WO1995029180A1 - Porphocyanine and cnc-expanded porphyrins - Google Patents
Porphocyanine and cnc-expanded porphyrins Download PDFInfo
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- WO1995029180A1 WO1995029180A1 PCT/CA1995/000242 CA9500242W WO9529180A1 WO 1995029180 A1 WO1995029180 A1 WO 1995029180A1 CA 9500242 W CA9500242 W CA 9500242W WO 9529180 A1 WO9529180 A1 WO 9529180A1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
- A61K51/0485—Porphyrins, texaphyrins wherein the nitrogen atoms forming the central ring system complex the radioactive metal
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
- A61K41/0057—Photodynamic therapy with a photosensitizer, i.e. agent able to produce reactive oxygen species upon exposure to light or radiation, e.g. UV or visible light; photocleavage of nucleic acids with an agent
- A61K41/0076—PDT with expanded (metallo)porphyrins, i.e. having more than 20 ring atoms, e.g. texaphyrins, sapphyrins, hexaphyrins, pentaphyrins, porphocyanines
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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
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/002—Heterocyclic compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/004—Acyclic, carbocyclic or heterocyclic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen, sulfur, selenium or tellurium
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
Definitions
- the invention relates to CNC-expanded porphyrins, such as the porphocyanines, to methods for their preparation and the use of these compounds to mediate the detection or destruction of target cells or tissues by light irradiation.
- the invention relates to the use of the compounds of the invention in radioimaging and magnetic resonance imaging methods.
- the uranyl complex of superphthalocyanine is another pentapyrrolic macrocyclic compound of historical importance. This compound was prepared by direct template condensation of dicyanobenzene with uranyl dichloride, however, the free base is unstable (Day et al. J Am Chem Soc (1975) .97:4519) . Demetalation resulted in contraction of the ring to form phthalocyanine (Marks, T.J. and D.R. Stojakovic J Am Chem Soc (1978) UQJ2.:1695) .
- Vinylogous porphyrins or platyrins are another important class of pyrrole-containing macrocycles first described by R.A. Berger and E. LeGoff (Tetra Lett (1978) 44.:4225; see also, LeGoff, E. and O.G. Weaver J Orq Chem (1977) 52:711; and Franck et al . Proc SPIE Int Soc Opt Enq, Ser 5 (1988) 997:107) . These compounds are generally synthesized by reacting a dipyrromethane with an acrylaldehyde-substituted dipyrromethane (Beckman et al . Anqew Chem Int Ed Enql (1990) 29:1395) .
- Tetravinylogous porphyrins were further expanded to tetravinylogous porphyrins in which all four of the meso bridges are enlarged.
- Tetravinylogous porphyrins are made by an acid-catalyzed self-condensation of the N-protected, pyrrole-substituted allyl alcohol.
- Tetravinylogous porphyrins have a very intense Soret-like band shift of more than 150 nm from that of the normal porphyrins (Gosmann, M. and B. Franck Anqew Chem Int Ed Enql (1986) 25:1100; Kn ⁇ bel, G. and B.
- Texaphyrins are synthesized by acid-catalyzed condensation of tripyrrane dialdehyde with o-phenylenediamine.
- Several texaphyrins have been prepared using similar strategies (Sessler et al . (1991) Abstract of the 201st Natl Soc Mtg, Inorganic Division; Sessler et al . Inorg Chem (1992) 28:529) .
- porphyrins combined with irradiation, for the detection and treatment of malignant cells has, by this time, some considerable history.
- Porphyrins such as hematoporphyrin, monohydrobenzoporphyrin derivatives (BPDs) and porfimer sodium have been conjugated to immunoglobulins specific for targeted cells to refine their ability to home to the desired cells or tissue.
- BPDs monohydrobenzoporphyrin derivatives
- porfimer sodium have been conjugated to immunoglobulins specific for targeted cells to refine their ability to home to the desired cells or tissue.
- One problem ancillary to the practice of photodynamic therapy is that the wavelength for irradiation required to activate certain porphyrins is in the range of 630 nm, which wavelength is also readily absorbed by other porphyrins and natural chromophores normally present in the blood and other tissues. Therefore, the depth of the effective treatment has been limited to a few millimeters because of blocking effects of light-absorbing natural chromophores such as hemoglobin. When greater penetration is desired it is desirable to administer compounds to mediate the effects of irradiation
- MRI magnetic resonance imaging
- MRI magnetic resonance imaging
- MRI is a noninvasive, nonionizing method that allows normal and abnormal tissue to be observed and recognized at the early stages of development.
- MRI has a significant drawback, in that the degree of signal enhancement for diseased versus normal tissues is often insufficient to allow this method to be used in many clinical situations.
- contrast reagents for MRI have been developed.
- Paramagnetic metal complexes, such as those derived from gadolinium(III) (Gd) have recently proven particularly efficient in clinical trials.
- the invention provides novel light-absorbing compounds suitable for use in detecting and/or treating target tissues, cells and pathogens.
- the compounds of the invention can be utilized in photodynamic therapy and in diagnosis in a manner analogous to that in which the porphyrins, phthalocyanines, BPDs, and related compounds can be used.
- the invention compounds may be administered in relatively low dosage due to their ability to absorb radiation in an energy range outside of that normally absorbed by the components present in high concentration in blood or other tissues, in particular the porphyrin residues normally associated with hemoglobin and myoglobin. This is advantageous when penetration of tissues by light is required. In some instances, where superficial treatment is sufficient, shorter wavelengths can be used.
- the invention is directed to CNC- expanded porphyrins of the formula
- n l-4; wherein each P> is independently a pyrrole residue of the formula
- each R ⁇ and R ib is independently a noninterfering substituent, and wherein each Zj is independently a covalent bond; or is a meso bridging group of the formula
- each R 1C , R id , R ic , R if and R lg is independently a noninterfering substituent; or is a CNC linkage of the formula
- At least one Zj is said CNC linkage.
- at least one Z ⁇ is said CNC linkage.
- the compounds of the invention also include the metalated forms and the salts of the compound of formula (1) .
- the invention is directed to pharmaceutical and diagnostic compositions containing the compounds of the invention, to conjugates wherein the invention compounds are covalently linked with specific targeting agents, such as immunoglobulins, and to the use of these compounds or conjugates in photodynamic therapy and diagnosis.
- the invention is directed to forms of the invention compounds suitable for use as radioimaging and magnetic resonance imaging contrast agents, as well as methods of using these. Another aspect relates to synthesis of the invention compounds.
- Figure 1 shows the emission spectrum of octaethylporphocyanine in the free-base form.
- Figure 2 shows the emission spectrum of octaethylporphocyanine in the acid-addition-salt form.
- FIG. 3 shows some preferred embodiments of the invention compounds.
- CNC-expanded porphyrins contain at least 3 pyrrole nuclei linked through covalent bonds, or through optionally substituted conventional meso linkages found natively in porphyrins, or through N-meso linkages, or through optionally substituted CC linkages as found in the phorphacenes or through optionally substituted CNCCNC linkages analogous to the o-phenylene diamine linkages found in the texaphins, or by CNC linkages, but wherein at least one linkage is a CNC linkage of the formula
- R substituents are those which do not interfere with the basic porphocyanine nucleus in its ability to absorb light of appropriate wavelengths and to achieve at least one desired effect, such as mediating the destruction of target tissues and cells in a photodynamic therapy context, serving as an MRI contrast agent, and the like.
- suitable R substituents which will not interfere is further discussed below.
- substituents may be employed without interfering with the usefulness of these compounds.
- the appropriate choice of these noninterfering substituents will depend on the specific intended use. For example, if intended for in vivo use, the substituents must be nontoxic. When employed in vi tro, especially if the possibility for removal of the compounds of the invention from the appropriately treated material is available, this may not be of concern.
- Those or ordinary skill will understand the parameters that constrain the choice of each R t .
- formula (1) can be represented by ⁇ Z wherein each P; and Z x is as above defined.
- At least one bridge between the four pyrrole nuclei must be a CNC linkage.
- the linkage may be a covalent bond or the conventional meso single-atom methine linkage optionally substituted by R ic , or the other linkages described above.
- the resultant arrangement of 7r-bonds in the CNC porphyrins of the invention will be dependent on the choice of linkage, as is understood by those of ordinary skill in organic chemistry. For example, replacing an odd number of meso linkages with CNC converts an aromatic system to a nonaromatic, albeit stable one; replacement of an even number retains aromaticity.
- each R is independently H, halo, nitro, cyano, NR' 2 , SR' , OR', SOR' , S0 2 R' , COOR' , CONR' 2 , optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, or optionally substituted arylalkyl.
- the substituent R' denotes hydrogen or alkyl (1-6C) .
- Amino, sulfhydryl and hydroxyl substituents may also be acylated (1-6C) .
- Suitable substituents for said optional substitutions include those named above, i.e., halo, nitro, cyano, NR' 2 , SR' , OR', and the like.
- aromatic nuclei may also be substituted by alkyl, alkenyl or alkynyl groups.
- alkyl, alkenyl and alkynyl are defined conventionally as hydrocarbyl substituents containing 1-6C, are either saturated or unsaturated, and are straight-chain, branched or cyclic moieties.
- alkyl would include methyl, tertiary butyl, cyclohexyl, n-hexyl and the like; alkenyl would include these carbon backbones with one or more double bonds; and alkynyl would include similar carbon frameworks with one or more triple bonds.
- Arylalkyl (5-18C) refers to an aryl substituent linked to the CNC-expanded porphyrin nucleus through an alkylene group, where alkylene is defined in a manner corresponding to the definition of alkyl (1-6C) .
- aryl is meant an aromatic moiety of 4-12C, optionally containing one or more heteroatoms.
- suitable aryl groups include phenyl, naphthyl, pyridyl, pyrimidyl, quinolyl, and the like.
- Salts of -COOH can be derived from inorganic or organic bases, including pharmaceutically acceptable nontoxic inorganic and organic bases.
- suitable inorganic bases include sodium, potassium, lithium, ammonium, calcium, and magnesium, hydroxides, and the like. Particularly preferred are the potassium and sodium salts.
- Pharmaceutically acceptable organic nontoxic bases include primary, secondary, tertiary and quaternary amines including cyclic amines, and basic ion- exchange resins.
- Examples include isopropylamine, trimethylamine, ethanolamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, glucosamine, theobromine, purines, piperazine, polyamine resins, and the like.
- any amino groups contained in the substituents may also be present in the form of their acid-addition salts.
- the CNC-expanded porphyrin nucleus itself may be present in the form of an acid-addition salt.
- These salts are formed from inorganic acids such as hydrochloric, sulfuric and phosphoric acid or with organic acids such as acetic, oxalic, benzoic acid and the like.
- R ⁇ and R ib include hydrogen, optionally substituted alkyl, optionally substituted aryl and optionally substituted arylalkyl.
- a particularly preferred substituent is carboxyl. Most preferred are hydrogen and alkyl.
- symmetries in the choice of these substituents facilitate the preparation of the compounds since the number of components in the resulting product mixture is reduced. While chromatographic separation techniques are adequate to permit an arbitrary number of components to be separated from the product mixture, yields are increased when the number of possible products is reduced.
- R h are the same and all R ib are the same, especially where all R ⁇ and R ib are the same.
- R la , R lb , R 4a and R 4b are the same and wherein R ⁇ , R 2b , R 3a and R 3b are the same as each other although different from R la , R lb , R 4a , and R 4b .
- Rj C - j g include H and optionally substituted aromatic (aryl) substituents.
- Particularly preferred embodiments of R ic are H and optionally substituted phenyl.
- Z is CNC
- Z 2 is meso wherein R 2c is H, Z 3 is a covalent bond, R la and R 2b are H, and R lb , R 2a , R 3a and R 3b are methyl;
- Zj is CNC
- Z 2 is meso wherein R 2c is phenyl
- Z 3 is a covalent bond
- R la , R 2a , R 3a and R 3b are (CH 2 ) 2 COOH
- R lb is methyl and 3 .
- Z, is CNC
- Z 2 is CNCCNC wherein R 2f and R 2g are H
- Z 3 is CC wherein R 3d and R 3e are H
- R la and R 2b are H
- R lb R 2a , R 3a and R 3b are methyl ;
- Z is CNC
- Z 2 is CNCCNC wherein R 2f and R 2g are phenyl
- Z 3 is CC wherein R 3d and R 3e are phenyl
- R la , R 2a , R 3a and R 3b are ( CH 2 ) 2 COOH
- R lb is methyl and R 2b is H
- R 2b is H
- Z is CNC
- Z 2 is CNCCNC wherein R 2f is phenyl and R 2g is H
- Z 3 a CC linkage wherein R 3d is phenyl and R 3e is H and wherein R la , R 2a and R 3a are phenyl and R Ib , R 2b and R 3b are H .
- Z j is CNC, Z 2 is N-2i?eso, Z 3 is meso wherein R 3c is methyl , and Z 4 is CNC and wherein R la and R 2b are H and R lb , R 2a , R 3a , R 3b , R 4a and R 4b are methyl ; 2 .
- Zi is CNC, Z 2 is N-meso, Z 3 is meso wherein R 3c is phenyl and Z 4 is CNC and wherein R la , R 2a , R 3a , R 3b and R 4a are (CH 2 ) 2 COOH and R lb , R 2b and R 4b are H;
- Z is CNC
- Z 2 is N- ⁇ ieso
- Z 3 is meso wherein R 3c is H
- Z 4 is CNC and wherein R Ja , R 2a , R 3a and R 4a are phenyl and R lb , R 2b , R 3b and R 4b are ethyl ;
- Z is CNC
- Z 2 is CNCCNC wherein R 2f and R 2g are both phenyl
- Z 3 is a CC linkage wherein R 3d and R 3e are H
- Z 4 is a covalent bond and wherein R la and R 2b are H and R lb , R 2a , R 3a , R 3b , R 4a and R 4b are methyl ; 5 .
- Z j is CNC
- Z 2 is CNCCNC wherein R 2f and R 2g are H, or
- Z 3 is a CC linkage wherein R 3d is ethyl and R 3e is H, and Z 4 is meso wherein R ⁇ is ethyl and wherein R la , R ⁇ , R 3a , R 3b and R 4a are (CH 2 ) 2 COOH and R lb , R 2b and R 4b are H;
- Z is CNC
- Z 2 is CNCCNC wherein R 2f is ethyl and R 2g is H
- Z 3 is meso wherein R 3c is phenyl and Z 4 is a CC linkage wherein R 3d and R 3e are methyl and wherein R la , R 2a , R 3a and R 4a are phenyl and R lb , R 2b , R 3b and R 4b are ethyl .
- Z is CNC
- Z 2 is meso wherein R 2c is methyl
- Z 3 is meso wherein R 3c is methyl
- Z 4 is a covalent bond
- Z 5 is CNC and wherein R la , R 2a , R 3a , R 4a and R Sa are methyl and R lb , R 2b , R 3b , R 4b and R 5b are H;
- Zj is CNC
- Z 2 is N-meso
- Z 3 is meso wherein R 3c is phenyl
- Z 4 is CNC
- Z 5 is CC wherein R 5d and R 5e are phenyl
- R ⁇ a , R lb , R 3a , R 3b , R 5a and R 5b are (CH 2 ) 2 COOH and R 2a , R 2b , R 4a and R 4b are methyl ;
- Z is CNC, Z 2 is N-meso, Z 3 is meso wherein R 3c is H, Z 4 is N-meso, and Z 5 is CNC and wherein R la , R 3a and R 5a are phenyl , R lb , R 3b and R 5b are H and R 2a , R 2b , R 4a and R 4b are methyl ; 4 .
- Z, is CNC, Z 2 is meso wherein R 2c is methyl , Z 3 is
- CNCCNC wherein R 3f and R 3g are phenyl , Z 4 is N- ⁇ ?eso, Z 5 is a CC linkage wherein R 3d and R 3e are H, and wherein R la and R 2b are H and R lb , R 2a , R 3a , R 3b , R 4a and R 4b are ethyl ; 5 .
- Z j is CNC
- Z 2 is CNCCNC wherein R 2f and R 2g are H
- Z 3 is a CC linkage wherein R 3d is ethyl and R 3e is H
- Z 4 is meso wherein R ⁇ is ethyl and Z 5 is a covalent bond
- R la , R 2a R 3a » R 3b and R 4a are ( CH 2 ) 2 COOH and R lb , R 2b , R 4b , R 5a and R 5b are H ; 6 .
- Zi is CNC
- Z 2 is CNCCNC wherein R 2f is ethyl and R 2g is H
- Z 3 is meso wherein R 3c is phenyl
- Z 4 is a CC linkage wherein R M and R 4e are methyl and Z 5 is CNC, and wherein R la , R 2a , R 3a , R 4a and R 5a are methyl and R lb , R 2b , R 3b , R 4b and R 5b are ethyl ;
- Zj is CNC
- Z 2 is a CC linkage wherein R 2d and R 2e are phenyl
- Z 3 is CNCCNC wherein R 3f and R 3g are H
- Z 4 is N-meso and Z 5 is meso wherein R Sc is methyl and wherein R la , R ⁇ b , R 3a , R 3b , R 5a and R 5b are (CH 2 ) 2 COOH and R ⁇ , R 2b , R 4a and R 4b are methyl ;
- Zj is CNC
- Z 2 is a covalent bond
- Z 3 is meso wherein R 3c is phenyl
- Z 4 is CNC
- Z 5 is a CC linkage wherein R 5d and R 5e are methyl and wherein R la , R 3a and R 5a are phenyl , R lb , R 3b and R jb are H and R ⁇ , R 2b , R 4a and R 4b are methyl .
- preferred embodiments include:
- Z x and Z 6 are CNC
- Z 2 and Z 5 are CC linkages where all of R 2d , R 2e , R 5d and R 5e are phenyl
- Z 3 and Z 4 are meso
- R 3c and R ⁇ are ethyl, and wherein R la , R ⁇ , R 3a R 4a , R 5a and R ⁇ are i-propyl and R lb , R 2b , R 3b , R 4b , Rj,, and R ⁇ are (CH 2 ) 2 COOH;
- Z is CNC
- Z 2 and Z 4 are N-meso
- Z 3 and Z 5 are covalent bonds
- Z 6 is meso wherein R & . is H and R la , R 2a , R 3a , R 4a , R 5a and R fc are phenyl and R lb , R 2b , R 3b , R 4b , R 5b and R 6b are methyl.
- the possibility of obtaining CNC-expanded porphyrins with a multiplicity of substituents has the advantage that the properties of the core CNC-expanded porphyrin nucleus can be modified by the choice of such substituents. For example, solubility of the compounds can be enhanced by employing substituents with polar groups.
- the compounds can be made ampiphilic, i.e., the compound will have a patterned distribution of + and - charges. This property is helpful in solving problems of biodistribution -- membrane transition and the like.
- the light-absorbing qualities of the core nucleus can be modified to some extent by conjugated -rr-bonds in the substituents giving the usual auxochromic shift .
- the CNC-expanded porphyrin compounds of the present invention include those where the CNC-expanded porphyrin itself is coupled with a radioisotope for radioimaging (scintigraphic imaging) or with certain metals for use as ions a magnetic resonance image contrast agent, or simply as a convenient form of the compound.
- radioisotopes which would be useful labels include Iodine-123, Iodine-131, Technetium-99m, Indium-Ill and gallium-67.
- metals which would be appropriate as MRI contrast agents include paramagnetic ions of elements such as Gd, Mn, Eu, Dy, Pr, Pa, Cr, Co, Fe, Cu, Ni, Ti, and V, preferably Gd and Mn.
- the compounds of the invention it is helpful to link the compounds of the invention to a target-specific moiety such as an immunoglobulin or a ligand for a receptor.
- a target-specific moiety such as an immunoglobulin or a ligand for a receptor.
- the ability of the invention compounds to home to diseased tissues and cells such as tumors, if desired, can be enhanced by coupling the compound to a moiety that specifically binds epitopes or receptors located on the surface of such target tissues or cells.
- target-specific moieties within the present invention include ligands such as steroids, such as estrogen and testosterone and derivatives thereof, peptides comprising -ligands for T cell receptors, saccharides, such as mannose for which monocytes and macrophages have receptors, and H2 agonists.
- ligands such as steroids, such as estrogen and testosterone and derivatives thereof, peptides comprising -ligands for T cell receptors, saccharides, such as mannose for which monocytes and macrophages have receptors, and H2 agonists.
- Target-specific moieties may also be immunospecific components.
- the TSM may be derived from polyclonal or monoclonal antibody preparations and may contain whole antibodies or immunologically reactive fragments of these antibodies such as (F(ab ' ) 2 , Fab, or Fab' fragments. Use of such immunologically reactive fragments as substitutes for whole antibodies is well known in the art. See, for example, Spiegelberg, H.L., Immunoassays in the Clinical Laboratory (1978) 2:1-23.
- Polyclonal antisera are prepared in conventional ways by injecting a suitable mammal with antigen to which antibody is desired, assaying the antibody level in serum against the antigen, and preparing antisera when the titers are high.
- Monoclonal antibody preparations may also be prepared conventionally such as by the method of Koehler and Milstein using peripheral blood lymphocytes or spleen cells from immunized animals and immortalizing these cells either by viral infection, by fusion with myelomas, or by other conventional procedures, and screening for production of the desired antibodies by isolated colonies. Formation of the fragments from either monoclonal or polyclonal preparations is effected by conventional means as described by Spiegelberg, H.L., supra .
- Particularly useful antibodies exemplified herein include the monoclonal antibody preparation CAMAL-1 which can be prepared as described by Malcolm et al . (Ex Hematol (1984) 12:539-547) ; polyclonal or monoclonal preparations of anti-Mi antibody as described by Mew et al . J Immunol (1983) 130:1473- 1477 and B16G antibody which is prepared as described by Maier et al . J Immunol (1983) 131:1843 and Steele et al . Cell Immunol (1984) .90:303.
- the foregoing list is exemplary and not limiting; once the target tissue is known, antibody specific for this tissue may be prepared by conventional means.
- the invention is applicable to effecting toxicity against any desired target.
- Coupling of the target-specific moiety to a CNC- expanded porphyrin of the present invention can be effected by any convenient means known in the art, depending on the nature of the substituents on the CNC-expanded porphyrin moieties.
- a covalent bond to an amino-containing TSM may be effected using a dehydrating agent such as a carbodiimide.
- a particularly preferred method of covalently binding a CNC-expanded porphyrin to the target-specific moiety is treatment with l-ethyl-3- (3- dimethylaminopropyl) carbodiimide (EDCI) in the presence of a reaction medium consisting essentially of dimethylsulfoxide (DMSO) .
- a reaction medium consisting essentially of dimethylsulfoxide (DMSO) .
- DMSO dimethylsulfoxide
- Other dehydrating agents such as dicyclohexylcarbodiimide or diethylcarbodiimide could also be used as well as conventional aqueous and partially aqueous media.
- the active moieties of the conjugate may also be coupled through linker compounds which are bifunctional, and are capable of covalently binding each of the two active components.
- linker compounds which are bifunctional, and are capable of covalently binding each of the two active components.
- linker compounds which are bifunctional, and are capable of covalently binding each of the two active components.
- linkers are either homo- or heterobifunctional moieties and include functionalities capable of forming disulfides, amides, hydrazones, and a wide variety of other linkages.
- Other linkers include polymers such as polyamines, polyethers, polyamine alcohols, derivatized to the components by means of ketones, acids, aldehydes, isocyanates, or a variety of other groups.
- the techniques employed in coupling the active moieties of the conjugate include any conventional means and the method for coupling does not form part of the invention.
- invention compounds can be used in photodynamic therapy protocols analogous to those known for porfimer sodium and the BPDs.
- the compounds can be used to destroy or impair the functioning of unwanted cells or tissues or to inactivate pathogens such as bacteria and viruses.
- target cells and tissues for which PDT is useful include, but are not limited to, tumors, including blood tumors, malignant bone marrow, virally-infected blood cells or bone marrow, dysplastic cells or tissues, sites of inflammation or infection, hyperproliferative tissue such as psoriatic plaque or papillomavirus lesions (warts) or neointimal hyperplasia lesions, hypervascularization such as portwine stains and hemangiomas, atherosclerotic plaque, hair follicles, free viruses, bacteria, protozoa or other pathogenic parasites.
- Pathogens that may be adversely affected by PDT include certain viruses, bacteria, protozoa and other pathogenic parasites.
- Viruses include enveloped viruses such as human cytomegaloviruses, Epstein-Barr virus, Marek's disease herpes virus, human herpes simplex viruses, varicella-zoster virus, members of the family Poxviridae, members of the family Hepadnaviridae such as human hepatitis A virus (HAV) , human hepatitis B virus (HBV) and non-A, non-B hepatitis viruses, including human hepatitis C virus, members of the family Orthomyxoviridae such as influenza virus types A, B and C, members of the family Retroviridae such as human T cell leukemia viruses, human immunodeficiency viruses, and members of the family Flaviviridae such as tick-borne encephalitis virus or yellow fever virus.
- enveloped viruses such as human cytomegaloviruses, Epstein-Barr virus, Marek's disease herpes virus, human herpes simplex viruses, varicella-zoster virus
- Illustrative parasites include Plasmodium malariae, P. falciparum, P. ovale, P. vivax and Trypanosoma cruzi .
- Bacteria include Bacillus subtilis, Streptococcus faecalis, Pseudomonas spp. , Mycobacterium spp. and other opportunistic organisms treatable by photodynamic activation.
- the manner of use of the invention compounds in these contexts follows procedures that are established in the art.
- the choice of wavelength absorption for the CNC-expanded porphyrin used in a particular technique may be influenced by the nature of the use.
- the target tissue is in a context with a number of interfering materials such as those found in the blood
- CNC-expanded porphyrins which have wavelength absorptions not shared with these contaminants.
- this consideration is not as relevant.
- the presence or absence of alternative compounds capable of absorbing light in the environment to be irradiated with light is taken into consideration in choosing an appropriate member of the class of CNC-expanded porphyrins of the invention and in the choice of wavelength.
- the compounds of the invention may be used for diagnosis in a manner analogous to that for porphyrins per ⁇ e .
- the CNC-expanded porphyrins are capable of fluorescence when excited by light of an appropriate wavelength.
- the CNC-expanded porphyrins like the porphyrins themselves, will home to certain target tissues, such as atherosclerotic plaques, tumors, and the like.
- the invention compounds can be provided with target-specific moieties to assure this "homing” .
- the compounds of the invention may thus be allowed to accumulate in such target tissues or cells if present, and these tissues or cells may be detected or localized by detecting the fluorescence.
- the compounds of the invention may include radioisotopes either as covalently bonded substituents or in the metalated complexes so that the invention compounds can be located by radio- or scintigraphic imaging.
- Certain metal ions also provide the compounds of the invention with the ability to serve as MRI contrast agents. These contrast agents are used conventionally in obtaining MRI scans with enhanced readability.
- a number of strategies may be employed to effect the CNC linkage of the invention.
- a single CNC linkage may be formed, for example, by reacting a pyrrole substituted in the 2-position with a carboxylic acid moiety with a pyrrole substituted in the 2-position with aminomethyl. This general method for forming the CNC linkage is shown in Reaction Scheme 1 .
- Reaction Scheme 2 which effects the linkage by condensation of two cyano groups, each linked to the 2-position of an adjoining pyrrole.
- Reaction Scheme 2 the cyano-substituted dipyrrole in this case is first reduced with lithium aluminum hydride and then treated with oxygen to form the resultant linkage.
- the reduced compound (3) is partly ionized and the ionized form combines with the compound of formula (3) in the presence of 0 2 to give the product (1) .
- An alternative to Reaction Scheme 2 is shown in
- Reaction Scheme 3 Instead of treating the lithium aluminum hydride-reduced dicyano compound with oxygen; DDQ in methylene chloride and THF are used.
- the starting materials could also comprise the J isaminomethyl-derived dipyrromethane shown as formula (3) .
- This starting material is especially advantageously employed in obtaining asymmetric forms of the porphocyanines of formula (la) .
- Reaction Scheme 3' illustrates the condensation of two different "halves" of the porphocyanine nucleus to obtain the desired asymmetric product.
- the two symmetric products are also formed, but these are readily separated from the desired asymmetric product using standard chromatographic techniques.
- the Jbisaldehyde (which can be obtained as an intermediate in Reaction Scheme 5 below) is added.
- the substituents on the compound of formula (3) shown in Reaction Scheme 3 can be different from those on the dialdehyde and a single asymmetric product is obtained.
- a dialdehyde form of the dipyrrole intermediate can be condensed directly using ammonia in ethanol and water as shown in Reaction Scheme 4.
- the dipyrrole moiety containing two cyano groups for condensation in Reaction Schemes 2 or 3, or the dialdehyde for condensation in Reaction Scheme 4 can be obtained as shown in Reaction Scheme 5.
- the dipyrrole is formed by the condensation of two molecules of 2-benzoyl carbonyl-4-acetoxylmethyl pyrrole.
- the resulting dipyrrole is reduced to the corresponding dialdehyde and converted to the cyano derivative using standard reagents.
- Reaction Scheme 6 shows an additional alternative for obtaining the dicyano intermediate typified by formula (2) .
- the dicyano compound can then be converted to the appropriate porphocyanine using the approaches set forth above in Reaction Schemes 2 or 3.
- benz- aldehyde optionally substituted with 1-5 independently selected substituents is used to form the meso bridge between the two condensed pyrrole nuclei.
- aldehydes can also be used, including formaldehyde and simple alkyl aldehydes such as acetaldehyde, butyraldehyde, hexylaldehyde, and the like.
- other aryl aldehydes such as 1-naphthylaldehyde, can also be used.
- a polar aprotic solvent such as DMF
- the 5-acetoxymethyl-2-benzyloxycarbonyl-3,4- diethylpyrrole is added to acetic acid in water and heated.
- the solid product is precipitated as large chunks when the foregoing solution cools to room temperature.
- Water is added and the product is collected by filtration and then washed with additional water.
- the filtrate is extracted with CH 2 C1 2 and then evaporated to produce a solid product.
- the solid products are combined, and then recrystallized from a solution of CH 2 C1 2 and hexanes to obtain 5, 5' -Jbis(benzyloxycarbonyl) -3,3'4,4' - tetraethyl-2,2' -dipyrromethane.
- This product is dissolved in tetrahydrofuran (THF) and stirred under hydrogen in the presence of Pd/C and triethylamine. After the catalyst is filtered through celite, the filtrate is evaporated to dryness, dissolved in N,N- dimethylformamide and heated to boiling under argon. The solution is chilled and an excess of chilled benzoyl chloride is added. The reaction mixture is stirred and the solid product collected by filtration. The solid product is added to water and basified using NaHC0 3 and heated to 60°C.
- the pale yellow product, 3,3' ,4,4' -tetraethyl-5,5' -diformyl-2,2' -dipyrromethane crystallizes from the solution and is filtered and washed with water.
- This product is dissolved in ethanol and bubbled with argon; hydroxylamine hydrogen chloride and sodium acetate are added. This mixture is heated under argon and the solvent is removed and the product dried overnight in vacuo.
- the resulting Jbisoxime is dissolved in acetic anhydride and saturated with argon to generate the crude Jbisnitrile product, which is obtained as a black solid after removal of acetic anhydride and dried under vacuum.
- the product obtained above can then be converted to the desired corresponding porphocyanine as illustrated in Reaction Scheme 2.
- the 3,3'4,4' -tetraethyl-5, 5' - cyanodipyrromethane in anhydrous THF is added to a THF suspension of LiAlH 4 under nitrogen at 0°C.
- the mixture is stirred and water is added to quench the reaction and the precipitate is filtered off.
- the golden colored solution is transferred to a two-neck flask containing equimolar portions of Pb(SCN) 2 and anhydrous sodium sulphate.
- Anhydrous methanol is added and the mixture is brought to reflux. The color gradually changes from purple to dark green.
- the reaction is stopped and air is bubbled slowly through the solution.
- the crude product was dissolved in methylene chloride and the solid was filtered off.
- the volume of the green solution is reduced to approximately 5 ml and then charged on an alumina column and eluted with ethylacetate in CH 2 C1 2 .
- the bright green eluent containing the porphocyanine is collected and evaporated to dryness.
- the solution turns dark green immediately.
- the crude product is dissolved in methylene chloride and the solid filtered off.
- the volume of the green solution is reduced to approximately 5 ml and then charged on an alumina column and eluted with ethylacetate in CH 2 C1 2 .
- the bright green eluent containing the porphocyanine is collected and evaporated to dryness. A significant increase in yield is obtained from this synthetic process as compared to the yield obtained via air oxidation.
- the 3,3'4,4' -tetraethyl-5, 5' -cyanodipyrromethane for example, is dissolved in THF and added to a THF suspension of LiAlH 4 . The resulting mixture is stirred and water is added. A solid product forms which is filtered off.
- the Jbisamine product is obtained after evaporation of the solvent by drying under vacuum.
- the Jbisamine is dissolved in anhydrous methanol and Jbisaldehyde is added. The solution is bubbled and brought to reflux with nitrogen.
- Lead thiocyanate (Pb(SCN 2 )) is added and the solution is refluxed.
- the scintigram is normally taken by a gamma imaging camera having one or more windows for detection of energies in the 50-500 KeV range.
- the contrast agents for magnetic resonance imaging is effected in an analogous method to administration for radioimaging except that the compounds of the invention will be in the metalated forms employing paramagnetic ions.
- the signal generated is correlated with the relaxation times of the magnetic moments of protons in the nuclei of the hydrogen atoms of water molecules in the region to be imaged.
- the magnetic resonance image contrast agent acts by increasing the rate of relaxation, thereby increasing the contrast between water molecules in the region where the imaging agent accretes and water molecules elsewhere in the body.
- the effect of the agent is to increase both T, and T 2 , the former resulting in greater contrast, while the latter results in lesser contrast.
- the phenomenon is concentration dependent, and there is normally an optimum concentration of a paramagnetic species for maximum efficiency.
- the optimum concentration will vary with the particular agent used, the locus of imaging, the mode of imaging, i . e . , spin- echo, saturation-recovery, inversion-recovery and for various other strongly T, dependent or T 2 dependent imaging techniques, and the composition of the medium in which the agent is dissolved or suspended. These factors, and their relative importance are known in the art. See, e.g., Pykett, Scientific American (1982) 246:78, and Runge et al . , Am J Radiol (1987) 141:1209.
- the MRI method of the invention is practiced by injecting an individual parenterally with an effective amount of the MRI contrast agent of the invention which includes a metallic element such as gadolinium. It is contemplated that an individual will receive a dosage of contrast agent sufficient to enhance the MRI signal at the targeted site by at least about 20%, preferably 50-500%, the amount being a function of the particular paramagnetic species and the mode of administration.
- a contrast agent within the present invention is conveniently provided as an injectable preparation for use, preferably a sterile injectable preparation for human use, for targeting an MRI agent to diseased tissues or cells, preferably comprising: a sterile injectable solution containing an effective amount of the contrast agent in a pharmaceutically acceptable sterile injection vehicle, preferably phosphate buffered saline.
- a pharmaceutically acceptable sterile injection vehicle preferably phosphate buffered saline.
- Other conventional pharmaceutically acceptable vehicles for parenteral administration may be utilized as required for the site of parenteral administration.
- a representative preparation to be parenterally administered in accordance with this invention will normally contain about 0.1 to 20 mg, preferably about 2 mg of contrast agent, in a sterile solution.
- the Jbisamine product was obtained after evaporation of the solvent by drying under vacuum overnight.
- the Jbisamine (3) was dissolved in 50 ml anhydrous methanol and Jbisaldehyde (6) (0.050 g, 1.6 X 10" 4 was added. The solution was bubbled with N 2 for 20 minutes and brought to reflux under N 2 .
- Lead thiocyanate (Pb(SCN 2 )) (0.055 g, 1.7 X 10 "4 mole) was added and the solution refluxed for 4 hours. Oxygen gas was bubbled through the solution at room temperature overnight. After evaporation of the solvent, the crude porphocyanine product was dried under vacuum overnight.
- the product was purified by Al 2 0 3 column (4% water added) with 10% ethyl acetate in CH 2 C1 2 .
- the green eluent was collected and concentrated on the roto-vap. Crystals of 2,3,9,10,14,15,21,22-octaethyl porphocyanine (1) were obtained after evaporation of the solvent.
- 3,3'4,4' -tetraethyl-5,5' -cyanodipyrromethane was prepared according to the methodology of Example 1. 0.102 g, 3.3 X 10 "4 mole of 3,3'4,4' -tetraethyl-5,5' -cyanodipyrromethane in 10 ml anhydrous THF was slowly added to a 20 ml THF suspension of LiAlH 4 under N 2 at
- Example 3 Synthesis of an Octaethyl Porphocyanine (Reaction Scheme 3) This example illustrates Reaction Scheme 3.
- 3,3'4,4'- tetraethyl-5,5' -cyanodipyrromethane (2) was prepared according to the methodology of Example 1.
- a ten-fold excess of 2,3- dichloro-5, 6-dicyano-l,4-benzoquinone (DDQ) was added to 69 mg of 3, 3'4,4' -tetraethyl-5,5' -cyanodipyrromethane in 10 ml anhydrous THF.
- the resulting solution turned dark green immediately.
- the residue was chromatographed according to the methodology of Example 2.
- a significant increase in yield was obtained when compared to air oxidation. Yield: 32 mg, 48%
- Example 4 Synthesis of Porphocyanine (Reaction Scheme 4) This example illustrates Reaction Scheme 4.
- the dialdehyde was prepared according to the methodology of Example 1. 25 mg of 3,3'4,4' -tetraethyl-5, 5' -diformyl-2,2' - dipyrromethane (6) was suspended in 30 ml dry EtOH. The resulting ethanol solution was chilled at 0°C and ammonia gas was bubbled through it for 30 minutes. The gas inlet was then removed and the flask placed in an oil bath at 60°C for 72 hours. The reaction was stopped and cooled at 0°C.
- Example 6 Condensation of 2, 2' -bis cyano meso aryl dipyrromethanes to Prepare Symmetric Porphocvanines This illustrates the method of Reaction Scheme 3 where at least one R ic is aryl.
- Example 8 Condensation to Obtain Asymmetric Porphocvanines This example employs the method of Reaction Scheme 3.
- Example 9 Application of the Method of Example 8 Using the method of Example 8, the following was prepared:
- 12-Phenyl-2, 3 ,21, 22-tetraethyl porphocyanine 51 mg 2,2' -bis cyano meso phenyl dipyrromethane + 58 mg 2,2' -bis cyano 3,3'4,4' -tetraethyl dipyrromethane gives 48 mg of crude mixed porphocyanine. After chromatography (C 18 reversed phase; 20% 0.1% aqueous trifluoroacetic acid in 0.1% trifluoroacetic acid/acetonitrile) 21.7 mg (21%) of the title compound is isolated.
- the bis cyano compound (0.11 mmol) is dissolved in dry THF (10 ml) and this solution is added dropwise to a stirred suspension of LiAlH 4 (1.3 mmol) in dry THF (10 ml) under an atmosphere of N 2 at 0°C.
- the reduction is monitored by TLC and when complete the excess LiAlH 4 is quenched with water, dichloromethane (15 ml) is added and the resulting slurry is gravity filtered. The filtrate is dried over anhydrous sodium sulfate and solvent is evaporated in vacuo .
- Example 11 Application of the Method of Example 10 Using the method of Example 10, the following was prepared:
- Example 12 In Vi tro Toxicity of Porphocyanine Cells are washed three times in serum-free medium (DME) , counted and made up to a concentration of 10 7 cells per ml.
- DME serum-free medium
- the cells are irradiated immediately upon addition of the test or control compound.
- the effect of irradiation is estimated using methods appropriate to the target cells.
- RBCs human erythrocytes
- the murine mastocytoma cell line P815 the results are determined as follows:
- the cells are labeled as above using concentrations of 10-50 ng/ml of Hp as control and the porphocyanine of formula (la) as the test substance.
- the resuspended cells are treated with 300-850 nm light for 30 minutes and the viability resulting is estimated by direct counting using eosin-Y exclusion, a standard procedure for differentiating living from dead cells.
- the cells recovered from light exposure are assayed for viability by incubating them for 18 hours in 10 ⁇ Ci/ml tritium-labeled thymidine according to the standard procedure whereby thymidine incorporation is equated with viability.
- the cells are harvested and radioactivity uptake is measured by a scintillation counter.
- Porphocyanine P815 cells are incubated as described in Example 12 using 1-200 ng/ml Hp or the porphocyanine of formula (la) .
- the cells are labeled in the dark for 30 minutes, washed free of -unabsorbed porphyrins, resuspended, and then exposed to 30 * 0-850 nm light for another 30 minutes.
- Viability of the cells is established by tritiated thymidine incorporation after labeling with 30 ⁇ Ci/ml tritiated thymidine and incubating at 37°C for 18 hours.
- Immunoconiugates This example describes methods of preparation for immunoconjugates of four different antibody preparations with either hematoporphyrin (Hp) or a porphocyanine (Pc) of formula (la) .
- the antibodies employed are CAMAL-1, anti-Mi antibody, and B16G antibody, all prepared as described hereinabove, and affinity purified rabbit anti-mouse Ig (R ⁇ MIg) .
- a purified irrelevant monoclonal preparation C-MAb is used where a control is desired.
- TSM-Hp and TSM-Pc conjugates wherein the TSM is comprised of an immunoglobulin are tested against cells in vi tro by mixing the conjugates with the appropriate cell types, along with suitable controls, and then exposing the labeled cells to irradiation.
- Procedures for carrying out this assay are described in detail in Mew et al . , Cancer Research (1985) for CAMAL-1, and by Mew et al., J. Immunol. (1983) for Anti-Mi, both references cited hereinabove are incorporated herein by reference. Briefly, for CAMAL-1, three cell lines, WC4, WC6 and
- WC2 (WC4 and WC6 produce the CAMAL antigen, but WC2 does not) , are labeled with the appropriate TSM-Hp or TSM-Pc preparation as described above in Example 14.
- the labeled cell preparations containing 10 6 cells each are introduced to Rose chambers and exposed to light activation with a laser at 630 nm. The results for various preparations are then compiled.
- Ml tumor cells are used as target cells and treated with the TSM-Hp, TSM-Pc conjugates or drug or antibody alone or the combination of antibody and drug, but uncoupled, by incubating them in 6% Co 2 humidified incubator at 37°C for two hours.
- the cells are washed three times in PBS and then plated and exposed to fluorescent light overnight.
- the cells are assessed for viability by tritiated thymidine uptake as above.
- A10, P815, and L1210 cells are used as target cells.
- A10 cells are a T cell hybridoma which secretes a B16G-reactive T-suppressor factor; P815 cells are also reactive with B16G.
- the in vi tro study is done using a direct method employing the B16G-Hp or B16G-Pc conjugate or indirectly using unlabeled B16G antibodies and labeled R ⁇ MIg-Hp or R ⁇ MIg-Pc.
- 5 x 10 5 cells are suspended in 1 ml DME/Hepes containing the appropriate TSM-drug conjugate as test or control at Hp or Pc concentrations of 320, 160, 80, 40 and 20 ng drug/ml.
- the cells are incubated in the dark at 37°C for 1 hour, then washed 3 times in 5 ml DME/Hepes, and then resuspended in 1 ml of the same buffer.
- Three 100 ⁇ l test portions of the labeled preparations are dispensed into flat bottom microtiter wells and the remainder of the cell suspensions (700 ⁇ l) are exposed to incandescent light (22.5 mW/cm 2 ) at a distance of 20 cm for 1 hour.
- DME/Hepes DME/Hepes, and then exposed for an additional 30 minutes at 4°C in the dark to varying concentrations of R ⁇ MIg-Hp or R ⁇ MIg-Pc between 2 ⁇ g/ml and 15 ng/ml of Hp or Pc.
- the cells are assessed for viability using labeled thymidine uptake as described above. .
- the in vivo test relies on the indirect effect of a population of T-suppressor cells on tumors, which then serve as means to assess the effectiveness of the irradiation treatment.
- P815 mastocytoma cells grown in syngeneic DBA/2 mice stimulate T-suppressor cells specific for the tumor. These T-suppressor cells impede the development of specific T-killer cells which would otherwise aid in the regression of the tumor.
- the T cell hybridoma designated A10 above secretes a T-suppressor factor which is associated with these T-suppressor cells.
- DBA/2 mice are injected in the right flank subcutaneously with 10 4 P815 cells to incorporate the tumor.
- the mice are randomly sorted into groups of eight and injected IV with 150 ⁇ l PBS containing nothing, Hp or Pc, B16G-Hp or B15G-PC, B16G plus either drug, B16G alone or C-MAb-Hp or C-MAb-Pc.
- the levels of Hp are 50 ⁇ g per animal in all cases and B16G 310 ⁇ g in all cases (where appropriate) .
- Example 17 Diagnostic Imaging A 32-year old female patient develops fever and abdominal pain. The patient is maintained on antibiotic therapy for a period of one week without effect. A CAT scan fails to demonstrate any abnormal mass. Radioimaging studies are performed using Tc-99m-labeled porphocyanine. An injection of 20 mCi of the radiolabeled porphocyanine is used and the patient is scanned with a gamma camera in SPECT mode. The scan of the patient's abdomen demonstrates a focus of accumulation of
- Tc-99m Surgery is performed and an abscess is found at the site of the Tc-99m activity.
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KR1019960706028A KR100241853B1 (en) | 1994-04-26 | 1995-04-26 | Porphosian and CNC-extended porphyrin |
NZ284413A NZ284413A (en) | 1994-04-26 | 1995-04-26 | Porphocyanines and other cnc-expanded porphyrins |
CA002188029A CA2188029C (en) | 1994-04-26 | 1995-04-26 | Porphocyanine and cnc-expanded porphyrins |
EP95916532A EP0757689A1 (en) | 1994-04-26 | 1995-04-26 | Porphocyanine and cnc-expanded porphyrins |
MX9604956A MX9604956A (en) | 1995-04-26 | 1995-04-26 | Porphocyanine and cnc-expanded porphyrins. |
AU23007/95A AU697139B2 (en) | 1994-04-26 | 1995-04-26 | Porphocyanine and CNC-expanded porphyrins |
JP7527197A JPH10500942A (en) | 1994-04-26 | 1995-04-26 | Porphosyanin and CNC-expanded porphyrin |
FI964267A FI964267A (en) | 1994-04-26 | 1996-10-23 | Porphocyanin and CNC-extended porphyrins |
NO964541A NO309481B1 (en) | 1994-04-26 | 1996-10-25 | CNC-expanded porphyrins, preparations and pharmaceutical preparations thereof, magnetic resonance imaging (MRI) contrast agent, and methods of preparation |
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US08/233,632 US5726304A (en) | 1992-10-30 | 1994-04-26 | Porphocyanine and CNC-expanded porphyrins |
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US20020022032A1 (en) * | 1999-04-23 | 2002-02-21 | Curry Patrick Mark | Immuno-adjuvant PDT treatment of metastatic tumors |
HUP0202635A3 (en) | 1999-07-29 | 2006-03-28 | Epix Medical Inc Cambridge | Targeting multimeric imaging agents through multilocus binding |
WO2001085212A2 (en) * | 2000-05-08 | 2001-11-15 | The University Of British Columbia | Drug delivery systems for photodynamic therapy |
WO2001085213A2 (en) | 2000-05-08 | 2001-11-15 | The University Of British Columbia | Supports for photosensitizer formulations |
TWI221406B (en) | 2001-07-30 | 2004-10-01 | Epix Medical Inc | Systems and methods for targeted magnetic resonance imaging of the vascular system |
US20110070154A1 (en) * | 2008-08-13 | 2011-03-24 | Hyde Roderick A | Artificial cells |
CA2747219C (en) | 2008-12-16 | 2017-12-12 | Qlt Inc. | Combination of photodynamic therapy and anti-vegf agents in the treatment of unwanted choroidal neovasculature |
EP2531206B1 (en) | 2010-02-04 | 2017-05-31 | Morphotek, Inc. | Chlorotoxin polypeptides and conjugates and uses thereof |
WO2013003507A1 (en) | 2011-06-27 | 2013-01-03 | Morphotek, Inc. | Multifunctional agents |
CA2853705C (en) | 2011-10-25 | 2021-10-12 | Memorial Sloan-Kettering Cancer Center | Free psa antibodies as diagnostics, prognostics and therapeutics for prostate cancer |
AU2013334102B2 (en) | 2012-10-26 | 2018-08-16 | Memorial Sloan-Kettering Cancer Center | Modulators of resistant androgen receptor |
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WO1994010172A1 (en) * | 1992-10-30 | 1994-05-11 | Quadra Logic Technologies, Inc. | Wavelength-specific photosensitive porphacyanine and expanded porphyrin-like compounds and methods for preparation and use thereof |
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1994
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1995
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US5726304A (en) | 1998-03-10 |
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NO964541L (en) | 1996-12-23 |
HU9602956D0 (en) | 1997-01-28 |
NZ284413A (en) | 1998-08-26 |
HUT77405A (en) | 1998-04-28 |
EP0757689A1 (en) | 1997-02-12 |
FI964267A0 (en) | 1996-10-23 |
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