,
2-(2-bromoethoxy)1,3,5-triiodobenzene,
(2,4,6-triiodophenoxy)acetamide,
2-(2,4,6-triiodophenoxy)ethanesulfonic acid,
3-hydroxy-2,4,6-triiodobenzoic acid, 3-amino-2,4,6-triiodobenzoic
acid, methyl 2-(2,4,6-triiodophenoxy)butyrate,
(2-(2,4,6-triiodophenoxy)-ethyl)trimethylammonium methanesulfonate,
5-amino-2,4,6-triiodoisophthalic acid,
.alpha.-ethyl-3-hydroxy-2,4,6-triiodohydrocinnamic acid, iopanoic
acid, 7-(3-amino-2,4,6-triiodophenyl)heptanoic acid,
7-(3-amino-2,4,6-triiodophenyl)heptanoic acid ethyl ester,
2-phenyl-2-(2,4,6-triiodophenoxy)acetic acid,
(2-(3-hydroxy-2,4,6-triiodobenzyl)butyrylamino)acetic acid,
N-(2-dimethylaminoethyl)-2-(3-hydroxy-2,4,6-triiodobenzyl)butyramide,
(2-(3-hydroxy-2,4,6-triiodobenzyl)butyrylamino)acetic acid ethyl
ester, 3-(acetylamino)-5-[acetyl(methyl)amino]-2,4,6-triiodobenzoic
acid, amidotrizoic acid, 3-acetamido-2,4,6-triiodobenzoic acid,
bis(2-hydroxyethyl)-ammonium salt, 3-acetamido-2,4,6-triiodobenzoic
acid, sodium salt dihydrate,
2-(3-hydroxy-2,4,6-triiodobenzyl)-N-(1-phenylethyl)butyramide,
sodium diatrizoate hydrate,
3-(4-HO-Ph)-2-(2-(3-hydroxy-2,4,6-triiodobenzyl)-butyrylamino)propionic
acid,
3-(acetylamino)-5-{[(2-hydroxyethyl)amino]carbonyl}-2,4,6-triiodobe-
nzoic acid,
2-(3-hydroxy-2,4,6-triiodobenzyl)-N-(2-trifluoromethylphenyl)butyramide,
meglumine diatrizoate, 3-acetamido-2,4,6-triiodobenzoic acid with
1-deoxy-1-(Me-amino)-glucit, 5-(N-2,3-dihydroxypropyl
acetamido)-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)isophthalamide,
(2-(2-(3-hydroxy-2,4,6-triiodobenzyl)butyrylamino)thiazol-4-yl)acetic
acid,
5-(N-2,3-dihydroxypropylacetamido)-2,4,6-triiodo-N,N'-bis(2,3-dihyd-
roxypropyl)isophthalamide,
5-[N-(propylacetamido]-2,4,6-triiodo-N,N'-bis(propyl)isophthalamide,
or any combination thereof.
[0009] In one embodiment, the linking monomers are diaminoethane,
diaminopropane, triamine, ethereal tetraamine, diisopropyl
ethylamine, polyethyleneimine,
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, dicarboxyethane,
suberic acid, tricarboxylic acid, citrate, carboxycellulose,
alginic acid, acrylic acid, carboxydextran,
diethylenetriaminepentaacetic dianhydride, carbohydrazide, succinic
dihydrazide, adipic acid dihydrazide, diglycidyl ether,
1,4-butadioldiglycidylether, polyethylene glycol diglycidyl,
ethylene diamine, polyethylene amine, 1,1'-carbonyldiimidazole, or
any combination thereof. In one embodiment, the linking monomers
are carbohydrazide, succinic dihydrazide,
diethylenetriaminepentaacetic dianhydride, adipic acid dihydrazide,
diglycidyl ether, 1,4-butadioldiglycidylether, polyethylene glycol
diglycidyl, ethylene diamine, polyethylene amine,
1,1'-carbonyldiimidazole, oxalyldihydrazide or any combination
thereof.
[0010] In one embodiment, the biocompatible polymers are amine
functionalized poly-N-vinylpyrrolidinone, polyvinyl alcohol,
polysulfone, polyethylene terephthalate, polyether-urethanes,
methoxy-polyethylene glycol, polyethyleneglycol-amine,
polydimethylsiloxane, ethylene-co-vinylacetate,
polymethylmethacrylate, polytetrafluoroethylene, polypropylene,
polyethylene, alginic acid, polylysine, or any combination thereof.
In one embodiment, the biocompatible polymers comprises
polyglycolide, polylactide, polylactide-co-glycolide,
polycaprolactone, polybutylene succinate and its copolymers,
poly-p-dioxanone, polycarbonate, aromatic copolyesters, polyamides,
polyester-amides, polyurethane, polyphosphazenes,
polyphosphoesters, or any combination thereof. In one embodiment,
the biocompatible polymers are collagen, albumin, gluten, chitosan,
hyaluronate, cellulose, alginate, gelatin, starch or any
combination thereof.
[0011] In one embodiment, the iodine nanoparticle has a diameter
from about 1 mm to about 100 mm, from about 1 mm to about 50 mm,
from about 0.25 .mu.m to about 100 .mu.m, from about 0.25 .mu.m to
about 50 .mu.m, from about 0.25 .mu.m to about 30 .mu.m, from about
1 nm to about 500 nm, from about 1 nm to about 250 nm, from about 1
nm to about 150 nm, from about 1 nm to about 100 nm, from about 1
nm to about 70 nm from about 1 nm to about 50 nm, from about 1 nm
to about 40 nm, from about 1 nm to about 30 nm from about 5 nm to
about 30 nm, or from about 10 nm to about 30 nm.
[0012] In one embodiment, the iodine nanoparticle has a diameter
from about 1 mm to about 100 mm, from about 1 mm to about 50 mm,
from about 0.25 .mu.m to about 100 .mu.m, from about 0.25 .mu.m to
about 50 .mu.m, from about 0.25 .mu.m to about 30 .mu.m, from about
1 nm to about 500 nm, from about 1 nm to about 250 nm, from about 1
nm to about 150 nm, from about 1 nm to about 100 nm, from about 1
nm to about 70 nm, from about 1 nm to about 50 nm, from about 1 nm
to about 40 nm, from about 1 nm to about 30 nm, from about 5 nm to
about 30 nm, or from about 10 nm to about 30 nm. In one embodiment,
In some embodiments of the iodine nanoparticle, the iodine
nanoparticle has a diameter from about 1 nm or more, from about 10
nm or more, from about 20 nm or more, from about 30 nm or more,
from about 40 nm or more, from about 50 nm or more, from about 60
nm or more, from about 70 nm or more, from about 80 nm or more,
from about 90 nm or more, from about 300 nm or less, from about 275
nm or less, from about 250 nm or less, from about 200 nm or less,
from about 175 nm or less, from about 150 nm or less, from about
125 nm or less, from about 100 nm or less, from about 90 nm or
less, from about 80 nm or less, from about 70 nm or less, from
about 60 nm or less, from about 50 nm or less, from about 40 nm or
less, from about 30 nm or less, from about 20 nm or less, from
about 10 nm or less, from about 1 nm to about 300 nm, from about 1
nm to about 250 nm, from about 1 nm to about 200 nm, from about 1
nm to about 150 nm, from about 1 nm to about 125 nm, from about 1
nm to about 100 nm, from about 1 nm to about 90 nm, from about 1 nm
to about 80 nm, from about 1 nm to about 70 nm, from about 1 nm to
about 60 nm, from about 1 nm to about 50 nm, from about 1 nm to
about 40 nm, from about 1 nm to about 30 nm, from about 5 nm to
about 30 nm, or from about 10 nm to about 30 nm. In some
embodiments, the iodine nanoparticle has a diameter from about 1 mm
to about 10 mm, from about 1 mm to about 5 mm, from about 0.25
.mu.m to about 1000 .mu.m, from about 0.25 .mu.m to about 50 .mu.m,
from about 0.25 .mu.m to about 30 .mu.m, from about 1 nm to about
500 nm, from about 1 nm to about 250 nm, or from about 1 nm to
about 50 nm.
[0013] One aspect described herein is an encapsulated iodine
particle comprising a hydrophobic core and an amphipathic
encapsulating layer wherein said hydrophobic core consists of a
hydrophobic iodine nanoparticle, a hydrophobic triiodobenzene
monomer or a hydrophobic triiodobenzene dimer; wherein said iodine
nanoparticle is a reaction product of functionalized triiodobenzene
and linking monomers; wherein said functionalized triiodobenzene
and said linking monomers are covalently cross-linked resulting in
the structure of said iodine nanoparticle being non-dendritic,
non-uniform, and non-linear; wherein said iodine nanoparticle has a
polydispersity index of about 0.5 or less; wherein said iodine
nanoparticle has sufficient iodine density to be imaged by an
imaging device following administration to a subject; and wherein
said iodine nanoparticle provides for an extended blood
half-life.
[0014] In one embodiment, the functionalized triiodobenzene is
functionalized 1,3,5-triiodobenzene or functionalized
2,4,6-triiodobenzene. In one embodiment, the functionalized
triiodobenzene has the structure:
##STR00002##
[0015] wherein R.sup.1, R.sup.2, and R.sup.3 are each independently
selected from a group consisting of optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted cycloalkyl, optionally substituted aryl,
optionally substituted heteroaryl, optionally substituted alkoxy,
optionally substituted aryloxy, optionally substituted amino,
optionally substituted thiol, and optionally substituted
phosphonate.
[0016] In one embodiment, the functionalized triiodobenzene is
2,4,6-triiodophenol, 2-(2,4,6-triiodophenoxy)ethanol,
2-(2-bromoethoxy)1,3,5-triiodobenzene,
(2,4,6-triiodophenoxy)acetamide,
2-(2,4,6-triiodophenoxy)ethanesulfonic acid,
3-hydroxy-2,4,6-triiodobenzoic acid, 3-amino-2,4,6-triiodobenzoic
acid, methyl 2-(2,4,6-triiodophenoxy)butyrate,
(2-(2,4,6-triiodophenoxy)-ethyl)trimethylammonium methanesulfonate,
5-amino-2,4,6-triiodoisophthalic acid,
.alpha.-ethyl-3-hydroxy-2,4,6-triiodohydrocinnamic acid, iopanoic
acid, 7-(3-amino-2,4,6-triiodophenyl)heptanoic acid,
7-(3-amino-2,4,6-triiodophenyl)heptanoic acid ethyl ester,
2-phenyl-2-(2,4,6-triiodophenoxy)acetic acid,
(2-(3-hydroxy-2,4,6-triiodobenzyl)butyrylamino)acetic acid,
N-(2-dimethylaminoethyl)-2-(3-hydroxy-2,4,6-triiodobenzyl)butyramide,
(2-(3-hydroxy-2,4,6-triiodobenzyl)butyrylamino)acetic acid ethyl
ester, 3-(acetylamino)-5-[acetyl(methyl)amino]-2,4,6-triiodobenzoic
acid, amidotrizoic acid, 3-acetamido-2,4,6-triiodobenzoic acid,
bis(2-hydroxyethyl)-ammonium salt, 3-acetamido-2,4,6-triiodobenzoic
acid, sodium salt dihydrate,
2-(3-hydroxy-2,4,6-triiodobenzyl)-N-(1-phenylethyl)butyramide,
sodium diatrizoate hydrate,
3-(4-HO-Ph)-2-(2-(3-hydroxy-2,4,6-triiodobenzyl)-butyrylamino)propionic
acid,
3-(acetylamino)-5-{[(2-hydroxyethyl)amino]carbonyl}-2,4,6-triiodobe-
nzoic acid,
2-(3-hydroxy-2,4,6-triiodobenzyl)-N-(2-trifluoromethylphenyl)butyramide,
meglumine diatrizoate, 3-acetamido-2,4,6-triiodobenzoic acid with
1-deoxy-1-(Me-amino)-glucit, 5-(N-2,3-dihydroxypropyl
acetamido)-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)isophthalamide,
(2-(2-(3-hydroxy-2,4,6-triiodobenzyl)butyrylamino)thiazol-4-yl)acetic
acid,
5-(N-2,3-dihydroxypropylacetamido)-2,4,6-triiodo-N,N'-bis(2,3-dihyd-
roxypropyl)isophthalamide,
5-[N-(propylacetamido]-2,4,6-triiodo-N,N'-bis(propyl)isophthalamide,
or any combination thereof.
[0017] In one embodiment, the linking monomers are diaminoethane,
diaminopropane, triamine, ethereal tetraamine, diisopropyl
ethylamine, polyethyleneimine,
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, dicarboxyethane,
suberic acid, tricarboxylic acid, citrate, carboxycellulose,
alginic acid, acrylic acid, carboxydextran,
diethylenetriaminepentaacetic dianhydride, carbohydrazide, succinic
dihydrazide, adipic acid dihydrazide, diglycidyl ether,
1,4-butadioldiglycidylether, polyethylene glycol diglycidyl,
ethylene diamine, polyethylene amine, 1,1'-carbonyldiimidazole,
alkylamines, dodecylamine, oleylamine, octaoic hydrazide, or any
combination thereof.
[0018] The encapsulated iodine particle according to claim 30
wherein said linking monomers are carbohydrazide, succinic
dihydrazide, diethylenetriaminepentaacetic dianhydride, adipic acid
dihydrazide, diglycidyl ether, 1,4-butadioldiglycidylether,
polyethylene glycol diglycidyl, ethylene diamine, polyethylene
amine, 1,1'-carbonyldiimidazole, oxalyldihydrazide, or any
combination thereof. In one embodiment, the amphipathic polymer is
polyethylene glycol, poly-D,L-lactic-coglycolic acid, polyethylene
glycol-poly lactic acid, polyethylene
glycol-polyepsilon-caprolactone, polysorbates, polyvinyl alcohol,
polyvinyl pyrrolidone, dextran, chitosan, alginic acid,
carboxycellulose, or any combination thereof.
[0019] In one embodiment, the encapsulated iodine particle has a
diameter from about 1 mm to about 100 mm, from about 1 mm to about
50 mm, from about 0.25 .mu.m to about 100 .mu.m, from about 0.25
.mu.m to about 50 .mu.m, from about 0.25 .mu.m to about 30 .mu.m,
from about 1 nm to about 500 nm, from about 1 nm to about 250 nm,
or from about 1 nm to about 50 nm.
[0020] One aspect described herein is the use of the iodine
nanoparticle or the encapsulated iodine particle for radiotherapy
enhancement. In one embodiment, the iodine nanoparticle or the
encapsulated iodine particle is injected intravenously or locally
into a body tissue and the tissue is subjected to irradiation. In
one embodiment, the tissue is cancerous. In one embodiment, the
irradiation is x-rays, visible light, lasers, infrared, microwave,
radio frequencies, ultraviolet radiation, ultrasound, electrons,
protons, ion beams, carbon ions, neutrons, or radioactive
elements.
[0021] One aspect described herein is a method of producing
enhanced imaging by exposing the iodine nanoparticle or the
encapsulated iodine particle to radiation. In one embodiment, the
radiation is x-rays, visible light, lasers, infrared, microwave,
radio frequencies, ultraviolet radiation, ultrasound, electrons,
protons, ion beams, carbon ions, neutrons, or radioactive
elements.
[0022] One aspect described herein is a computer-implemented system
comprising: a digital processing device comprising: at least one
processor, an operating system configured to perform executable
instructions, a memory, and a computer program including
instructions executable by the digital processing device to create
an application that provides improved iodine nanoparticle imaging,
wherein the application comprises: [0023] a) a software module or
hardware module collecting raw image data from an X-ray imaging
device; [0024] b) a software module or hardware module removing or
greatly reducing motion in said image data; [0025] c) a software
module or hardware module increasing contrast in said image data;
and [0026] d) a software module or hardware module automatically
generating a processed image.
[0027] A computer-implemented system comprising: a digital
processing device comprising: at least one processor, an operating
system configured to perform executable instructions, a memory, and
a computer program including instructions executable by the digital
processing device to create an application that provides improved
iodine nanoparticle imaging, wherein the application comprises:
[0028] a) a software module or hardware module collecting raw image
data from an X-ray imaging device; [0029] b) a software or hardware
module averaging images over time to reduce noise; [0030] c) a
software or hardware module increasing contrast in said image data;
and [0031] d) a software or hardware module automatically
generating a processed image.
[0032] A computer-implemented system comprising: a digital
processing device comprising: at least one processor, an operating
system configured to perform executable instructions, a memory, and
a computer program including instructions executable by the digital
processing device to create an application that provides improved
iodine nanoparticle imaging, wherein the application comprises:
[0033] a) a software module or hardware module collecting raw image
data from an X-ray imaging device; [0034] b) a software module or
hardware module removing or greatly reducing motion in said image
data; [0035] c) a software module or hardware module averaging
images over time to reduce noise; [0036] d) a software module or
hardware module increasing contrast in said image data; and [0037]
e) a software module or hardware module automatically generating a
processed image.
BRIEF DESCRIPTION OF THE DRAWINGS
[0038] The novel features of the invention are set forth with
particularity in the appended claims. A better understanding of the
features and advantages of the present invention will be obtained
by reference to the following detailed description that sets forth
illustrative embodiments, in which the principles of the invention
are utilized, and the accompanying drawings of which:
[0039] FIG. 1 is an electron micrograph of the polymer prepared in
Example 1. Bar=500 nm.
[0040] FIG. 2 is a dynamic light scattering graph of the polymer
prepared in Example 1. This graph shows that the polymer prepared
pursuant to Example 1 has an effective diameter of 19.5 nm and a
polydispersity index of 0.188.
[0041] FIG. 3 shows a comparison of the weights of mice after the
polymer prepared in Example 1 was injected intravenously to provide
an effective dose of 4 g iodine/kg ("Iodine NPs"); and weights of
control mice injected intravenously with saline ("Saline"). The
graph shows that both groups of mice indistinguishably gained
weight over 40 days.
[0042] FIG. 4 is a graph showing the blood half-life of the polymer
prepared in Example 1.
[0043] FIG. 5 is a bar graph demonstrating the liver clearance of
the polymer prepared in Example 1 over 7 days. Approximately 40% of
the injected dose of iodine/g of liver was found in the liver 24
hours after an intravenous injection of the polymer prepared in
Example 1 at an effective dose of 1.8 g iodine/kg. Only 10% of the
injected dose of iodine/g of liver was still present in the liver
after 7 days.
[0044] FIG. 6A and FIG. 6B show planar x-ray images of a mouse.
FIG. 6A is before an intravenous injection and FIG. 6B is 3 minutes
after an intravenous injection, showing an increase in
radiodensity. The mouse was injected with the polymer prepared in
Example 1 with an effective dose of 1.6 g iodine/kg.
[0045] FIG. 7A and FIG. 7B show planar x-ray images of mice after
an intravenous injection of the polymer prepared in Example 1. FIG.
7A shows a mouse injected with the polymer prepared in Example 1
size selected to be greater than 50 kDaltons, at an effective dose
of 1.6 g iodine/kg. This image was obtained 42 minutes after
injection. FIG. 7B shows a mouse injected with nanoparticles
prepared in Example 1, but size selecting the fraction of low
molecular weight polymer produced, between 10 kDaltons and 50
kDaltons, at an effective dose of 600 mg iodine/kg. This image was
obtained 22 minutes after injection. The accumulation of iodine in
the bladder is highlighted by an arrow.
[0046] FIG. 8A and FIG. 8B show microCT scans of the kidney region
in a mouse. FIG. 8A shows a mouse injected with the polymer
prepared in Example 1 at an effective dose of 1.75 g iodine/kg.
This image was obtained two minutes after injection. FIG. 8B shows
a mouse injected with a standard iodine contrast agent (Iohexol) at
an effective dose of 2.5 g iodine/kg. This image was obtained two
minutes after injection.
[0047] FIG. 9A and FIG. 9B show microCT scans of the lung region in
a mouse. FIG. 9A shows a mouse injected with the polymer prepared
in Example 1 at an effective dose of 1.75 g iodine/kg. This image
was obtained 30 minutes after injection. FIG. 9B shows a mouse
injected with a standard iodine contrast agent (Iohexol) at an
effective dose of 1.75 g iodine/kg. This image was obtained 30
minutes after injection.
[0048] FIGS. 10A and 10B show the microCT images of a mouse brain
with a glioma brain tumor. FIG. 10A is an image obtained 1 day
after intravenous injection of nanoparticles at a dose of 2.8 g
iodine/kg. FIG. 10B is an image obtained 3 days after intravenous
injection of nanoparticles at a dose of 2.8 g iodine/kg.
[0049] FIG. 11 shows two images demonstrating how iodine leaks out
along vessels opened by migrating glioma cells.
[0050] FIG. 12 is a flow diagram of processing software or hardware
which enhances iodine nanoparticle images.
DETAILED DESCRIPTION OF THE INVENTION
Iodine Nanoparticle
[0051] As used herein, the term "iodine nanoparticle" refers to a
reaction product of functionalized triiodobenzene, linking
monomers, and biocompatible polymers; wherein said functionalized
triiodobenzene, said linking monomers, and said biocompatible
polymers are covalently cross-linked resulting in the structure of
said iodine nanoparticle being non-dendritic, non-uniform, and
non-linear; wherein said iodine nanoparticle has a polydispersity
index of about 0.5 or less; wherein said iodine nanoparticle has
sufficient iodine density to be imaged by an imaging device
following administration to a subject; and wherein said iodine
nanoparticle provides for an extended blood half-life.
[0052] As used herein, the term "functionalized triiodobenzene"
refers to either functionalized 1,3,5-triiodobenzene or
functionalized 2,4,6-triiodobenzene. In some embodiments,
functionalized triiodobenzene has the structure:
##STR00003##
wherein R.sub.1, R.sub.2, and R.sub.3 are each independently
selected from a group consisting of optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted cycloalkyl, optionally substituted aryl,
optionally substituted heteroaryl, optionally substituted alkoxy,
optionally substituted aryloxy, optionally substituted amino,
optionally substituted thiol, and optionally substituted
phosphonate.
[0053] As used herein, the term "alkyl" refers to substituted or
unsubstituted, straight and branched chain alkyl radicals
containing from one to fifteen carbon atoms. The may be both
straight and branched chain alkyl radicals containing from one to
six carbon atoms and includes methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, tert-butyl and the like. The alkyl group may be
optionally substituted with one or more substituents selected from
halogen, --CN, --NO.sub.2, --C(O).sub.2R, --C(O)R, --O--R,
--N(R.sup.N).sub.2, --N(R.sup.N)C(O)R, --N(R.sup.N)S(O).sub.2R,
--SR, --C(O)N(R.sup.N).sub.2, --OC(O)R, --OC(O)N(R.sup.N).sub.2,
--SOR, --SO.sub.2R, --SO.sub.3R, --S(O).sub.2N(R.sup.N).sub.2,
phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and
heteroaryl.
[0054] As used herein, the term "optionally substituted alkenyl"
refers to substituted or unsubstituted, straight and branched chain
alkene radicals, including both the E- and Z-forms, containing from
two to eight carbon atoms. The alkenyl group may be optionally
substituted with one or more substituents selected from the group
consisting of halogen, --CN, --NO.sub.2, CO.sub.2R, C(O)R, --O--R,
--N(R.sup.N).sub.2, --N(R.sup.N)C(O)R, --N(R.sup.N)S(O).sub.2R,
--SR, --C(O)N(R.sup.N).sub.2, --OC(O)R, --OC(O)N(R.sup.N).sub.2,
S(O)R, SO.sub.2R, --SO.sub.3R, --S(O).sub.2N(R.sup.N).sub.2,
phosphate, phosphonate, cycloalkyl, cycloalkenyl, aryl and
heteroaryl.
[0055] As used herein, the term "optionally substituted alkynyl"
refers to substituted or unsubstituted, straight and branched
carbon chain containing from two to eight carbon atoms and having
at least one carbon-carbon triple bond. The term alkynyl includes,
for example ethynyl, 1-propynyl, 2-propynyl, 1-butynyl,
3-methyl-1-butynyl and the like. The alkynyl group may be
optionally substituted with one or more substituents selected from
halo, --CN, NO.sub.2, CO.sub.2R, C(O)R, --O--R, --N(R.sup.N).sub.2,
--N(R.sup.N)C(O)R, --N(R.sup.N)S(O).sub.2R, --SR,
--C(O)N(R.sup.N).sub.2, --OC(O)R, --OC(O)N(R.sup.N).sub.2, --SOR,
--SO.sub.2R, --SO.sub.3R, --S(O).sub.2N(R.sup.N).sub.2, phosphate,
phosphonate, cycloalkyl, cycloalkenyl, aryl and heteroaryl.
[0056] As used herein, the term "optionally substituted cycloalkyl"
refers to substituted or unsubstituted cyclic alkyl radicals
containing from three to twelve carbon atoms and includes
cyclopropyl, cyclopentyl, cyclohexyl and the like. The term
"cycloalkyl" also includes polycyclic systems having two rings in
which two or more atoms are common to two adjoining rings (the
rings are "fused"). The cycloalkyl group may be optionally
substituted with one or more substituents selected from halogen,
alkyl, --CN, --NO.sub.2, --CO.sub.2R, --C(O)R, --O--R,
--N(R.sup.N).sub.2, --N(R.sup.N)C(O)R, --N(R.sup.N)S(O).sub.2R,
--SR, --C(O)N(R.sup.N).sub.2, --OC(O)R, --OC(O)N(R.sup.N).sub.2,
--SOR, --SO.sub.2R, --SO.sub.3R, --S(O).sub.2N(R.sup.N).sub.2,
--SiR.sub.3, --P(O)R, phosphate, phosphonate, cycloalkyl,
cycloalkenyl, aryl and heteroaryl.
[0057] As used herein, the term "optionally substituted aryl"
refers to substituted or unsubstituted single-ring and multiple
aromatic groups (for example, phenyl, pyridyl and pyrazole, etc.)
and polycyclic ring systems (naphthyl and quinolinyl, etc.). The
polycyclic rings may have two or more rings in which two atoms are
common to two adjoining rings (the rings are "fused") wherein at
least one of the rings is aromatic, e.g., the other rings can be
cycloalkyls, cycloalkenyls, aryl, heterocycles and/or heteroaryls.
The aryl group may be optionally substituted with one or more
substituents selected from halogen, alkyl, --CN, --NO.sub.2,
--CO.sub.2R, --C(O)R, --O--R, --N(R.sup.N).sub.2,
--N(R.sup.N)C(O)R, --N(R.sup.N)S(O).sub.2R, --SR,
--C(O)N(R.sup.N).sub.2, --OC(O)R, --OC(O)N(R.sup.N).sub.2, --SOR,
--SO.sub.2R, --SO.sub.3R, --S(O).sub.2N(R.sup.N).sub.2,
--SiR.sub.3, --P(O)R, phosphate, phosphonate, cycloalkyl,
cycloalkenyl, aryl and heteroaryl.
[0058] As used herein, the term "optionally substituted heteroaryl"
refers to substituted or unsubstituted aromatic and non-aromatic
cyclic radicals having at least one heteroatom as a ring member.
Preferred heterocyclic groups are those containing five or six ring
atoms which includes at least one hetero atom and includes cyclic
amines such as morpholino, piperidino, pyrrolidine and the like and
cyclic ethers, such as tetrahydrofuran, tetrahydropyran and the
like. Aromatic heterocyclic groups, also termed "heteroaryl"
groups, contemplates single-ring hetero-aromatic groups that may
include from one to three heteroatoms, for example, pyrrole, furan,
thiophene, imidazole, oxazole, thiazole, triazole, pyrazole,
oxodiazole, thiadiazole, pyridine, pyrazine, pyridazine, pyrimidine
and the like. The term heteroaryl also includes polycyclic
hetero-aromatic systems having two or more rings in which two or
more atoms are common to two adjoining rings (the rings are
"fused") wherein at least one of the rings is a heteroaryl, e.g.,
the other rings can be cycloalkyls, cycloalkenyls, aryl,
heterocycles and/or heteroaryls. Examples of polycyclic
heteroaromatic systems include quinoline, isoquinoline, cinnoline,
tetrahydroisoquinoline, quinoxaline, quinazoline, benzimidazole,
benzofuran, benzothiophene, benzoxazole, benzothiazole, indazole,
purine, benzotriazole, pyrrolepyridine, pyrrazolopyridine and the
like. The heterocyclic group may be optionally substituted with one
or more substituents selected from the group consisting halogen,
alkyl, --CN, --NO.sub.2, --CO.sub.2R, --C(O)R, --O--R,
--N(R.sup.N).sub.2, --N(R.sup.N)C(O)R, --N(R.sup.N)S(O).sub.2R,
--SR, --C(O)N(R.sup.N).sub.2, --OC(O)R, --OC(O)N(R.sup.N).sub.2,
--SOR, --SO.sub.2R, --SO.sub.3R, --S(O).sub.2N(R.sup.N).sub.2,
--SiR.sub.3, --P(O)R, phosphate, phosphonate, cycloalkyl,
cycloalkenyl, aryl and heteroaryl.
[0059] As used herein, the term "optionally substituted alkoxy"
refers to substituted or unsubstituted oxygen with a alkyl group as
a substituent and includes methoxy, ethoxy, butoxy, trifluromethoxy
and the like. It also includes divalent substituents linked to two
separated oxygen atoms such as, without limitation,
--O--(CH.sub.2).sub.1-4--O--,
--O--(CH.sub.2).sub.1-4--O--(CH.sub.2CH.sub.2--O).sub.1-4-- and
--(O--CH.sub.2CH.sub.2--O).sub.1-4--.
[0060] As used herein, the term "optionally substituted aryloxy"
refers to substituted or unsubstituted oxy with an aryl group as a
substituent and includes phenyloxy, benzyloxy and the like.
[0061] As used herein, the term "optionally substituted amino"
refers to a group of the structure --NR.sup.N.sub.2.
[0062] As used herein, the term "substituted thiol" refers to a
thiol group having the hydrogen replaced with, for example a
C.sub.1-6 alkyl group ("--S(C.sub.1-6 alkyl)"), an aryl
("--S(aryl)"), or an aralkyl ("--S(alkyl)(aryl)") and so on
[0063] As used herein, the term "optionally substituted
phosphonate" refers to the moieties having the following
structures, respectively:
##STR00004##
[0064] Each R.sup.N is independently selected from the group
consisting of hydrogen, --OH, C.sub.1 to C.sub.12 alkyl, C.sub.1 to
C.sub.12 heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycle,
aryl, heteroaryl, arylalkyl, alkoxy, alkoxycarbonyl, alkanoyl,
carbamoyl, substituted sulfonyl, sulfonate and sulfonamide. Two
R.sup.N may be taken together with C, O, N or S to which they are
attached to form a five- to seven-membered ring which may
optionally contain a further heteroatom.
[0065] In some embodiments the functionalized triiodobenzene is
2,4,6-triiodophenol, 2-(2,4,6-triiodophenoxy)ethanol,
2-(2-bromoethoxy)1,3,5-triiodobenzene,
(2,4,6-triiodophenoxy)acetamide,
2-(2,4,6-triiodophenoxy)ethanesulfonic acid,
3-hydroxy-2,4,6-triiodobenzoic acid, 3-amino-2,4,6-triiodobenzoic
acid, methyl 2-(2,4,6-triiodophenoxy)butyrate,
(2-(2,4,6-triiodophenoxy)-ethyl)trimethylammonium methanesulfonate,
5-amino-2,4,6-triiodoisophthalic acid,
.alpha.-ethyl-3-hydroxy-2,4,6-triiodohydrocinnamic acid, iopanoic
acid, 7-(3-amino-2,4,6-triiodophenyl)heptanoic acid,
7-(3-amino-2,4,6-triiodophenyl)heptanoic acid ethyl ester,
2-phenyl-2-(2,4,6-triiodophenoxy)acetic acid,
(2-(3-hydroxy-2,4,6-triiodobenzyl)butyrylamino)acetic acid,
N-(2-dimethylaminoethyl)-2-(3-hydroxy-2,4,6-triiodobenzyl)butyramide,
(2-(3-hydroxy-2,4,6-triiodobenzyl)butyrylamino)acetic acid ethyl
ester, 3-(acetylamino)-5-[acetyl(methyl)amino]-2,4,6-triiodobenzoic
acid, amidotrizoic acid, 3-acetamido-2,4,6-triiodobenzoic acid,
bis(2-hydroxyethyl)-ammonium salt, 3-acetamido-2,4,6-triiodobenzoic
acid, sodium salt dihydrate,
2-(3-hydroxy-2,4,6-triiodobenzyl)-N-(1-phenylethyl)butyramide,
sodium diatrizoate hydrate,
3-(4-HO-Ph)-2-(2-(3-hydroxy-2,4,6-triiodobenzyl)-butyrylamino)propionic
acid,
3-(acetylamino)-5-{[(2-hydroxyethyl)amino]carbonyl}-2,4,6-triiodobe-
nzoic acid,
2-(3-hydroxy-2,4,6-triiodobenzyl)-N-(2-trifluoromethylphenyl)butyramide,
meglumine diatrizoate, 3-acetamido-2,4,6-triiodobenzoic acid with
1-deoxy-1-(Me-amino)-glucit, 5-(N-2,3-dihydroxypropyl
acetamido)-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)isophthalamide,
(2-(2-(3-hydroxy-2,4,6-triiodobenzyl)butyrylamino)thiazol-4-yl)acetic
acid,
5-(N-2,3-dihydroxypropylacetamido)-2,4,6-triiodo-N,N'-bis(2,3-dihyd-
roxypropyl)isophthalamide,
5-[N-(propylacetamido]-2,4,6-triiodo-N,N'-bis(propyl)isophthalamide,
or any combination thereof.
[0066] As used herein, the term "linking monomers" refers to
monomers that crosslink the functionalized triiodobenzene and/or
the biocompatible polymers. In some embodiments, linking monomers
are diaminoethane, diaminopropane, triamine, ethereal tetraamine,
diisopropyl ethylamine, polyethyleneimine,
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, dicarboxyethane,
suberic acid, tricarboxylic acid, citrate, carboxycellulose,
alginic acid, acrylic acid, carboxydextran,
diethylenetriaminepentaacetic dianhydride, carbohydrazide, succinic
dihydrazide, adipic acid dihydrazide, diglycidyl ether,
1,4-butadioldiglycidylether, polyethylene glycol diglycidyl,
ethylene diamine, polyethylene amine, 1,1'-carbonyldiimidazole, or
any combination thereof. In some embodiments, linking monomers are
carbohydrazide, succinic dihydrazide, diethylenetriaminepentaacetic
dianhydride, adipic acid dihydrazide, diglycidyl ether,
1,4-butadioldiglycidylether, polyethylene glycol diglycidyl,
ethylene diamine, polyethylene amine, 1,1'-carbonyldiimidazole,
oxalyldihydrazide, or any combination thereof.
[0067] As used herein, the term "biocompatible polymer" refers to
polymers that are synthetic or natural polymers which are tolerated
by the body. In some embodiments, biocompatible polymers are amine
functionalized poly-N-vinylpyrrolidinone, polyvinyl alcohol,
polysulfone, polyethylene terephthalate, polyether-urethanes,
methoxy-polyethylene glycol, polyethyleneglycol-amine,
polydimethylsiloxane, ethylene-co-vinylacetate,
polymethylmethacrylate, polytetrafluoroethylene, polypropylene,
polyethylene, alginic acid, polylysine, polyglycolide, polylactide,
polylactide-co-glycolide, polycaprolactone, polybutylene succinate
and its copolymers, poly-p-dioxanone, polycarbonate, aromatic
copolyesters, polyamides, polyester-amides, polyurethane,
polyphosphazenes, polyphosphoesters, collagen, albumin, gluten,
chitosan, hyaluronate, cellulose, alginate, gelatin, starch, or any
combination thereof.
[0068] As used herein, the term "diameter" is used to describe the
size of the polymer as determined from dynamic light scattering. In
some embodiments, the iodine nanoparticle has a diameter from about
1 nm to about 1000 nm, about 1 nm to about 250 nm, or from about 1
nm to about 50 nm. In some embodiments, the iodine nanoparticle can
be further polymerized to sizes of about 1 mm to about 10 mm, from
about 1 mm to about 5 mm, from about 1 .mu.m to about 1000 .mu.m,
from about 1 .mu.m to about 50 .mu.m, or from about 1 .mu.m to
about 30 .mu.m.
[0069] In some embodiments, to prepare the iodine nanoparticle,
functionalized triiodobenzene is dissolved in water. In some
embodiments, triiodobenzene is functionalized 1,3,5-triiodobenzene
or functionalized 2,4,6-triiodobenzene. In some embodiments,
functionalized triiodobenzene has the structure:
##STR00005##
[0070] wherein R.sub.1, R.sub.2, and R.sub.3 are each independently
selected from a group consisting of optionally substituted alkyl,
optionally substituted alkenyl, optionally substituted alkynyl,
optionally substituted cycloalkyl, optionally substituted aryl,
optionally substituted heteroaryl, optionally substituted alkoxy,
optionally substituted aryloxy, optionally substituted amino,
optionally substituted thiol, and optionally substituted
phosphonate. In some embodiments, functionalized triiodobenzene is
2,4,6-triiodophenol, 2-(2,4,6-triiodophenoxy)ethanol,
2-(2-bromoethoxy)1,3,5-triiodobenzene,
(2,4,6-triiodophenoxy)acetamide,
2-(2,4,6-triiodophenoxy)ethanesulfonic acid,
3-hydroxy-2,4,6-triiodobenzoic acid, 3-amino-2,4,6-triiodobenzoic
acid, methyl 2-(2,4,6-triiodophenoxy)butyrate,
(2-(2,4,6-triiodophenoxy)-ethyl)trimethylammonium methanesulfonate,
5-amino-2,4,6-triiodoisophthalic acid,
.alpha.-ethyl-3-hydroxy-2,4,6-triiodohydrocinnamic acid, iopanoic
acid, 7-(3-amino-2,4,6-triiodophenyl)heptanoic acid,
7-(3-amino-2,4,6-triiodophenyl)heptanoic acid ethyl ester,
2-phenyl-2-(2,4,6-triiodophenoxy)acetic acid,
(2-(3-hydroxy-2,4,6-triiodobenzyl)butyrylamino)acetic acid,
N-(2-dimethylaminoethyl)-2-(3-hydroxy-2,4,6-triiodobenzyl)butyramide,
(2-(3-hydroxy-2,4,6-triiodobenzyl)butyrylamino)acetic acid ethyl
ester, 3-(acetylamino)-5-[acetyl(methyl)amino]-2,4,6-triiodobenzoic
acid, amidotrizoic acid, 3-acetamido-2,4,6-triiodobenzoic acid,
bis(2-hydroxyethyl)-ammonium salt, 3-acetamido-2,4,6-triiodobenzoic
acid, sodium salt dihydrate,
2-(3-hydroxy-2,4,6-triiodobenzyl)-N-(1-phenylethyl)butyramide,
sodium diatrizoate hydrate,
3-(4-HO-Ph)-2-(2-(3-hydroxy-2,4,6-triiodobenzyl)-butyrylamino)propionic
acid,
3-(acetylamino)-5-{[(2-hydroxyethyl)amino]carbonyl}-2,4,6-triiodobe-
nzoic acid,
2-(3-hydroxy-2,4,6-triiodobenzyl)-N-(2-trifluoromethylphenyl)butyramide,
meglumine diatrizoate, 3-acetamido-2,4,6-triiodobenzoic acid with
1-deoxy-1-(Me-amino)-glucit, 5-(N-2,3-dihydroxypropyl
acetamido)-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)isophthalamide,
(2-(2-(3-hydroxy-2,4,6-triiodobenzyl)butyrylamino)thiazol-4-yl)acetic
acid,
5-(N-2,3-dihydroxypropylacetamido)-2,4,6-triiodo-N,N'-bis(2,3-dihyd-
roxypropyl)isophthalamide,
5-[N-(propylacetamido]-2,4,6-triiodo-N,N-bis(propyl)isophthalamide,
or any combination thereof.
[0071] In some embodiments sodium metaperiodate is added to the
solution of functionalized triiodobenzene in water. This mixture is
reacted from about 10 minutes to about 24 hours. In some
embodiments, the mixture is reacted from about 20 minutes to about
40 minutes. Then the excess sodium metaperiodate is optionally
quenched with ethylene glycol. After quenching, the product mixture
is dried under vacuum and then resuspended in water. To this
solution, a linking monomer is added. In some embodiments, the
linking monomers are diaminoethane, diaminopropane, triamine,
ethereal tetraamine, diisopropyl ethylamine, polyethyleneimine,
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide, dicarboxyethane,
suberic acid, tricarboxylic acid, citrate, carboxycellulose,
alginic acid, acrylic acid, carboxydextran,
diethylenetriaminepentaacetic dianhydride, carbohydrazide, succinic
dihydrazide, adipic acid dihydrazide, diglycidyl ether,
1,4-butadioldiglycidylether, polyethylene glycol diglycidyl,
ethylene diamine, polyethylene amine, 1,1'-carbonyldiimidazole, or
any combination thereof. In some embodiments, linking monomers are
carbohydrazide, succinic dihydrazide, diethylenetriaminepentaacetic
dianhydride, adipic acid dihydrazide, diglycidyl ether,
1,4-butadioldiglycidylether, polyethylene glycol diglycidyl,
ethylene diamine, polyethylene amine, 1,1'-carbonyldiimidazole,
oxalyldihydrazide, or any combination thereof.
[0072] Biocompatible polymers are then added to the reaction
mixture. In some embodiments, biocompatible polymers are amine
functionalized poly-N-vinylpyrrolidinone, polyvinyl alcohol,
polysulfone, polyethylene terephthalate, polyether-urethanes,
methoxy-polyethylene glycol, polyethyleneglycol-amine,
polydimethylsiloxane, ethylene-co-vinylacetate,
polymethylmethacrylate, polytetrafluoroethylene, polypropylene,
polyethylene, alginic acid, polylysine, polyglycolide, polylactide,
polylactide-co-glycolide, polycaprolactone, polybutylene succinate
and its copolymers, poly-p-dioxanone, polycarbonate, aromatic
copolyesters, polyamides, polyester-amides, polyurethane,
polyphosphazenes, polyphosphoesters, collagen, albumin, gluten,
chitosan, hyaluronate, cellulose, alginate, gelatin, starch, or any
combination thereof. The reaction mixture is allowed to react for
about 6 hours to about 24 hours. In one embodiment, the reaction
mixture is allowed to react for about 12 hours to about 18 hours.
Sodium borohyride is then added and the reaction mixture is allowed
to react further for about 1 hour to about 5 hours. In one
embodiment, the reaction mixture is allowed to react further for 2
hours to about 24 hours. The reaction mixture is then filtered and
the iodine nanoparticle is obtained. The iodine nanoparticle is
characterized using dynamic light scattering and electron
microscopy.
[0073] Scheme 1 is one embodiment of the preparation of the iodine
nanoparticle.
##STR00006## ##STR00007##
[0074] In one embodiment, the iodine nanoparticle is formulated as
a liposome or encapsulated in one or more layers of surfactants. To
prepare the liposomes, a biocompatible polymer is diluted with
water. Then a solution of functionalized triiodobenzene is added
and incubated with a base. In some embodiments the incubation is
for about 0.5 hours to about 2 hours. Parallel to this, a
hydrophobic solution is prepared. Then the mixture containing the
biocompatible polymer and functionalized triiodobenzene is added to
solution the hydrophobic solution. In one embodiment, addition
occurs using a rotating blade homogenizer. The liposomes formed are
then purified and collected for administration to a subject.
[0075] In one embodiment, the iodine nanoparticle is a dimer of
functionalized triiodobenzene. To prepare the dimers,
functionalized triiodobenzene is dissolved in a polar solvent. In
one embodiment, the polar solvent is dimethylformamide. The
solution of functionalized triiodobenzene is then reacted with a
linking monomer. In one embodiment the linking monomer is
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. The product mixture
is vacuum dried and then resuspended in hexane. An aqueous solution
of a biocompatible polymer is added to the suspended product
mixture and then heated. In one embodiment the mixture is heated at
about 70.degree. C. to about 90.degree. C. In one embodiment the
mixture is heated for about 0.5 hours to about 2 hours.
Encapsulated Iodine Particles
[0076] As used herein, the term "encapsulated iodine particles"
comprises a core of hydrophobic iodine nanoparticle described
herein, a hydrophobic triiodobenzene monomer or a hydrophobic dimer
encapsulated by an amphipathic polymer. Said iodine nanoparticle is
a reaction product of functionalized triiodobenzene, linking
monomers and biocompatible polymers; wherein said functionalized
triiodobenzene, said linking monomers, and said biocompatible
polymers are covalently cross-linked resulting in the structure of
said iodine nanoparticle being non-dendritic, non-uniform, and
non-linear; wherein said iodine nanoparticle has a polydispersity
index of about 0.5 or less; wherein said iodine nanoparticle has
sufficient iodine density to be imaged by an imaging device
following administration to a subject; and wherein said iodine
nanoparticle provides for an extended blood half-life.
[0077] As used herein, the term "amphipathic polymer" refers to a
polymer with hydrophobic and hydrophilic characteristics. In some
embodiments, the amphipathic polymer is polyethylene
glycol-poly-D,L-lactic-coglycolic acid, polyethylene glycol-poly
lactic acid, polyethylene glycol-polyepsilon-caprolactone,
polysorbates, polyvinyl alcohol, polyvinyl pyrrolidone, dextran,
chitosan, alginic acid, carboxycellulose, or any combination
thereof.
[0078] In some embodiments, the encapsulated iodine particle has a
diameter from about 1 mm to about 100 mm, from about 1 mm to about
50 mm, from about 0.50 .mu.m to about 100 .mu.m, from about 0.25
.mu.m to about 50 .mu.m, from about 0.25 .mu.m to about 30 .mu.m,
from about 1 nm to about 500 nm, from about 1 nm to about 250 nm,
or from about 1 nm to about 50 nm.
[0079] In some embodiments, to prepare the encapsulated iodine
particles, the iodine nanoparticle is dissolved in a solvent. In
some embodiments, the solvent is a non-aqueous polar solvent. In
some embodiments, the non-aqueous polar solvent is
dimethylsulfoxide, dimethylformamide, tetrahydrofuran, acetone, or
acetonitrile. In some embodiments, the solvent is an organic
solvent. In some embodiments, the organic solvent is
dichloromethane, chloroform, cyclohexane, diethyl ether, hexane,
xylene, ethyl acetate, or benzene. The amphipathic polymer is then
added. In some embodiments the amphipathic polymer is polyethylene
glycol-poly-D,L-lactic-coglycolic acid, polyethylene glycol-poly
lactic acid, polyethylene glycol-polyepsilon-caprolactone,
polysorbates, polyvinyl alcohol, polyvinyl pyrrolidone, dextran,
chitosan, alginic acid, or carboxycellulose. This mixture is then
added to a larger volume of liquid which contains water and
optionally a water-soluble polymer. In some embodiments, the
water-soluble polymer is polyvinyl alcohol or polyvinyl
pyrrolidone. This final mixture is agitated to form an emulsion. In
one embodiment, the agitation is by way of sonication. After
agitation, the solvent is removed. In some embodiments, the solvent
is removed by way of solvent extraction, vacuum drying, heat drying
or freeze drying. The removal of solvent results in the
encapsulated iodine particles which are characterized using dynamic
light scattering and electron microscopy.
[0080] In some embodiments, the storage of the encapsulated iodine
particles is at room temperature, at about 4.degree. C., at about
-20.degree. C. or rapidly frozen in liquid nitrogen and then
stored. In some embodiments, the storage of the encapsulated iodine
particles occurs after the dried encapsulated iodine particles are
resuspended in a biocompatible excipient. In one embodiment, the
biocompatible excipient is phosphate buffered saline at about pH
7.4.
Methods and Uses
[0081] X-ray imaging has the advantage of having the highest
spatial resolution. This resolution may be 1-10 .mu.m in a microCT
image, compared to about 2 mm in microPET and about 200 .mu.m in
microMRI. Clinical resolutions also show X-ray/CT imaging to be
best. X-ray radiography and CT not only have important clinical
applications in anatomical/physiological imaging, including
angiography and tumor imaging, but also have advantages over PET
and MM in their relatively low cost, higher resolution, and greater
availability.
[0082] The term "radiotherapy enhancement" refers to treatment
using radiation that is improved or increased in some manner.
[0083] The term "radiation" refers to forms of radiation suitable
for use and may include, but are not limited to, x-rays,
radioactivity, electrons, protons, neutrons, ions, visible light,
lasers, infrared, microwave, radio frequencies, ultraviolet
radiation, other electromagnetic radiation at various frequencies,
and ultrasound. X-rays can be produced electrons bombarding a
target, by orthovoltage equipment (less than 500 kVp), by
synchrotrons, by linear accelerators, and with equipment producing
X-rays in the 500 kV-100 MV range, or electrons in the 1-300 MeV
range. Various other sources may be employed, including, but not
limited to electrons, protons, ion beams, carbon ions, and
neutrons. Many of these sources produce secondary effects that can
be useful for the intended purpose of ablating a target tissue, for
example, specific heating caused by energy absorption of the
sample. Radioisotopes may also be used that have emissions
favorable for iodine absorption, such as I-125, Yb-169, Au-198,
Pd-103, Cs-137, Co-60, Ir-192.
[0084] Radiotherapy using the iodine nanoparticle or the
encapsulated iodine particle can be further enhanced by spatially
fractionated beams. A collimator, scan pattern, or other method can
be used to produce an irradiation pattern that consists of peaks
and valleys of dose. The peak and valley regions can be micrometers
to centimeters in size. This spares the tissue first impinged upon
since radiation leaves un-irradiated or less irradiated tissue
allowing the tissue to heal. The source can be arranged or the
energy used to spread out the beams with depth, eventually forming
overlapping peak regions thus producing a more damaging and more
continuous irradiation region. This region can be designed to cover
various tumors at depth while better sparing normal tissue closer
to the source. It also allows lower energy beams to be used to
treat regions at deeper depths. Another variation is to irradiate
spatially fractionated beams from two or various angles
(cross-firing) such that they interleave in the target volume,
creating a continuous or quasi-continuous beam there. This spares
tissues outside the target volume which are exposed to spatially
fractionated beams, but achieves a more damaging irradiation in the
target volume where the beams are overlapped or interleaved
creating essentially a more destructive continuous beam.
Stereotactic irradiation of pencil-like beams may also be used to
better focus the radiation on the treatment or tumor volume such as
with the cyberknife or gamma-knife systems.
[0085] Radiotherapy using the iodine nanoparticle or the
encapsulated iodine particle can be improved by applying the
radiation from various directions (tomotherapy), but all focused on
the target volume, compared to a unidirectional irradiation. This
has the effect of spreading out the incident beam and sparing skin
or other superficial tissues. Collimators are adjustable at the
various irradiation directions to sculpt the dose topography.
Mathematical treatment planning can be used to optimize the dose to
the target region and minimize dose to surrounding and critical
tissues or structures.
[0086] Current radiotherapy tries to focus the maximal dose on the
central tumor site, using, for example, IMRT (Intensity Modulated
RadioTherapy). However, although this strategy avoids ancillary
damage, it leaves poorly irradiated surrounding areas that may
contain migrated or metastasized tumor cells that will lead to
recurrence. Recurrent cancers are more difficult to treat. In the
method disclosed here, the iodine nanoparticle or encapsulated
iodine particle are targeted to the tumor cells that have spread
beyond the main tumor mass and will boost the radiation just near
these tumor cells, since the tumor cells secrete vascular
endothelial growth factor, vascular permeability factor, and other
cytokines that stimulate angiogenesis and leaky blood vessels.
Tumor targeting may also be by addition of other agents
facilitating tumor uptake, such as RGD peptides, drugs, or
ultrasound, or by attachment of targeting agents such as
antibodies, peptides, or other targeting moieties to the iodine
nanoparticle or encapsulated iodine particle. The volume of
irradiation is expanded significantly from what would typically be
irradiated, but at lower dose than that currently used. The dose
will now be boosted only in tumor locations, enough to eradicate
migrating tumor cells and greatly reducing the frequently deadly
tumor recurrence. The irradiated volume can be increased 25% or
more than that currently practiced with radiotherapy.
[0087] The methods described herein can be optionally combined with
chemotherapy, immunotherapy, hyperthermia, ultrasound, high
intensity focused ultrasound, X-ray therapy, proton therapy, carbon
ion therapy, surgery, microwave therapy, and other therapies to
result in a better treatment. In many cases, combination treatments
show a synergistic effect where the combined treatment produces a
better result than the sum of each therapy applied separately. For
example, hyperthermia given at or near the same time as
radiotherapy can greatly enhance the radiotherapy. Immunotherapy
has been shown to be enhanced when combined with radiotherapy.
Similarly, radiotherapy using the iodine nanoparticle or
encapsulated iodine particle can enhance the effects of
hyperthermia or immunotherapy. Radiotherapy using the iodine
nanoparticle or encapsulated iodine particle can alter the
microenvironment in a tumor resulting in better penetration and
effectiveness of drugs. Radiotherapy using the iodine nanoparticle
or encapsulated iodine particle allows immune cells better access
and effectiveness. Radiotherapy using the iodine nanoparticle or
encapsulated iodine particle exposes and creates more
cancer-specific antigens when cells are killed by the radiation,
thus better stimulating the immune system.
[0088] Some of the iodine nanoparticles described herein
unexpectedly exhibited strong visible fluorescence (see Examples 8
and 9). These might be used as probes for microscopy or in vivo to
delineate tumors and other structures.
[0089] The iodine nanoparticle or encapsulated iodine particle can
be optionally imaged or detected by fluorescent x-rays emitted
after bombardment with an X-ray beam. This provides an image
modality distinct from X-ray absorption and attenuation of a beam.
The iodine nanoparticle or encapsulated iodine particle can be
localized to a target by various means including vascular leakage,
a property of tumors and tissue damage, or attaching a targeting
moiety such as an antibody, antibody fragment, protein, peptide,
nucleic acid, carbohydrate, drug, or any compound that has affinity
to the target. The imaging can also be used in a straightforward
detection mode, in vivo or ex-vivo, to qualitatively or
quantitatively detect a material.
[0090] In one embodiment, the iodine nanoparticle or encapsulated
iodine particle may be used for the imaging of the urinary system
(see FIG. 7).
Toxicity
[0091] The current state of x-ray radiography with iodine-based
contrast agents suffers from several important inadequacies.
Commercially available contrast agents cause adverse reactions in
many patients, including those with allergies, asthma, kidney
diseases, and diabetes. These reactions can be severe or fatal. For
a person with kidney disease, injection of commercially available
iodine agents needed for heart stenting or correcting vascular
blockages in the leg and elsewhere can permanently damage the
kidneys and the patient will have to go on dialysis the rest of
their lives. If a heart attack is imminent, the interventional
cardiologist treating a patient that also has weak but functioning
kidneys must make the choice of stenting to correct the heart
problem and permanently destroying the patient's kidneys or not
stenting and risk heart failure. Another deficiency with respect to
toxicity of commercially available imaging agents is none are
safely available for persons with kidney diseases.
[0092] The iodine nanoparticle or encapsulated iodine particle
described herein may be size selected to pass through the kidneys.
Because of its biocompatible aspect, it may be used in patients
with poorly functioning kidneys. This would greatly help in the
diagnosis of kidney failure, enabling the proper corrective
treatment to be applied before any additional kidney injury
occurs.
[0093] Some of the preparations described have been tested in
animals and show no signs of toxicity after an intravenous
injection of 4 grams of iodine per kg body weight (see Example 26
and FIG. 3). They gained weight similar to age-matched controls.
This is a higher level of injection than any other iodine
nanoparticle larger than 5 nm and is a surprising finding.
[0094] Some of the preparations described become viscous when
highly concentrated and are more easily handled diluted. In order
to reach the tested intravenous administration of 4 g iodine/kg
level, some preparations were intravenously injected at 100 mg
iodine/mL requiring an injection volume of 0.8 mL for a 20 g mouse.
This was administered in two doses spaced 3 hours apart. The
animals showed no signs of toxicity and gained weight similar to
age-matched controls. This is surprising since the whole blood
volume of the mouse is about 1.5 mL. Approximately one-half the
total blood volume of the animal was injected without significant
toxicity, even though the material was quite viscous and greater
than 5 nm, thus largely or completely avoiding kidney clearance and
designed for extended blood half-life.
[0095] In one embodiment, the iodine nanoparticle or the
encapsulated iodine particle described herein is biodegradable. In
the one embodiment, the iodine nanoparticle or the encapsulated
iodine particle is injected into a subject. When the iodine
nanoparticle or the encapsulated iodine particle is present in the
body, the iodine nanoparticle or encapsulated iodine particle
undergoes catabolism. Since this occurs slowly, the actual
concentration of iodine nanoparticle or the encapsulated iodine
particle breakdown products presented to the subject are at a low
concentrations. Thus in one embodiment the iodine nanoparticle or
encapsulated iodine particle described herein is less toxic than
commercially available iodine contrast agents.
Extended Blood Half-Life Useful for Imaging
[0096] An extended blood half-life contrast agent is needed for
diagnostic imaging as well as therapy. For example, aneurisms in
the brain and dorsal aorta are difficult to detect, but a vascular
contrast agent would make this straightforward. The condition of
the coronary arteries could be assessed non-invasively, thus
preventing many heart attacks, the number one cause of death. The
method disclosed herein would address this need and could impact
the number of heart attack deaths.
[0097] The iodine nanoparticle or encapsulated iodine particle
described herein can be size controlled, composition, and coating
controlled. These parameters can be used to control the blood
half-life, route of body clearance, rate of body clearance,
biodistribution, pharmacokinetics, pharmacodynamics, and toxicity
profile. This enables such applications as tumor imaging, heart
imaging, vascular imaging, and organ imaging.
[0098] Many other vascular diseases could be better assessed by the
iodine nanoparticle or encapsulated iodine particle described
herein including: dorsal aorta aneurism, brain aneurism,
arteriovenous malformations, deep vein thrombosis, claudication,
renal artery stenosis, peripheral artery disease, Buerger's
disease, and intravascular coagulation.
Enhancing Images
[0099] One aspect described herein is a method of using the iodine
nanoparticle or encapsulated iodine particle for treating cancer by
administering the iodine nanoparticle or encapsulated iodine
particle which accumulates in the tumor by any mechanism, waiting a
time for the tumor-to-local non-tumor concentration ratio to be
favorable (greater than 2) and applying radiation. As an example,
X-rays may be used that are absorbed by the iodine nanoparticle or
encapsulated iodine particle and which results in electrons and
other products being emitted by the iodine which can then create
free radicals and ionizations or other events that lead to tumor
damage.
[0100] Cancers treated by this method may include acute
lymphoblastic leukemia, acute myeloid leukemia, cancer in
adolescents, adrenocortical carcinoma, AIDS-related cancers,
AIDS-related lymphoma, anal cancer, astrocytomas, atypical
teratoid/rhabdoid tumor, basal cell carcinoma, bile duct cancer,
bladder cancer, bone cancer, brain and spinal cord tumors, brain
stem glioma, brain tumor, breast cancer, bronchial tumors, Burkitt
Lymphoma, carcinoid tumor, carcinoma of unknown primary, cardiac
tumors, central nervous system embryonal tumors, central nervous
system germ cell tumors, cervical cancer, childhood cancers,
cholangiocarcinoma, chordoma, chronic lymphocytic leukemia, chronic
myelogenous leukemia, chronic myeloproliferative neoplasms, colon
cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell
lymphoma, ductal carcinoma in situ, embryonal tumors, endometrial
cancer, ependymoma, esophageal cancer, esthesioneuroblastoma, Ewing
Sarcoma family of tumors, extracranial germ cell tumor,
extragonadal germ cell tumor, eye cancer, fallopian tube cancer,
fibrous histiocytoma of bone, osteosarcoma, gallbladder cancer,
gastric cancer, gastrointestinal carcinoid tumor, castrointestinal
stromal tumors, germ cell tumor, gestational trophoblastic disease,
glioma and brain tumor, Hairy Cell leukemia, head and neck cancer,
heart cancer, hepatocellular cancer, histiocytosis, Langerhans
Cell, Hodgkin Lymphoma, hypopharyngeal cancer, intraocular
melanoma, Islet Cell tumors, pancreatic neuroendocrine tumors,
Kaposi sarcoma, Langerhans cell histiocytosis, laryngeal cancer,
leukemia, lip and oral cavity cancer, liver cancer (primary), low
malignant potential tumor, lung cancer, lymphoma, primary
macroglobulinemia, Waldenstrom, male breast cancer, melanoma,
Merkel cell carcinoma, mesothelioma, mouth cancer, multiple
endocrine neoplasia syndromes, multiple myeloma/plasma cell
neoplasm, mycosis fungoides, myelodysplastic syndromes,
myelodysplastic/myeloproliferative neoplasms, myeloma, multiple
myeloproliferative neoplasms, nasal cavity and paranasal sinus
cancer, nasopharyngeal cancer, neuroblastoma, non-Hodgkin lymphoma,
non-melanoma, non-small cell lung cancer, oral cavity cancer,
oropharyngeal cancer, ovarian cancer, pancreatic cancer, pancreatic
neuroendocrine tumors (Islet cell tumors), papillomatosis,
paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid
cancer, penile cancer, pharyngeal cancer, pheochromocytoma,
pituitary tumor, plasma cell neoplasm/multiple myeloma,
pleuropulmonary, blastoma, pregnancy and breast cancer, primary
central nervous system lymphoma, primary peritoneal cancer,
prostate cancer, rectal cancer, renal cell cancer, transitional
cell cancer, retinoblastoma, rhabdomyosarcoma, salivary gland
cancer, sarcoma, Sezary syndrome, small cell lung cancer, small
intestine cancer, squamous cell carcinoma, squamous neck cancer,
stomach cancer, T-cell lymphoma, testicular cancer, throat cancer,
thymoma and thymic carcinoma, thyroid cancer, unknown primary
carcinomas, urethral cancer, uterine cancer, endometrial, uterine
sarcoma, vaginal cancer, vulvar cancer, Waldenstrom
Macroglobulinemia, Wilms Tumor and other kidney tumors.
Software Module or Hardware Module for Enhanced Imaging
[0101] One aspect described herein are methods to improve iodine
nanoparticle imaging. There are two major modules that can be used
separately, but in some cases greatly benefitted by their combined
use. The first module comprises tracking software that removes or
greatly reduces motion in the real-time acquisition. An alternative
to this is gating the input so that the same position in a
repetitive sequence is acquired. However, gating in its simplest
form is less efficient since useful data during the non-gated time
may be discarded. Tracking may be used, for example, to remove or
reduce the motion caused by breathing and/or heart beating. The
second module is image averaging, where the data is combined over
time to reduce the noise and permit increased contrast, i.e.,
better detection. Minor modules or operations can be included to
enhance the imaging, including, but not limited to: binning, edge
enhancement/detection, Gaussian and other filters, unsharp masking,
brightness and contrast adjustment, thresholding, and
sharpening.
[0102] A problem exists with standardly used coronary or carotid
angiography using standardly available iodine contrast agents.
Here, a catheter is inserted, usually in the femoral artery, but
sometimes in the radial artery, and it is guided to the hilus of a
major coronary artery (right coronary artery, left coronary artery
or its two branches, the circumflex artery and the left anterior
descending artery), or proximal to the carotid artery entering the
neck. The standard iodine agent is injected from the catheter and
visualized by fluoroscopy on a TV monitor. The iodine agent is
dense enough (about 300-400 mg iodine/cc) to visualize the artery
and any blockage or stenosis that may be there. Although the
imaging is brief from the iodine injection, it is usually adequate
for the purposes of diagnosis, clot removal, stent deployment,
balloon angioplasty, or other procedures. The interventional
cardiologist can easily follow the angiogram by eye since the heart
beats about once per second, and no specialized software is
required. A significant problem in these procedures is that
patients with kidney disease, poor glomerular filtration, diabetes,
or other conditions resulting in compromised kidney function, may
have their kidneys completely destroyed for life, necessitating
dialysis for the rest of their lives, due to the rapid accumulation
of the iodine agent in the kidneys and its severe toxicity when not
rapidly eliminated as with normally functioning kidneys.
[0103] In some embodiments, the iodine nanoparticle or encapsulated
iodine particle is used in an angiography. The iodine nanoparticle
or encapsulated iodine particle can have a size greater than about
5 nm and avoid filtration into the kidneys, thus protecting them.
In some embodiments the iodine nanoparticle or encapsulated iodine
particle has a concentration lower than commercially available
contrast agents, for example, about 100 mg iodine/cc. In some
embodiments the software disclosed is used to rapidly a) track the
heart beat and breathing motion, thus stabilizing the image, and b)
image average over time to reduce noise and boost contrast to an
acceptable level. Other imaging process, can also be employed, the
end result being that iodine nanoparticles could be used in
angiographic procedures. This could spare the kidneys of many
patients. A block diagram of this computer program is shown in FIG.
12
Migrating Glioma Cells
[0104] Iodine nanoparticles can increase local dose of iodine to
tumors. Standard iodine contrast media have been tried in animals
and in a clinical trial, but found to have too short a blood
half-life for adequate tumor uptake and tumor:non-tumor ratios. To
overcome these drawbacks the iodine nanoparticle or encapsulated
iodine particle described herein can be used. The iodine
nanoparticle or encapsulated iodine particle described herein are
nearly colorless, do not color the skin, are organic and can be
metabolized, are non-toxic (LD50>4 g Iodine/kg), and are low
cost. Preliminary tests showed highly specific localization in
gliomas after an intravenous injection.
[0105] As mentioned, one of the biggest problems with treating
gliomas are the migrating cells which later cause inevitable
recurrence. Surgery, radiotherapy, and chemotherapy cannot fully
eradicate these migrating cells. Studies show these migrating cells
follow blood vessels. In iodine nanoparticle described herein
treated mice with gliomas, spider-like projections of iodine
density were found emanating from the tumor (Example 35 and FIG.
11). These result from migrating tumor cells making the blood
vessels leaky, allowing the nanoparticles to extravasate. By
increasing the radiotherapy volume to include these, the radiation
dose will be boosted by the iodine precisely where these migrating
tumor cells reside, and provide a way to effectively eradicate
them.
[0106] Thus in one embodiment is a method for treating migrating
glioma cells using the iodine nanoparticle or encapsulated iodine
particle described herein.
EXAMPLES
Example 1: Preparation of Polymer
[0107] 172 mg of
5-(N-2,3-Dihydroxypropylacetamido)-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypr-
opyl)isophthalamide was dissolved in 230 .mu.L of water and mixed
with 267 mg of sodium metaperiodate dissolved in 1.2 mL of water
and reacted in the dark for 30 min. Excess periodate was optionally
quenched with a molar excess of ethylene glycol. The product was
then dried under vacuum and resuspended in water. 28 mg of
carbohydrazide was added and after 10 minutes, 630 mg of 2,000 MW
amino-terminated polyethylene glycol. After 16 hours, 79 mg of
sodium borohydride was added and reacted for 2.5 hours. The final
product was filtered through a 50 KDa ultrafiltration device. The
retentate and flow through were both collected. The retentate was
washed twice with phosphate buffered saline. Dynamic light
scattering showed a diameter of 19.6 nm with a polydispersity index
of 0.188 (FIG. 2). Electron microscopy showed dense particles
consistent with the dynamic light scattering results (FIG. 1).
Example 2: In Vivo Imaging Using Polymer
[0108] 1.6 g Iodine/kg of the >50 kDa polymer of example 1 was
intravenously injected into a mouse. Before and 3 min. after
injection images were taken using 60 kVp X-rays, shown in FIG. 6.
An increase in density was noticeable after injection, especially
in the lung region, but also other tissues as well, due to the
polymer in the blood perfusing the whole body.
Example 3
[0109] The filtrate produced in Example 1 (<50 kDa) was further
filtered and washed on a 10 KDa filter and the retentate was
intravenously injected into the tail vein of a mouse (600 mg of
iodine/kg). No adverse reaction or clinical signs were observed.
X-ray imaging after 22 min. revealed substantial accumulation of
the contrast agent in the bladder (FIG. 7). This demonstrates a use
for urinary system imaging.
Example 4: Scale Up
[0110] The preparation of Example 1 was scaled up to produce
significantly more polymer. The retentate on a 50 kDa filter was
injected in two doses spaced 3 hours apart into mice to achieve a
total dose of 4 g iodine per kg body weight. Animals showed this
dose was well-tolerated and behaved normally (FIG. 3).
Example 5
[0111] 43 mg
5-(N-2,3-Dihydroxypropylacetamido)-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypr-
opyl)isophthalamide was dissolved in 60 .mu.L of water and mixed
with 80 mg of sodium metaperiodate dissolved in 0.4 mL of water and
reacted in the dark for 30 min. Excess periodate was quenched with
a molar excess of ethylene glycol. The product was then dried under
vacuum and resuspended in water. The pH was adjusted to 12 with
sodium hydroxide. After 3 hours, 160 mg of 2,000 MW
amino-terminated polyethylene glycol was added. After 16 hours, the
product was filtered through a 50 KDa ultrafiltration device. The
retentate was washed twice with phosphate buffered saline. Dynamic
light scattering showed a diameter of 30.9 nm with a polydispersity
index of 0.175.
Example 6
[0112] 26 mg of 2,3,5-Triiodobenzoic acid was dissolved in 0.50 mL
of methanol. 5 mL of cylclohexane was added, then 0.10 mL of Triton
X-100. The resultant mixture was then sonicated. The sample was
heated to 80.degree. C. for 30 min. 0.02 mL of Triton X-114 was
added and the sample slowly added into 8 mL of water while mixing,
then sonicated. After 24 hours the sample was filtered with a 0.45
micron filter and dynamic light scattering indicated nanoparticles
that were 201 nm in size with a polydispersity index of 0.36.
Example 7
[0113] 43 mg
5-(N-2,3-Dihydroxypropylacetamido)-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypr-
opyl)isophthalamide was dissolved in 60 .mu.L of water and mixed
with 80 mg of sodium metaperiodate dissolved in 0.4 mL of water and
reacted in the dark for 30 min. Excess periodate was quenched with
a molar excess of ethylene glycol. The product was then dried under
vacuum and resuspended in water. 8 mg of adipic acid dihydrazide
was added followed by 79 mg of 1,000 MW amino-terminated PEG. After
24 hours, the product was isolated using a 50 KDa filter and washed
with phosphate buffered saline. The polymer was concentrated to 150
mg Iodine/mL.
Example 8
[0114] 11 mg
5-(N-2,3-Dihydroxypropylacetamido)-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypr-
opyl)isophthalamide was dissolved in 0.10 mL of dry
dimethyformamide. 8 mg of poly(hexamethylene diisocynaate),
viscosity 1,300-2,200 cp, was added and the solution heated to
80.degree. C. for 2 hours. Subsequently, 79 mg of 2,000 MW
amino-terminated polyethylene glycol was added. After 16 hours the
resulting polymer exhibited a strong yellow-green fluorescence.
Example 9
[0115] 11 mg
5-(N-2,3-Dihydroxypropylacetamido)-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypr-
opyl)isophthalamide was dissolved in 0.05 mL of dry
dimethyformamide. 14 mg of diethylenetriaminepentaacetic
dianhydride dissolved in 0.2 mL of dry dimethyformamide was added
and the solution heated for 2 hours at 80.degree. C. for 2 hours.
79 mg of 2,000 MW amino-terminated polyethylene glycol was then
added. After 16 hours 1.4 mL of water was added. The resultant
polymer showed a strong blue fluorescence.
Example 10
[0116] 11 mg
5-(N-2,3-Dihydroxypropylacetamido)-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypr-
opyl)isophthalamide was dissolved in 0.5 mL of 1.5 M sodium
hydroxide. 4 microliters of epichlorohydrin was added and the
solution heated at 50.degree. C. for 16 hours. 1 mL of water was
added and the resulting polymer was isolated using a 50 kDa
filter.
Example 11
[0117] 11 mg
5-(N-2,3-Dihydroxypropylacetamido)-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypr-
opyl)isophthalamide was dissolved in 0.1 mL of dry dimethyformamide
and reacted with a molar amount of diglycidyl ether, 1,4
butandioldiglycidylether, or poly(ethylene glycol) diglycidyl ether
for 24 hours. 79 mg of 2,000 MW amino-terminated polyethylene
glycol was then added. After 16 hours 1.4 mL of water was added.
The resulting polymers were isolated using a 50 kDa filter.
Example 12
[0118] 43 mg
5-(N-2,3-Dihydroxypropylacetamido)-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypr-
opyl)isophthalamide was dissolved in 60 .mu.L of water and mixed
with 80 mg of sodium metaperiodate dissolved in 0.4 mL of water and
reacted in the dark for 30 min. Excess periodate was quenched with
a molar excess of ethylene glycol. The product was then dried under
vacuum and resuspended in water. This was reacted with 10 mg of
NH2-(PEG)4-NH2 for 24 hours. The resulting iodine polymers were
isolated using a 50 kDa filter.
Example 13: Preparation of Encapsulated Iodine Particle
[0119] 22 mg
5-(N-2,3-Dihydroxypropylacetamido)-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypr-
opyl)isophthalamide was dissolved in 30 .mu.L of water and mixed
with 40 mg of sodium metaperiodate dissolved in 0.2 mL of water and
reacted in the dark for 30 min. Excess periodate was quenched with
a molar excess of ethylene glycol. The product was then dried under
vacuum and resuspended in 2 mL of methanol and spun at 3 krpm for 5
min. The supernatant was then reacted with 15 mg dodecylamine with
17 mg sodium triacetoxyborohydride for 3 hours. The solution was
rotary evaporated to dryness and redissolved in 0.3 mL of
cyclohexane. This was added to 2 mL of water with 0.05 mL of Tween
80 and sonicated to form an emulsion. The cyclohexane was then
removed by heating at 90.degree. C. for 1 hour, reducing the size
of the encapsulated iodine particles. Dynamic light scattering
indicated an average hydrodynamic size of 343 nm with a
polydispersity index of 0.41.
Example 14
[0120] 38 mg
5-(N-2,3-Dihydroxypropylacetamido)-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypr-
opyl)isophthalamide was dissolved in 30 .mu.L of water and mixed
with 0.09 mL of 8% glutaraldehyde (in water). 0.06 mL of
concentrated hydrochloric acid was added and the solution rotary
evaporated at 40.degree. C., then resuspended in water. Micron to
mm-sized iodine encapsulated iodine particles were formed.
Example 15
[0121] 11 mg
5-(N-2,3-Dihydroxypropylacetamido)-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypr-
opyl)isophthalamide was dissolved in 0.015 mL of water. 2 mg of
gluataraldehyde in 0.025 mL and 0.005 mL of concentrated
hydrochloric acid were added. This solution was then added to 0.5
mL xylene containing 113 mg sodium dodecyl sulfate, sonicated, and
rotary evaporated at 50.degree. C. To the material was added 1 mL
dichloromethane containing 0.05 mg 2,000 MW amino-PEG. Sonication
formed a stable emulsion. After 1 hour 0.4 mL water was added and
the solution rotary evaporated at 50.degree. C. to 0.2 mL. Light
microscopy revealed nanoparticles 0.5 to 2 microns in diameter.
Example 16
[0122]
5-(N-2,3-Dihydroxypropylacetamido)-2,4,6-triiodo-N,N'-bis(2,3-dihyd-
roxypropyl)isophthalamide was dissolved in water and mixed with 1.2
molar excess of sodium metaperiodate and reacted in the dark for 30
min. The product was then dried under vacuum and resuspended in
methanol and spun at 3 krpm for 5 min. The supernatant was reacted
with 1.5 molar excess (to the iodine compound) of either: a)
carbohydrazide, b) ethylenediamine, c) polyethyleneamine. A 1.5
molar excess of sodium triacetoxyborohydride was added and reacted
for 24 hours. Subsequently, the samples were dried, dissolved in
dichloromethane, and added to a 10-fold volume excess of water
containing the biodegradable surfactant polycaprolactone-PEG and
sonicated. Nanoparticles were concentrated and purified on a 50 kDa
molecular centrifugal filter.
Example 17
[0123] 2,3,5-Triiodobenzoic acid was dissolved dry
dimethylformamide. It was reacted with ethylenediamine using
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide as a crosslinking
agent to form triiodobenzoic acid dimers. These were hydrophobic.
The reaction was vacuum dried and the product suspended in hexane.
An emulsion was formed using 1 mL of the hexane dissolved product
mixed with 10 mL of water containing 10 microliters of polysorbate
80 upon sonication. The hexane was removed by heating at 80.degree.
C. for 1 hour, resulting in smaller nanoparticles. These were then
concentrated using a 50 kDa centrifugal filter followed by washing
in phosphate buffered saline.
Example 18
[0124]
5-(N-2,3-Dihydroxypropylacetamido)-2,4,6-triiodo-N,N'-bis(2,3-dihyd-
roxypropyl)isophthalamide was dissolved in dry dimethylformamide
and reacted with a 0.3 molar amount of 1,1'-carbonyldiimidazole.
The polymers produced were added to a 10-fold volume excess of
water containing the biodegradable surfactant polycaprolactone-PEG
and sonicated. Iodine encapsulated iodine particles were
concentrated and purified on a 50 kDa molecular centrifugal filter.
This produced encapsulated iodine particles with both a core and
shell that were biodegradable. The core material, linked by ester
bonds, then reverts upon hydrolysis to the original
5-(N-2,3-Dihydroxypropylacetamido)-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypr-
opyl)isophthalamide compound which is FDA approved and has an
intravenous LD50 value of 24.2 g iodine/kg in mice. This refers to
an acute dose, but since the encapsulated iodine particle will
degrade slowly it will present a lower concentration to the body,
thus making it even less toxic.
Example 19
[0125] 3 mg
5-(N-2,3-Dihydroxypropylacetamido)-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypr-
opyl)isophthalamide was dissolved in 0.1 mL dry dimethylsulfoxide.
92 mg of polyethylene glycol (3400 MW) was added along with 87 mg
1,1'-carbonyldiimidazole. After 1 hour, 1 mL of water was added and
the product was put through a high pressure homogenizer at 30 kpsi
until a nearly clear solution was obtained. This was then 0.2
micrometer filtered and the nanoparticles collected, washed and
concentrated on a 50 kDa centrifugal filter.
Example 20
[0126] Liposome preparation: 2 microliters of poly(ethylene glycol)
diglycidyl ether (500 MW) was diluted in 1 mL of water. 25
microliters of this solution was added to 20 mg
5-(N-2,3-Dihydroxypropylacetamido)-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypr-
opyl)isophthalamide with 1 microliter of 1 Normal sodium hydroxide
and incubated for 1 hour (solution 1). In another container, 200 mg
lecithin was dissolved in 0.2 mL of dichloromethane and added to 10
mL of mineral oil (solution 2). Solution 1 was injected through a
28 gauge needle into solution 2, and homogenized using a rotating
blade homogenizer. The product was then further dispersed into
smaller particles using a high pressure homogenizer operating at 30
kpsi. The product was centrifuged at 3 kg and the pellet washed 2
times with hexane. 2 mL of water was added to the pellet, the
sample sonicated, and heated to 80 degrees C. to remove remaining
hexane. The product was filtered through a 0.2 micron filter, then
concentrated and purified further on a 50 kDa molecular centrifugal
filter.
Example 21: Crosslinking to a Shell Component
[0127] 6 mg
5-(N-2,3-Dihydroxypropylacetamido)-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypr-
opyl)isophthalamide was mixed in 10 microliters of water with 3
microliters of 8% glutaraldehyde. This was mixed with 0.5 mL of
toluene containing 5 mg of oleic acid. This was sonicated to form
an emulsion and reacted for 1 hour. The precipitate formed was
washed with hexane and the final product dispersed in water using
Brij S100 surfactant.
Example 22: Silane Coating
[0128] 17 mg
5-(N-2,3-Dihydroxypropylacetamido)-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypr-
opyl)isophthalamide or iodobenzene polymers in 0.05 mL of water was
mixed with a solution made of 5 microliters of trichloro(octadecyl)
silane, 200 microliters of dichloromethane and 1 mL of mineral oil.
The mixture was sonicated. In some preparations, NaOH was mixed in
the water phase to enhance silane polymerization. The emulsion was
then centrifuged and washed with hexane. Finally, the pellet was
dissolved in 0.5 mL of water with 10 microliters of Brij 100 as
surfactant.
Example 23
[0129] 5-Amino-2,4,6-triiodoisophthalic acid was dissolved in water
and mixed with a 0.5 molar amount of ethylenediamine hydrochloride.
The water soluble crosslinker
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide in equimolar amount
was used to form the polymer.
Example 24
[0130] 3 mg 5-Amino-2,4,6-triiodoisophthalic acid was mixed with 7
mg 1,1'-carbonyldiimidazole as dry chemicals and ground with a
pestle. After reacting, 0.7 mg polyethyleneamine (MW 800) was added
and also ground for reaction. The product was recovered in 2 mL of
water and purified on centrifugal filters.
Example 25
[0131] 8 mg 5-Amino-2,4,6-triiodoisophthalic acid was mixed with
5.5 mg 1,1'-carbonyldiimidazole and ground with a pestle. After
reacting, 56 mg of amino-PEG was added along with 0.5 microliters
of concentrated hydrochloric acid. After 4 hours, 1 mL of water was
added and the product purified on a centrifugal filter.
Example 26: Toxicity Testing
[0132] Three outbred CD1 mice were dosed at 4 g Iodine/kg,
administered via tail vein in 2 equal doses 3 hours apart. An
age-matched control group was injected with the same volume of
saline. Mice were weighed regularly the two groups showed no
significant differences (FIG. 3). Weight gain was normal.
Example 27: Toxicity Testing
[0133] This toxicity test involved the metabolic effects as
measured by blood analysis of serum clinical chemistry analytes and
hematocrits. Three outbred CD1 mice were dosed at 4 g Iodine/kg of
the polymer of Example 1, administered via tail vein in 2 equal
doses 3 hours apart. An age-matched control group was injected with
the same volume of saline. After one month, blood samples were
taken and analyzed. Results are given in Table 1. Surprisingly, no
toxicity was detected and the iodine polymer group was
indistinguishable from the control group.
TABLE-US-00001 TABLE 1 GROUP SALINE POLYMER FROM EXAMPLE 1 Patient
1 8 10 mean 2 4 5 mean ALP 79 121 133 111 49 60 94 67.67 ALT 18 28
28 24.7 27 19 14 20 AST 58 105 71 78 133 51 47 77 Creatine Kinase
149 384 217 250 608 127 109 281.33 GGT 1 1 1 1 1 1 1 1 Albumin 2.8
2.4 2.7 2.63 2.9 2.6 2.6 2.7 Total Protein 5 4.4 5 4.8 5.1 4.6 4.8
4.83 Globulin 2.2 2 2.3 2.17 2.2 2 2.2 2.13 Total Bilirubin 0.1 0.1
0.1 0.1 0.1 0.1 0.1 0.1 Bulirubin - Conj. <0.1 <0.1 <0.1
<0.1 <0.1 <0.1 <0.1 <0.1 BUN 12 25 24 20.3 18 6 18
14 Creatinine <0.1 0.1 0.1 0.1 0.1 <0.1 <0.1 0.1
Cholesterol 108 100 126 111 105 111 95 103.67 Glucose 217 239 255
237 223 215 271 236.33 Calcium 8.3 8.3 8.7 8.43 9.2 8.8 8.5 8.83
Phosphorus 6.5 44 6.4 5.77 6.8 6.2 4.5 5.83 TCO2 (Bicarbonate) 17
18 18 17.7 16 19 18 17.67 Chloride 112 112 112 112 110 13 113 78.67
Potassium 5.9 4.7 5.2 5.27 4.8 4.9 4.8 4.83 Sodium 144 144 143 144
144 146 144 144.67 ALB/GLOB Ratio 1.3 1.2 12 1.23 1.3 1.3 1.2 1.27
BUN/Creatinine Ratio 120 250 240 203 180 160 180 173.33 Bilirubin -
Unconj. 0 0 0 0 0 0 0 0 NA/K Ratio 24 31 28 27.7 30 30 30 30 Anion
Gap 21 19 18 19.3 23 19 18 20 SDMA 5 7 6 6 5 7 5 5.67 WBC 6 3.5 3.1
4.2 4.5 2.9 2.4 3.27 RBC 8.56 8.12 7.38 8.02 8.92 7.27 8.36 8.18
HGB 13.6 11.9 11.4 12.3 13.1 11.4 11.9 12.13 HCT 41.8 38.8 37 39
41.9 35.5 39.1 38.83 MCV 49 47 50 48.7 47 49 47 47.67 MCH 15.9 14.7
15.4 15.3 14 15.7 14.2 14.63 MCHC 32.5 31.1 30.8 31.5 31.3 32.1
30.4 31.27 % Neutrophil 10 16.4 5 10.5 12.5 16 13.7 14.07 %
Lymphocyte 88 68.6 93 83.2 74.7 81 71.4 75.7 % Monocyte 2 2.8 0 1.6
7.3 2 13.3 7.53 % Eosinophil 0 11.6 1 4.2 5.1 1 0.8 2.3 % Basophil
0 0.6 1 0.53 0.4 0 0.8 0.4 Auto Platelet 1305 1311 647 1308 1297
180 1730 1069 Neutrophil 600 574 155 443 563 464 329 452 Lymphocyte
5280 2401 2883 3521 3362 2349 1714 2475 Monocyte 120 98 0 72.7 329
58 319 235.33 Eosinophil 0 406 31 146 229 29 19 92.33 Basophil 0 21
31 17.3 18 0 19 12.33 T3 51 47 57 51.7 46 39 49 44.67 T4 6.8 5 5.7
5.83 8.5 5 7.1 6.87 cTSH 0.03 0.05 0.04 0.04 0.04 0.04 0.04
0.04
Example 28: Blood Half-Life of Polymer
[0134] 20 mg of the iodine nanoparticles of Example 1 were injected
IV into mice and blood samples taken at various times thereafter.
Blood was allowed to clot, centrifuged, and serum iodine spectrally
quantified. The blood half-life was determined to be 6.5 hours (see
FIG. 4).
Example 29: Liver Clearance of Polymer
[0135] The iodine content of the liver was measured over time. At
24 hours after injection of 1.8 g iodine/kg, 39% of the injected
dose of iodine was found in the liver. The liver weight was 0.94 g,
calculating to 41.8% of the injected dose/g(liver). Iodine content
was then measured 1 week after IV injection and the liver loading
dropped to 10.4% id/g. This represents a 75% clearance from the
liver in 6 days (see FIG. 5), indicating that these iodine
nanoparticles appear to be slowly metabolized and cleared.
Example 30: In Vivo Imaging Using Polymer
[0136] 1.6 g Iodine/kg of the >50 kDa polymer of example 1 was
intravenously injected into a mouse. Before and 3 min. after
injection images were taken using 60 kVp X-rays, shown in FIG. 6.
An increase in density was noticeable after injection, especially
in the lung region, but also other tissues as well, due to the
polymer in the blood perfusing the whole body.
Example 31
[0137] The filtrate produced in Example 1 (<50 kDa) was further
filtered and washed on a 10 KDa filter and the retentate was
intravenously injected into the tail vein of a mouse (600 mg of
iodine/kg). No adverse reaction or clinical signs were observed.
X-ray imaging after 22 min. revealed substantial accumulation of
the contrast agent in the bladder (FIG. 7). This demonstrates a use
for urinary system imaging.
Example 32: Comparison with Commercially Available Agent (in
Kidneys)
[0138] A mouse was injected with the polymer prepared in Example 1
at an effective dose of 1.75 g iodine/kg. FIG. 8(a) was obtained
two minutes after injection and shows a clear visual of the
vascular blood supply to the kidneys of the mouse. A mouse was
injected with a standard iodine contrast agent at an effective dose
of 2.5 g iodine/kg. FIG. 8(b) was obtained two minutes after
injection and shows the iodine has rapidly entered the kidneys and
is being quickly removed from the blood.
Example 33: Comparison with Commercially Available Agent (in
Lung)
[0139] A mouse was injected with the polymer prepared in Example 1
at an effective dose of 1.75 g iodine/kg. FIG. 9(a) was obtained 30
minutes after injection and shows a clear visual of the vasculature
in the lugs. A mouse was injected with a standard iodine contrast
agent at an effective dose of 1.75 g iodine/kg. FIG. 9(b) was
obtained 30 minutes after injection and shows no clear
visualization of any vasculature.
Example 34: Brain Tumor Imaging with Polymer
[0140] U87 human glioma brain tumor cells were implanted in nude
mouse brains. After growing for 3 weeks, mice were intravenously
injected with the polymer of Example 1 at 2.8 g iodine/kg. 24 hours
later the mice were imaged by microCT. A representative image is
shown in FIG. 10(a). Using standards, it was found that the tumor
loaded to .about.0.6% iodine by weight by 24 hours.
16.times.16.times.16 .mu.m3 voxels were averaged so the microscopic
iodine concentrations could actually be higher. Some voxels showed
as high as 3.4% iodine loading. 0.6% actual concentration is
calculated to give a Dose Enhancement Factor (DEF) of 2.1. 3.4%
will give a never before achieved in animals DEF of 12.3. After 3
days, the tumor concentration only decremented slightly to 0.5% as
shown in FIG. 10(b).
Example 35: Migrating Glioma Cells
[0141] U87 human glioma brain tumor cells were implanted in nude
mouse brains. After growing for 3 weeks, mice were intravenously
injected with the polymer of Example 1 at 2.8 g iodine/kg. 24 hours
later the mice were imaged by microCT. After computationally
removing the skull, tentacle-like strands could be seen emanating
from the main tumor mass. Their visibility was caused by a high
concentration of the iodine nanoparticles. Gliomas are known to
spread by migrating along blood vessels, also making them leaky to
nanoparticles. These tentacles are therefore believed to be direct
imaging of the migrating glioma cells. Since radiation would be
boosted where there is iodine, this surprisingly provides a way,
hitherto impossible, to treat and eliminate migrating glioma cells,
the current cause of glioma recurrence and invariable death.
Example 36
[0142]
5-(N-2,3-Dihydroxypropylacetamido)-2,4,6-triiodo-N,N'-bis(2,3-dihyd-
roxypropyl)isophthalamide was dissolved in water and mixed with a
2.1 molar excess of sodium metaperiodate and reacted in the dark
for 30 min. The product was then dried under vacuum and resuspended
in water. An equal volume of hexane containing a 6 molar excess of
dodecylamine was added and reacted for 16 hours with stirring. The
product was centrifuged and the upper hexane layer became yellow in
color. It was removed and dried by rotary evaporation to a yellow
oil. This product was dissolved in tetrahydrofuran containing 10
mg/ml of the surfactant polycapriolactone-polyethylene glycol, and
mixed with a 10-fold volume amount of water and sonicated.
Core-shell nanoparticles formed that were 260 nm in size.
Example 37
[0143]
3-Dihydroxypropylacetamido)-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypro-
pyl)isophthalamide was dissolved in water and mixed with a 2.1
molar excess of sodium metaperiodate and reacted in the dark for 30
min. The product was then dried under vacuum and resuspended in
water. An equal volume of hexane containing a 6 molar excess of
oleylamine was added and reacted for 16 hours with stirring. The
product was centrifuged and the upper hexane layer became yellow in
color. It was removed and dried by rotary evaporation to a yellow
oil. This product was dissolved in tetrahydrofuran containing 10
mg/ml of the surfactant polycapriolactone-polyethylene glycol, and
mixed with a 10-fold volume amount of water and sonicated.
Core-shell nanoparticles formed that were about 200 nm in size.
Example 38
[0144]
(Droxypropylacetamido)-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)i-
sophthalamide was dissolved in water and mixed with a 2.1 molar
excess of sodium metaperiodate and reacted in the dark for 30 min.
The product was then dried under vacuum and extracted with
methanol. A 6-fold excess of octanoic hyrazide was added and
reacted for 16 hours. The product was extracted into hexane and
dried by rotary evaporation. This material was dissolve in
tetrahydrofuran containing 10 mg/ml of the surfactant
polycapriolactone-polyethylene glycol, and mixed with a 10-fold
volume amount of water and sonicated. Core-shell nanoparticles
formed that were about 150 nm in size.
[0145] While preferred embodiments of the present invention have
been shown and described herein, it will be obvious to those
skilled in the art that such embodiments are provided by way of
example only. Numerous variations, changes, and substitutions will
now occur to those skilled in the art without departing from the
invention. It should be understood that various alternatives to the
embodiments of the invention described herein may be employed in
practicing the invention. It is intended that the following claims
define the scope of the invention and that methods and structures
within the scope of these claims and their equivalents be covered
thereby.
* * * * *