WO2003023341A2 - Thermographic metthod - Google Patents

Thermographic metthod Download PDF

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Publication number
WO2003023341A2
WO2003023341A2 PCT/GB2002/003782 GB0203782W WO03023341A2 WO 2003023341 A2 WO2003023341 A2 WO 2003023341A2 GB 0203782 W GB0203782 W GB 0203782W WO 03023341 A2 WO03023341 A2 WO 03023341A2
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WO
WIPO (PCT)
Prior art keywords
contrast agent
photothermal
photothermal contrast
optionally substituted
independently
Prior art date
Application number
PCT/GB2002/003782
Other languages
French (fr)
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WO2003023341A3 (en
Inventor
Kathryn Carr
Original Assignee
Avecia Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GB0121795A external-priority patent/GB0121795D0/en
Priority claimed from GB0121673A external-priority patent/GB0121673D0/en
Application filed by Avecia Limited filed Critical Avecia Limited
Priority to AU2002321479A priority Critical patent/AU2002321479A1/en
Publication of WO2003023341A2 publication Critical patent/WO2003023341A2/en
Publication of WO2003023341A3 publication Critical patent/WO2003023341A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A61K49/0021—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules the fluorescent group being a small organic molecule
    • A61K49/0032—Methine dyes, e.g. cyanine dyes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
    • A61B5/00—Measuring for diagnostic purposes; Identification of persons
    • A61B5/01—Measuring temperature of body parts ; Diagnostic temperature sensing, e.g. for malignant or inflamed tissue
    • A61B5/015—By temperature mapping of body part
    • C—CHEMISTRY; METALLURGY
    • C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
    • C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
    • C09B47/00—Porphines; Azaporphines
    • C09B47/04—Phthalocyanines abbreviation: Pc
    • C09B47/045—Special non-pigmentary uses, e.g. catalyst, photosensitisers of phthalocyanine dyes or pigments

Definitions

  • This invention relates to a method of enhancement of images which result from thermal differences between a subject and its surroundings.
  • the invention also relates to the use of such a method, for example, for the optimisation of dosages of medicaments.
  • thermal imaging or thermography is based on variations of radiated heat energy.
  • Thermal imaging using infra-red cameras or other IR detection systems finds application in a wide variety of areas, namely medicine, agriculture, horticulture, manufacturing industries, non-destructive testing of building and engineering constructions and inspection of electrical transmission and distribution systems from a safe distance.
  • the technique has become established in the medical field where it is ideally suited to look at heat changes as a consequence of altered blood flow due to infection, injury, disease or circulatory problems.
  • Imaging which relies on inherent temperature differences in living tissue or other non-biological subject material is limited in the amount of information that it can ultimately provide. Often the differences in such energy variations between the subject and its surroundings are too small to give sufficient definition or resolution to the resulting image thereby restricting the scope of such a technique. Attempts to overcome these difficulties have involved the administering of agents which will locate themselves in the subject under investigation to directly enhance the inherent temperature difference, for instance chemically induced intracellular hyperthermia described in WO0006143, but the reagents used are restricted to mitochondrial uncoupling agents limiting their use as imaging agents to eukaryotic cell systems.
  • a method for creating and detecting a thermal energy difference between a material and its surroundings which comprises the following steps:
  • the photothermal contrast agent is added to a material only or to the surroundings of a material only. In yet a further aspect, the photothermal contrast agent is added to both the material and its surroundings.
  • a photothermal contrast agent in the present invention improves the signal to noise ratio of the thermal image.
  • Photothermal contrast agents may be selected from a range of structural types, the common feature of which is a strong absorbance of energy within the wavelength range of input energy.
  • the photothermal contrast agent absorbs in the region 200 to 2000nm. Preferably this range will be from 650 to 1500nm, more preferably from 650 to 1200nm.
  • the photothermal contrast agent absorbs in the region 200 to 850nm. Preferably the absorption maximum of the photothermal contrast agent will be at or close to the wavelength of input energy.
  • the photothermal contrast agent preferably comprises a conjugated unsaturated hydrocarbon or a pigment.
  • the conjugated unsaturated hydrocarbon may be selected from the following classes of compound: phthalocyanines, naphthalocyanines, polymethines, squaryliums, croconiums, iminiums, di-iminiums, pyryliums, quinones, azo dyes and their metal complexes, each of which may be optionally substituted.
  • Preferred phthalocyanines are selected from compounds as shown in Formula 1 in which at least one of the peripheral carbon atoms in the 1-16 positions of the phthalocyanine nucleus (M k Pc) is linked either directly or via an oxygen atom or sulphur atom or a nitrogen atom to an organic radical hereinafter referred to as a pendant organic radical, the remaining peripheral carbon atoms being unsubstituted or substituted by any combination of atoms or groups and sulphonated derivatives thereof.
  • M k Pc phthalocyanine nucleus
  • M represents hydrogen, a metal, metal oxide, metal hydroxide, metal halide such as a fluoride, chloride, bromide or iodide; k is the inverse of half the valency of M.
  • suitable metals include but are not restricted to copper, zinc, cobalt, nickel, iron, vanadium, titanium, iridium, tin, palladium, aluminium; metal oxides include vanadyl, titanyl; metal hydroxides include aluminium, scandium, gallium, rhodium, indium, ruthenium; metal halides include CIAI, CISc, CIRh, CIGa, Clln, Brln, CIRu.
  • Preferred phthalocyanines are those which absorb electromagnetic radiation at a wavelength from 650nm to 1500nm.
  • each of the pendant organic radicals linked to the phthalocyanine nucleus is independently selected from aromatic, heterocyclic, aliphatic and alicyclic radicals, such that any one phthalocyanine nucleus may carry two or more different organic radicals. It is preferred that each pendant organic radical is independently selected from mono- and bi-cyclic aromatic and aliphatic radicals.
  • Preferred mono- and bi-cyclic aromatic and heterocyclic radicals are ph ' enyl, naphthyl, especially naphth-2-yl, phenylene, especially 1 ,2-phenylene, pyridyl, phenoxy, thiophenyl, furanyl, quinolinyl, thiazolyl, benzothiazolyl and pyrimidyl each of which may be substituted.
  • aromatic radical is 1 ,2-phenylene this is attached to the phthalocyanine nucleus via two atoms independently selected from sulphur, oxygen and nitrogen. These atoms are attached to the adjacent positions of each phenylene radical, and are preferably attached to the phthalocyanine nucleus via the 2- and 3- and/or 6- and
  • the pendant organic radical is an aliphatic or alicyclic radical it is preferred that it is selected from C ⁇ -2 o-alkyl, especially C- M o-alkyl, more especially C 1-4 -alkyl ; C 2-20 - alkenyl especially C 3- ⁇ 0 -alkenyl and C 4-8 -cycloalkyl especially cyclohexyl, each of which may be substituted.
  • Optional substituents for the pendant organic radicals are preferably selected from C 1-20 -alkyl, especially C 1-4 -alkyl; C 1-20 -alkoxy, especially C-i -4 -alkoxy; C 2-20 -alkenyl, especially C 2- -alkenyl; C 1-20 -alkylthio, especially C 1-4 -alkylthio; C 1-20 -alkoxycarbonyl, especially C 1-4 -alkoxycarbonyl; hydroxyC 1-4 -alkoxy; aryl, especially phenyl; C 1-4 -alkylaryl, especially benzyl; arylthio, especially phenylthio and phenoxy; halogen, especially fluoro, chloro and bromo; -CN; -NO 2 ; -CF 3 ; -SO 3 A in which A is H, or a metal or ammonium ion or substituted ammonium ion; -COR 1 , -COOR
  • a sub-group of phthalocyanines of the present invention has from 8 to 16, optionally from 12 to 16, and optionally all 16 of the peripheral carbon atoms linked preferably via an oxygen or sulphur atom, more preferably by an oxygen atom, to a pendant optionally substituted mono- and/or bi-cyclic aromatic radical and/or aliphatic radical more preferably phenyl and/or naphthyl and/or C ⁇ -10 -alkyl radical, most preferably a phenyl radical.
  • suitable atoms or groups which can be attached to any of the remaining peripheral carbon atoms of the phthalocyanine nucleus are hydrogen, halogen, sulphonate groups -SO 3 A in which A is H, or a metal or ammonium ion or a substituted ammonium ion, and any of the pendant organic radicals described above and hereinafter represented by R. It is preferred that the atoms or groups attached to the remaining peripheral carbon atoms are selected from -H, -F, -Cl, -Br, -I, -SO 3 H, -SO 3 Na, -SO 3 K, - SO 3 Li and -SO 3 NH 4 or any combination thereof. It is especially preferred that these atoms or groups are -H, -Cl, -Br, -SO 3 H, -SO 3 Na or -SO 3 NH 4 .
  • the sulphonated derivatives of the phthalocyanines used in the present invention carrying up to 50 SO 3 A groups, preferably up to 40 SO 3 A groups, more preferably up to 30 SO 3 A groups and especially up to 16 SO 3 A groups, which are attached directly to the phthalocyanine nucleus and/or to the pendant organic radicals are a preferred group of compounds for the present invention.
  • the average number of SO 3 A groups is preferably from 2 to 40 and more preferably from 2 to 30 and especially from 4 to 16. It is also preferred that for each pendant organic radical there is on average at least one SO 3 A group, although each organic radical may carry none, one or more than one SO 3 A group.
  • A is a metal ion it is preferably an alkali metal ion such as a sodium, potassium or lithium ion.
  • A is an ammonium ion it is preferably NH + 4 or a substituted ammonium ion which enhances the water-solubility of the compound or a substituted ammonium ion of the formula NQ + 4 which enhances the alcohol solubility of the compound.
  • Suitable substituted ammonium ions which enhance the water solubility of the compound are mono, di, tri and tetra alkyl and hydroxyalkyl ammonium ions in which the alkyl groups preferably contain from 1 to 4 carbon atoms such as N + (CH 3 ) 4 ; N + (C 2 H 5 ) 4 ; N + (C 2 H 4 OH) 4 ; NH + 3 CH 3 ; NH + 2 (CH 3 ) 2 and NH + (CH 3 ) 3 .
  • At least one Q is a fatty aliphatic group and any remaining Q groups are C -4 -alkyl or H.
  • the fatty aliphatic group represented by Q preferably contains from 4 to 16, more preferably from 7 to 12 and especially preferably 7 to 9 carbon atoms.
  • Preferred fatty aliphatic groups are alkyl and alkenyl groups which have straight- or branched-chains.
  • Preferred alkyl groups, represented by Q, containing 8 or 9 carbon atoms are, 3,5,5-trimethyl-hexyl, 1 ,1 ,3,3-tetramethylbutyl and 2-ethylhexyl.
  • Examples of other suitable aliphatic chains are 1-ethyl-3-methylpentyl, 1,5-dimethylhexyl, 1-methylheptyl, 1,4-dimethylheptyl, 1 ,2,2-trimethylpropyl, 2-ethylbutyl, 1-propylbutyl, 1 ,2-dimethylbutyl, 2-methylpentyl, 1-ethylpentyl, 1 ,4-dimethylpentyl, 1-methylhexyl, 3-methylhexyl, 1 ,3,3-trimethylbutyl, 1-methylnonyl.
  • the substituted ammonium ion represented by A preferably has one fatty alkyl group as described above, the remaining groups being preferably H or C 1-4 -alkyl, especially H or methyl.
  • Especially preferred ammonium ions include 2-ethylhexylammonium, 1 ,1,3,3-tetramethylbutylammonium and 3,5,5-trimethylhexylammonium.
  • Preferred phthalocyanines for use as photothermal contrast agents are compounds of Formula (2): M k Pc(X-R) a Y b (SO 3 A) d Formula (2) wherein:
  • M k Pc is a phthalocyanine nucleus as defined in Formula (1); each R independently is an organic radical;
  • X is O, S, N, Se, Te; each Y independently is halogen or hydrogen;
  • A is selected from H, a metal, ammonium ion or substituted ammonium ion as described above; a is from 4 to 16; b is from 0 to 12; d is an average value from 0.1 to 30; and a+b is from 4 to 16; the X-R and Y groups being attached to one or more of the 16 peripheral carbon atoms of the phthalocyanine nucleus.
  • each of the radicals denoted by R may be selected from any of the pendant organic radicals hereinbefore defined in relation to Formula (1) above.
  • each halogen denoted by Y is preferably independently selected from -F, -Cl, -Br and -I more preferably from -Cl or -Br.
  • a+b When a+b is ⁇ 16 the remainder of the 16 peripheral carbon atoms, not carrying a group X-R, may carry a sulphonate group -SO 3 A or a group represented by R. It is however preferred that the sum of a+b is 16. It is also preferred that a is 4, 8, 12 or 16.
  • the metal ion denoted by A is preferably an alkali or alkaline earth metal ion and more preferably is selected from lithium, sodium and potassium ion. It is especially preferred that A is a sodium or an ammonium ion or hydrogen.
  • Especially preferred phthalocyanine compounds of the present invention are ZnPc(O-Phenyl) 16 (SO 3 Na)i6, H 2 Pc(O-Phenyl) 16 (SO 3 Na) 18 , CuPc(S-4- Methylphenyl) 15 (SO 3 Na) 12 .
  • the photothermal contrast agent is a cyanine or a polymethine, it is preferably a compound of Formula (A) or a salt thereof:
  • R a and R b are independently optionally substituted C 1-8 alkyl -X 1 wherein X 1 is H, F, Cl, Br, optionally substituted phenyl, optionally substituted C 3-7 cycloalkyl, optionally substituted C 1-3 alkoxy or CO 2 A or SO_lk, where A is H, a metal, ammonium ion or substituted ammonium ion;
  • Z 1 and Z 2 independently represent the atoms necessary to complete an indole, benzindole or naphthindole nucleus;
  • B is CR e R f , O or S
  • R c and R d independently represent methyl, ethyl, methoxy, ethoxy, hydroxy, F, Cl or Br substitutions on Z 1 and Z 2 , respectively;
  • R e , R f each independently represent optionally substituted C 1-4 alkyl or R e and R f ,when taken together with the carbon atoms to which they are attached may form an optionally substituted 5- or 6-membered cycloalkyl group;
  • R 9 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, substituted aryl, F, Cl, or Br, or Q-R h ;
  • Q is S, O, N;
  • R h is optionally substituted aryl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, hydrogen; and n is an integer from 2 to 4.
  • the compound A typically has a counter ion (anion) associated with it or else may be an internal salt, i.e. having a negative charge located within the molecule to balance the positive.
  • a counter ion anion
  • an internal salt i.e. having a negative charge located within the molecule to balance the positive.
  • a preferred cyanine or a polymethine is of Formula (3) or a salt thereof:
  • R 1 and R 8 each independently is H, NO 2 , alkyl, aryl, SO 2 R 9 , SO 3 A 1 , halo, OR 9 , CO 2 A 1 , CO 2 R 9 , OCR 9 , OCOR 9 , or connected to R 2 and R 7 respectively in a fused optionally substituted carbocyclic aromatic ring;
  • R 9 is optionally substituted alkyl or optionally substituted aryl;
  • a 1 is H or an alkali metal cation;
  • R 2 and R 7 each independently is H or connected to R 1 and R 8 respectively in a fused optionally substituted carbocyclic aromatic ring;and D and E each independently is -S-, -O-, or C(R 10 ) 2 and each R 10 is independently H or C 1-3 alkyl.
  • R 2 , R 7 , R 9 , R a , R b , R e , R f and R g are as preferred above for the phthalocyanine organic radical R.
  • the compound of formula (3) typically has a counter ion (anion) associated with it or else may be an internal salt, i.e. having a negative charge located within the molecule to balance the positive.
  • the photothermal contrast agent is a pigment
  • it is preferably selected from carbon blacks, such as channel black, furnace black, or lamp black, or suitably functionalised carbon blacks, for example by introduction of water-solubilising groups such as -SO 3 H or -COOH or salts thereof; suitable salts include alkali metal, ammonium or substituted ammonium as described above.
  • Suitable commercially available pigment dispersions include the Hostafine®pigments available from Hoechst Celanese Corporation, including Hostafine®Black T and Hostafine®Black TS; pigment dispersions available from Bayer include Levanyl®Black A-SF; pigment dispersions available from Columbia include Raven® 7000, Raven® 5750, Raven® 5250, Raven® 5000 and Raven® 3500; pigment dispersions available from Degussa Company include Derussol®carbon black pigment dispersions such as Derussol®Z350S, Derussol®VU 25/L, Derussol®345, Derussol ®3450S, Color Black FW 200, Color Black FW 2, Color Black FW 2V Color Black FW 1 , Color Black FW 18, Color Black S160, Color Black FW S170, Special Black 6, Special Black 5, Special black 4A,Special black 4, Printex® 140U, Printex® U, Printex® V and Printex® 140V; pigment dispersions available form BASF Corporation include Novofil® Black and Disperse Black
  • the pigment particle size may be between 0.0005 and 15 microns.
  • Preferred pigment particle sizes are generally from about 0.001 to about 5 microns, and more preferably from about 0.001 to about 3 microns, and most preferably from about 0.001 to about 1.2 microns.
  • the photothermal contrast agent may be used in solid form, in solution or, in the case of pigments, as a dispersion, or vapourised or atomised to form an aerosol, and when administered will locate itself substantially at the target site or sites for imaging. Such location may occur by a natural affinity of the photothermal contrast agent for the particular target site, or may be achieved by a targeted imaging process where a carrier is used, which may comprise vectors such as antibodies or other similar systems or the photothermal contrast agent may be directly placed in the target area . Alternatively location may occur by restricting the mobility of the photothermal contrast agent such that it remains substantially in the target area, for example by controlling the inherent solubility, pH or lipid/water partition of the photothermal contrast agent.
  • the photothermal contrast agent comprises a substance which associates specifically with another corresponding substance which is located only in the target area to form a conjugate which demonstrates enhanced absorption of radiation.
  • the material may comprise any part of: a human or animal body, a plant or other vegetation, a building or engineering construction, a motor vehicle and applications in aviation transport or substrates such as paper, including rag paper, printer quality paper, currency grade paper, plastics-coated or laminated paper or other substrates typically used as documents or packaging.
  • the input energy is preferably a radiation source of preferably electronic energy of wavelength between 200 and 2000 nm, most preferably of wavelength between 650 and 1000 nm and desirably of a wavelength substantially equal to the absorption maximum of the photothermal contrast agent.
  • Typical irradiation sources range from a simple halogen bulb, which has an emission spectrum substantially, that is, at least 20%, in the near infra- red (above 700nm) and can be filtered if necessary, through to Light Emitting Diodes (LEDs) and ultimately to infrared semiconductor lasers, available at a range of wavelengths such as 785, 805, 940 and 980 nm for example.
  • LEDs Light Emitting Diodes
  • Illumination times may be selected appropriately to give optimum imaging, preferably less than 30 seconds, most preferably flash imaging (short bursts of light of approximate duration up to 1 second) in order to avoid direct heating of the subject which results in a lower signal-to-noise ratio.
  • the thermal image detector is any device able to detect a thermal energy difference between or within a material and/or its surroundings.
  • the thermal image detector may also be any device able to provide data from which a temperature change may be determined and is preferably a thermal imaging camera such as, for example, a ThermaCAM ® SC1000 camera, available from FLIR Systems, Boston, USA.
  • the thermal imaging camera preferably comprises a charge couple device (CCD) which is sensitive to light of wavelength preferably between 1.5 and 15 microns, most preferably between 3.4 and 5 microns.
  • CCD charge couple device
  • Image manipulation and data handling are achieved using appropriate computer software such as Thermagram ® PRO95 software available from Thermoteknix Systems Limited, Cambridge, UK.
  • the photothermal contrast agent is preferably added to the material and/or its surroundings in the form of a composition, which comprises a photothermal contrast agent as described above, a liquid medium or low melting point solid medium and optionally one or more additives.
  • the photothermal contrast agent may be fully dissolved in the liquid medium to give a homogeneous solution, or be present as a suspension, dispersion, colloidal suspension or otherwise.
  • Preferred liquid media include water, a mixture of water and an organic solvent and an organic solvent free from water. It is preferred that the organic solvent present in the mixture of water and organic solvent is a water-miscible organic solvent or mixture of such solvents.
  • Preferred water-miscible organic solvents include C ⁇ -6 -alkanols, preferably methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, n-pentanol, cyclopentanol and cyclohexanol; linear amides, preferably dimethylformamide or dimethylacetamide; ketones and ketone-alcohols, preferably acetone, methyl ethyl ketone, cyclohexanone and diacetone alcohol; water-miscible ethers, preferably tetrahydrofuran and dioxane; diols, preferably diols having from 2 to 12 carbon atoms, for example pentane-1 ,5-diol, ethylene glycol, propylene glycol, butylene glycol, pentylene glycol, hexylene glycol and
  • Especially preferred water-soluble organic solvents are alcohols, more especially methanol, ethanol; dimethylsulfoxide; cyclic amides, especially 2-pyrrolidone, N-methyl- pyrrolidone and N-ethyl-pyrrolidone; diols, especially 1 ,5-pentane diol, ethyleneglycol, thiodiglycol, diethyleneglycol and triethyleneglycol; and mono- C 1- -alkyl and C 1-4 -alkyl ethers of diols, more preferably mono- C 1-4 -alkyl ethers of diols having 2 to 12 carbon atoms, especially ((2-methoxy)-2-ethoxy)-2-ethoxyethanol.
  • alcohols more especially methanol, ethanol; dimethylsulfoxide; cyclic amides, especially 2-pyrrolidone, N-methyl- pyrrolidone and N-ethyl-pyrrolidone
  • one or more additives may be present to modify the properties of the composition in some beneficial way, for example to prolong stability or to optimise the performance of the solution/dispersion both before and after contact with the substrate.
  • additives may include one or more of the following types: surfactants to modify surface tension; hydrotroping agents to disaggregate the system and prevent excess moisture loss; co-solvents to improve solubility or prevent excess moisture loss; acids or alkalis to achieve the optimum pH of the composition; buffers to maintain the optimum pH range of the composition; polymers to act as viscosity modifiers; crystal poisoners to prevent crystallisation in dispersions; associative thickeners for dispersion stability; biocides where solutions/dispersions are expected to have a finite shelf life; penetrating solvents; resins to fix the agents (especially the pigmentary materials) to the substrate surface.
  • the composition may be prepared by addition of a photothermal contrast agent in given quantity to a liquid medium in which it is known to dissolve or disperse, followed by stirring for such time until a homogeneous solution or dispersion of known molarity or weight per unit volume is obtained, followed by the addition of such additives as are necessary to maintain the stability and improve the properties of this solution or dispersion.
  • carboxylic acid or sulphonic acid groups occur in water soluble photothermal contrast agents
  • these may be used unmodified or may be converted to alkali metal salts or salts of ammonium or alkylammonium compounds; where amino groups occur these may be used unmodified or may be quaternised and used as acid salts
  • a composition is obtained by the addition of a water soluble photothermal contrast agent as the sodium salt to water at room temperature followed by stirring for five minutes.
  • the photothermal contrast agent is a non-self dispersing pigment
  • a method is described for the optimisation of dosages of medicaments to a subject by use of photothermal contrast agents as described above, which comprises the introduction of one of more photothermal contrast agents to the subject, and wherein a photothermal contrast agent becomes located preferentially at the target area for treatment within the subject, and whereby subsequent irradiation as described above gives rise to an image of the target area which can be monitored with time.
  • the agent may not be retained in the subject for long enough and re-administration may be necessary, or one may need to observe the reaction to addition of medicaments in order to allow the level of such medicaments to be optimised.
  • Figure 1 is a graph showing the change in temperature post flash irradiation of a phthalocyanine (Agent 1) photothermal contrast agent printed onto HP Glossy Photographic Paper.
  • Figure 2 is a graph showing the increase in temperature of a phthalocyanine (Agent 1) photothermal contrast agent printed onto HP Glossy Photographic Paper on constant irradiation and the decay of the temperature increase following the end of the irradiation.
  • Agent 1 a phthalocyanine
  • Test sheets were prepared using the photothermal contrast agents as follows:
  • Example 4 used Agent 4 which was prepared according to EP626427A1 page 6, lines 30-31 and page 7, line 1 to line 30 and using processes as described on page 9, lines 15 to 21 and lines 39 to 55 which are incorporated herein by reference;
  • R 1 SO 3 K
  • D, E C(CH 3 ) 2
  • R 3 -(CH 2 ) 4 SO 3 K
  • R 6 -(CH 2 ) 4 SO 3 K
  • R 8 SO 3 K
  • Example 5 used TinoluxTM BBS (an aluminium chloride phthalocyanine carrying 4 sulpho groups obtained from Ciba Specialty Chemicals, Consumer Care Division);
  • Example 6 used Cab-O-Jet 200 (a sulphonated carbon black available from Cabot
  • Example 7 used Cab-O-Jet IJX 157 (a carboxylated carbon black available from Cabot
  • Solutions of three different concentrations of Agents 1 to 4 and Tinolux BBS in de- ionized water were prepared (1 x 10 "3 M, 1 x 10 "4 M and 1 x 10 "5 M).
  • the two Cab-O-Jet pigments were dispersed in de-ionized water at concentrations of 0.1 , 0.01 and 0.001 weight percent.
  • De-ionized water was used as the control.
  • Test sheets were prepared for each agent by spreading 10 ⁇ l of each concentration and the control evenly over four separate 1cm diameter circles spaced 1cm apart drawn on the top (glossy) surface of a piece of HP Glossy Photographic Paper. The paper allowed to dry for a period of at least 1 hour at room temperature before being used.
  • test sheets were then placed in a three sided verticle holding frame at a distance of 30cm from the lens of a Inframetrics SC1000 camera which is sensitive to light in the 3.4-5 micron range.
  • the sheet was orientated so that the side bearing the photothermal contrast agent was facing away from the camera. This avoids aberrations due to light reflection from the glossy substrate.
  • a Miranda 700CD electronic flash set on a manual setting and at maximum output and fully charged was held at a distance of 5cm from the face of the sheet bearing the photothermal contrast agents. Immediately after a one second burst of light, an image was captured followed by three subsequent images 10, 20 and 30 seconds later.
  • ThermaGRAM® PRO95 software was converted into graphical form using the ThermaGRAM® PRO95 software, by: i) Using the cursor, a circle of 1 cm diameter was drawn over the point on the screen where the first circular image appeared (containing 1x10 "3 M agent). The software could then be used to calculate the average temperature over that area, ii) Data were collected for each circular area on the test sheet including the control for each concentration for the images recorded after 1 , 10, 20 and 30 second intervals following illumination, iii) A graph of temperature versus time was constructed for each separate concentration plus the control.
  • a test sheet was prepared using a series of six different concentrations (1x10 "1 M to 1x10 "6 M) of Agent 1 in de-ionized water with each concentration and the control spread, as described above, over a 1cm diameter circular area on the surface of a sheet of HP Photographic Paper.
  • the control was de-ionized water.
  • the test sheet was illuminated with a 150W xenon bulb with a 850nm short pass filter. The bulb was positioned 3.8cm from the sample. The use of a 850nm short pass filter removes the direct heating effect resulting from longer wavelength incident radiation. Imaging was carried out using an Inframetrics SC1000 camera in a darkened constant temperature (23°C) chamber .
  • a cuvette was half-filled with a hot agar (1% agar) solution and a stainless steel rod 2 mm in diameter was suspended vertically in the agar to a depth of 3 mm. The agar was then allowed to set. The metal rod was removed and a photothermal contrast agent solution was pipetted into the cavity as follows:
  • Example 9 10 ⁇ l of a 10% by weight dispersion of Cab-O-JetTM IJX 157;
  • Example 10 10 - 10 ⁇ l of a 10% by weight dispersion of Cab-O-JetTM 200;
  • Example 11 10 ⁇ l of a 1x10 "1 M solution of Agent 1 ;
  • Example 12 10 ⁇ l of a 1x10 "1 M solution of Agent 4;
  • Example 13 10 ⁇ l of a 1x10 "1 M solution of TinoluxTM BBS;
  • the cavity was then carefully sealed with sufficient molten agar to fill the cavity. This prevents disturbance of the photothermal contrast agent when the cuvette is finally topped up with agar.
  • this agar plug had set (after about 15 minutes) the cuvette was carefully filled with molten agar and this was allowed to set. The top of the cuvette was then sealed with petroleum jelly.
  • the cuvettes containing the samples were irradiated for a total of 30 seconds using a 150W halogen bulb directed onto the cuvette using a 40cm fibre optic light guide. After this period, the light was switched off and a single image of the whole cuvette was recorded.
  • ThermaGRAM® PRO95 software two spot temperatures were measured for each sample, one at the centre of the photothermal contrast agent inclusion ('inclusion temperature' below) and the other in an area which was free of agent (the latter is referred to below as the 'control temperature'). These two measurements could then be used to generate a ⁇ T values by subtraction of the control temperature from the inclusion temperature as before. The data are shown in Table 2. Table 2
  • Table 2 clearly shows the increase in the temperature change of the agar which is achieved by the inclusion of a photothermal contrast agent.

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Abstract

A method for creating and detecting a thermal energy difference betweeen a material and its surroundings which comprises the following steps: (i) adding one or more photothermal contrast agents to the material and/or to its surroundings; (ii) exposing the material and/or its surroundings to an input energy to create a thermal image; and (iii) measuring a change in the temperature of the material and/or its surroundings by means of a thermal image detector. Typically, the photothermal contrast agent comprises a phthalocyanine, cyanine, or carbon black pigment.

Description

IMAGING PROCESS
This invention relates to a method of enhancement of images which result from thermal differences between a subject and its surroundings. The invention also relates to the use of such a method, for example, for the optimisation of dosages of medicaments.
The detection of spatial and time variations of radiated energy from a subject with respect to its surroundings and transforming them to a visual display is a key prerequisite for all aspects of imaging. A particular example, thermal imaging or thermography, is based on variations of radiated heat energy. Thermal imaging using infra-red cameras or other IR detection systems finds application in a wide variety of areas, namely medicine, agriculture, horticulture, manufacturing industries, non-destructive testing of building and engineering constructions and inspection of electrical transmission and distribution systems from a safe distance. In recent years, the technique has become established in the medical field where it is ideally suited to look at heat changes as a consequence of altered blood flow due to infection, injury, disease or circulatory problems. Its appeal is reinforced by the fact that the technique is non-invasive in nature and hence it is relatively convenient to carry out with minimum trauma to the patient. More recently, there has been a move towards thermal imaging on a much smaller scale, looking at the heat generated as a result of cellular metabolism. This forms the basis of a new method of high throughput screening of drug candidates described in WO9960630 which allows the effect of novel active compounds to be quickly assessed by the effect they have on cellular metabolism and subsequent heat output. Thermography has become particularly established in the medical field for the diagnosis of abnormalities in parts of human or animal bodies such as tumour growth, relying on the extra heat produced by areas of rapidly dividing cells and the increased vasculature around the tumour.
Imaging which relies on inherent temperature differences in living tissue or other non-biological subject material is limited in the amount of information that it can ultimately provide. Often the differences in such energy variations between the subject and its surroundings are too small to give sufficient definition or resolution to the resulting image thereby restricting the scope of such a technique. Attempts to overcome these difficulties have involved the administering of agents which will locate themselves in the subject under investigation to directly enhance the inherent temperature difference, for instance chemically induced intracellular hyperthermia described in WO0006143, but the reagents used are restricted to mitochondrial uncoupling agents limiting their use as imaging agents to eukaryotic cell systems. The use of thionin as a stain for cellular material to distinguish the nuclear portion from the cytoplasm by infra-red imaging has also been described (US5168066) but this relies for its activity on the formation of a complex with cellular material such as nucleic acids. Other related techniques which have been used for medical imaging have been equally limited, such as the use of trans-illuminated infra-red radiation described in DE4327798, and the widespread use of infra-red fluorophores such as indocyanine green, as described in US6175759, which have the disadvantage of relatively short lifetime as a result of photodegradation, which results in significant fading.
Surprisingly we have found that difficulties encountered when energy differences are too small to give sufficient detection or resolution can be overcome by the use of agents which respond selectively to incident radiant energy, converting it to a thermal response which can be detected and measured to give an enhanced image. A method has been devised where because of the transparency of the subject to the incident radiation (eg human tissue to near infra-red radiation) unexpected benefits arise from the use of such agents. In contrast to the prior art, imaging experiments can be conducted using polychromatic radiant energy to illuminate the target, and without the need for special conditions or modified surroundings such as an adiabatic chamber. The images so generated can be manipulated and prepared easily using a PC, appropriate software and output device.
According to the present invention there is provided a method for creating and detecting a thermal energy difference between a material and its surroundings which comprises the following steps:
(i) adding one or more photothermal contrast agents to the material and/or to its surroundings;
(ii) exposing the material and/or its surroundings to an input energy to create a thermal image; and
(iii) measuring a change in the temperature of the material and/or its surroundings by means of a thermal image detector.
In further aspects of the invention, the photothermal contrast agent is added to a material only or to the surroundings of a material only. In yet a further aspect, the photothermal contrast agent is added to both the material and its surroundings.
Preferably the use of a photothermal contrast agent in the present invention improves the signal to noise ratio of the thermal image.
Photothermal contrast agents may be selected from a range of structural types, the common feature of which is a strong absorbance of energy within the wavelength range of input energy. In a preferred embodiment, the photothermal contrast agent absorbs in the region 200 to 2000nm. Preferably this range will be from 650 to 1500nm, more preferably from 650 to 1200nm. In a further preferred embodiment, the photothermal contrast agent absorbs in the region 200 to 850nm. Preferably the absorption maximum of the photothermal contrast agent will be at or close to the wavelength of input energy. The photothermal contrast agent preferably comprises a conjugated unsaturated hydrocarbon or a pigment. The conjugated unsaturated hydrocarbon may be selected from the following classes of compound: phthalocyanines, naphthalocyanines, polymethines, squaryliums, croconiums, iminiums, di-iminiums, pyryliums, quinones, azo dyes and their metal complexes, each of which may be optionally substituted.
Preferred phthalocyanines are selected from compounds as shown in Formula 1 in which at least one of the peripheral carbon atoms in the 1-16 positions of the phthalocyanine nucleus (MkPc) is linked either directly or via an oxygen atom or sulphur atom or a nitrogen atom to an organic radical hereinafter referred to as a pendant organic radical, the remaining peripheral carbon atoms being unsubstituted or substituted by any combination of atoms or groups and sulphonated derivatives thereof.
Figure imgf000004_0001
Formula (1) M represents hydrogen, a metal, metal oxide, metal hydroxide, metal halide such as a fluoride, chloride, bromide or iodide; k is the inverse of half the valency of M. Examples of suitable metals include but are not restricted to copper, zinc, cobalt, nickel, iron, vanadium, titanium, iridium, tin, palladium, aluminium; metal oxides include vanadyl, titanyl; metal hydroxides include aluminium, scandium, gallium, rhodium, indium, ruthenium; metal halides include CIAI, CISc, CIRh, CIGa, Clln, Brln, CIRu.
Preferred phthalocyanines are those which absorb electromagnetic radiation at a wavelength from 650nm to 1500nm.
In the phthalocyanines of the present invention each of the pendant organic radicals linked to the phthalocyanine nucleus is independently selected from aromatic, heterocyclic, aliphatic and alicyclic radicals, such that any one phthalocyanine nucleus may carry two or more different organic radicals. It is preferred that each pendant organic radical is independently selected from mono- and bi-cyclic aromatic and aliphatic radicals. Preferred mono- and bi-cyclic aromatic and heterocyclic radicals are ph'enyl, naphthyl, especially naphth-2-yl, phenylene, especially 1 ,2-phenylene, pyridyl, phenoxy, thiophenyl, furanyl, quinolinyl, thiazolyl, benzothiazolyl and pyrimidyl each of which may be substituted.
Where the aromatic radical is 1 ,2-phenylene this is attached to the phthalocyanine nucleus via two atoms independently selected from sulphur, oxygen and nitrogen. These atoms are attached to the adjacent positions of each phenylene radical, and are preferably attached to the phthalocyanine nucleus via the 2- and 3- and/or 6- and
7- and/or the 10- and 11- and/or the 14- and 15-positions or are preferably attached to the phthalocyanine nucleus via the 1- and 2- and/or 3- and 4- and/or 5- and 6- and/or 7- and
8- and/or 9- and 10- and/or 11- and 12- and/or 13- and 14- and/or 15- and 16-positions.
Where the pendant organic radical is an aliphatic or alicyclic radical it is preferred that it is selected from Cι-2o-alkyl, especially C-Mo-alkyl, more especially C1-4-alkyl ; C2-20- alkenyl especially C3-ι0-alkenyl and C4-8-cycloalkyl especially cyclohexyl, each of which may be substituted.
Optional substituents for the pendant organic radicals are preferably selected from C1-20-alkyl, especially C1-4-alkyl; C1-20-alkoxy, especially C-i-4-alkoxy; C2-20-alkenyl, especially C2- -alkenyl; C1-20-alkylthio, especially C1-4-alkylthio; C1-20-alkoxycarbonyl, especially C1-4-alkoxycarbonyl; hydroxyC1-4-alkoxy; aryl, especially phenyl; C1-4-alkylaryl, especially benzyl; arylthio, especially phenylthio and phenoxy; halogen, especially fluoro, chloro and bromo; -CN; -NO2; -CF3; -SO3A in which A is H, or a metal or ammonium ion or substituted ammonium ion; -COR1, -COOR1, -CONR1R2, -SO2R1, -SO2NR1R2, -NR1R2 and -OR1 in which R1 and R2 are independently selected from -H; alkyl, especially C1- -alkyl; aryl, especially phenyl; and C1- -alkylary[, especially benzyl.
A sub-group of phthalocyanines of the present invention has from 8 to 16, optionally from 12 to 16, and optionally all 16 of the peripheral carbon atoms linked preferably via an oxygen or sulphur atom, more preferably by an oxygen atom, to a pendant optionally substituted mono- and/or bi-cyclic aromatic radical and/or aliphatic radical more preferably phenyl and/or naphthyl and/or Cι-10-alkyl radical, most preferably a phenyl radical.
Examples of suitable atoms or groups which can be attached to any of the remaining peripheral carbon atoms of the phthalocyanine nucleus are hydrogen, halogen, sulphonate groups -SO3A in which A is H, or a metal or ammonium ion or a substituted ammonium ion, and any of the pendant organic radicals described above and hereinafter represented by R. It is preferred that the atoms or groups attached to the remaining peripheral carbon atoms are selected from -H, -F, -Cl, -Br, -I, -SO3H, -SO3Na, -SO3K, - SO3Li and -SO3NH4 or any combination thereof. It is especially preferred that these atoms or groups are -H, -Cl, -Br, -SO3H, -SO3Na or -SO3NH4.
The sulphonated derivatives of the phthalocyanines used in the present invention carrying up to 50 SO3A groups, preferably up to 40 SO3A groups, more preferably up to 30 SO3A groups and especially up to 16 SO3A groups, which are attached directly to the phthalocyanine nucleus and/or to the pendant organic radicals are a preferred group of compounds for the present invention.
In a preferred sub-group of compounds the average number of SO3A groups is preferably from 2 to 40 and more preferably from 2 to 30 and especially from 4 to 16. It is also preferred that for each pendant organic radical there is on average at least one SO3A group, although each organic radical may carry none, one or more than one SO3A group.
Where A is a metal ion it is preferably an alkali metal ion such as a sodium, potassium or lithium ion. Where A is an ammonium ion it is preferably NH+ 4 or a substituted ammonium ion which enhances the water-solubility of the compound or a substituted ammonium ion of the formula NQ+ 4 which enhances the alcohol solubility of the compound. Examples of suitable substituted ammonium ions which enhance the water solubility of the compound are mono, di, tri and tetra alkyl and hydroxyalkyl ammonium ions in which the alkyl groups preferably contain from 1 to 4 carbon atoms such as N+(CH3)4; N+(C2H5)4; N+(C2H4OH)4; NH+ 3CH3; NH+ 2(CH3)2 and NH+(CH3)3.
Where the substituted ammonium ion of the formula NQ+ 4 enhances the alcohol solubility of the compound, at least one Q is a fatty aliphatic group and any remaining Q groups are C -4-alkyl or H. The fatty aliphatic group represented by Q preferably contains from 4 to 16, more preferably from 7 to 12 and especially preferably 7 to 9 carbon atoms. Preferred fatty aliphatic groups are alkyl and alkenyl groups which have straight- or branched-chains. Preferred alkyl groups, represented by Q, containing 8 or 9 carbon atoms are, 3,5,5-trimethyl-hexyl, 1 ,1 ,3,3-tetramethylbutyl and 2-ethylhexyl. Examples of other suitable aliphatic chains are 1-ethyl-3-methylpentyl, 1,5-dimethylhexyl, 1-methylheptyl, 1,4-dimethylheptyl, 1 ,2,2-trimethylpropyl, 2-ethylbutyl, 1-propylbutyl, 1 ,2-dimethylbutyl, 2-methylpentyl, 1-ethylpentyl, 1 ,4-dimethylpentyl, 1-methylhexyl, 3-methylhexyl, 1 ,3,3-trimethylbutyl, 1-methylnonyl. The substituted ammonium ion represented by A preferably has one fatty alkyl group as described above, the remaining groups being preferably H or C1-4-alkyl, especially H or methyl. Especially preferred ammonium ions include 2-ethylhexylammonium, 1 ,1,3,3-tetramethylbutylammonium and 3,5,5-trimethylhexylammonium.
Preferred phthalocyanines for use as photothermal contrast agents are compounds of Formula (2): MkPc(X-R)aYb(SO3A)d Formula (2) wherein:
MkPc is a phthalocyanine nucleus as defined in Formula (1); each R independently is an organic radical;
X is O, S, N, Se, Te; each Y independently is halogen or hydrogen;
A is selected from H, a metal, ammonium ion or substituted ammonium ion as described above; a is from 4 to 16; b is from 0 to 12; d is an average value from 0.1 to 30; and a+b is from 4 to 16; the X-R and Y groups being attached to one or more of the 16 peripheral carbon atoms of the phthalocyanine nucleus.
In the phthalocyanine of Formula (2) each of the radicals denoted by R may be selected from any of the pendant organic radicals hereinbefore defined in relation to Formula (1) above.
In the phthalocyanine of Formula (2) each halogen denoted by Y is preferably independently selected from -F, -Cl, -Br and -I more preferably from -Cl or -Br.
When a+b is <16 the remainder of the 16 peripheral carbon atoms, not carrying a group X-R, may carry a sulphonate group -SO3A or a group represented by R. It is however preferred that the sum of a+b is 16. It is also preferred that a is 4, 8, 12 or 16.
In phthalocyanines of Formula (2) the metal ion denoted by A is preferably an alkali or alkaline earth metal ion and more preferably is selected from lithium, sodium and potassium ion. It is especially preferred that A is a sodium or an ammonium ion or hydrogen.
Especially preferred phthalocyanine compounds of the present invention are ZnPc(O-Phenyl)16(SO3Na)i6, H2Pc(O-Phenyl)16(SO3Na)18, CuPc(S-4- Methylphenyl)15(SO3Na)12 .
When the photothermal contrast agent is a cyanine or a polymethine, it is preferably a compound of Formula (A) or a salt thereof:
Figure imgf000008_0001
Formula (A)
wherein
Ra and Rb are independently optionally substituted C1-8alkyl -X1 wherein X1 is H, F, Cl, Br, optionally substituted phenyl, optionally substituted C3-7 cycloalkyl, optionally substituted C1-3alkoxy or CO2A or SO_lk, where A is H, a metal, ammonium ion or substituted ammonium ion;
Z1 and Z2 independently represent the atoms necessary to complete an indole, benzindole or naphthindole nucleus; B is CReRf, O or S
Rc and Rd independently represent methyl, ethyl, methoxy, ethoxy, hydroxy, F, Cl or Br substitutions on Z1 and Z2 , respectively;
Re, Rf each independently represent optionally substituted C1-4alkyl or Re and Rf,when taken together with the carbon atoms to which they are attached may form an optionally substituted 5- or 6-membered cycloalkyl group;
R9 is hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, substituted aryl, F, Cl, or Br, or Q-Rh;
Q is S, O, N;
Rh is optionally substituted aryl, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aralkyl, hydrogen; and n is an integer from 2 to 4.
The compound A typically has a counter ion (anion) associated with it or else may be an internal salt, i.e. having a negative charge located within the molecule to balance the positive.
A preferred cyanine or a polymethine is of Formula (3) or a salt thereof:
Figure imgf000008_0002
Formula (3) wherein:
R1 and R8 each independently is H, NO2, alkyl, aryl, SO2R9, SO3A1, halo, OR9, CO2A1, CO2R9, OCR9, OCOR9, or connected to R2 and R7 respectively in a fused optionally substituted carbocyclic aromatic ring;
R9 is optionally substituted alkyl or optionally substituted aryl; A1 is H or an alkali metal cation;
R2 and R7 each independently is H or connected to R1 and R8 respectively in a fused optionally substituted carbocyclic aromatic ring;and D and E each independently is -S-, -O-, or C(R10)2 and each R10 is independently H or C1-3 alkyl.
R3 and R6 are as defined for Ra and Rb above, especially C1-8 alkyl and C1-8 alkyl-X1 where X1 = CO2A or SO3A.
Optional substituents for R2, R7, R9, Ra, Rb, Re, Rf and Rg are as preferred above for the phthalocyanine organic radical R.
The compound of formula (3) typically has a counter ion (anion) associated with it or else may be an internal salt, i.e. having a negative charge located within the molecule to balance the positive.
When the photothermal contrast agent is a pigment, it is preferably selected from carbon blacks, such as channel black, furnace black, or lamp black, or suitably functionalised carbon blacks, for example by introduction of water-solubilising groups such as -SO3H or -COOH or salts thereof; suitable salts include alkali metal, ammonium or substituted ammonium as described above. Suitable commercially available pigment dispersions include the Hostafine®pigments available from Hoechst Celanese Corporation, including Hostafine®Black T and Hostafine®Black TS; pigment dispersions available from Bayer include Levanyl®Black A-SF; pigment dispersions available from Columbia include Raven® 7000, Raven® 5750, Raven® 5250, Raven® 5000 and Raven® 3500; pigment dispersions available from Degussa Company include Derussol®carbon black pigment dispersions such as Derussol®Z350S, Derussol®VU 25/L, Derussol®345, Derussol ®3450S, Color Black FW 200, Color Black FW 2, Color Black FW 2V Color Black FW 1 , Color Black FW 18, Color Black S160, Color Black FW S170, Special Black 6, Special Black 5, Special black 4A,Special black 4, Printex® 140U, Printex® U, Printex® V and Printex® 140V; pigment dispersions available form BASF Corporation include Novofil® Black and Disperse Black 006607; pigment dispersions from Sun Chemical Corporation include Sunsperse® 9303; pigment dispersions available from DuPont include Tipure® R-101 ; chemically modified, self-dispersing pigments, including the water dispersible materials for use in ink jet printing, are available from the Cabot Company such as the Cab-O-Jet®series, eg Cab-O-Jet 300 and Cab-O-Jet 200, and Cabot IJX®series and the like which include those carbon blacks comprising carboxylic acid salts (anionic), sulphonate salts (anionic) and ammonium salts (cationic). Other pigments available from Cabot® include Monarch® 1400, Monarch® 1300, Monarch® 1100, Monarch® 1000, Monarch® 900, Monarch® 880, Monarch® 800 and Monarch® 700.
The pigment particle size may be between 0.0005 and 15 microns. Preferred pigment particle sizes are generally from about 0.001 to about 5 microns, and more preferably from about 0.001 to about 3 microns, and most preferably from about 0.001 to about 1.2 microns.
The photothermal contrast agent may be used in solid form, in solution or, in the case of pigments, as a dispersion, or vapourised or atomised to form an aerosol, and when administered will locate itself substantially at the target site or sites for imaging. Such location may occur by a natural affinity of the photothermal contrast agent for the particular target site, or may be achieved by a targeted imaging process where a carrier is used, which may comprise vectors such as antibodies or other similar systems or the photothermal contrast agent may be directly placed in the target area . Alternatively location may occur by restricting the mobility of the photothermal contrast agent such that it remains substantially in the target area, for example by controlling the inherent solubility, pH or lipid/water partition of the photothermal contrast agent.
In a further embodiment of the invention, the photothermal contrast agent comprises a substance which associates specifically with another corresponding substance which is located only in the target area to form a conjugate which demonstrates enhanced absorption of radiation.
The material may comprise any part of: a human or animal body, a plant or other vegetation, a building or engineering construction, a motor vehicle and applications in aviation transport or substrates such as paper, including rag paper, printer quality paper, currency grade paper, plastics-coated or laminated paper or other substrates typically used as documents or packaging.
The input energy is preferably a radiation source of preferably electronic energy of wavelength between 200 and 2000 nm, most preferably of wavelength between 650 and 1000 nm and desirably of a wavelength substantially equal to the absorption maximum of the photothermal contrast agent. Typical irradiation sources range from a simple halogen bulb, which has an emission spectrum substantially, that is, at least 20%, in the near infra- red (above 700nm) and can be filtered if necessary, through to Light Emitting Diodes (LEDs) and ultimately to infrared semiconductor lasers, available at a range of wavelengths such as 785, 805, 940 and 980 nm for example. Illumination times may be selected appropriately to give optimum imaging, preferably less than 30 seconds, most preferably flash imaging (short bursts of light of approximate duration up to 1 second) in order to avoid direct heating of the subject which results in a lower signal-to-noise ratio.
The thermal image detector is any device able to detect a thermal energy difference between or within a material and/or its surroundings. The thermal image detector may also be any device able to provide data from which a temperature change may be determined and is preferably a thermal imaging camera such as, for example, a ThermaCAM® SC1000 camera, available from FLIR Systems, Boston, USA. The thermal imaging camera preferably comprises a charge couple device (CCD) which is sensitive to light of wavelength preferably between 1.5 and 15 microns, most preferably between 3.4 and 5 microns. Image manipulation and data handling are achieved using appropriate computer software such as Thermagram® PRO95 software available from Thermoteknix Systems Limited, Cambridge, UK.
The photothermal contrast agent is preferably added to the material and/or its surroundings in the form of a composition, which comprises a photothermal contrast agent as described above, a liquid medium or low melting point solid medium and optionally one or more additives. The photothermal contrast agent may be fully dissolved in the liquid medium to give a homogeneous solution, or be present as a suspension, dispersion, colloidal suspension or otherwise. Preferred liquid media include water, a mixture of water and an organic solvent and an organic solvent free from water. It is preferred that the organic solvent present in the mixture of water and organic solvent is a water-miscible organic solvent or mixture of such solvents. Preferred water-miscible organic solvents include Cι-6-alkanols, preferably methanol, ethanol, n-propanol, isopropanol, n-butanol, sec-butanol, tert-butanol, n-pentanol, cyclopentanol and cyclohexanol; linear amides, preferably dimethylformamide or dimethylacetamide; ketones and ketone-alcohols, preferably acetone, methyl ethyl ketone, cyclohexanone and diacetone alcohol; water-miscible ethers, preferably tetrahydrofuran and dioxane; diols, preferably diols having from 2 to 12 carbon atoms, for example pentane-1 ,5-diol, ethylene glycol, propylene glycol, butylene glycol, pentylene glycol, hexylene glycol and thiodiglycol and oligo- and poly-alkyleneglycols, preferably diethylene glycol, triethylene glycol, polyethylene glycol and polypropylene glycol; triols, preferably glycerol and 1,2,6-hexanetriol;
Figure imgf000011_0001
alkyl ethers of diols, preferably mono-C1-4-alkyl ethers of diols having 2 to 12 carbon atoms, especially 2-methoxyethanoI, 2-(2-methoxyethoxy)ethanol, 2-(2-ethoxyethoxy)-ethanol, 2-[2- (2-methoxyethoxy)ethoxy]ethanol, 2-[2-(2-ethoxyethoxy)-ethoxy]-ethanol and ethyleneglycol monoallylether; cyclic amides, preferably 2-pyrrolidone, N-methyl-2-pyrrolidone, N-ethyl-2- pyrrolidone, caprolactam and 1 ,3-dimethylimidazolidinone; cyclic esters, preferably caprolactone; sulphoxides, preferably dimethyl sulphoxide and sulpholane.
Especially preferred water-soluble organic solvents are alcohols, more especially methanol, ethanol; dimethylsulfoxide; cyclic amides, especially 2-pyrrolidone, N-methyl- pyrrolidone and N-ethyl-pyrrolidone; diols, especially 1 ,5-pentane diol, ethyleneglycol, thiodiglycol, diethyleneglycol and triethyleneglycol; and mono- C1- -alkyl and C1-4-alkyl ethers of diols, more preferably mono- C1-4-alkyl ethers of diols having 2 to 12 carbon atoms, especially ((2-methoxy)-2-ethoxy)-2-ethoxyethanol.
Optionally one or more additives may be present to modify the properties of the composition in some beneficial way, for example to prolong stability or to optimise the performance of the solution/dispersion both before and after contact with the substrate. Such additives may include one or more of the following types: surfactants to modify surface tension; hydrotroping agents to disaggregate the system and prevent excess moisture loss; co-solvents to improve solubility or prevent excess moisture loss; acids or alkalis to achieve the optimum pH of the composition; buffers to maintain the optimum pH range of the composition; polymers to act as viscosity modifiers; crystal poisoners to prevent crystallisation in dispersions; associative thickeners for dispersion stability; biocides where solutions/dispersions are expected to have a finite shelf life; penetrating solvents; resins to fix the agents (especially the pigmentary materials) to the substrate surface. The composition may be prepared by addition of a photothermal contrast agent in given quantity to a liquid medium in which it is known to dissolve or disperse, followed by stirring for such time until a homogeneous solution or dispersion of known molarity or weight per unit volume is obtained, followed by the addition of such additives as are necessary to maintain the stability and improve the properties of this solution or dispersion. For example, where carboxylic acid or sulphonic acid groups occur in water soluble photothermal contrast agents, these may be used unmodified or may be converted to alkali metal salts or salts of ammonium or alkylammonium compounds; where amino groups occur these may be used unmodified or may be quaternised and used as acid salts Alternately a composition is obtained by the addition of a water soluble photothermal contrast agent as the sodium salt to water at room temperature followed by stirring for five minutes. Where the photothermal contrast agent is a non-self dispersing pigment, it is necessary to add the correct proportion of a dispersing agent that may be non-ionic, anionic or cationic, and this would normally be done during pigment milling although additional dispersing agent may be added to the final composition for stability. In a second aspect of the invention a method is described for the optimisation of dosages of medicaments to a subject by use of photothermal contrast agents as described above, which comprises the introduction of one of more photothermal contrast agents to the subject, and wherein a photothermal contrast agent becomes located preferentially at the target area for treatment within the subject, and whereby subsequent irradiation as described above gives rise to an image of the target area which can be monitored with time. For example the agent may not be retained in the subject for long enough and re-administration may be necessary, or one may need to observe the reaction to addition of medicaments in order to allow the level of such medicaments to be optimised.
The invention will now be illustrated by way of example and with reference to the accompanying drawings in which:
Figure 1 is a graph showing the change in temperature post flash irradiation of a phthalocyanine (Agent 1) photothermal contrast agent printed onto HP Glossy Photographic Paper.
Figure 2 is a graph showing the increase in temperature of a phthalocyanine (Agent 1) photothermal contrast agent printed onto HP Glossy Photographic Paper on constant irradiation and the decay of the temperature increase following the end of the irradiation.
Examples 1 to 7 Surface imaging on paper
Test sheets were prepared using the photothermal contrast agents as follows:
Examples 1-3 used Agents 1-3 respectively
MkPc(X-R1)a (X-R2)b (X-R3)c (X-R4)d Ye
Agent 1: M = Cu ; X = S ; R1 1 = —
Figure imgf000013_0001
R2 = Y = H ; k = 1 ; A = Na; a
12; b = 3; c = 0; d = 0; e = 1
Agent 2: M = H; X = O; R1 = ^ °-* ; R2 = \=/ ; R3 is disodium disulphophenyl; R4 = Ph; Y = X-R4 ; k = 2 ; A = Na; a = 8; b = 2; c = 4; d = 1 ; e = 1 Agent 3: M = Zn; X = O; R1 = °→ ; R2 = ; R3 is disodium disulphophenyl ; R4= Ph; Y = X-R4 ; k = 1 ; A = Na; a = 8; b = 4; c = 2; d = 1 ; e = 1 Agent 1 may be prepared as described in EP 155780, Agents 2 and 3 may be made as described in GB2260996.
Example 4 used Agent 4 which was prepared according to EP626427A1 page 6, lines 30-31 and page 7, line 1 to line 30 and using processes as described on page 9, lines 15 to 21 and lines 39 to 55 which are incorporated herein by reference;
Figure imgf000014_0001
R1 = SO3K; D, E = C(CH3)2; R3 = -(CH2)4SO3K ; R6 = -(CH2)4SO3K; R8 = SO3K;
Example 5 used Tinolux™ BBS (an aluminium chloride phthalocyanine carrying 4 sulpho groups obtained from Ciba Specialty Chemicals, Consumer Care Division);
Example 6 used Cab-O-Jet 200 (a sulphonated carbon black available from Cabot
Corporation); and
Example 7 used Cab-O-Jet IJX 157 (a carboxylated carbon black available from Cabot
Corporation).
Solutions of three different concentrations of Agents 1 to 4 and Tinolux BBS in de- ionized water were prepared (1 x 10"3M, 1 x 10"4M and 1 x 10"5M). The two Cab-O-Jet pigments were dispersed in de-ionized water at concentrations of 0.1 , 0.01 and 0.001 weight percent. De-ionized water was used as the control. Test sheets were prepared for each agent by spreading 10μl of each concentration and the control evenly over four separate 1cm diameter circles spaced 1cm apart drawn on the top (glossy) surface of a piece of HP Glossy Photographic Paper. The paper allowed to dry for a period of at least 1 hour at room temperature before being used.
The test sheets were then placed in a three sided verticle holding frame at a distance of 30cm from the lens of a Inframetrics SC1000 camera which is sensitive to light in the 3.4-5 micron range. The sheet was orientated so that the side bearing the photothermal contrast agent was facing away from the camera. This avoids aberrations due to light reflection from the glossy substrate. A Miranda 700CD electronic flash set on a manual setting and at maximum output and fully charged was held at a distance of 5cm from the face of the sheet bearing the photothermal contrast agents. Immediately after a one second burst of light, an image was captured followed by three subsequent images 10, 20 and 30 seconds later.
Initial ΔT values were obtained by taking the average temperature (calculated by the software) over the 1 cm circular areas containing the photothermal contrast agent and subtracting the average temperature over the same sized area containing the control on the same test sample sheet. ΔT values obtained immediately after illumination of each of the test samples are shown in Table 1.
Table 1
Figure imgf000015_0001
The data generated were converted into graphical form using the ThermaGRAM® PRO95 software, by: i) Using the cursor, a circle of 1 cm diameter was drawn over the point on the screen where the first circular image appeared (containing 1x10"3M agent). The software could then be used to calculate the average temperature over that area, ii) Data were collected for each circular area on the test sheet including the control for each concentration for the images recorded after 1 , 10, 20 and 30 second intervals following illumination, iii) A graph of temperature versus time was constructed for each separate concentration plus the control.
The graphical results obtained with Agent 1 are shown in Figure 1 and they show the increase in temperature post illumination of the test sheet and the decay of this increase over the next 30 seconds.
Example 8 Prolonged Surface Imaging
A test sheet was prepared using a series of six different concentrations (1x10"1M to 1x10"6M) of Agent 1 in de-ionized water with each concentration and the control spread, as described above, over a 1cm diameter circular area on the surface of a sheet of HP Photographic Paper. The control was de-ionized water. The test sheet was illuminated with a 150W xenon bulb with a 850nm short pass filter. The bulb was positioned 3.8cm from the sample. The use of a 850nm short pass filter removes the direct heating effect resulting from longer wavelength incident radiation. Imaging was carried out using an Inframetrics SC1000 camera in a darkened constant temperature (23°C) chamber . After each set of measurements on a single circle, the system was allowed to re-equilibrate to the original chamber temperature. Data were collected for each individual circle in sequence as follows: i) An image of the circle was recorded before illumination. ii) The light source was switched on. iii) Images were recorded automatically every 10 seconds for a total duration of 90 seconds. iv) The light source was switched off. v) Image collection was continued every 10 seconds for a further 60 seconds.
The data were analysed as described above. The results are depicted graphically in Figure 2 and show that under the experimental conditions used, all the illuminated areas increased in temperature until a steady state was reached. After switching off the illumination, a normal thermal decay pattern ensues until the sample reaches ambient temperature.
Examples 9 to 13 Subsurface Imaging
A cuvette was half-filled with a hot agar (1% agar) solution and a stainless steel rod 2 mm in diameter was suspended vertically in the agar to a depth of 3 mm. The agar was then allowed to set. The metal rod was removed and a photothermal contrast agent solution was pipetted into the cavity as follows:
Example 9 - 10μl of a 10% by weight dispersion of Cab-O-Jet™ IJX 157;
Example 10 - 10μl of a 10% by weight dispersion of Cab-O-Jet™ 200;
Example 11 - 10μl of a 1x10"1M solution of Agent 1 ;
Example 12 - 10μl of a 1x10"1M solution of Agent 4;
Example 13 - 10μl of a 1x10"1M solution of Tinolux™ BBS;
The cavity was then carefully sealed with sufficient molten agar to fill the cavity. This prevents disturbance of the photothermal contrast agent when the cuvette is finally topped up with agar. When this agar plug had set (after about 15 minutes) the cuvette was carefully filled with molten agar and this was allowed to set. The top of the cuvette was then sealed with petroleum jelly.
The cuvettes containing the samples were irradiated for a total of 30 seconds using a 150W halogen bulb directed onto the cuvette using a 40cm fibre optic light guide. After this period, the light was switched off and a single image of the whole cuvette was recorded. Using the ThermaGRAM® PRO95 software, two spot temperatures were measured for each sample, one at the centre of the photothermal contrast agent inclusion ('inclusion temperature' below) and the other in an area which was free of agent (the latter is referred to below as the 'control temperature'). These two measurements could then be used to generate a ΔT values by subtraction of the control temperature from the inclusion temperature as before. The data are shown in Table 2. Table 2
Figure imgf000018_0001
Table 2 clearly shows the increase in the temperature change of the agar which is achieved by the inclusion of a photothermal contrast agent.

Claims

Claims
1. A method for creating and detecting a thermal energy difference between a material and its surroundings which comprises the following steps:
(i) adding one or more photothermal contrast agents to the material and/or to its surroundings;
(ii) exposing the material and/or its surroundings to an input energy to create a thermal image; and
(iii) measuring a change in the temperature of the material and/or its surroundings by means of a thermal image detector.
2. A method according to claim 1 where the photothermal contrast agent improves the signal to noise ratio of the thermal image.
3. A method according to either claims 1 or claim 2 where the photothermal contrast agent has an absorption in the region 200 to 2000nm.
4 A method according to any one of claims 1 to 3 where the photothermal contrast agent has an absorption in the region 650 to 1500nm.
5. A method according to any one of claims 1 to 4 where the photothermal contrast agent has an absorption in the region 650 to 1200nm.
6. A method according to any one of Claims 1 to 5 where the photothermal contrast agent comprises a conjugated unsaturated hydrocarbon.
7. A method according to claim 6 where the photothermal contrast agent is selected from the following classes of conjugated unsaturated hydrocarbon compound: phthalocyanines, naphthalocyanines, polymethines, squaryliums, croconiums, iminiums, di-iminiums, pyryliums, quinones, azo dyes and their metal complexes.
8. A method according to either claim 6 or claim 7 where the photothermal contrast agent is a phthalocyanine.
9. A method according to claim 8 where the photothermal contrast agent is of Formula (2): MkPc(X-R)aYb(SO3A)d Formula (2) wherein:
MkPc is a phthalocyanine nucleus as defined in Formula (1); each R independently is an organic radical; X is O, S, N, Se, Te; each Y independently is halogen or hydrogen;
A is selected from H, a metal, ammonium ion or substituted ammonium ion as described above; a is from 4 to 16; b is from 0 to 12; d is an average value from 0.1 to 30; and a+b is from 4 to 16; the X-R and Y groups being attached to one or more of the 16 peripheral carbon atoms of the phthalocyanine nucleus.
10. A method according to either claim 6 or claim 7 where the photothermal contrast agent is a cyanine or a polymethine.
11. A method according to claim 10 where the photothermal contrast agent is of Formula (3) or a salt thereof :
Figure imgf000020_0001
Formula (3) wherein:
R1 and R8 each independently is H, NO2, alkyl, aryl, SO2R9, SO3A1, halo, OR9, CO2A1, CO2R9, OCR9, OCOR9, or connected to R2 and R7 respectively in a fused optionally substituted carbocyclic aromatic ring;
R9 is optionally substituted alkyl or optionally substituted aryl; A1 is H or an alkali metal cation;
R2 and R7 each independently is H or connected to R1 and R8 respectively in a fused optionally substituted carbocyclic aromatic ring;
R3 and R6 are independently optionally substituted C1-8alkyl -X1 wherein X1 is H, F, Cl, Br, optionally substituted phenyl, optionally substituted C3.7 cycloalkyl, optionally substituted C1-3alkoxy or CO2A or SO3A, where A is H, a metal, ammonium ion or substituted ammonium ion; and
D and E each independently is -S-, -O-, or C(R10)2 and each R10 independently is H or C1-3 alkyl.
12. A method according to any one of claims 1 to 5 where the photothermal contrast agent comprises a pigment.
13. A method according to claim 12 where the pigment is carbon black, optionally functionalised.
14. A method according to any one of claims 1 to 13 wherein the material comprises any part of: a human or animal body, a plant or other vegetation or composition containing an extract thereof, a building or engineering construction, aviation or motor vehicle or substrates such as paper, including rag paper, printer quality paper, currency grade paper, plastics-coated or laminated paper or other substrates typically used as documents or packaging.
15. A method according to any one of claims 1 to 14 where the thermal image detector is a thermal imaging camera.
16. A method according to claim 15 where the thermal imaging camera comprises a charge couple device (CCD).
17. A method according to claim 16 where the CCD is sensitive to light of wavelength between 1.5 and 15 microns.
18. A method according to either claim 16 or claim 17 where the CCD is sensitive to light of wavelength between 3.4 and 5 microns.
19. A method for the optimisation of administered dosages of medicaments by use of photothermal contrast agents according to any of Claims 1 to 18 which comprises the introduction of one of more photothermal contrast agents to the subject, wherein a photothermal contrast agent becomes located preferentially at the target area for treatment within the subject, and whereby subsequent irradiation as described above gives rise to an image of the target area which can be monitored with time to observe the reaction to addition of medicaments, for example, where the agent may not be retained in the subject for long enough and re-administration may be necessary, or where the reaction to addition of medicaments needs to be observed in order to allow the level of such medicaments to be optimised.
PCT/GB2002/003782 2001-09-08 2002-08-15 Thermographic metthod WO2003023341A2 (en)

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WO2013186735A2 (en) * 2012-06-14 2013-12-19 Bar-Ilan Research And Development Company Ltd. Photothermal detection
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CN112419184A (en) * 2020-11-19 2021-02-26 重庆邮电大学 Spatial attention map image denoising method integrating local information and global information

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