U.S. patent application number 15/412798 was filed with the patent office on 2017-08-10 for ionizing-radiation-responsive compositions, methods, and systems.
The applicant listed for this patent is GEARBOX LLC. Invention is credited to EDWARD S. BOYDEN, RODERICK A. HYDE, MURIEL Y. ISHIKAWA, EDWARD K.Y. JUNG, JORDIN T. KARE, NATHAN P. MYHRVOLD, CLARENCE T. TEGREENE, THOMAS ALLAN WEAVER, LOWELL L. WOOD, JR., VICTORIA Y.H. WOOD.
Application Number | 20170224821 15/412798 |
Document ID | / |
Family ID | 40562540 |
Filed Date | 2017-08-10 |
United States Patent
Application |
20170224821 |
Kind Code |
A1 |
BOYDEN; EDWARD S. ; et
al. |
August 10, 2017 |
IONIZING-RADIATION-RESPONSIVE COMPOSITIONS, METHODS, AND
SYSTEMS
Abstract
A method, composition and system respond to ionizing radiation
to adjust biological activity. In some approaches the ionizing
radiation is X-ray or extreme ultraviolet radiation that produces
luminescent responses that induce biologically active
responses.
Inventors: |
BOYDEN; EDWARD S.; (CHESTNUT
HILL, MA) ; HYDE; RODERICK A.; (REDMOND, WA) ;
ISHIKAWA; MURIEL Y.; (LIVERMORE, CA) ; JUNG; EDWARD
K.Y.; (BELLEVUE, WA) ; KARE; JORDIN T.; (SAN
JOSE, CA) ; MYHRVOLD; NATHAN P.; (MEDINA, WA)
; TEGREENE; CLARENCE T.; (MERCER ISLAND, WA) ;
WEAVER; THOMAS ALLAN; (SAN MATEO, CA) ; WOOD, JR.;
LOWELL L.; (BELLEVUE, WA) ; WOOD; VICTORIA Y.H.;
(LIVERMORE, CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
GEARBOX LLC |
Bellevue |
WA |
US |
|
|
Family ID: |
40562540 |
Appl. No.: |
15/412798 |
Filed: |
January 23, 2017 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
12012217 |
Jan 30, 2008 |
9557635 |
|
|
15412798 |
|
|
|
|
11975702 |
Oct 18, 2007 |
8164074 |
|
|
12012217 |
|
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 41/008 20130101;
A61K 41/0042 20130101; G03C 1/731 20130101; A61K 41/00
20130101 |
International
Class: |
A61K 41/00 20060101
A61K041/00 |
Claims
1-142. (canceled)
143. A method, comprising: delivering to at least one region an
ionizing-radiation-responsive composition, the
ionizing-radiation-responsive composition including: a luminescent
material, the luminescent material being responsive to ionizing
radiation in at least one ionizing radiation energy band to produce
optical energy in at least one optical wavelength band; a
photosensitive biologically active material, the photosensitive
biologically active material being responsive to optical energy in
the at least one optical wavelength band; and a matrix material
disposed to at least partially sustain proximity of the luminescent
material and the photosensitive biologically active material; and
irradiating at least a portion of the at least one region with
ionizing radiation in the at least one ionizing radiation energy
band.
144. A method, comprising: delivering to at least one region an
ionizing-radiation-responsive composition, the
ionizing-radiation-responsive composition including: a luminescent
material, the luminescent material being responsive to ionizing
radiation in at least one ionizing radiation energy band to produce
optical energy in at least one optical wavelength band; a
photosensitive biologically active material, the photosensitive
biologically active material being responsive to optical energy in
the at least one optical wavelength band; and an
optically-inhibiting material disposed to at least partially block
coupling of optical energy in the at least one optical wavelength
band to the photosensitive biologically active material; and
irradiating at least a portion of the at least one region with
ionizing radiation in the at least one ionizing radiation energy
band.
145. A method, comprising: delivering to at least one region an
ionizing-radiation-responsive composition, the
ionizing-radiation-responsive composition including: a luminescent
material, the luminescent material being responsive to ionizing
radiation in at least one ionizing radiation energy band to produce
optical energy in at least one optical wavelength band; a
photosensitive biologically active material, the photosensitive
biologically active material being responsive to optical energy in
the at least one optical wavelength band; and a coating material of
a type selected to adjust at least one of the solubility,
durability, suspension stability, bioactivity, biocompatibility,
and non-toxicity of the ionizing-radiation-responsive composition;
and irradiating at least a portion of the at least one region with
ionizing radiation in the at least one ionizing radiation energy
band.
146-214. (canceled)
Description
BRIEF DESCRIPTION OF THE FIGURES
[0001] FIG. 1 depicts irradiation of an
ionizing-radiation-responsive composition.
[0002] FIG. 2 depicts a photolabile material.
[0003] FIG. 3 depicts a photoisomerizable material.
[0004] FIGS. 4A-4C depict ionizing-radiation-responsive
compositions.
[0005] FIGS. 5A-5C and 6A-6C depict configurations of a
photosensitive bioactivity-adjusting material and a biologically
active material.
[0006] FIG. 7 depicts irradiation of an
ionizing-radiation-responsive composition.
[0007] FIGS. 8A-8G, 9A-9H, 10A-10B, 11A-11D, and 12 depict
ionizing-radiation-responsive compositions.
[0008] FIGS. 13-14 depict irradiation of an
ionizing-radiation-responsive composition.
[0009] FIGS. 15-17 depict process flows.
DETAILED DESCRIPTION
[0010] In the following detailed description, reference is made to
the accompanying drawings, which form a part hereof. In the
drawings, similar symbols typically identify similar components,
unless context dictates otherwise. The illustrative embodiments
described in the detailed description, drawings, and claims are not
meant to be limiting. Other embodiments may be utilized, and other
changes may be made, without departing from the spirit or scope of
the subject matter presented here.
[0011] FIG. 1 depicts an illustrative embodiment in which an
ionizing radiation emitter 100 produces ionizing radiation 102. The
ionizing radiation irradiates at least a portion of a region 104
that contains a luminescent material 110 and a photosensitive
biologically active material 112. The region 104 might include, for
example, a human or animal patient or a portion thereof, such as
the head, neck, limb, thorax, spine, abdomen, or pelvis; or a
particular tissue, organ, or gland; or a particular lesion caused
by disease or injury; or any other area selected for treatment. In
the illustrative embodiment depicted in FIG. 1, the beam of
ionizing radiation partitions the region 104 into an irradiated
region 106 and a non-irradiated region 108. In the irradiated
region 106, the luminescent material responds to ionizing radiation
102 to produce optical energy 114, and the photosensitive
biologically active material responds to the optical energy 114 to
become biologically active, as indicated schematically in FIG. 1 by
the radial lines 116 (other embodiments provide other responses of
the photosensitive biologically active material; for example, the
photosensitive biologically active material may respond to the
optical energy 114 to become biologically inactive, to partially
increase or decrease a level of biological activity, to change from
a first mode of biological activity to second mode of biological
activity, etc.). In the non-irradiated region 108, the luminescent
material does not receive ionizing radiation, so it does not
produce optical energy to activate the photosensitive biologically
active material.
[0012] In general, the term "photosensitive biologically active
material" can encompass any material having a biological activity
that changes in response to optical energy. For example, the
photosensitive biologically active material can include a material
that is biologically inactive and responds to optical energy to
become biologically active, a material that is biologically active
and responds to optical energy to become biologically inactive, a
material that has a first level of biological activity and responds
to optical energy to change to a second level of biological
activity, a material that has a first mode of biological activity
and responds to optical energy to change to a second mode of
biological activity, or any other material or combination of
materials having any response to optical energy that may affect its
biological activity.
[0013] In some embodiments, the photosensitive biologically active
material is a photosensitizer that responds to optical light by
generating a reactive oxygen species (such as singlet oxygen) or
another cytotoxic agent. Photosensitizers are sometimes used to
destroy cancerous or diseased cells by a procedure known as
photodynamic therapy (PDT). Generally this procedure involves: (1)
administration of a photosensitizing drug; (2) selective uptake or
retention of the photosensitizing drug in the target tissue or
lesion; (3) delivery of optical light to the target tissue or
lesion; (4) light absorption by the photosensitizing drug to
generate a cytotoxic agent that damages or destroys the target
tissue or lesion; and (5) metabolism or excretion of the
photosensitizing drug to reduce sunlight sensitivity. Photodynamic
therapy and photosensitizers and their uses are further described
in S. A. Unger, "Photodynamic Therapy," Buffalo Physician, Autumn
2004, 8-19; Paras N. Prasad, Introduction to Biopholonics,
Wiley-Interscience, 2003, 433-463; and Tuan Vo-Dinh et al,
Biomedical Photonics Handbook, CRC Press, 2003, 36-1 to 38-16;
which are herein incorporated by reference. Some examples of
photosensitizers include porphyrins, chlorins, bacteriochlorins,
benzoporphyrins, flavins, texaphyrins, phthalocyanines,
naphthalocyanines, cationic dyes, halogenated xanthenes,
dendrimers, fullerenes, organometallic complexes, and semiconductor
nanoparticles; also, combinations or derivatives of these various
compounds, and pharmaceutical preparations thereof. Some
applications involve the administration of a photosensitizer
metabolic precursor; an example is 5-aminolaevulinic acid (ALA),
which endogenously generates the photosensitizer photoporphyrin
IX.
[0014] In some embodiments, the photosensitive biologically active
material can include a photolabile material. FIG. 2 is a schematic
depiction of a photolabile material 200, having a first component
201 and a second component 202 joined by a photolabile component
203. Those elements depicted with dashed lines are optional in some
embodiments. The material is responsive to optical energy in at
least one wavelength band, as depicted by the arrow 204 labeled
with a wavelength .lamda., to divide the photolabile component into
two fragments 205. Those of skill in the art use various terms to
describe this response to optical energy, including for example
"photolysis," "photodissociation," "photo-release," and
"photo-uncaging." If the photolabile component 203 is the only
structure that couples the first component and the second
component, then the material may be completely cleaved in response
to optical energy in the at least one wavelength band. If the
material 200 optionally includes a third component 206 joined to
the first component 201 and the second component 202 by
non-photolabile components 207, then the structure is modified in
response to optical energy in the at least one wavelength band, but
the material is not completely cleaved and the first and second
components remain indirectly coupled. The modified or cleaved
structure can have a biological activity that differs from that of
the unmodified or uncleaved structure.
[0015] Various photosensitive biologically active materials that
include photolabile materials are known to those skilled in the
art. Some representative examples are as follows; other embodiments
will be apparent to those skilled in the art. Fay et al,
"Photosensitive caged macromolecules," U.S. Pat. No. 5,998,580,
herein incorporated by reference, describes various peptides
incorporating a photolabile molecule (e.g. 2-nitrophenyl,
2-nitrobenzyloxycarbonyl, or .alpha.-carboxy 2-nitrobenzyl) and
responsive to optical energy to become biologically active or
inactive. Grissom et al, "Bioconjugates and delivery of bioactive
agents," U.S. Pat. No. 6,777,237, herein incorporated by reference,
describes an example of a bioactive agent bonded to a cobalt atom
in an organocobalt complex, where the complex responds to light to
cleave the bond between the bioactive agent and the cobalt atom,
thereby releasing the bioactive agent. Kehayova et al,
"Phototriggered delivery of hydrophobic carbonic anhydrase
inhibitors," Photochem. Photobiol. Sci. 1 (2002), 774-779, herein
incorporated by reference, describes a carbonic anhydrase inhibitor
bearing a photolabile cage compound, o-nitrodimethoxyphenylglycine
(o-NDMPG) and responsive to optical light to photo-uncage (and
thereby activate) the inhibitor molecule. W. Neuberger, "Device and
method for photoactivated drug therapy," U.S. Pat. No. 6,397,102,
herein incorporated by reference, describes a drug that is
encapsulated in or attached to a photolabile fullerene molecule;
when the inactive drug-fullerene complex is subjected to selective
irradiation, the complex is broken and the drug is released in an
active form. A. Momotake et al, "The nitrodibenzofuran chromophore:
a new caging group for ultra-efficient photolysis in living cells,"
Nature Methods 30 (2006), 35-40, and W. H. Li, "Crafting new
cages," Nature Methods 30 (2006), 13-15, both herein incorporated
by reference, describe a photolabile nitrodibenzofuran caging
group. V. Tassel et al, "Photolytic drug delivery systems,"
International Application No. PCT/US96/01333, and A. W. Lindall,
"Catheter system for controllably releasing a therapeutic agent at
a remote tissue site," U.S. Pat. No. 5,470,307, both herein
incorporated by reference, describe a therapeutic or diagnostic
agent bound to a polymer, metal, glass, silica, quartz, or other
substrate by a photolabile linking agent (e.g. a 2-nitrophenyl,
acridine, nitroaromatic, arylsulfonamide, or similar chromophore),
responsive to optical light to release the therapeutic or
diagnostic agent from the substrate. Guillet et al, "Drug delivery
systems," U.S. Pat. No. 5,482,719, herein incorporated by
reference, describes in one embodiment a polymer and a therapeutic
compound, chemically bonded together through a photolabile covalent
chemical linkage (e.g. a photolabile peptide blocker compound), and
responsive to light to release the therapeutic compound from the
polymer combination.
[0016] In some embodiments, the photosensitive biologically active
material can include a photoisomerizable material. FIG. 3 is a
schematic depiction of a photoisomerizable material 300, having a
first component 301 and a second component 302 joined by a
photoisomer component in a first isomeric form 303. The material is
responsive to optical energy in at least a first wavelength band,
as depicted by the arrow 204 labeled with a wavelength
.lamda..sub.1, to convert the photoisomer component to a second
isomeric form 305. The shape change depicted in the figure is a
schematic representation of isomerization and is not intended to be
limiting. In some embodiments the two isomeric forms of the
photoisomer component are cis and trans isomers. In some
embodiments the transition from the first isomeric form to the
second isomeric form is irreversible. In other embodiments the
transition from the first isomeric form to the second isomeric form
is reversible, as indicated by the dashed arrow 306. The reverse
transition may occur in response to optical energy in at least a
second wavelength band (as indicated by the label .lamda..sub.2) or
the reverse transition may occur in response to a reduction or
absence of optical energy at least the first wavelength band (as
indicated by the label "dark"). The different isomeric forms of the
photoisomerizable material can have different biological
activities.
[0017] Various photosensitive biologically active materials that
include photoisomerizable materials are known to those skilled in
the art. Some representative examples are as follows; other
embodiments will be apparent to those skilled in the art. Volgraf
et al, "Allosteric control of an ionotropic glutamate receptor with
an optical switch," Nat. Chem. Biol. 2 (2006), 47-52; Banghart et
al, "Light-activated ion channels for remote control of neuronal
firing," Nature Neuroscience 7 (2004), 1381-1386; and Isacoff et
al, "Photoreactive regulator of protein function and methods of use
thereof," U.S. Patent Application Publication No. US2007/0128662
A1, all of which are herein incorporated by reference, describe
photoisomerizable materials responsive to optical light to regulate
protein functions. Kumita et al, "Photo-control of helix content in
a short peptide," PNAS 97 (2000), 3803-3808, herein incorporated by
reference, describes a peptide modified to include an azobenzene
photoisomer and responsive to optical energy to increase the helix
content of the peptide.
[0018] In some embodiments the photosensitive biologically active
material includes a binding partner of a protein, wherein the
photosensitive biologically active material is responsive to
optical energy to modify an interaction between the binding partner
and the protein. The protein and binding partner might be, for
example: a receptor and a corresponding receptor ligand (e.g. an
agonist, inverse-agonist, antagonist, pore blocker, etc.); an
enzyme and a corresponding enzyme ligand (e.g. an allosteric
effector, inhibitor, activator, etc.); or any other protein,
protein fragment, or protein complex and a corresponding ligand
(e.g. an element, molecule, peptide, etc.) capable of binding to
the protein, protein fragment, or protein complex and subsequently
affecting the behavior of the protein, protein fragment, or protein
complex. In some embodiments the binding partner has a probability
of binding to the protein that is changeable in response to optical
energy in the at least one wavelength band. For example, the
photosensitive biologically active material may include a
photolabile component that cages or inhibits the binding partner;
in response to optical energy, the photolabile component is removed
and the binding partner can bind to its corresponding protein. As
another example, the photosensitive biologically active material
may include a photoisomer, where the isomeric form of the
photoisomer affects the ability or the binding partner to bind to
its corresponding protein. Volgraf et al, Banghart et al, and
Isacoff et al, as cited above, provide examples of a binding
partner (e.g. a pore blocker or a receptor agonist) tethered to a
photoisomer, where isomerization causes the binding partner to
change its position relative to a binding site. In other
embodiments a bound combination of the protein and the binding
partner has a level of biological activity that is changeable in
response to optical energy in the at least one wavelength band. For
example, Eisenman et al, "Anticonvulsant and anesthetic effects of
a fluorescent neurosteriod analog activated by visible light,"
Nature Neuroscience 10 (2007), 523-530, herein incorporated by
reference, describes a fluorescently-tagged neurosteriod
(NBD-allopregnanolone) that binds to the GABA.sub.A receptor and
responds to optical light to potentiate receptor function.
[0019] In some embodiments, the photosensitive biologically active
material includes a combination of a biologically active material
and a photosensitive bioactivity-adjusting material, where the
photosensitive bioactivity-adjusting material is responsive to
optical energy to increase, decrease, or otherwise affect the
biological activity of the biologically active material. For
example, the photosensitive bioactivity-adjusting material may be
disposed to at least partially inhibit biological activity of the
biologically active material and responsive to optical energy to at
least partially uninhibit biological activity of the biologically
active material. Alternatively or additionally, the photosensitive
bioactivity-adjusting material may be a material having a first
state causing at least a first degree of inhibition of biological
activity of the biologically active material and a second state
causing at most a second degree of inhibition of biological
activity of the biologically active material, where the first
degree of inhibition is greater than the second degree of
inhibition, and where the photosensitive bioactivity-adjusting
material is responsive to optical energy in at least the first
wavelength band to at least partially convert from an unconverted
state to a converted state, the unconverted state and converted
state being uniquely selected from the group consisting of the
first state and the second state. In some embodiments the
conversion from the unconverted state to the converted state may be
irreversible. In other embodiments the conversion from the
unconverted state to the converted state may be reversible, and the
reverse conversion (or reversion) from the converted state to the
unconverted state may occur in response to optical energy in at
least a second wavelength band or in response to a reduction or
absence of optical energy at least the first wavelength band. The
biologically active material may include any substance having a
biological or pharmaceutical activity, including but not limited to
analgesics, anti-infectives, antineoplastics (or other cytotoxic or
chemotherapeutic agents), cardiovascular agents, diagnostic agents,
dermatological agents, EENT agents, endocrine or metabolic agents,
gastrointestinal agents, gynecological agents, hematological
agents, immunological agents, neurological agents,
psychotherapeutics, pulmonary agents, respiratory agents, or
urological agents; also, vitamins, anti-oxidants, and other
nutritional or nutriceutical agents. A biologically active material
may or may not have an intrinsic response to optical energy to
change its biological activity, but the combination of a
biologically active material and a photosensitive
bioactivity-adjusting material can constitute a photosensitive
biologically active material that is responsive to optical energy.
Throughout this document, the term "photosensitive biologically
active material" is intended to encompass materials that are a
combination of a biologically active material and a photosensitive
bioactivity-adjusting material, unless context dictates
otherwise.
[0020] FIGS. 4A-4C depict some exemplary configurations of an
ionizing-radiation-responsive composition 400 comprising a
luminescent material 110, a photosensitive bioactivity-adjusting
material 404, and a biologically active material 410. These are
illustrative configurations only, and are not intended to be
limiting. FIG. 4A shows a photosensitive bioactivity-adjusting
material 404 disposed as a photosensitive matrix material that
occupies the interstices between, or otherwise encloses, embeds, or
absorbs, a plurality of portions of a biologically active material
410. FIG. 4B shows a photosensitive bioactivity-adjusting material
404 disposed as a photosensitive layer that encloses or envelops a
biologically active material 410. FIB. 4C shows a photosensitive
bioactivity-adjusting material 404 disposed as a substrate material
having a surface that attaches, adsorbs, or otherwise couples to a
biologically active material 410. Each configuration in FIGS. 4A-4C
depicts a core-shell structure having a core of luminescent
material 110, but this is an illustrative disposition of the
luminescent material and is not intended to be limiting. In other
embodiments of the ionizing-radiation-responsive composition 400,
the luminescent material is unattached to either the biologically
active material or the photosensitive bioactivity-adjusting
material, at least partially attached to one or the other, or
variously disposed in configurations that combine all three
materials. Some configurations of an ionizing that combine a
luminescent material and a photosensitive biologically active
material (where the latter may itself comprise a biologically
active material and a photosensitive bioactivity-adjusting
material) are described elsewhere. In each configuration in FIGS.
4A-4C, the photosensitive bioactivity-adjusting material is
responsive to optical energy in at least a first wavelength band,
as depicted by the arrow 204 labeled with a wavelength
.lamda..sub.1, to at least partially allow release of the
biologically active material 410. In some embodiments the response
to optical energy is irreversible; in other embodiments the
response is reversible, as indicated by the dashed arrow 304
depicting a reversion. The reversion may occur in response to
optical energy in at least a second wavelength band (as indicated
by the label .lamda..sub.2) or the reversion may occur in response
to a reduction or absence of optical energy at least the first
wavelength band (as indicated by the label "dark").
[0021] In some embodiments, the photosensitive
bioactivity-adjusting material may include a substrate material
having a surface that attaches, adsorbs, or otherwise couples to a
biologically active material, and responsive to optical energy to
release the biologically active material from the surface
(optionally, embodiments include a linking agent, e.g. a
bifunctional photolytic linker, that connects the substrate
material and the biologically active material, and that responds to
optical energy to disconnect the substrate material and the
biologically active material, e.g. by photolysis). For example,
embodiments may use materials such as those in Van Tassel et al and
in Lindall (both cited previously and herein incorporated by
reference). Various substrate materials include natural polymers,
synthetic polymers, silica, glass, quartz, metal, and any other
materials capable of directly or indirectly binding to the
biologically active material (in some embodiments the luminescent
material, or another constituent of the
ionizing-radiation-responsive composition, may serve as the
substrate material). Various linking agents include 2-nitrophenyl
groups, acridines, nitroaromatics, arylsulfonamides, or similar
photolytic agents capable of directly or indirectly binding to both
the substrate material and the biologically active material.
[0022] In some embodiments, the photosensitive
bioactivity-adjusting material includes a material that responds to
optical energy to change a diffusion characteristic of the
material, which may affect a rate of diffusion of the biologically
active material through the photosensitive bioactivity-adjusting
material. For example, embodiments may use materials such as those
in Fink et al, "Photoactivated drug therapy," U.S. Patent
Application Publication No. 2003/0216284, herein incorporated by
reference; in this reference, optical energy (in the form of a
resonant mode of a cavity) causes a change in a diffusion
characteristic of at least one component of the cavity, in turn
causing release of a pharmaceutical from the cavity (in one
embodiment described therein, the at least one component is a
polymeric material and the resonance causes heating whereby the
polymeric material exceeds a glass transition temperature).
[0023] In some embodiments, the photosensitive
bioactivity-adjusting material may include a material that responds
to optical energy to undergo a shape change (e.g. an expansion,
contraction, or bending); the shape change may correspond to a
change of a diffusion characteristic, or the shape change may
affect some other means for release of the biologically active
material (e.g. a shrinkage may create a pressure that expels the
biologically active material, or a bending may open a gate-like
structure to release the biologically active material), or both.
For example, embodiments may use materials such as those in
Rosenthal et al, "Triggered release hydrogel drug delivery system,"
U.S. Pat. No. 7,066,904, herein incorporated by reference; this
reference describes catheters that include a polymer or polymer gel
disposed to incorporate and immobilize a drug, and responsive to
optical light to swell or contract such that the drug is released.
Embodiments may use a light-sensitive copolymer or copolymer gel,
where a first component of the light-sensitive copolymer or
copolymer gel is polyacrylamide, poly(N-isopropylacrylamide),
hydroxyethyl methacrylate, dihydroxypropyl methacrylate, a
copolymer or mixture thereof, or the like, and a second component
of the light-sensitive copolymer or copolymer gel is a
light-sensitive compound that induces swelling (as with malachite
green derivatives, leucocyanides, leucohydroxides, or similar
compounds, e.g. as described in "Photoinduced phase transition of
gels," Macromolecules 23 (1990), 1517-1519, herein incorporated by
reference, and in Guillet et al, supra) or that induces contraction
(as with chlorophyllin, rhodamine, or similar compounds, e.g. as
described in "Phase transition in polymer gels induced by visible
light," Nature 346 (1990), 345-347, herein incorporated by
reference) of the light-sensitive copolymer or copolymer gel in
response to optical energy.
[0024] In some embodiments, the photosensitive
bioactivity-adjusting material may include a material that responds
to optical energy to at least partially photodegrade,
photodissociate, or photodisintegrate (such terms may be used
interchangeably); the photodegradation, photodissociation, or
photodisintegration may correspond to a change of a diffusion
characteristic, or affect some other means for release of the
biologically active material (e.g. a mechanical disintegration of
the photosensitive bioactivity-adjusting material may cause an
exposure or dispersal of the biologically active material), or
both. For example, embodiments may use photochemically degradable
polymers such as those described in Guillet et al, supra (e.g.
copolymers of ethylenically unsaturated monomers with unsaturated
ketones).
[0025] In some embodiments, the photosensitive
bioactivity-adjusting material may include a material that responds
to optical energy to change its hydrophobicity, hydrophilicity, or
amphiphilicity; this change may correspond to a change of a
diffusion characteristic, or affect some other means for release of
the biologically active material (e.g. the change may compel a
phase separation of immiscible hydrophilic and hydrophobic
components), or both. For example, embodiments may use polymers
that convert photochemically from a hydrophobic form to a
hydrophilic form, such as those described in Guillet et al, supra
(e.g. polymers incorporating a t-butyl ketone group in a side chain
immediately adjacent to the polymer backbone).
[0026] With reference now to FIGS. 5A-5C, some illustrative
examples of the preceding embodiments are shown, including a
photosensitive bioactivity-adjusting material 404 and a
biologically active material 410. For purposes of clarity, a
luminescent material is not depicted in these examples, but this
omission is not intended to be limiting, and embodiments provide a
luminescent material that is enclosed, attached, or otherwise
disposed in a vicinity of the photosensitive bioactivity-adjusting
material and/or the biologically active material. FIG. 5A depicts
an example of a photosensitive bioactivity-adjusting material 404
disposed as a photosensitive matrix material enclosing a
biologically active material 410, and responsive to optical energy
in at least a first wavelength band (as depicted by the arrow 204
labeled with a wavelength .lamda..sub.1) to expand, the expansion
causing a release (e.g. by diffusion) of the biologically active
material 410. FIG. 5B depicts an example of a photosensitive
bioactivity-adjusting material 404 disposed as a photosensitive
matrix material enclosing a biologically active material 410, and
responsive to optical energy in at least a first wavelength band
(as depicted by the arrow 204 labeled with a wavelength 31) to
contract, the contraction causing a release (e.g. by pressure
expulsion) of the biologically active material 410. Alternatively
or additionally, in relation to FIG. 5B, the photosensitive matrix
material may be initially disposed to at least partially allow
release (e.g. by diffusion) of the biologically active material,
and responsive to optical energy to contract, the contraction at
least partially inhibiting release (e.g. by reducing diffusion) of
the biologically active material. FIG. 5C depicts an example of a
photosensitive bioactivity-adjusting material 404 disposed as a
photosensitive matrix material enclosing a biologically active
material 410, and responsive to optical energy in at least a first
wavelength band (as depicted by the arrow 204 labeled with a
wavelength .lamda..sub.1) to at least partially photodegrade,
photodissociate, or photodisintegrate, thereby releasing the
biologically active material 410 (and optionally releasing
fragments 500 of the photosensitive bioactivity-adjusting
material). In some embodiments, a process depicted in FIGS. 5A-5C
is irreversible; in other embodiments the process is reversible, as
indicated by the dashed arrow 304 depicting a reverse process. The
reverse process may occur in response to optical energy in at least
a second wavelength band (as indicated by the label .lamda..sub.2)
or the reverse process may occur in response to a reduction or
absence of optical energy at least the first wavelength band (as
indicated by the label "dark").
[0027] In some embodiments, the photosensitive
bioactivity-adjusting material may include a photosensitive layer
(or a plurality thereof) disposed to at least partially enclose or
envelop at least a portion of the biologically active material, and
responsive to optical energy to at least partially allow release of
the biologically active material. The term "layer" is intended to
encompass a variety of structures including membranes, films,
coatings, shells, coverings, patches, etc., as well as
multi-layered structures. The term "layer" further encompasses
micelles, vesicles, liposomes, lipid membranes, and other
monolayers, bilayers, etc. as assembled from phospholipids,
amphiphilic block copolymers, or other amphiphiles. In some
embodiments the photosensitive layer may include one or more
materials such as those described supra, e.g. a material that
responds to optical energy to change a diffusion characteristic, a
material that responds to optical energy to undergo a shape change
(e.g. an expansion, contraction, or bending), a material that
responds to optical energy to at least partially photodegrade,
photodissociate, or photodisintegrate (thereby rupturing,
perforating, or otherwise disrupting the layer), or a material that
responds to optical energy to change its hydrophobicity,
hydrophilicity, or amphiphilicity. Embodiments may use a
photosensitive layer that embeds one or more light-sensitive
channel proteins such as those described in Kocer et al, "A
light-actuated nanovalve derived from a channel protein," Science
309 (2005), 755-758, and Kocer et al, "Modified MscL protein
channel," U.S. Patent Application Publication No. US2006/0258587,
both herein incorporated by reference; these references describe a
modified channel protein embedded in a membrane and responsive to
optical energy to irreversibly open (or reversibly open/close) a
pore in the membrane. Other embodiments may use materials such as
those described in P. Ball, "Light pumps drugs from nanoparticles,"
Nanozone News, Jun. 9, 2005, herein incorporated by reference;
e.g., a liposomal membrane (or similar monolayer/bilayer/etc.) that
is at least partially comprised of photoisomerizable phospholipids
(or similar photoisomizable amphiphiles), or that incorporates
photoisomerizable cholesterol (or other photoisomerizable molecules
that can attach to or embed within the membrane, e.g. integral
membrane proteins), or both, whereby the photosensitive layer
responds to optical energy to change porosity (e.g. open pores),
become ruptured or perforated, or otherwise allow release of the
enclosed biologically active material.
[0028] With reference now to FIGS. 6A-6C, some illustrative
examples of the preceding embodiments are shown, including a
biologically active material 410 and a photosensitive
bioactivity-adjusting material 404 disposed as a photosensitive
layer that encloses the biologically active material. For purposes
of clarity, a luminescent material is not depicted in these
examples, but this omission is not intended to be limiting, and
embodiments provide a luminescent material that is enclosed,
attached, or otherwise disposed in a vicinity of the photosensitive
bioactivity-adjusting material and/or the biologically active
material. FIG. 6A depicts an example of a photosensitive layer that
is responsive to optical energy in at least a first wavelength band
(as depicted by the arrow 204 labeled with a wavelength
.lamda..sub.1) to become ruptured or perforated, whereby the
biologically active material is released through one or more
ruptured or perforated areas 600. FIG. 6B depicts an example of a
photosensitive layer embedding one or more pore-like structures
(e.g. channel proteins) in a closed configuration 602, the one or
more pore-like structures being responsive to optical energy in at
least a first wavelength band (as depicted by the arrow 204 labeled
with a wavelength .lamda..sub.1) to convert to an open
configuration 604, whereby the biologically active material is
released. FIG. 6C depicts an example of a photosensitive layer that
embeds one or more photoisomerizable molecules (e.g.
photoisomerizable phospholipids or cholesterols) in a first
isomeric form 606, the one or more photoisomerizable molecules
being responsive to optical energy in at least a first wavelength
band (as depicted by the arrow 204 labeled with a wavelength
.lamda..sub.1) to convert to a second isomeric form 608, thereby
changing a diffusion, porosity, or other characteristic of the
photosensitive layer to allow release of the biologically active
material. In some embodiments, a process depicted in FIGS. 6A-6C is
irreversible; in other embodiments the process is reversible, as
indicated by the dashed arrow 304 depicting a reverse process. The
reverse process may occur in response to optical energy in at least
a second wavelength band (as indicated by the label .lamda..sub.2)
or the reverse process may occur in response to a reduction or
absence of optical energy at least the first wavelength band (as
indicated by the label "dark").
[0029] Treating a tissue or lesion with a photosensitive
biologically active material typically involves locally irradiating
the tissue or region with optical light (or otherwise locally
applying some form of optical energy). Optical light or optical
energy generally includes electromagnetic radiation in the visible
portion of the electromagnetic spectrum (e.g. having wavelengths in
the range of 380 nm to 750 nm or frequencies in the range of 400 to
800 THz) as well as neighboring regions of the electromagnetic
spectrum (including but not limited to far-infrared, infrared,
near-infrared, near-ultraviolet, ultraviolet, and
extreme-ultraviolet). The terms "optical light" and "optical
energy" also encompass quantized electromagnetic radiation (i.e.
photons) and non-radiative forms of electromagnetic energy (e.g.
standing waves, evanescent fields, Forster resonance energy
transfer (FRET), etc.). Optical light in the red and near-infrared
region of the spectrum (the most penetrating) has a penetration
depth of about 2 to 6 mm, depending on the wavelength and the
tissue. The challenge of delivering optical light to a
non-superficial region is therefore a substantial limitation of
existing therapies, often involving interstitial, intracavitary, or
intravascular placement of optical fibers capped with diffuser tips
and coupled to a laser light source. Some embodiments offer an
alternate mode of optical light delivery, wherein the optical light
or optical energy is locally emitted by a luminescent material in
response to ionizing radiation, which can be highly penetrative and
precisely delivered to a region of interest.
[0030] Ionizing radiation is radiation having an ability to ionize
an atom or molecule. Radiation may be referred to as ionizing
radiation whether or not the radiation causes ionization in any
particular embodiment or use of the aspects described herein. For
example, ionizing radiation may have energy sufficient to ionize a
first kind of atom or molecule, but insufficient to ionize a second
kind of atom or molecule. Therefore, in some embodiments where the
ionizing radiation interacts only with the second kind of atom or
molecule, it may not cause ionization. The ionizing radiation can
be electromagnetic radiation such as extreme ultraviolet (EUV)
rays, soft or hard x-rays, or gamma-rays, or charged particle
radiation in the form of electrons, protons, or ions (e.g., carbon
and neon).
[0031] The ionizing radiation emitter 100 can include a
high-voltage vacuum tube or field emitter, EUV or x-ray laser,
discharge- or laser-produced plasma device, synchrotron, particle
accelerator, or similar device; or, a radioactive material
comprising one or more radioactive isotopes; or, a combination of
such materials and/or devices. If the ionizing radiation emitter
includes a radioactive isotope, the ionizing radiation may be a
direct radioactive decay product (e.g. an electron, position, or
gamma ray), or a product of a subsequent process (e.g.
bremsstrahlung or characteristic x-rays, gamma rays from
electron-positron annihilation, or electrons created by
photoelectric, Auger, or pair production processes).
[0032] If the region 104 includes a human or animal patient or a
portion thereof, the ionizing radiation emitter can be positioned
outside, adjacent to, or inside the patient. Examples of ionizing
radiation emitters that can be positioned outside the patient
include x-ray radiograph instruments, computed tomography (CT)
instruments, fluoroscopes, radiosurgery instruments (such as the
Cyberknife or Gamma Knife), teletherapy or external beam
radiotherapy devices, and proton or ion beam devices. Examples of
ionizing radiation emitters that can be positioned adjacent to or
inside the patient include catheter-mounted miniaturized x-ray
tubes, sealed radioactive sources that are applied as molds or
implanted by surgery, catheter, or applicator; and
radiopharmaceuticals that are directly injected or ingested (these
include beta-active isotopes of iodine, phosphorus, etc. as used
for radiotherapy, gamma-active isotopes of gallium, technetium,
etc. as used for imaging, and positron-emitting isotopes of carbon,
fluorine, etc. as used for positron-emission tomography (PET)).
[0033] In various embodiments the ionizing radiation 102 can be
substantially monochromatic, quasi-monochromatic, or polychromatic.
Examples of substantially monochromatic or quasi-monochromatic
ionizing radiation include characteristic x-rays, beta and gamma
rays from radioactive decay, undulator synchrotron rays, and
accelerated proton or ion beams. Examples of polychromatic ionizing
radiation include wiggler and bending magnet synchrotron rays and
bremsstrahlung rays. The energy spectrum and intensity of the
ionizing radiation can be modified, shaped, or varied in time by
various means known to those skilled in the art; for example, by
adjusting the cathode-anode voltage in an x-ray vacuum tube, or
using x-ray optics devices such as Bragg monochromators and
attenuation filters.
[0034] Various embodiments utilize different space and time
configurations of the ionizing radiation 102. The particular
depictions of the ionizing radiation that are shown in the figures
are schematic and not intended to be limiting. For example, the
ionizing radiation may be substantially isotropic (i.e. radiating
in most or all directions), fan-shaped, cone-shaped, collimated in
a thin ray, etc.; these and other irradiation patterns can be
achieved by various means known to those skilled in the art, e.g.
deployment of lenses, mirrors, zone plates, baffles, slots, or
apertures, or positioning of leaves in a multileaf collimator
(MLC). In those embodiments where the ionizing radiation is
deployed as a beam, the orientation and position of the beam can be
varied with respect to the target region 104, for example by
mounting the emitter and/or the target on a moveable pivot, track,
arm, or gantry, or manually adjusting the position of an
intravascular catheter with an emitter on its distal end. The
extent of the irradiated region 106 is determined by the energy,
intensity, shape, orientation, and position of the ionizing
radiation beam, and by the scattering and absorption properties of
the region 104. For example, depth-dose characteristics of typical
radiotherapy x-ray and proton beams are described in A. Boyer et
al, "Radiation in the Treatment of Cancer," Physics Today,
September 2002, which is herein incorporated by reference.
Typically, hard x-rays are more penetrating than soft x-rays, and
protons have a longer range than electrons, with a characteristic
Bragg peak at the end of their range. In some embodiments the
irradiation may comprise multiple ionizing radiation beams, either
emitted in a time sequence by a single emitter, or emitted by a
plurality of emitters, or both. The multiple beams may have
different energies, intensities, orientations, and/or positions;
alternatively, a continuously or stroboscopically emitting beam (or
a plurality thereof) may continuously or intermittently change its
energy, intensity, orientation, and/or position. In some
embodiments, techniques such as those used in radiotherapy and
stereotactic radiosurgery can be utilized to deliver an effective
amount of radiation to a region of therapeutic interest (such as a
tumor) while reducing radiation damage to neighboring tissues;
these techniques include 3D conformal radiotherapy (3DCRT) and
intensity-modulated radiotherapy (IMRT), as described in A. Boyer,
"The Physics of Intensity-Modulated Radiation Therapy," Physics
Today, September 2002, which is herein incorporated by
reference.
[0035] The luminescent material 110 is a material that is
responsive to ionizing radiation to produce optical energy.
Generally, the term "luminescent material" encompasses all
materials that respond to radiation (ionizing or non-ionizing) to
produce optical energy (the term "phosphor" is sometimes used with
equivalent meaning), and it produces the optical energy by a
process called luminescence. The term "luminescence" encompasses
various processes including fluorescence, phosphorescence, and
afterglow. Many luminescent materials are known to those skilled in
the art, with various characteristics of absorption, emission, and
efficiency, for example as described in G. Blasse and B. C.
Grabmaier, Luminescent Materials, Springer-Verlag, Berlin 1994,
which is herein incorporated by reference.
[0036] When the incident radiation is ionizing radiation, the
luminescent material is often referred to as a scintillator.
Scintillators can comprise organic or inorganic materials, in the
form of crystals (including micro- and nano-scale crystals),
particles (including micro- and nano-scale particles), powders,
composites, ceramics, glasses, plastics, liquids, and gases. Some
scintillation materials and detectors are described in M. Nikl,
"Scintillation detectors for x-rays," Meas. Sci. Technol. 17
(2006), R37-R54 and in C. W. E. van Eijk, "Inorganic scintillators
in medical imaging," Phys. Med. Biol. 47 (2002), R85-R106, which
are both herein incorporated by reference. Scintillators are
sometimes referred to as phosphors, especially in applications
where the material is deployed as a powder screen, viz. lamp
phosphors, cathode ray tube (CRT) phosphors, x-ray intensifying
screen phosphors, and x-ray storage phosphors (c.f. G. Blasse and
B. C. Grabmaier, supra; storage phosphors are additionally
described in H. von Seggern, "Photostimulable x-ray storage
phosphors: a review of present understanding," Braz. J. Phys. 29
(1999), 254-268, and in W. Chen, "Nanophase luminescence
particulate material," U.S. Pat. No. 7,067,072, which are both
herein incorporated by reference).
[0037] A luminescent material generally comprises one or more
sensitizers and/or one or more activators embedded in a host
material, although in some cases an activator also plays the role
of sensitizer, or the host material plays the role of sensitizer or
activator or both. The luminescence process generally proceeds as
follows: (1) incident radiation is absorbed by the sensitizer; (2)
the energy is transferred through the host material to the
activator, raising it to an excited state; and (3) the activator
returns to the ground state by emission of optical radiation. A
first example is the lamp phosphor Ca.sub.5(PO.sub.4).sub.3F:
Sb.sup.3+, Mn.sup.2+, where an Sb.sup.3+ sensitizer/activator and
an Mn.sup.2+ activator are embedded as dopants in a fluorapatite
host material. A second example is described in Y. L. Soo et al,
"X-ray excited luminescence and local structures in Tb-doped
Y.sub.2O.sub.3 nanocrystals," J. Appl. Phys. 83 (1998), 5404-5409,
which is herein incorporated by reference; in this material, the
yttrium in the host nanocrystal is a sensitizer, and the dopant
terbium is a sensitizer/activator with green luminescence. A third
example is a class of organometallic lanthanide-cryptate
scintillators described in G. Blasse et al, "X-ray excited
luminescence of samarium(III), europium(III), gadolinium(III), and
terbium(III) 2.2.1 cryptates," Chem. Phys. Lett. 158 (1989),
504-508, which is herein incorporated by reference; in these
materials, the cryptate bypyridine is a sensitizer, and the caged
lanthanide is a sensitizer/activator. A fourth example is the x-ray
phosphor described in W. Chen et al, "The origin of x-ray
luminescence from CdTe nanoparticles in CdTe/BaFBr:Eu.sup.2+
nanocomposite phosphors," J. Appl. Phys. 99 (2006), 034302, which
is herein incorporated by reference; in this material, the BaFBr
host material is a sensitizer, the Eu.sup.2+ dopant is a
sensitizer/activator emitting at 390 nm, and the CdTe nanoparticle
is an activator emitting at a wavelength of 541, 610, or 650 nm for
a nanoparticle size of 2, 4, or 6 nm, respectively.
[0038] The absorption of incident radiation by a sensitizer (or a
host material component acting as a sensitizer) generally varies
with the energy of the incident radiation according to a
characteristic absorption spectrum; some embodiments provide a
plurality of sensitizers (or a plurality of host material
components acting as sensitizers, or a combination thereof) having
a plurality of characteristic absorption spectra. The emission of
radiation by an activator (or a host material component acting as
an activator) generally varies with the energy of the emitted
radiation according to a characteristic emission spectrum; some
embodiments provide a plurality of activators (or a plurality of
host material components acting as activators, or a combination
thereof) having a plurality of characteristic emission spectra. In
some embodiments, selective transfer of energy from the plurality
of sensitizers to the plurality of activators (e.g. as
characterized by a matrix of energy transfer efficiencies) can be
used to provide selective wavelength/energy conversion of incident
radiation to emitted radiation; viz, incident radiation in a first
(second) absorption energy band substantially excites a first
(second) sensitizer, the excitation energy is substantially
transferred to a first (second) activator, and the first (second)
activator substantially emits radiation in a first (second)
emission energy band.
[0039] The overall effectiveness of the luminescent material for
converting incident ionizing radiation into optical energy is
determined in part by the absorption characteristics of the
material. Absorption of ionizing radiation in matter, and detection
thereof, are described in W. M. Yao et al, Review of Particle
Physics, J. Phys. G: Nucl. Part. Phys. 33 (2006), 258-292, which is
herein incorporated by reference. If the ionizing radiation
consists of charged particles (including electrons, protons, and
ions), the charged particles lose energy through Coulomb
interactions with the electrons in the material; ionization is the
dominant Coulomb process except at ultrarelativistic energies. A
material with a high electron density (i.e. a high mass density) is
typically a better absorber of charged particle radiation. If the
ionizing radiation consists of photons (ultraviolet rays, x-rays,
or gamma rays), absorption is dominated by the photoelectric effect
at low energies, then by Compton and pair production processes at
successively higher energies. For Compton and pair production
processes, the absorption is proportional to electron density, and
a material with a high electron density (i.e. a high mass density)
is a better absorber. For the photoelectric effect, the absorption
cross section is approximately proportional to Z.sup.3/E.sup.3,
where E is the energy of the incident photon and Z is the atomic
number of the target atom. A material with a high effective atomic
number Z.sub.eff (i.e. as averaged over its constituent elements)
is therefore a better photoelectric absorber. Overall, a material
with a high mass density, and a high effective atomic number
Z.sub.eff, is a better absorber of both charged particle energy and
photon energy.
[0040] Moreover, the photoelectric cross section is characterized
by discontinues, known as absorption edges, as thresholds for
ionization of various atomic shells are reached. The absorption
edges for successive shells with principal quantum numbers n=1,
n=2, n=3, etc. are respectively called the K-edge, L-edge, M-edge,
etc. In some embodiments, the ionizing radiation includes one or
more substantially monochromatic beams of photons, each having an
energy E just above a photoelectric absorption edge of the
luminescent material; or, the ionizing radiation includes a
polychromatic beam of photons, where the energy spectrum of the
polychromatic beam consists essentially of a plurality of peaks
coinciding with a plurality of absorption edges for the luminescent
material. In these embodiments the ionizing radiation is
substantially absorbed by the luminescent material, and the
absorption by neighboring tissues may be mitigated, especially in
those embodiments where the absorption edges of the luminescent
material are distinct from those of the neighboring tissues.
[0041] In some embodiments, the luminescent material has a host
material that includes a heavy metal selected from the group
consisting of alkaline metals, alkaline earth metals, transition
metals, poor metals, and metalloids. The term "heavy metal" is
taken to include any metal or metalloid element having an atomic
number greater than or equal to 37 (i.e. elements in periods 5, 6,
or 7). The term "alkaline metals" is taken to include elements in
group 1 of the periodic table (excluding hydrogen), i.e. lithium,
sodium, potassium, rubidium, cesium, and francium. The term
"alkaline earth metals" is taken to include elements in group 2 of
the period table, i.e. beryllium, magnesium, calcium, strontium,
barium, and radium. The term "transition metals" is taken to
include elements in groups 3 to 12 of the periodic table. The term
"poor metals" is taken to include aluminum, gallium, indium, tin,
thallium, lead, and bismuth. The term "metalloids" is taken to
include boron, silicon, germanium, arsenic, antimony, tellurium,
and polonium.
[0042] In some embodiments, the emission spectrum of the
luminescent material should substantially overlap or coincide with
the absorption spectrum of the photosensitive biologically active
material. The emission spectrum is partially determined by
intrinsic properties of the activator component of the luminescent
material, and by its local environment in the host material (e.g.
the activator's crystal field, coordination, chelation. etc.). If
the luminescent material comprises nanoparticles or nanocrystals, a
quantum size effect can occur, whereby the spatial confinement of
the valence electron wavefunctions causes smaller particles of the
same composition to have emission spectra that are shifted to
smaller wavelengths (e.g. as observed in W. Chen et al, supra).
[0043] In some embodiments, the luminescent material can include
quantum dots. These are nanocrystals comprised of various
semiconductor materials, which can include but are not limited to
group IV elements (C, Si, Ge), group IV binary compounds (SiC,
SiGe), III-V binary compounds (AlSb, AlAs, AlN, AlP, BN, BP, BAs,
GaSb, GaAs, GaN, GaP, InSb, InAs, InN, InP, etc.), III-V ternary
compounds (AlGaAs, InGaAs, AlInAs, AlInSb, GaAsN, GaAsP, AlGaN,
AlGaP, InGaN, InAsSb, InGaSb, etc.), III-V quaternary compounds
(AlGaInP, AlGaAsP, InGaAsP, AlInAsP, AlGaAsN, InGaAsN, InAlAsN,
etc.), III-V quinary compounds (GaInNAsSb), II-VI binary compounds
(CdSe, CdS, CdTe, ZnO, ZnSe, ZnTe, etc.), II-VI ternary compounds
(CdZnTe, HgCdTe, HgZnTe, HgZnSe, etc.), I-VII binary compounds
(CuCl, etc.), IV-VI binary compounds (PbSe, PbS, PbTe, SnS, SnTe,
etc.), IV-VI ternary compounds (PbSnTe, Tl.sub.2SnTe.sub.5,
Tl.sub.2GeTe.sub.5, etc.), V-VI binary compounds (Bi.sub.2Te.sub.3,
Bi.sub.2S.sub.3 etc.), II-V binary compounds (Cd.sub.3P.sub.2,
Cd.sub.3As.sub.2, Cd.sub.3Sb.sub.2, Zn.sub.3P.sub.2,
Zn.sub.3As.sub.2, Zn.sub.3Sb.sub.2, etc.), miscellaneous oxides
(TiO.sub.2, Cu.sub.2O, CuO, UO.sub.2, UO.sub.3, etc.), other
miscellaneous inorganic compounds (PbI.sub.2, MoS.sub.2, GaSe,
CuInGaSe, PtSi, BiI.sub.3, HgI.sub.2, TlBr, etc.), and organic
semiconductors. In some embodiments, the quantum dots comprise
heavier elements such as mercury, lead, bismuth, or polonium, to
enhance the absorption of ionizing radiation. The quantum dots can
also be doped, e.g. as described in Erwin et al, "Doping
semiconductor nanocrystals," Nature 436 (2005), 91-94, which is
herein incorporated by reference; accordingly some embodiments
provide quantum dots that are doped with heavier elements, such as
the lanthanides or other period 6 elements, again to enhance the
absorption of ionizing radiation. In some embodiments the quantum
dots may have a core-shell structure, with the core consisting of a
first semiconductor material, and a shell consisting of a second
semiconductor material. Additionally, one or more coatings and/or
functional groups may be applied or attached to the quantum dot, to
improve solubility, durability, suspension characteristics,
bioactivity, etc. as discussed infra. Desired optical properties of
the quantum dot (e.g. quantum efficiency, Stokes shift, emission
wavelength) can be further adjusted by controlling the size, shape,
and structure of the quantum dot through various fabrication
processes know to those skilled in the art (for example, W. Chen,
supra, describes how to control the emission wavelength by
adjusting the nanoparticle size; accordingly, the emission
wavelength can be matched to a peak in the absorption spectrum of
the photosensitive biologically active material).
[0044] FIG. 7 depicts another illustrative embodiment and use in
which an ionizing radiation emitter 100 emits an ionizing radiation
102. The ionizing radiation irradiates at least a portion of a
region 104 that contains a ionizing-radiation-responsive
composition 400, which is a bound composition comprising a
luminescent material 110 and a photosensitive biologically active
material 112. As in FIG. 1, the luminescent material responds to
ionizing radiation to produce optical energy, and the
photosensitive biologically active material responds to optical
energy to become biologically active, as indicated schematically by
the radial lines 116 (other embodiments provide other responses of
the photosensitive biologically active material; for example, the
photosensitive biologically active material may respond to the
optical energy to become biologically inactive, to partially
increase or decrease a level of biological activity, to change from
a first mode of biological activity to second mode of biological
activity, etc.). When the luminescent material and the
photosensitive biologically active material are bound together as
in FIG. 7, the optical energy may be transferred from the
luminescent material to the photosensitive biologically active
material by either radiative or nonradiative processes. An example
of a nonradiative energy transfer process is Forster resonance
energy transfer (FRET), as described in G. Blasse and B. C.
Grabmaier, supra.
[0045] FIG. 7 illustrates the ionizing-radiation-responsive
composition in cross-section as having a core-shell structure, with
the core consisting of luminescent material and a shell consisting
of photosensitive biologically active material. This is only a
schematic depiction of the bound composition and is not intended to
be limiting. Some configurations of the bound composition include
but are not limited to those depicted in cross section in FIGS.
8A-8G. In various configurations the two materials form a
core-shell structure, with one material comprising the core and the
other material comprising either a complete shell or one or more
spots or patches on the surface of the core: a binary aggregate
structure, with one or more adjoining regions of the two materials:
a host-inclusion structure, where one material is an inclusion or
dopant of the other material; and other configurations. Various
techniques known to those skilled in the art can be used to produce
or synthesize these bound compositions. For example, W. Chen and J.
Zhang, "Using nanoparticles to enable simultaneous radiation and
photodynamic therapies for cancer treatment," J. Nanosci. Nanotech.
6 (2006), 1159-1166, which is herein incorporated by reference,
describes a conjugation of porphyrins to nanoparticles using
L-cysteine as a bifunctional ligand. M. Wieder et al,
"Intracellular photodynamic therapy with
photosensitizer-nanoparticle conjugates: cancer therapy using a
`Trojan horse,`" Photochem. Photobiol. Sci. 5 (2006), 727-734,
herein incorporated by reference, describes a derivatization of a
phthalocyanine photosensitizer with a thiol moiety to provide a
direct linkage to a nanoparticle surface via self-assembly. Other
functional ligands and conjugation methods are described in G. T.
Hermanson, Bioconjugate Techniques, Academic Press (1996). L. Shi
et al, "Singlet oxygen generation from water-soluble quantum
dot-organic dye nanocomposites,", J. Am. Chem. Soc. 128 (2006),
6278-6279, herein incorporated by reference, describes a synthesis
of a nanocomposite consisting of
meso-tetra(4-sulfonatophenyl)porphine dihydrochloride (TSPP), a
photosensitizer, bound to CdTe nanocrystals via electrostatic
interaction.
[0046] In some embodiments, the ionizing-radiation-responsive
composition further comprises an adjuvant matrix or coating
material. Some configurations of the bound composition include but
are not limited to those depicted in cross section in FIGS. 9A-9H,
where the unshaded region 900 represents the adjuvant matrix or
coating material. In general, the adjuvant matrix or coating
material is a material that is selected and disposed to improve
various biological and pharmaceutical characteristics of the
ionizing-radiation-responsive composition, including but not
limited to solubility, durability, suspension stability,
bioactivity, biocompatibility, chemical affinity, biological
affinity, porosity, permeability, non-toxicity, and radiation
responsiveness. The adjuvant matrix or coating material may also
provide a mechanical means to embed, confine, attach, adhere, or
bind together at least a portion of the constituents of the
ionizing-radiation-responsive composition, or at least partially
sustain the proximity of at least a portion of the consistuents,
either permanently or temporarily (an example of the latter is a
slow-release polymer). Generally, a matrix material is a material
that at least partially embeds one or more other materials, or at
least partially occupies interstices in the spatial configuration
of one or more other materials, and a coating material is a
material that at least partially surrounds or envelops one or more
other materials; however, those of skill in the art will recognize
that the terms "matrix material" and "coating material" encompass
other configurations, and that in some contexts the terms have
overlapping meaning (e.g. a matrix material that is also a coating
material, or vice versa). The use of the term "adjuvant" is
intended in this context to denote that the adjuvant matrix or
coating material is not substantially a photosensitive biologically
active material, nor substantially a photosensitive
bioactivity-adjusting material, nor substantially a luminescent
material responsive to ionizing radiation to produce optical energy
to activate a photosensitive biologically active material or a
photosensitive bioactivity-adjusting material; rather, the adjuvant
matrix or coating is a material that potentiates, moderates,
improves, or otherwise modifies the individual or cumulative
biological or pharmaceutical characteristics of these other
constituents of the ionizing-radiation-responsive composition. An
adjuvant matrix or coating material is therefore understood to be
distinct from a photosensitive bioactivity-adjusting material
disposed as a photosensitive matrix or coating. The intended
meaning of "matrix" or "coating" (e.g. photosensitive matrix or
adjuvant matrix) will be apparent from the context in which said
term is used
[0047] Various adjuvant matrix and coating materials, and methods
of deploying such materials in a bound composition, are known to
those skilled in the art. Some representative examples are as
follows; other embodiments will be apparent to those skilled in the
art. A first example is a porous glass, such as that used to embed
CdSe/ZnS quantum dot alpha particle scintillators as described in
S. E. Letant and T. F. Wang, "Study of porous glass doped with
quantum dots or laser dyes under alpha irradiation,", Appl. Phys.
Lett. 88 (2006), 103110, herein incorporated by reference. A second
example is a silica shell, which can enclose a photosensitizer as
described in Wang et al, "Nanomaterials and singlet oxygen
photosensitizers: potential applications in photodynamic therapy,"
J. Mater. Chem. 14 (2004), 487-493; E. Bergey and P. Prasad, "Small
spheres, big potential," OE Magazine, July 2003, 26-29; and P.
Prasad et al, "Ceramic based nanoparticles for entrapping
therapeutic agents for photodynamic therapy and method of using
same," U.S. Patent App. Pub. No. US 2004/0180096; which
publications are herein incorporated by reference. The silica shell
can be made hydrophobic, hydrophilic, or both, as appropriate for
biological context, and the porosity of the silica shell can be
tailored, e.g. to allow permeation of singlet oxygen from a
photosensitizer. Silica shells can also be used to coat quantum
dots (cf. X. Michalet, "Quantum dots for live cells, in vivo
imaging, and diagnostics," Science 307 (2005), 538-544, herein
incorporated by reference), magnetic nanoparticles (c.f. L. Levy et
al, "Nanochemistry: synthesis and characterization of
multifunctional nanoclinics for biological applications," Chem.
Mater. 14 (2002), 3715-3721; B. A. Holm et al, "Nanotechnology in
biomedical applications," Mol. Cryst. Liq. Cryst. 374 (2002),
589-598; and P. Prasad et al, "Magnetic nanoparticles for selective
therapy," U.S. Pat. No. 6,514,481; which publications are herein
incorporated by reference), and other particles or nanoparticles,
and they can be functionalized with PEG groups for enhanced
biocompatibility, e.g. as described in T. Zhang et al, "Cellular
effect of high doses of silica-coated quantum dot profiled with
high throughput gene expression analysis and high content cellomics
measurements," Nano Letters 6 (2006), 800-808, herein incorporated
by reference. A third example is a micellular agent such as PEG-PE,
which can be used, for example, to encapsulate a photosensitizer
(cf. A. Roby et al, "Solubilization of poorly soluble PDT agent,
meso-tetraphenylporphin, in plain or immunotargeted PEG-PE micelles
results in dramatically improved cancer cell killing in vitro,"
Eur. J. Pharm. Biopharm. 62 (2006), 235-240, herein incorporated by
reference) or a quantum dot (c.f. B. Dubertret et al, "In vivo
imaging of quantum dots encapsulated in phospholipid micelles,"
Science 298 (2002), 1759-1762, herein incorporated by reference). A
fourth example is a matrix material comprising polyacrylamide
hydrogel, sol gel silica, or cross-linked decyl methacrylate;
nanoparticles utilizing these matrix materials are described in E.
Monson et al, "PEBBLE nanosensors for in vitro bioanalysis,"
Biomedical Photonics Handbook, CRC Press, 2003, 59.1-59.14;
"Nanotechnology tackles brain cancer," Monthly Feature, December
2005, NCI Alliance for Nanotechnology in Cancer; and "Watery
nanoparticles deliver anticancer therapy," Nanotech News, Mar. 5,
2007, NCI Alliance for Nanotechnology in Cancer; which publications
are herein incorporated by reference. A fifth example is a chelant
material (either a natural chelant such as a porphyrin or porphyrin
derivative, or a synthetic chelant such as
ethylenediaminetetraacedit acid (EDTA) or
diethylenetriaminepentaacetic acid (DTPA)) or cryptand material
(such as bypiridine), which materials can form a coordination
complex to enclose various substrates including metals and cations.
A sixth example is a fullerene or a fullerene derivative (e.g. a
carbon nanotube or buckyball), where the interior volume can be
used to contain various materials; for example, B. Sitharaman et
al, "Superparamagnetic gadonanotubes are high-performance MRI
contrast agents," Chem. Commun. (2005), 3915-3917, herein
incorporated by reference, describes a carbon nanotube loaded with
Gd.sup.3+ ions as an MRI contrast agent.
[0048] Because a photosensitive biologically active material can be
undesirably activated by ambient optical energy such as sunlight,
special procedures are sometimes necessary to avoid undesirable
activation during storage, administration, treatment, and
post-treatment. For example, patients treated with the
photosensitizing drug porfimer sodium are instructed to avoid
sunlight or bright indoor light for at least 30 days after
treatment. In some embodiments, the ionizing-radiation-responsive
composition includes an optically-inhibiting material disposed to
at least partially block coupling of optical energy to the
photosensitive biologically active material. In an embodiment, the
optically-inhibiting material is disposed to selectively block
coupling of optical energy from sources other than the luminescent
material. In such an embodiment, the ionizing-radiation-responsive
composition can become biologically active when irradiated with
ionizing radiation, but the optically-inhibiting material may at
least partially prevent the composition from becoming biologically
active when irradiated with optical energy. This can simplify
storage, administration, and treatment procedures, and mitigate any
ambient light photosensitivity of the patient. In some embodiments
the optically-inhibiting material may comprise one or more thin
metallic layers, optionally configured in a mesh or porous
structure. Lower-Z metallic elements such as beryllium, aluminum,
or titanium may be utilized to provide optical blocking without
substantial attenuation of ionizing radiation such as x-rays. In
other embodiments the optically-inhibiting material may comprise
chromophores that are embedded in the adjuvant matrix or coating
material to enhance absorption of optical energy in a wavelength
range corresponding to an absorption band of the photosensitive
biologically active material. For example, organic dye molecules
can be added to a polymer matrix or coating, or various metals
(such as cobalt, gold, selenium, copper, etc. and salts, oxides,
etc. thereof) can be added to a silica matrix or coating. In other
embodiments the optically-inhibiting material may comprise a
polymeric photonic band gap material (e.g. as described in Fink et
al, "Polymeric photonic band gap materials," U.S. Pat. No.
6,433,931, herein incorporated by reference) having a band gap that
at least partially coincides with an absorption band of the
photosensitive biologically active material.
[0049] In some embodiments the ionizing-radiation-responsive
composition further comprises a biotargeting agent conveying a
selective biological affinity to the ionizing-radiation-responsive
composition. Some configurations of the bound composition include
but are not limited to those depicted in cross section in FIGS. 10A
and 10B, in which an ionizing-radiation-responsive material 1000
(comprising a luminescent material and a photosensitive
biologically active material, and optionally including other
materials, e.g. an adjuvant matrix or coating material) is linked
to or coated with a biotargeting agent 1010. The depictions are
schematic and not intended to be limiting. In FIG. 10A, the
biotargeting agent 1010 is depicted as having a y-shape, which may
suggest an exemplary embodiment in which the biotargeting agent is
an antibody, but this is a symbolic depiction that encompasses all
biotargeting agents, including but not limited to: proteins and
glycoproteins, monoclonal and polyclonal antibodies, lectins,
receptor ligands (including but not limited to vitamins, hormones,
toxins, and analogues or fragments thereof), peptides and
polypeptides, aptamers, polysaccharides, sugars, and various other
bioactive ligands and moieties. Various bioconjugation methods are
known to those skilled in the art to deploy these biotargeting
agents as a component of the ionizing-radiation-responsive
composition. For example, W. Chen and J. Zhang, supra, describes a
use of nanoparticle-conjugated folic acid as a tumor-specific
ligand. E. Bergey and P. Prasad, supra, L. Levy et al, supra, and
P. Prasad et al, supra, describe an exemplary conjugation of
silica-coated nanoparticles with peptides, polypeptides, or
leutinizing hormone-releasing hormone (LH-RH). Various illustrative
bioconjugations of quantum dots are described in R. Hardman, "A
toxicologic review of quantum dots: toxicity depends on
physicochemical and environmental factors," Environmental Health
Perspectives 114 (2006), 165-172, herein incorporated by reference;
S. Weiss et al, "Semiconductor nanocrystal probes for biological
applications and process for making and using such probes," U.S.
Pat. No. 6,207,392, herein incorporated by reference; and X.
Michalet, supra. B. Storrie et al, "B/B-like fragment targeting for
the purposes of photodynamic therapy and medical imaging," U.S.
Pat. No. 6,631,283, herein incorporated by reference, illustrates
the conjugation of a targeting fragment of a toxin molecule or
lectin to a photosensitizing or imaging agent. A. Roby et al,
supra, and B. Dubertret et al, supra, describe bioconjugations of
micelles with antibodies and DNA, respectively. H. Dees and T.
Scott, "Method for improved imaging and photodynamic therapy," U.S.
Pat. No. 6,493,570, herein incorporated by reference, describes a
derivatization of a halogenated xanthene photosensitizer with
various targeting moieties.
[0050] Some embodiments of the invention provide a first bound
composition that includes a photosensitive biologically active
material and a first affinity agent, and a second bound composition
that includes a luminescent material and a second affinity agent.
The first and second affinity agents are any two agents (which may
be identical) having a tendency to induce a proximity (e.g. in
situ) of the photosensitive biologically active material and the
luminescent material, whereby the photosensitive biologically
active material may respond to optical energy produced by the
luminescent material. In some embodiments the first and second
affinity agents may include, respectively, first and second
biotargeting agents having first and second selective biological
affinities, where the first and second selective biological
affinities are at least partially overlapping (e.g. the first and
second biotargeting agents each have at least some common affinity
for a particular tissue, lesion, organ, or other region, whereby
the photosensitive biologically active material and the luminescent
material can be brought into proximity in situ). In other
embodiments the first and second affinity agents may include,
respectively, first and second binding partners selected from a
pair of binding partners. Binding partners are pairs of molecules
(or functional groups) having an affinity to bind together. Some
examples include: an antigen and a corresponding antibody or
fragment thereof; a hapten and a corresponding anti-hapten; biotin
and avidin or streptavadin; folic acid and folate binding protein;
a hormone and a corresponding hormone receptor; a lectin and a
corresponding carbohydrate, and enzyme and a corresponding
cofactor, substrate, inhibitor, effector, etc.; vitamin B12 and
intrinsic factor; complementary nucleic acid fragments (including
DNA, RNA, and PNA (peptide nucleic acid) sequences), an antibody
and Protein A or G; a polynucleotide and a corresponding
polynucleotide binding protein; other proteins and corresponding
ligands; also, various covalent binding pairs such as sulfhydryl
reactive groups, amine reactive groups, carbodiimide reactive
groups, etc. Various methods are known to those skilled in the art
to deploy such binding partners in bound compositions. For example,
Amaratunga et al, "Pharmaceuticals for enhanced delivery to disease
targets," U.S. Patent Application Pub. No. US2005/0260131, herein
incorporated by references, describes pairs of compounds conjugated
to complementary oligopeptide sequences (e.g. PNA sequences).
Pomato et al, "In vivo binding pair pretargeting," U.S. Pat. No.
5,807,534, herein incorporated by reference, describes methods that
deploy an enzyme and a corresponding enzyme inhibitor as a binding
pair for in-situ pretargeting of an effector molecule (e.g. a
radiometal). Croker et al, "Sol-gel coated glass microspheres for
use in bioassay," U.S. Patent Application Pub. No. US 2007/0117089,
herein incorporated by reference, describes glass microspheres with
a sol-gel coating that comprises a bioactive probe, where the
bioactive probe can include one binding partner selected from a
pair of binding partners.
[0051] Some examples of the preceding embodiments are depicted in
FIGS. 11A-11D. These are schematic depictions of exemplary
configurations, and are not intended to be limiting. In FIG. 11A, a
first bound composition comprises a luminescent material 110 and a
first biotargeting agent 1101, and a second bound composition
comprises a photosensitive biologically active material 112 and a
second biotargeting agent 1102 (which may be the same as or
different than the first biotargeting agent). FIG. 11B depicts an
example in which the first and second bound compositions of FIG.
11A attach to a common substrate 1103 by way of the biotargeting
agents 1101 and 1102, whereby the luminescent material and the
photosensitive biologically active material are brought into
proximity. The common substrate 1103 could be, for example, a tumor
cell, a macromolecule (such as a protein), or some other feature
for which the biotargeting agents 1101 and 1102 share an affinity.
The biotargeting agents 1101 and 1102 are depicted as having a
"y"-shape, which may suggest an exemplary embodiment in which the
biotargeting agents are antibodies, and the common substrate 1103
is depicted as having a notched surface, which may suggest an
exemplary embodiment in which the substrate is a cell that presents
antigens on its surface, but these are symbolic depictions that are
intended to encompass all manner of biotargeting agents and all
manner of targets thereof. In FIG. 11C, a first bound composition
comprises a luminescent material 110 and a first binding partner
1110 selected from a pair of binding partners, and a second bound
composition comprises a photosensitive biologically active material
112 and a second binding partner 1112 selected from the pair of
binding partners. In FIG. 11D, the first and second binding
partners are bound together, whereby the luminescent material and
the photosensitive biologically active material are brought into
proximity. The binding partners 1110 and 1112 are depicted as
having a complementary "lock" and "key" shapes, which may suggest
an exemplary embodiment in which the binding partners are a protein
and a corresponding protein ligand, but this is a symbolic
depiction that is intended to encompass all manner of binding
partners and binding action thereof.
[0052] FIG. 12 depicts in cross section an embodiment of the
ionizing-radiation-responsive composition. The figure shows an
illustrative configuration and is not intended to be limiting;
other configurations will be apparent to those skilled in the art.
In this configuration, the ionizing-radiation-responsive
composition includes a core comprising a luminescent material 110,
surrounded by an inner shell comprising a photosensitive
biologically active material 112 and an outer shell comprising an
adjuvant matrix or coating material 900. A biotargeting agent 1010
is attached to the outer shell. The embodiment further comprises a
tagant material 1200. In the configuration depicted in FIG. 12, the
tagant material is distributed as patches on the surface of the
photosensitive biologically active material, but this is only an
illustrative configuration and other configurations will be
apparent to those skilled in the art. For example, the tagant
material may be deposited on the outer surface of the bound
composition, embedded in the interior of the bound composition,
etc. In general, a tagant material is a material that facilitates
detection, imaging, or dosimetry of the
ionizing-radiation-responsive composition in situ, or that
facilitates imaging, sensing, assay, or other measurement of the in
situ environment. In a first embodiment, the tagant material may
include a radioactive material, e.g. a gamma-active isotope of
thallium, technetium, etc. that can be imaged with a SPECT camera
or similar instrument. In a second embodiment, the tagant material
may include a radiocontrast agent, e.g. a high-Z material (such as
iodine, xenon, barium, or a lanthanide) that strongly absorbs or
scatters imaging x-rays. In a third embodiment, the tagant material
may include an MRI contrast agent, e.g. a gadolinium chelate or a
magnetic nanoparticle. An MRI contrast agent can also function as a
sensor, for example by conjugating the contrast agent to a sensing
moiety such as a calcium-binding calmodulin protein (c.f. T.
Atanasijevic et al, "Calcium-sensitive MRI contrast agents based on
superparamagnetic iron oxide nanoparticles and calmodulin," PNAS
103 (2006), 14707-14712). In a fourth embodiment, the tagant
material may include a fluorescent material, e.g. an organic dye,
an inorganic dye, or a quantum dot. The fluorescent material can
also function as a sensor or indicator dye; an example is the
ruthenium-based dye [Ru(dpp).sub.3].sup.2+, which has an intensity
decrease due to excited state quenching in the presence of
molecular oxygen. Some examples of fluorescent dyes,
sensor/indicator dyes, and quantum dot labels are described in T.
Vo-Dinh et al, Biomedical Photonics Handbook, CRC Press, 2003, 56-1
to 56-20 and 58-1 to 58-14, herein incorporated by reference. E.
Monson, supra, describes how various reference and indicator dyes
can be incorporated into a nanoparticle matrix.
[0053] FIG. 13 depicts another illustrative embodiment and use in
which an ionizing radiation emitter 100 produces ionizing radiation
102. The ionizing radiation irradiates at least a portion of a
region 104 that contains an ionizing-radiation-responsive
composition 200. As in FIG. 1 and FIG. 7, the luminescent material
responds to ionizing radiation to produce optical energy, and the
photosensitive biologically active material responds to optical
energy to become biologically active (other embodiments provide
other responses of the photosensitive biologically active material;
for example, the photosensitive biologically active material may
respond to the optical energy to become biologically inactive, to
partially increase or decrease a level of biological activity, to
change from a first mode of biological activity to second mode of
biological activity, etc.). In the present embodiment, the
ionizing-radiation-responsive composition additionally responds to
ionizing radiation to produce scattered or luminescent radiation
1300. A first radiation detector 1302 is disposed to receive at
least a portion of the scattered or luminescent radiation, and a
second radiation detector 1304 is disposed to receive at least a
portion of the ionizing radiation that is transmitted or forward
scattered through the region 104. Other embodiments may include
only the first radiation detector 1302 or only the second radiation
detector 1304. The scattered or luminescent radiation 1300 might
include, for example, Compton-scattered x-rays, pair production
gamma rays, characteristic x-rays, or optical fluorescence. In
those embodiments wherein the ionizing-radiation-responsive
composition further comprises a tagant material, the scattered or
luminescent radiation can originate from the tagant material. The
first radiation detector 1302 can include, for example, one or more
optical, x-ray, or gamma-ray sensors, optionally configured as a
planar or tomographic imaging system (such as a CCD camera, optical
tomograph, gamma camera, fluoroscope, PET scanner, SPECT scanner,
or CT device). The second radiation detector 1304 can include, for
example, one or more ionizing radiation sensors (e.g. a
semiconductor, phosphor, or scintillator detector), optionally
configured as a planar or tomographic system (ibid).
[0054] The embodiment depicted in FIG. 13 further comprises a
controller unit 1306 that is coupled to the ionizing radiation
emitter, the first radiation detector, and the second radiation
detector. The controller unit is configured to operate the ionizing
radiation emitter, e.g. to activate or deactivate the emitter (or
some portion thereof), change its mechanical position and
orientation, and modulate the spectrum, intensity, beam shape, time
sequence, etc. of the ionizing radiation. The controller unit is
also configured to operate the first and/or second radiation
detectors, e.g. to activate or deactivate either detector, change
its mechanical position and orientation, vary the imaging or
detection settings (such as the gain, spectral range, or field of
view), and receive detection or imaging data. The controller unit
can receive data from the first and/or second radiation detectors,
determine a correlated photoactivated dosage of the photosensitive
biologically active material, compare the correlated photoactivated
dosage to a target photoactivated dosage, and adjust the operation
of the ionizing radiation emitter to improve the correspondence
between the correlated photoactivated dosage and the target
photoactivated dosage. Additionally or alternatively, the
controller unit can receive data from the first and/or second
radiation detectors, which data comprises a map or image of the
target region, and generate a radiation dosage profile
corresponding to the map or image of the target region. For
example, the ionizing-radiation-responsive composition may have a
selective biological affinity for a particular tissue, tumor, or
lesion, and thereby serve as an imaging contrast agent to reveal
the spatial extent of the particular tissue, tumor, or lesion.
Optionally the controller includes an interface module, which may
include one or more user input devices (keyboards, pointing
devices, microphones, etc.), one or more user output devices (video
displays, speakers, etc.), one or more network interfaces (e.g. to
access a computer network or database), or any combination
thereof.
[0055] FIG. 14 depicts another illustrative embodiment and use in
which an ionizing radiation emitter 100 produces ionizing radiation
102. The ionizing radiation irradiates at least a portion of a
region 104 that contains an ionizing-radiation-responsive
composition 200. The luminescent material responds to the ionizing
radiation to produce optical energy, and the photosensitive
biologically active material responds to optical energy to become
biologically active (other embodiments provide other responses of
the photosensitive biologically active material; for example, the
photosensitive biologically active material may respond to the
optical energy to become biologically inactive, to partially
increase or decrease a level of biological activity, to change from
a first mode of biological activity to second mode of biological
activity, etc.). The present embodiment further comprises a probe
radiation emitter 1400, which emits probe radiation 1402 that
irradiates at least a portion of the region 104. The spatial
extents of the ionizing radiation 102 and the probe radiation 1402
may be disjoint, as depicted in FIG. 14, or they may at least
partially overlap. The ionizing-radiation-responsive composition
responds to the probe radiation to produce scattered or luminescent
radiation 1300. A first radiation detector 1302 is disposed to
receive at least a portion of the scattered or luminescent
radiation, a second radiation detector 1304 is disposed to receive
at least a portion of the ionizing radiation that is transmitted or
forward scattered through the region 104, and a third radiation
detector 1404 is disposed to receive at least a portion of the
probe radiation that is transmitted or forward scattered through
the region 104. Other embodiments may include any one or any two of
the three radiation detectors shown in FIG. 14. The probe radiation
emitter 1400 might include, for example, an ionizing radiation
emitter, an optical radiation emitter (especially one that operates
at deeper-penetrating red or near-infrared wavelengths), or an RF
antenna for nuclear magnetic resonance (when used in combination
with an NMR magnet system, not shown). The scattered or luminescent
radiation 1300 might include, for example, Compton-scattered
x-rays, pair production gamma rays, characteristic x-rays, optical
fluorescence, or NMR dipole radiation. In those embodiments wherein
the ionizing-radiation-responsive composition further comprises a
tagant material, the scattered or luminescent radiation can
originate from the tagant material. The first radiation detector
1302 and the third radiation detector 1404 can include, for
example, or one or more optical, x-ray, or gamma-ray sensors,
optionally configured as a planar or tomographic imaging system
(such as a CCD camera, optical tomograph, gamma camera,
fluoroscope, PET scanner, SPECT scanner, or CT device). The first
radiation detector can include one or more RF antennas, optionally
configured as part of a magnetic resonance imaging system. The
second radiation detector 1304 can include, for example, one or
more ionizing radiation sensors (e.g. a semiconductor, phosphor, or
scintillator detector), optionally configured as a planar or
tomographic system (ibid).
[0056] The embodiment depicted in FIG. 14 further comprises a
controller unit 1306 that is coupled to the ionizing radiation
emitter, the probe radiation emitter, and the three radiation
detectors. The controller unit is configured to operate the
ionizing radiation and probe radiation emitters, e.g. to activate
or deactive each emitter (or some portion thereof), change its
mechanical position and orientation, and modulate the spectrum,
intensity, beam shape, time sequence, etc. of the emitted
radiation. The controller unit is also configured to operate the
radiation detectors, e.g. to activate or deactivate a detector,
change its mechanical position and orientation, vary the imaging or
detection settings (such as the gain, spectral range, or field of
view), and receive detection or imaging data. The controller unit
can receive data from any or all of the radiation detectors,
determine a correlated photoactivated dosage of the photosensitive
biologically active material, compare the correlated photoactivated
dosage to a target photoactivated dosage, and adjust the operation
of the ionizing radiation emitter to improve the correspondence
between the correlated photoactivated dosage and the target
photoactivated dosage. Additionally or alternatively, the
controller unit can receive data from any or all of the radiation
detectors, which data comprises a map or image of the target
region, and generate a radiation dosage profile corresponding to
the map or image of the target region. For example, the
ionizing-radiation-responsive composition may have a selective
biological affinity for a particular tissue, tumor, or lesion, and
thereby serve as an imaging contrast agent to reveal the spatial
extent of the particular tissue, tumor, or lesion. Optionally the
controller includes an interface module, which may include one or
more user input devices (keyboards, pointing devices, microphones,
etc.), one or more user output devices (video displays, speakers,
etc.), one or more network devices (e.g. to access a computer
network or database), or similar devices and combinations
thereof.
[0057] An illustrative embodiment is depicted as a process flow
diagram in FIG. 15. This process flow may characterize, for
example, the operation of the controller unit 1306 depicted in
FIGS. 13 and 14. Flow 1500 includes step 1510--identifying a first
process that at least partially converts ionizing radiation to an
amount of optical energy. For example, ionizing radiation such as
gamma rays or x-rays may be converted to optical energy by a
luminescent material such as a scintillator or phosphor particle.
Flow 1500 further includes step 1520--identifying a second process
that at least partially converts the amount of optical energy to
biological activity. For example, a photosensitive biologically
active material may respond to optical energy to become
biologically active, or a photosensitive bioactivity-adjusting
material may respond to optical energy to allow release of a
biologically active material. Flow 1500 further includes step
1530--responsive to the identifying a first process and the
identifying a second process, determining an amount of ionizing
radiation whereby a selected amount of biological activity is
produced by a combination of the first process and the second
process. For example, the first process may be characterized by an
efficiency or cross section for conversion of ionizing radiation to
optical energy (including spectral and in-situ dependencies
thereof) and/or by a spatial distribution of a luminescent material
that may accomplish the first process; the second process may be
characterized by an efficiency or sensitivity for conversion of
optical energy to biological activity (including spectral and
in-situ dependencies thereof) and/or by a spatial distribution of a
photosensitive biologically active material that may accomplish the
second process; these characterizations of the first process and
the second process can be used to determine an amount of ionizing
radiation which should be delivered to obtain a selected amount of
biological activity. The amount of ionizing radiation may include a
specification of an irradiation energy spectrum, time profile, or
spatial profile. Flow 1500 further includes step 1540--irradiating
at least one region with the determined amount of ionizing
radiation. For example, an ionizing radiation emitter (e.g. a
teletherapy device or CT instrument) may be operated to delivered
the determined amount of ionizing radiation (optionally according
to a specified time, space, and or energy profile). Flow 1500
optionally includes step 1550--detecting an amount of ionizing
radiation that is transmitted or forward scattered through at least
a portion of the at least one region. For example, an ionizing
radiation detector (e.g. a semiconductor, phosphor, or scintillator
detector, optionally configured as a planar or tomographic system)
may be operated to detect the transmitted or forward-scattered
ionizing radiation. Flow 1500 optionally further includes step
1555--determining an amount of biological activity corresponding to
the detected amount of ionizing radiation. For example, there may
be a correlation between the detected amount of transmitted or
forward scattered ionizing radiation and the actual amount of
biological activity caused by the irradiation in step 1540.
Alternatively or additionally, the detected amount of transmitted
or forward scattered ionizing radiation may reveal characteristics
of the in-situ environment (e.g. a spatial extent of a particular
tissue, tumor, or lesion) whereon the amount of biological activity
may depend (e.g. the biological activity is specific to a
particular tissue, tumor, or lesion). Flow 1500 optionally further
includes step 1580--adjusting the irradiating to obtain the
selected amount of biological activity. For example, the ionizing
radiation emitter may be adjusted (e.g. by activating or
deactivating all or part of the emitter, changing its mechanical
position or orientation, or modifying the spectrum, intensity, beam
shape, time sequence, etc. of the ionizing radiation), whereby a
discrepancy between the selected amount of biological activity (as
used in step 1530 to determine an amount of ionizing radiation to
administer) and the determined amount of biological activity (e.g.
as obtained in step 1555, 1564, or 1576) may be at least partially
removed or reduced.
[0058] Another illustrative embodiment is depicted as a process
flow diagram in FIG. 16. This process flow may characterize, for
example, the operation of the controller unit 1306 depicted in
FIGS. 13 and 14. Flow 1600 includes steps 1510, 1520, 1530, and
1540, as described above. Flow 1600 optionally includes step
1560--identifying a third process that at least partially converts
ionizing radiation to detectable radiation in at least one
radiation mode, where the conversion by the third process at least
partially corresponds to the conversion of ionizing radiation to
biological activity by the combination of the first process and the
second process. For example, an agent that accomplishes the first
process and/or the second process (e.g. a luminescent material or a
photosensitive biologically active material or a combination
thereof), or a tagant material paired with such an agent, may
respond to ionizing radiation to produce scattered or luminescent
radiation (e.g. Compton-scattered x-rays, pair production gamma
rays, characteristic x-rays, or optical fluorescence). Flow 1600
optionally further includes step 1562--detecting an amount of
radiation in the at least one radiation mode. For example, a
radiation detector (e.g. an optical, x-ray, or gamma-ray sensor,
optionally configured as a planar or tomographic imaging system
such as a CCD camera, gamma camera, fluoroscope, etc.) may be
operated to detect radiation in the at least one radiation mode.
Flow 1600 optionally further includes step 1564--determining an
amount of biological activity corresponding to the detected amount
of radiation in the at least one radiation mode. For example, there
may be a correlation between the detected amount of radiation in
the at least one radiation mode and the actual amount of biological
activity caused by the irradiation in step 1540. Alternatively or
additionally, the detected amount of radiation in the at least one
radiation mode may reveal characteristics of the in-situ
environment (e.g. a spatial extent of a particular tissue, tumor,
or lesion) whereon the amount of biological activity may depend
(e.g. the biological activity is specific to a particular tissue,
tumor, or lesion). Flow 1500 optionally further includes step 1580,
as described above.
[0059] Another illustrative embodiment is depicted as a process
flow diagram, in FIG. 17. This process flow may characterize, for
example, the operation of the controller unit 1306 depicted in
FIGS. 13 and 14. Flow 1700 includes steps 1510, 1520, 1530, and
1540, as described above. Flow 1700 optionally includes step
1570--identifying a third process that at least partially converts
radiation in at least a first radiation mode to radiation in at
least a second radiation mode, where the conversion by the third
process at least partially corresponds to the conversion of
ionizing radiation to biological activity by the combination of the
first process and the second process. For example, an agent that
accomplishes the first process and/or the second process (e.g. a
luminescent material or a photosensitive biologically active
material or a combination thereof), or a tagant material paired
with such an agent, may respond to radiation in at least the first
radiation mode (e.g. ionizing radiation, optical radiation, or RF
radiation--the latter optionally originating from an RF antenna
deployed as part of an NMR system) to produce scattered or
luminescent radiation in at least the second radiation mode (e.g.
Compton-scattered x-rays, pair production gamma rays,
characteristic x-rays, optical fluorescence, or NMR dipole
radiation). Flow 1700 optionally further includes step
1572--irradiating at least a portion of the at least one region
with an amount of radiation in at least the first radiation mode.
For example, a probe radiation emitter (e.g. ionizing radiation
emitter, an optical radiation emitter, or an RF antenna used in
combination with an NMR magnet system) may be operated to deliver
the amount of radiation in at least the first radiation mode. Flow
1700 optionally further includes step 1574--detecting an amount of
radiation in at least the second radiation mode. For example, a
radiation detector (e.g. an optical, x-ray, or gamma-ray sensor,
optionally configured as a planar or tomographic imaging system
such as a CCD camera, gamma camera, fluoroscope, etc.; or one or
more RF antennas, optionally configured as part of a magnetic
resonance imaging system) may be operated to detect radiation in at
least the second radiation mode. Flow 1700 optionally further
includes step 1576--determining an amount of biological activity
corresponding to the detected amount of radiation in at least the
second radiation mode. For example, there may be a correlation
between the detected amount of radiation in at least the second
radiation mode and the actual amount of biological activity caused
by the irradiation in step 1540. Alternatively or additionally, the
detected amount of radiation in at least the second radiation mode
may reveal characteristics of the in-situ environment (e.g. a
spatial extent of a particular tissue, tumor, or lesion) whereon
the amount of biological activity may depend (e.g. the biological
activity is specific to a particular tissue, tumor, or lesion).
Flow 1500 optionally further includes step 1580, as described
above.
[0060] Those having skill in the art will recognize that the state
of the art has progressed to the point where there is little
distinction left between hardware and software implementations of
aspects of systems; the use of hardware or software is generally
(but not always, in that in certain contexts the choice between
hardware and software can become significant) a design choice
representing cost vs. efficiency tradeoffs. Those having skill in
the art will appreciate that there are various vehicles by which
processes and/or systems and/or other technologies described herein
can be effected (e.g., hardware, software, and/or firmware), and
that the preferred vehicle will vary with the context in which the
processes and/or systems and/or other technologies are deployed.
For example, if an implementer determines that speed and accuracy
are paramount, the implementer may opt for a mainly hardware and/or
firmware vehicle; alternatively, if flexibility is paramount, the
implementer may opt for a mainly software implementation; or, yet
again alternatively, the implementer may opt for some combination
of hardware, software, and/or firmware. Hence, there are several
possible vehicles by which the processes and/or devices and/or
other technologies described herein may be effected, none of which
is inherently superior to the other in that any vehicle to be
utilized is a choice dependent upon the context in which the
vehicle will be deployed and the specific concerns (e.g., speed,
flexibility, or predictability) of the implementer, any of which
may vary. Those skilled in the art will recognize that optical
aspects of implementations will typically employ optically-oriented
hardware, software, and or firmware.
[0061] The foregoing detailed description has set forth various
embodiments of the devices and/or processes via the use of block
diagrams, flowcharts, and/or examples. Insofar as such block
diagrams, flowcharts, and/or examples contain one or more functions
and/or operations, it will be understood by those within the art
that each function and/or operation within such block diagrams,
flowcharts, or examples can be implemented, individually and/or
collectively, by a wide range of hardware, software, firmware, or
virtually any combination thereof. In one embodiment, several
portions of the subject matter described herein may be implemented
via Application Specific Integrated Circuits (ASICs), Field
Programmable Gate Arrays (FPGAs), digital signal processors (DSPs),
or other integrated formats. However, those skilled in the art will
recognize that some aspects of the embodiments disclosed herein, in
whole or in part, can be equivalently implemented in integrated
circuits, as one or more computer programs running on one or more
computers (e.g., as one or more programs running on one or more
computer systems), as one or more programs running on one or more
processors (e.g., as one or more programs running on one or more
microprocessors), as firmware, or as virtually any combination
thereof, and that designing the circuitry and/or writing the code
for the software and or firmware would be well within the skill of
one of skill in the art in light of this disclosure. In addition,
those skilled in the art will appreciate that the mechanisms of the
subject matter described herein are capable of being distributed as
a program product in a variety of forms, and that an illustrative
embodiment of the subject matter described herein applies
regardless of the particular type of signal bearing medium used to
actually carry out the distribution. Examples of a signal bearing
medium include, but are not limited to, the following: a recordable
type medium such as a floppy disk, a hard disk drive, a Compact
Disc (CD), a Digital Video Disk (DVD), a digital tape, a computer
memory, etc.; and a transmission type medium such as a digital
and/or an analog communication medium (e.g., a fiber optic cable, a
waveguide, a wired communications link, a wireless communication
link, etc.).
[0062] In a general sense, those skilled in the art will recognize
that the various aspects described herein which can be implemented,
individually and/or collectively, by a wide range of hardware,
software, firmware, or any combination thereof can be viewed as
being composed of various types of "electrical circuitry."
Consequently, as used herein "electrical circuitry" includes, but
is not limited to, electrical circuitry having at least one
discrete electrical circuit, electrical circuitry having at least
one integrated circuit, electrical circuitry having at least one
application specific integrated circuit, electrical circuitry
forming a general purpose computing device configured by a computer
program (e.g., a general purpose computer configured by a computer
program which at least partially carries out processes and/or
devices described herein, or a microprocessor configured by a
computer program which at least partially carries out processes
and/or devices described herein), electrical circuitry forming a
memory device (e.g., forms of random access memory), and/or
electrical circuitry forming a communications device (e.g., a
modem, communications switch, or optical-electrical equipment).
Those having skill in the art will recognize that the subject
matter described herein may be implemented in an analog or digital
fashion or some combination thereof.
[0063] Those skilled in the art will recognize that it is common
within the art to describe devices and/or processes in the fashion
set forth herein, and thereafter use engineering practices to
integrate such described devices and/or processes into image
processing systems. That is, at least a portion of the devices
and/or processes described herein can be integrated into an image
processing system via a reasonable amount of experimentation. Those
having skill in the art will recognize that a typical image
processing system generally includes one or more of a system unit
housing, a video display device, a memory such as volatile and
non-volatile memory, processors such as microprocessors and digital
signal processors, computational entities such as operating
systems, drivers, and applications programs, one or more
interaction devices, such as a touch pad or screen, control systems
including feedback loops and control motors (e.g., feedback for
sensing lens position and/or velocity; control motors for
moving/distorting lenses to give desired focuses). A typical image
processing system may be implemented utilizing any suitable
commercially available components, such as those typically found in
digital still systems and/or digital motion systems.
[0064] Those skilled in the art will recognize that it is common
within the art to describe devices and/or processes in the fashion
set forth herein, and thereafter use engineering practices to
integrate such described devices and/or processes into data
processing systems. That is, at least a portion of the devices
and/or processes described herein can be integrated into a data
processing system via a reasonable amount of experimentation. Those
having skill in the art will recognize that a typical data
processing system generally includes one or more of a system unit
housing, a video display device, a memory such as volatile and
non-volatile memory, processors such as microprocessors and digital
signal processors, computational entities such as operating
systems, drivers, graphical user interfaces, and applications
programs, one or more interaction devices, such as a touch pad or
screen, and/or control systems including feedback loops and control
motors (e.g., feedback for sensing position and/or velocity;
control motors for moving and/or adjusting components and/or
quantities). A typical data processing system may be implemented
utilizing any suitable commercially available components, such as
those typically found in data computing/communication and/or
network computing/communication systems.
[0065] All of the above U.S. patents, U.S. patent application
publications, U.S. patent applications, foreign patents, foreign
patent applications and non-patent publications referred to in this
specification and/or listed in any Application Data Sheet, are
incorporated herein by reference, to the extent not inconsistent
herewith.
[0066] One skilled in the art will recognize that the herein
described components (e.g., steps), devices, and objects and the
discussion accompanying them are used as examples for the sake of
conceptual clarity and that various configuration modifications are
within the skill of those in the art. Consequently, as used herein,
the specific exemplars set forth and the accompanying discussion
are intended to be representative of their more general classes. In
general, use of any specific exemplar herein is also intended to be
representative of its class, and the non-inclusion of such specific
components (e.g., steps), devices, and objects herein should not be
taken as indicating that limitation is desired.
[0067] With respect to the use of substantially any plural and/or
singular terms herein, those having skill in the art can translate
from the plural to the singular and/or from the singular to the
plural as is appropriate to the context and/or application. The
various singular/plural permutations are not expressly set forth
herein for sake of clarity.
[0068] The herein described subject matter sometimes illustrates
different components contained within, or connected with, different
other components. It is to be understood that such depicted
architectures are merely exemplary, and that in fact many other
architectures can be implemented which achieve the same
functionality. In a conceptual sense, any arrangement of components
to achieve the same functionality is effectively "associated" such
that the desired functionality is achieved. Hence, any two
components herein combined to achieve a particular functionality
can be seen as "associated with" each other such that the desired
functionality is achieved, irrespective of architectures or
intermedial components. Likewise, any two components so associated
can also be viewed as being "operably connected", or "operably
coupled", to each other to achieve the desired functionality, and
any two components capable of being so associated can also be
viewed as being "operably couplable", to each other to achieve the
desired functionality. Specific examples of operably couplable
include but are not limited to physically mateable and/or
physically interacting components and/or wirelessly interactable
and/or wirelessly interacting components and/or logically
interacting and/or logically interactable components.
[0069] While particular aspects of the present subject matter
described herein have been shown and described, it will be apparent
to those skilled in the art that, based upon the teachings herein,
changes and modifications may be made without departing from the
subject matter described herein and its broader aspects and,
therefore, the appended claims are to encompass within their scope
all such changes and modifications as are within the true spirit
and scope of the subject matter described herein. Furthermore, it
is to be understood that the invention is defined by the appended
claims. It will be understood by those within the art that, in
general, terms used herein, and especially in the appended claims
(e.g., bodies of the appended claims) are generally intended as
"open" terms (e.g., the term "including" should be interpreted as
"including but not limited to," the term "having" should be
interpreted as "having at least," the term "includes" should be
interpreted as "includes but is not limited to," etc.). It will be
further understood by those within the art that if a specific
number of an introduced claim recitation is intended, such an
intent will be explicitly recited in the claim, and in the absence
of such recitation no such intent is present. For example, as an
aid to understanding, the following appended claims may contain
usage of the introductory phrases "at least one" and "one or more"
to introduce claim recitations. However, the use of such phrases
should not be construed to imply that the introduction of a claim
recitation by the indefinite articles "a" or "an" limits any
particular claim containing such introduced claim recitation to
inventions containing only one such recitation, even when the same
claim includes the introductory phrases "one or more" or "at least
one" and indefinite articles such as "a" or "an" (e.g., "a" and/or
"an" should typically be interpreted to mean "at least one" or "one
or more"); the same holds true for the use of definite articles
used to introduce claim recitations. In addition, even if a
specific number of an introduced claim recitation is explicitly
recited, those skilled in the art will recognize that such
recitation should typically be interpreted to mean at least the
recited number (e.g., the bare recitation of "two recitations,"
without other modifiers, typically means at least two recitations,
or two or more recitations). Furthermore, in those instances where
a convention analogous to "at least one of A, B, and C, etc." is
used, in general such a construction is intended in the sense one
having skill in the art would understand the convention (e.g., "a
system having at least one of A, B, and C" would include but not be
limited to systems that have A alone, B alone, C alone, A and B
together, A and C together, B and C together, and/or A, B, and C
together, etc.). In those instances where a convention analogous to
"at least one of A, B, or C, etc." is used, in general such a
construction is intended in the sense one having skill in the art
would understand the convention (e.g., "a system having at least
one of A, B, or C" would include but not be limited to systems that
have A alone, B alone, C alone, A and B together, A and C together,
B and C together, and/or A, B, and C together, etc.). It will be
further understood by those within the art that virtually any
disjunctive word and/or phrase presenting two or more alternative
terms, whether in the description, claims, or drawings, should be
understood to contemplate the possibilities of including one of the
terms, either of the terms, or both terms. For example, the phrase
"A or B" will be understood to include the possibilities of "A" or
"B" or "A and B."
[0070] With respect to the appended claims, those skilled in the
art will appreciate that recited operations therein may generally
be performed in any order. Examples of such alternate orderings may
include overlapping, interleaved, interrupted, reordered,
incremental, preparatory, supplemental, simultaneous, reverse, or
other variant orderings, unless context dictates otherwise. With
respect to context, even terms like "responsive to," "related to,"
or other past-tense adjectives are generally not intended to
exclude such variants, unless context dictates otherwise.
[0071] While various aspects and embodiments have been disclosed
herein, other aspects and embodiments will be apparent to those
skilled in the art. The various aspects and embodiments disclosed
herein are for purposes of illustration and are not intended to be
limiting, with the true scope and spirit being indicated by the
following claims.
* * * * *