Photodynamic Therapy

Treatment of Cancer Using Photodynamic Therapy

Patent(s): Pending
U.S. Patent Application Number: 12/462,606

Summary: A method for treatment of cancerous tissue in the upper respiratory system including the steps of: injecting HPPH in a physiologically compatible medium into a patient having the cancerous tissue at a level of 3 through 5 mg/m.sup.2 of body surface area, waiting for a time period of 24 through 60 hours to permit preferential absorption of the HPPH into the cancerous tissue, and exposing the cancerous tissue to light at a wavelength of about 665.+-.5 nm at an energy of about 75 to about 200 Joules/cm.

Detail: In accordance with the invention, we have surprisingly discovered that HPPH, like porfimer sodium also ablates cancers that involve epithelial type tissue in the upper respiratory system, when combined with exposure of such tissue to light at 665.+-.5 nm. However, it has been surprisingly discovered that HPPH accomplishes the desired result at lower dosages and importantly with less damage to normal tissues than does porfimer sodium. HPPH is effective at doses of only 0.08 to 0.13 mg/kg of body weight (3.5 mg/m2 of body surface area) versus a minimum of 2 mg/kg of body weight for porfimer sodium. Further, it has been surprisingly discovered that HPPH concentrates in a much greater amount in tumors in epithelial type tissue than in normal tissue when compared with porfimer sodium thus leading to less normal tissue damage at effective treatment levels. The invention is a method for treatment of cancerous tissue in the upper respiratory system including the steps of: injecting HPPH in a physiologically compatible medium into a patient having the cancerous tissue to provide a dose level of 3 through 5 mg/m.sup.2 of body surface area, waiting for a time period of 24 through 60 hours to permit preferential absorption of the HPPH into the cancerous tissue, and exposing the cancerous tissue to light at a wavelength of about 665.+-.5 nm at an energy of about 75 to about 200 Joules/cm. The invention also includes HPPH for use in the above described method.

Therapeutic HPPH Dosage for PDT

Patent(s): Pending
U.S. Patent Application Number: PCT/US2007/020818

Summary: A method for treating cancer and other hyperproliferative tissues in humans that can be exposed to light comprising injection of HPPH at the equivalent to a dose of 0.05 to 0.1 1 mg/kg of body weight 24 hours post injection and exposing the tumor or other hyperproliferative tissue to 665 ± 10 nm of light at 50 to 200 Joules/cm2.

Detail: In accordance with the invention it has been unexpectedly discovered that in humans many cancers and other hyperproliferative tissues can be effectively treated by injection of HPPH at the equivalent to a dose of 0.05 to 0.1 1 mg/kg of body weight 24 hours post injection and exposed to 665 ± 10 nm of light at a total delivered light dose of 50 to 200 joules/cm2. The lower limit is preferably 75 almost preferably 100 Joules/cm2 and the upper limit is preferably 150 Joules/cm2.

Treatment of Esophageal High Grade Dysplasia Using Photodynamic Therapy

Patent(s): Pending
U.S. Patent Application Number: PCT/US2007/020816

Summary: A method for treatment of esophageal high grade dysplasia comprising the steps of: injecting HPPH in a physiologically compatible medium into a patient having high grade dysplasia tissue to provide a dose level of 3 through 5 mg/m2 of body surface area, waiting for a time period of 24 through 60 hours to permit preferential absorption of the HPPH into esophageal cancer tissue, and exposing the esophageal cancer tissue to light at a wavelength of about 670 ± 5 nm at an energy of from about 75 to about 200 Joules/cm.

Detail: In accordance with the invention, we have discovered that HPPH is effective against high grade dysplasia at significantly lower doses upon exposure of such tissue to light at the preferential absorption wavelength of HPPH (670 ± 5 nm) at dose of from 3 to 5 mg/m2 (0.5 to 0.13 mg/kg) of body surface area, and is more effective against high grade dysplasia with fewer side effects than PHOTOFRINTM. The method of the invention includes the steps of: injecting HPPH in a physiologically compatible medium into a patient having high grade esophageal dysplasia to provide a dose level of 3 through 5 mg/m2 of body surface area, preferably 3 through 4 mg/m2 of body surface area. wait- ing for a time period of 24 through 60 hours to permit preferential absorption of the HPPH into the high grade dyplasia tissue, and exposing the esophageal high grade dysplasia tissue to light at a wavelength of about 670 ± 5 nm at an energy of from about 75 to about 200 Joules/cm, preferably 75 to about 150 Joules/cm.

Treatment of Barrett’s Esophagus Using Photodynamic Therapy

Patent(s): Pending
U.S. Patent Application Number: PCT/US2007/020817

Summary: A method for treatment of Barrett's esophagus comprising the steps of: injecting HPPH in a physiologically compatible medium into a patient having Barrett's esophagus tissue to provide a dose level of 3 through 5 mg/m2 of body surface area, waiting for a time period of 24 through 60 hours to permit preferential absorption of the HPPH into Barrett's esophagus tissue, and exposing the Barrett's esophagus tissue to light at a wavelength of about 670 ± 5 nm at an energy of from about 75 to about 200 Joules/cm.

Detail: In accordance with the invention, we have discovered that HPPH, like porfimer sodium, also ablates Barrett's esophagus when combined with exposure of such tissue to light at the preferential absorption wavelength of HPPH (670 ± 5 nm). However, it has been surprisingly discovered that HPPH accomplishes the desired result with higher success at lower dosages and importantly with fewer esophageal strictures. HPPH is effective at doses of only 0.08 to 0.13 mg/kg of body weight (3-5 mg/m2 of body surface) versus a minimum of 2 mg/kg of body weight for porfimer sodium. The method of the invention includes the steps of: injecting HPPH in a physiologically compatible medium into a patient having Barrett's esophagus tissue to provide a dose level of 3 through 5 mg/m2 of body surface area, preferably 3 through 4 mg/m2 of body surface area, waiting for a time period of 24 through 60 hours to permit preferential absorption of the HPPH into Barrett's esophagus tissue, and exposing the Barrett's esophagus tissue to light at a wavelength of about 670 ± 5 nm at an energy of from 75 to 200 Joules/cm, preferably 75 to 200 Joules/cm.

Method for Enhancing PDT Efficacy Using a Tyrosine Kinase Inhibitor

Patent(s): Pending
U.S. Patent Application Number: PCT/US2007/015263

Summary: A method for treating hyperproliferative tissue in a mammal which tissue expresses ABCG2 including the steps of: a) systemically introducing from about 100 to about 1000 mg/kg of body weight of a tyrosine kinase inhibiting compound into the mammal; b) within from about 0.5 to about 24 hours after the introducing in step a) systemically introducing from about 0.05 to about 0.5 &mgr;mol per kilogram of body weight of a tumor avid photosensitizing compound, that acts as a substrate for ABC family transport protein, ABCG2 and that has a preferential light absorbance frequency; and c) exposing the hyperproliferative tissue to light at a fluence of from about 50 to about 150 J/cm2 delivered at a rate of from about 5 to about 25 mW/cm2 at the light absorbance frequency. The photosensitizing compound is preferably a tetrapyrollic photosensitizer compound where the tetrapyrollic compound is a chlorin, bacteriochlorin, porphyrin, pheophorbide including pyropheophorbides, purpurinimide, or bacteriopurpurinimide and derivatives thereof; provided that, the photosensizing compound is not a meso-tetra (3-hydroxyphenyl) derivative, is not a saccharide derivative and is not a hematoporphyrin.

Detail: The invention is a method for treating hyperproliferative tissue in a mammal which tissue expresses ABCG2 including the steps of: a) systemically introducing from about 100 to about 1000 mg/kg of body weight of a tyrosine kinase inhibiting compound into the mammal; b) within from about 0.5 to about 24 hours after the introducing in step a) systemically introducing from about 0.05 to about 0.5 μmol per kilogram of body weight of a tumor avid photosensitizing compound, that acts as a substrate for ABC family transport protein, ABCG2 and that has a preferential light absorbance frequency; and c) exposing the hyperproliferative tissue to light at a fluence of from about 50 to about 150 J/cm2 delivered at a rate of from about 5 to about 25 mW/cm2 at the light absorbance frequency. The photosensitizing compound is preferably a tetrapyrollic photosensitizer compound where the tetrapyrollic compound is a chlorin, bacteriochlorin, porphyrin, pheophorbide including pyropheophorbides, purpurinimide, or bacteriopurpurinimide and derivatives thereof; provided that, the photosensizing compound is not a meso-tetra (3- hydroxyphenyl) derivative, is not a saccharide derivative and is not a hematoporphyrin. The photosensitizing compound is usually a protoporphyrin IX (PpIX), a pheophorbide a (Pha), a pyropheophorbide-a alkyl ester, a chlorin e6 or a 5-aminolevulinic acid (ALA)-induced PpIX.

Galectin Recognized Photosensitizers for Photodynamic Therapy

Patent(s): Issued
U.S. Patent Number: 6,849,607
Date Issued: February 1, 2005

Summary: Purpurin-carbohydrate conjugates and their method of preparation and use for treatment of cancer cells. The conjugates have the general formula: ##STR1## wherein R.sub.6 and R.sub.7 taken together are .dbd.NR.sub.11 or are independently --OR.sub.11, where at least one R.sub.11 is preferably a mono or polysaccharide moiety and R.sub.1 -R.sub.8 are various groups formed from carbon and hydrogen and optionally oxygen and nitrogen where R.sub.3 and R.sub.4 may together from a covalent bond.

Detail: Our invention deals with: (i) An efficient approach for the preparation of .beta.-galactose conjugated photosensitizers with required photophysical properties. (ii) The galectin-1 (Gal-1) inhibition binding affinity (by ELISA assay) of the conjugates with the parent molecule. (iii) The comparative in vitro photosensitizing efficacy of the conjugates with the parent molecule. The invention includes compounds of the invention having the following generic formula: ##STR2##. where R.sub.1 is lower alkyl, vinyl, aryl, alkyl ether, aryl, lower carboxy, or --CH(OR.sub.9)CH.sub.3 where R.sub.9 is alkyl of 1 to about 20 carbon atoms, a cyclic containing substituent containing 1 to about 20 carbon atoms connected to the a ring through a carbon-carbon or --O-- bond; R.sub.2 and R.sub.5 are independently hydrogen or lower alkyl, R.sub.3 and R.sub.4 are independently --H, lower alkyl, or --OR.sub.10, where R.sub.10 is H or lower alkyl, or R.sub.3 and R.sub.4, together form a covalent bond; R.sub.6 and R.sub.7 taken together are .dbd.NR.sub.11 or are independently --OR.sub.11, where R.sub.11 is independently --H, alkyl of 1 to about 20 carbon atoms, a cyclic containing substituent containing 1 to about 20 carbon atoms, an amide group or a mono or polysaccharide containing substituent connected through an intermediate group containing one or more of a saturated or unsaturated lower alkylene group, a saturated or unsaturated heterocylic or hydrocarbon five or six membered ring, an ether linkage, an amide linkage or an ester group; R.sub.8 is --CH.sub.2 CH.sub.2 COR.sub.12 where R.sub.12 is an amino acid residue, --NHR.sub.13 or --OR.sub.14 where R.sub.13 is hydrogen, alkyl of 1 to about 20 carbon atoms, or a substituent containing a mono or polysaccharide and R.sub.14 is hydrogen, or alkyl of 1 to about 20 carbon atoms, where lower alkyl includes alkyl and alkylene groups of 1 to 5 carbon atoms and alkyl includes linear, branched and cyclic unsubstituted alkyl and linear, branched and cyclic alkyl and alkylene groups substituted with hydroxy, carboxy, alkyl, vinyl, amino, amido, keto, heterocyclic, mono and polysaccharide and amino acid groups; provided that the compound contains at least one mono or polysaccharide group that will combine with galectin-1. and M is a chelated metal or is two hydrogens bound to the unsaturated nitrogens in the a and c rings. The invention especially includes such compounds containing at least one galactose or lactose saccharide group and M is two hydrogens as above described. In the most preferred compounds R.sub.6 and R.sub.7 together are .dbd.NR.sub.11 where R.sub.11 contains a mono or polysaccharide moiety. The invention further includes a method for treating cancer cells by contacting the cells with the above compound and exposing the cells to light.

Chlorin and Bacteriochlorin-based Aminophenyl DTPA and N2S2 Conjugates for MR Contrast Media and Radiopharmaceuticals

Patent(s): Issued
U.S. Patent Number: 6,534,040
Date Issued: March 18, 2003
International Pending Applications: SE, NL, IT, GB, FR, DK, DE, CH, CA, JP, BE, AT, AU

Summary: Compositions that are a chemical combination of porphyrins, chlorins, bacteriochlorins, and related tetra-pyrrolic compounds with radioactive elements such as Technetium.sup.99, Gadolinium, Indium.sup.111 and radioactive iodine. When the element can form cations, the compound is usually a chelate with the porphyrin or chlorin structure. When the element forms anions, the compound is usually a direct chemical combination of the radioactive element into the porphyrin or chlorin structure. The invention further includes the method of using the compounds of the invention for diagnostic imaging of hyperproliferative tissue such as tumors and new blood vessel growth as is associated with the wet form of age related macular degeneration and methods of making the compounds. Compounds for MRI contrast imaging of the invention are usually Tc.sup.99, In.sup.111 or Gd(III) complexes of compounds of the formula: ##STR1##

Detail: The invention includes compositions that are chemical combination of porphyrins and chlorins and related tetra-pyrrolic compounds with radioactive elements such as Technetium.sup.99, Gadolinium, Indium.sup.111 and radioactive iodine. When the element can form cations, the compound is usually a chelate with the porphyrin or chlorin structure. When the element forms anions, the compound is usually a direct chemical combination of the radioactive element into the porphyrin or chlorin structure. Examples of porphyrin and chlorin structures that can form compounds with radioactive elements, when modified in accordance with the present invention, are for example described in U.S. Pat. Nos. 5,756,541; 5,028,621; 4,866,168; 4,649,151; 5,438,071; 5,198,460; 5,002,962; 5,093,349; 5,171,741; 5,173,504; 4,968,715; 5,314,905; 5,459,159; 5,770,730; 5,864,035; 5,190,966; and 5,952,366 all of which are incorporated by reference as background art. The invention further includes the method of using the compounds of the invention for diagnostic imaging of hyperproliferative tissue such as tumors and new blood vessel growth as is associated with the wet form of age related macular degeneration. Unexpectedly, porphyrins and chlorins, as above described, upon injection, carry the element into cells of hyperproliferative tissue and dramatically enhance the signal produced by tumor tissue in MR imaging. Compounds of the invention usually have the formula ##STR2##. In the above formula, ##STR3##. --(CH.sub.2).sub.2 CONHphenyleneCH.sub.2 DTPA, ##STR4## or ##STR5##

Porphyrin-Based Compounds for Tumor Imaging and Photodynamic Therapy

Patent(s): Pending
U.S. Patent Application Number: 11/353,626
International Issued Patents: SE, PT, NL, IT, GR, GB, FR, ES, DK, DE, AT
International Pending Applications: KR, JP, IN, CN

Summary: This invention describes a first report on the synthesis of certain .sup.124I-labelled photosensitizers related to chlorines and bacteriochlorins with long wavelength absorption in the range of 660-800 nm. In preliminary studies, these compounds show a great potential for tumor detection by positron emission tomography (PET) and treatment by photodynamic therapy (PDT). The development of tumor imaging or improved photodynamic therapy agent(s) itself represent an important step, but a dual function agent (PET imaging and PDT) provides the potential for diagnostic body scan followed by targeted therapy.

Detail: In accordance with the invention, we have discovered a series of compounds that overcome the problems associated with methods in the prior art for radiation imaging of deep tumors. In particular, these compounds are .sup.124I-phenyl derivatives of a chlorin, bacteriochlorin, porphyrin, pyropheophorbide, purpurinimide, or bacteriopupurinimide. More particularly, preferred compounds of the invention include compounds of the formula: or a phamaceutically acceptable derivative thereof, wherein: R.sub.1 and R.sub.2 are each independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, --C(O)R.sub.a or --COOR.sub.a or --CH(CH.sub.3)(OR.sub.a) or -- CH(CH.sub.3)(O(CH.sub.2).sub.nXR.sub.a) where R.sub.a is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl where R.sub.2 may be CH.dbd.CH.sub.2, CH(OR.sub.20)CH.sub.3, C(O)Me, C(.dbd.NR.sub.20)CH.sub.3 or CH(NHR.sub.20)CH.sub.3; where X is an aryl or heteroaryl group; n is an integer of 0 to 6; where R.sub.20 is methyl, butyl, heptyl, docecyl or 3,5-bis(trifluoromethyl)- benzyl; and R.sub.1a and R.sub.2a are each independently hydrogen or substituted or unsubstituted alkyl, or together form a covalent bond R.sub.3 and R.sub.4 are each independently hydrogen or substituted or unsubstituted alkyl; R.sub.3a and R.sub.4a are each independently hydrogen or substituted or unsubstituted alkyl, or together form a covalent bond; R.sub.5 is hydrogen or substituted or unsubstituted alkyl; R.sub.5 is hydrogen or substituted or unsubstituted alkyl; [0022] R.sub.6 and R.sub.6a are each independently hydrogen or substituted or unsubstituted alkyl, or together form .dbd.O; R.sub.7 is a covalent bond, alkylene, azaalkyl, or azaaraalkyl or .dbd.NR.sub.20 where R.sub.20 is --CH.sub.2X--R.sup.1 or --YR.sup.1 where Y is an aryl or heteroaryl group; R.sub.8 and R.sub.8a are each independently hydrogen or substituted or unsubstituted alkyl or together form .dbd.O; R.sub.9 and R.sub.10 are each independently hydrogen, or substituted or unsubstituted alkyl and R.sub.9 may be -- CH.sub.2CH.sub.2COOR.sub.a where R.sub.a is an alkyl group; each of R.sub.a-- R.sub.10, when substituted, is substituted with one or more substituents each independ- ently selected from Q, where Q is alkyl, haloalkyl, halo, pseudohalo, or --COOR.sub.b where R.sub.b is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, araalkyl, or OR.sub.c where R.sub.c is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, or aryl or CONR.sub.dR.sub.e where R.sub.d and R.sub.e are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, or aryl, or NR.sub.fR.sub.g where R.sub.f and R.sub.g are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, or aryl, or .dbd.NR.sub.h where R.sub.h is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, or aryl, or is an amino acid residue; each Q is independently unsubstituted or is substituted with one or more substituents each independently selected from Q.sub.1, where Q.sub.1 is alkyl, haloalkyl, halo, pseudohalo, or --COOR.sub.b where R.sub.b is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, araalkyl, or OR.sub.c where R.sub.c is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, or aryl or CONR.sub.dR.sub.e where R.sub.d and R.sub.e are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, or aryl, or NR.sub.fR.sub.g where R.sub.f and R.sub.g are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, or aryl, or .dbd.NR.sub.h where R.sub.h is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, or aryl, or is an amino acid residue, with the proviso that the compound contains at least one Q containing a .sup.124I-phenyl group. These compounds provide high tumor absorption with appropriate radiological life for tumor imaging. The invention also includes the method of using these compounds for imaging and simultaneously permit nuclear imaging guided implantation of optical fibers within deep tumors would enable to treat by PDT.

Adduct of Fluorescent Dye and Tumor Avid Tetrapyrrole

Patent(s): Pending
U.S. Patent Application Number: 11/632,433
International Issued Patents: EP
International Pending Applications: KR, JP, IN, HK, CN, AU

Summary: A compound having preferential localization in tumor tissue relative to normal tissue, a preferential electromagnetic absorption at a wavelength between about 660 and 900 nm, and a fluorescence at a wavelength shifted from the preferential absorption by at least +30 nm and preferably at least +50 nm. The compound further preferably destroys tumor tissue in which it is absorbed when exposed to light at its preferential absorption wavelength. In a preferred embodiment of the invention, the compound is a conjugate of a tumor avid tetrapyrrole compound with a fluorescent dye, and more preferably the fluorescent dye is an indocyanine dye such as indocyanine green. The tumor avid tetrapyrrole compound is preferably a porphyrin derivative selected from the group consisting of chlorins, bacteriochlorins, purpurins and derivatives thereof.

Detail: The invention comprises a compound having preferential localization in tumor tissue relative to normal tissue, a preferential electromagnetic absorption at a wavelength between about 660 and 900 nm, and a fluorescence at a wavelength shifted from the preferential absorption by at least +30 nm and preferably at least +50 nm. The compound further preferably destroys tumor tissue in which it is absorbed when exposed to light at its preferential absorption wavelength. In a preferred embodiment of the invention, the compound is a conjugate of a tumor avid tetrapyrrole compound with a fluorescent dye, and more preferably the fluorescent dye is an indocyanine dye such as indocyanine green. The tumor avid tetrapyrrole compound is preferably a porphyrin derivative selected from the group consisting of chlorins, bacteriochlorins, purpurins and derivatives thereof (collectively "porphyrins") and usually has the generic formula: where:R.sub.1 is, substituted or unsubstituted, --CH.dbd.CH.sub.2, --CHO, COOH, or where:R.sub.1 is, substituted or unsubstituted, --CH.dbd.CH.sub.2, --CHO, COOH, or ##STR00002## where R.sub.9=--OR.sub.10 where R.sub.10 is lower alkyl of 1 through 8 carbon atoms, or --(CH.sub.2--O).sub.nCH.sub.3; R.sub.2, R.sub.2a, R.sub.3, R.sub.3a, R.sub.4, R.sub.5, R.sub.5a, R.sub.7, and R.sub.7a are independently hydrogen, lower alkyl, substituted lower alkyl, lower alkylene or substituted lower alkylene or two R.sub.2, R.sub.2a, R.sub.3, R.sub.3a, R.sub.5, R.sub.5a, R.sub.7, and R.sub.7a groups on adjacent carbon atoms may be taken together to form a covalent bond or two R.sub.2, R.sub.2a, R.sub.3, R.sub.3a, R.sub.5, R.sub.5a, R.sub.7, and R.sub.7a groups on the same carbon atom may form a double bond to a divalent pen- dant group; R.sub.2 and R.sub.3 may together form a 5 or 6 membered heterocyclic ring containing oxygen, nitrogen or sulfur; R.sub.6 is --CH.sub.2--, --NR.sub.11--, where R.sub.11 is, substituted or unsubstituted, lower alkyl, or lower alkylene; or a R.sub.6 is a covalent bond; R.sub.8 is --(CH.sub.2).sub.2CO.sub.2R.sub.12 where R.sub.12 is, substituted or unsubstituted, lower alkyl, lower alkylene or --NH.sub.2. Usually at least one of R.sub.1, R.sub.2a, R.sub.3, R.sub.3a, R.sub.4, R.sub.5, R.sub.5a, R.sub.7, R.sub.7a, R.sub.8, R.sub.9, R.sub.10, R.sub.11, or R.sub.12 is substituted with a dye fluorescing at a wave length of from about 800 to about 900 nm. The fluorescent dye may be any non-toxic dye that causes the conjugate to preferentially emit (fluoresce) at a wave length of 800 to about 900 mu. Such dyes usually have at least two resonant ring structures, often chromophores, connected together by an intermediate resonant structure of conjugated double bonds, aromatic carbon rings, resonant heterocylic rings, or combinations thereof Examples of such dyes include bis indole dyes wherein two indole or modified indole ring structures are connected together at their 32 and 21 carbon atoms respectively by an intermediate resonant structure as previously described. Such dyes are commonly known as tricarboclyanine dyes. Such dyes almost always have at least one, and usually at least two, hydrophilic substituents making the dye water soluble. Such water solubility facilitates entry of the structure into an organism and its cellular structures and reduces the likelihood of toxicity because of reduced storage in fatty tissues and fast elimination from the system. The intermediate resonant structure usually contains a plurality of double bonded carbon atoms that are usually conjugated double bonds and may also contain unsaturated carbocyclic or heterocyclic rings. Such rings permit conjugation to the porphyrin structure without significantly interfering with the resonance of the intermediate structure. The invention further includes a method for using the compound of the invention for detection of tumors by injection into an organism, allowing sufficient time for preferential absorption into tumor tissue, exposing the absorbed compound to light at its preferential absorption wavelength and detecting the location of emissions from the preferentially absorbed compound to locate tumor tissue and includes a method for treating tumor tissue by injection into an organism, allowing sufficient time for preferential absorption into tumor tissue, and exposing the absorbed compound to light at its preferential absorption wavelength to cause destruction of tumor tissue. It is to be understood that the destruction of tumor tissue in accordance with the invention may be accomplished at a part of the method for detection.

Fluorinated Photosensitizers Related to Chlorins and Bacteriochlorins for Photodynamic Therapy

Patent(s): Issued
U.S. Patent Number: 7,166,719
Date Issued: January 23, 2009
International Issued Patents: EP

Summary: Provided herein are compounds for detection, diagnosis and treatment of target tissues or target compositions, including hyperproliferative tissues such as tumors, using photodynamic methods. In particular, photosensitizer compounds that collect in hyperproliferative tissue are provided. In another embodiment, compounds that absorb light at a wavelength of from about 700 to about 850 nm are provided. In a further embodiment, compounds that are detectable by magnetic resonance imaging are provided.

Detail: Provided herein are fluorinated compounds for use in PDT, diagnostic and therapeutic applications. In one embodiment, the compounds preferentially absorb into target tissue, including hyperproliferative tissue. In another embodiment, the compounds absorb light at a wavelength of between about 700 and about 850 nm. In one embodiment, provided herein are tetrapyrrole compounds containing a fluorinated substituent where the compound is a chlorin or bacteriochlorin. Also provided herein are compounds of the formula: ##STR00001## or a pharmaceutically acceptable derivative thereof, where R.sub.1, R.sub.1a, R.sub.2, R.sub.2a, R.sub.3, R.sub.3a, R.sub.4, R.sub.4a, R.sub.5, R.sub.6, R.sub.6a, R.sub.8, R.sub.8a, R.sub.9, and R.sub.10 are independently hydrogen, lower alkyl of about 1 through 8 carbon atoms, lower alkenyl of about 1 through 8 carbon atoms, or lower alkyl of about 1 through 8 carbon atoms substituted with at least one halogen, hydroxy, carboxy, ester, aromatic, heterocyclic, ether, amide, or amine group; where two R.sub.1, R.sub.1a, R.sub.2, R.sub.2a, R.sub.4, R.sub.4a, R.sub.6, R.sub.6a, R.sub.8, R.sub.8a R.sub.9 and R.sub.10 groups on adjacent carbon atoms may be taken together to form a covalent bond or two R.sub.1, R.sub.1a, R.sub.2, R.sub.2a, R.sub.3, R.sub.3a, R.sub.4, R.sub.4a, R.sub.6, R.sub.6a, R.sub.8, and R.sub.8a groups on the same carbon atom may form a double bond to a divalent pendant group; R.sub.1 or R.sub.2 may additionally be --CH.dbd.CH.sub.2, --CHO, --COOH, -- COOR.sub.a, or ##STR00002## R.sub.7 is --CH.sub.2--, or .dbd.NR.sub.12, or a covalent bond, where R.sub.11 and R.sub.12 are independently hydrogen, lower alkyl of about 1 through 8 carbon atoms, lower alkenyl of about 1 through 8 carbon atoms, or lower alkyl of about 1 through 8 carbon atoms substituted with at least one halogen, hydroxy, carboxy, ester, aromatic, heterocyclic, ether, amino acid, amide, or amine group; provided that at least one of R.sub.1, R.sub.1a, R.sub.2, R.sub.2a R.sub.3, R.sub.3a, R.sub.4, R.sub.4a, R.sub.5, R.sub.5, R.sub.6, R.sub.6a R.sub.7, R.sub.8, R.sub.8a, R.sub.9 and R.sub.10 contains at least one fluorinated pendant group selected from the group consisting of fluorinated alkyl groups, fluorinated phenyl groups and fluorinated heterocyclic moieties. Also provided are compounds of the formula ##STR00003## or a pharmaceutically acceptable derivative thereof, where R.sub.1 and R.sub.2 are each independently substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, --C(O)R.sub.a or -- COOR.sub.a, where R.sub.a is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl; R.sub.1a and R.sub.2a are each independently hydrogen or substituted or unsubstituted alkyl, or together form a covalent bond; R.sub.3 and R.sub.4 are each independently hydrogen or substituted or unsubstituted alkyl; R.sub.3a and R.sub.4a are each independently hydrogen or substituted or unsubstituted alkyl, or together form a covalent bond; R.sub.5 is hydrogen or substituted or unsubstituted alkyl; R.sub.6 and R.sub.6a are each independently hydrogen or substituted or unsubstituted alkyl, or together form .dbd.O; R.sub.7 is a covalent bond, alkylene, azaalkyl, or azaaralkyl; R.sub.8 and R.sub.8a are each independently hydrogen or substituted or unsubstituted alkyl, or together form .dbd.O; R.sub.9 and R.sub.10 are each independently hydrogen, or substituted or unsubstituted alkyl; each of R.sub.1 R.sub.10, when substituted, is substituted with one or more substituents, in one embodiment one to five substituents, in another embodiment one, two or three substituents, each independently selected from Q, where Q is alkyl, haloalkyl, halo, pseudohalo, --COOR.sub.b where R.sub.b is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or aryl, aryl, heteroaryl, cycloalkyl, heterocyclyl, OR.sub.c where R.sub.c is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl, or aryl, CONR.sub.dR.sub.e where R.sub.d and R.sub.e are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or aryl, NR.sub.fR.sub.g where R.sub.f and R.sub.g are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl or aryl, .dbd.NR.sub.h where R.sub.h is alkyl, alkenyl, alkynyl, cycloalkyl, aralkyl or aryl, or is an amino acid residue; each Q is independently unsubstituted or is substituted with one or more substituents, in one embodiment one to five substituents, in another embodiment one, two or three substituents, each independently selected from Q.sub.1, where Q.sub.1 is alkyl, haloalkyl, halo, pseudohalo, -- COOR.sub.b where R.sub.b is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or aryl, aryl, heteroaryl, cycloalkyl, heterocyclyl, OR.sub.c where R.sub.c is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or aryl, CONR.sub.dR.sub.e where R.sub.d and R.sub.e are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or aryl, NR.sub.fR.sub.g where R.sub.f and R.sub.g are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl or aryl, or is an amino acid residue. In another embodiment the compounds are selected with the proviso that the compound contains at least one fluorine atom. Also provided are methods for detecting target tissue or target compositions. Further provided herein is a method for photodynamic therapy using the compounds provided herein. Also provided herein is a method for detecting hyperproliferative tissue using the compounds provided herein. Also provided is the use of the compounds provided herein for the treatment of target compositions or target tissue, including hyperproliferative tissue and neovascular tissue. Provided herein is also a method for detecting the presence of hyperproliferative tissue in a subject. Also provided is a method of diagnosing hyperproliferative disorders in a patient. Further provided is a method of diagnosing an infecting agent in a patient. Provided herein is also a method of generating an image of a target tissue in a subject. Also provided herein is a method of labeling a target tissue for diagnostic radiology. Further provided is a kit to treat hyperproliferative disorders. Also provided is a kit to label specific tissues for diagnostic radiology. Further provided is a combination, including a compound provided herein and a light source. Further provided is a combination including a photosensitizer compound provided herein and a magnetic resonance imaging device.

Long Wavelength Absorbing Bacteriochlorin Alkyl Ether Analogs

Patent(s): Issued
U.S. Patent Number: 6,624,187
Date Issued: September 23, 2003
International Issued Patents: GB, FR, DE
International Pending Applications: JP, CA, AU

Summary: Novel compounds that either preferentially absorb into hyperproliferative tissue and absorb light efficiently at a wavelength of between about 700 and about 850 nm or act as intermediates for such absorbing compounds. More particularly, the compounds of the invention have the formula: ##STR1## where R.sup.1, R.sup.5, R.sup.9, and R.sup.10 are independently lower alkyl of 1 to 3 carbon atoms provided that at least three of R.sup.1, R.sup.5, R.sup.9, and R.sup.10 are methyl; R.sup.2 is --OH, -- OR.sup.11, --NHR.sup.11, aryl, or -aminoacid; R.sup.3 and R.sup.4 are independently --COR.sup.11 or taken together are ##STR2## R.sup.6 and R.sup.7 are independently lower alkyl of 1 to 3 carbon atoms; R.sup.8 is O-alkyl of 1 to about 12 carbon atoms, S-alkyl of 1 to about 12 carbon atoms, --O-aryl, or --O-heterocyclic ring of 5 or 6 car- bon atoms; R.sup.11 is alkyl of 1 to 6 carbon atoms; and R.sup.12 is lower alkyl of 1 to about 12 carbon atoms, aryl, or aminoalkyl of 1 to 8 carbon atoms; provided that at least one of R.sup.8, R.sup.11, and R.sup.12 is hydrophobic and together contain at least 10 carbon atoms. The invention also includes method of making and using the compounds.

Detail: In accordance with the invention novel compounds are therefore provided that either preferentially absorb into hyperproliferative tissue and absorb light efficiently at a wavelength of between about 700 and about 850 nm or act as intermediates for such absorbing compounds. More particularly, the compounds of the invention have the formula: ##STR3## where R.sup.1, R.sup.5, R.sup.9, and R.sup.10 are independently lower alkyl of 1 to 3 carbon atoms provided that at least three of R.sup.1, R.sup.5, R.sup.9, and R.sup.10 are methyl; R.sup.2 is --OH, --OR.sup.11, --NHR.sup.11, aryl, or -aminoacid; R.sup.3 and R.sup.4 are independently --COR.sup.11 or taken together are ##STR4## R.sup.6 and R.sup.7 are independently lower alkyl of 1 to 3 carbon atoms; R.sup.8 is O-alkyl of 1 to about 12 carbon atoms and usually 1 to 8 carbon atoms, S-alkyl of 1 to about 12 carbon atoms and usually 1 to 8 carbon atoms, --O- aryl, or --O-heterocyclic ring of 5 or 6 carbon atoms; R.sup.11 is alkyl of 1 to 6 carbon atoms; and R.sup.12 is lower alkyl of 1 to about 12 carbon atoms, aryl, or aminoalkyl of 1 to 8 carbon atoms; provided that at least one of R.sup.8, R.sup.11, and R.sup.12 is hydrophobic and together contain at least 10 carbon atoms. Especially suitable absorbing compounds of the invention have at least one pendant group sufficiently hydrophobic to cause the compound to enter hyperproliferative tissue. Such pendant group usually includes an aliphatic or aromatic structure containing at least two carbon atoms and, when acting as the primary hydrophobic moiety, usually contains at least seven carbon atoms. The compound may have more than one pendant hydrophobic group. Examples of specific structures that are able to preferentially collect in hyper- proliferative tissue are those compounds wherein R.sup.2 is --OR.sup.11 and R.sup.11 is n-alkyl of 3 to about 10 carbon atoms, e.g. n-propyl; those compounds wherein R.sup.3 and R.sup.4 taken together are ##STR5## where R.sup.12 is alkyl of 3 to about 10 carbon atoms, e.g. n-hexyl; and those compounds where R.sup.8 is O-alkyl of 3 to about 10 carbon atoms, e.g. n-heptyl. In preferred compounds of the invention, R.sup.1, R.sup.5, R.sup.7, R.sup.9, and R.sup.10 are all methyl and R.sup.6 is ethyl. The invention also includes the methods for treating and detecting hyperproliferative tissue such as tumors, by exposing the tissue to an amount of the absorbing compound of the invention which is effective for detecting or reducing the growth of the tissue upon exposure to sufficient light at a wave length between 700 and 850 nm. In a pre- ferred embodiment, the invention further includes facile approaches for the preparation of bacteriopurpurin-18-N-alkyl imides and their conversion into the corresponding 3- deacetyl-3-alkylether analogs with carboxylic acid, ester or amide functionalities and for the preparation of bacteriochlorin p.sub.6 and its conversion into a series of alkyl ether analogs with carboxylic acid, ester or amide functionalities. The invention also includes use of these novel bacteriochlorins for the treatment of cancer or other non-oncological diseases by photodynamic therapy. The compounds of the invention are unique in that they are bacteriochlorins, i.e., they have diagonally opposite fused reduced pyrrol rings (rings b and d) and have an alkyl ether group attached to the "a" fused pyrrol ring. The compounds of the invention have peak light absorbance at a wave length of between about 700 and about 850 nm and usually between 750 and 825 nm. The compounds further are uniquely stable due to the presence of an electron withdrawing group attached to the "c" fused pyrrol ring. The electron withdrawing group is preferably a stable six member fused imide ring, or the substituent R.sub.4 on ring "c" is the radical --COR.sup.11 where R.sup.11 is --OH; --O-alkyl of 1 to about 10 carbon atoms; --NH-alkyl of 1 to about 12 carbon atoms; aryl, electron withdrawing at its position of attachment; or an amino acid radical. The compounds of the invention suitable for injection into a mammal for preferential accumulation in hyper- proliferative tissue also have at least one and preferably at least two pendant hydrophobic groups that assist in causing the compound to enter the hyperproliferative tissue. "Hyperproliferative tissue" as used herein means tissue that grows out of control and includes tumors and unbridled vessel growth such as blood vessel growth found in age related macular degeneration. In using compounds of the invention for photodynamic therapy, the compounds are usually injected into the mammal, e.g. human, to be diagnosed or treated. The level of injection is usually between about 0.1 and about 0.5 .mu.mol/kg of body weight. In the case of treatment, the area to be treated is exposed to light at the desired wave length and energy, e.g. from about 100 to 200 J/cm.sup.2. In the case of detection, fluorescence is determined upon exposure to light at the desired wave length. The energy used in detection is sufficient to cause fluorescence and is usually significantly lower than is required for treatment. The invention includes a method for preparing compounds of the invention without requiring complex and inefficient synthesis steps. For the preparation of bacteriopurpurin 1 (FIG. 2), the n-propyl alcohol extract of Rb Sphaeroides, which contains bacteriochlorophyll-a (.lambda..sub.max 774 nm), was directly reacted with KOH/n-propanol in presence of air. It was immediately treated with HCl or H.sub.2 SO.sub.4 (pH 2 to 3) to produce bacteriopurpurin-18 propyl ester and the related carboxylic acid 2 which in reacting with H.sub.2 SO.sub.4 /n-propanol can be converted into the related propyl ester analog 1. Compared to the naturally occurring bacteriochlorophyll-a, bacteriopurpurin with a fused anhydride ring system 2 (813 nm) was found to be extremely stable at room temperature. However, it was found to be unstable in vivo. Compared to the anhydride ring system, compounds with fused imide ring system in other compounds have shown stability in vivo. For example, among non-porphyrin systems, amonafide, an imide derivative and its structural analogs are reported as anti-neoplastic agents in vitro as well as in vivo with good stability. While we could not know how this might apply to non-porphyrin systems, we investigated the effect of such cyclic structures in the bacteriochlorin system. Initially we followed our own methodology developed for the preparation of purpurin-18-N-alkylimides (U.S. Pat. No. 5,952,366 incorporated herein by reference). Unfortunately, that approach produced a complex reaction mixture. Thus, in a modified approach, bacteriopurpurin-a 2 was first reacted with an alkyl amine (e.g. n-hexyl amine). The formation of the intermediate amide was monitored by spectrophotometry and analytical thin layer chromatography. The intermediate amide analog 3, obtained as a mixture of two isomers, was reacted with diazomethane, and the solvent was removed under vacuum. The residue so obtained was re-dissolved in tetrahydrofuran, and solvent was evaporated. This procedure was repeated several times until the disappearance of the absorption at 765 nm and appearance of a new peak at 822 nm. The bacteriochlorin-N-hexylimide so obtained had the required spec- troscopic characteristic necessary for an "ideal" photosensitizer, and was stable in vitro and in vivo, but unfortunately did not produce any significant in vivo PDT efficacy. Our next step was to investigate the effect of alkyl ether substitutions in bacteriochlorin series since similar substitutions in non-bacteriochlorin systems sometimes enhanced tumor localization see e.g. U.S. Pat. Nos. 5,459,159 and 5,952,366 both of which are incorporated herein by reference. In order to introduce various alkyl ether substituents at the peripheral position, the bacteriopurpurinimide 4 containing an acetyl group at position 3 was first reduced to the corresponding 3-(1-hydroxyethyl) 5 by reacting with sodiumborohydride in excellent yield, which on dehydration by refluxing in odichlorobenzene for 5 min produced the vinyl analog 6 in >80% yield. For the preparation of the desired alkyl ether analog, the hydroxy analog 5 was treated with HBr/acetic acid, and the intermediate bromo- derivative was immediately reacted with various alkyl alcohols, and the corresponding alkyl ether analogs (e.g. 7) were isolated in about 70% yield. Under similar reaction conditions, the vinyl bacteriopurpurin-imide 6 also produced the desired alkyl ether derivatives, but in low yield (FIG. 2). This invention also deals with the synthesis of the alkyl ether analogs of bacteriopurpurin p.sub.6 and their amide derivatives (.lambda..sub.max 760 nm). For the preparation of these compounds, bacteriopurpurin-18 methyl ester 8 was reacted with aqueous sodium carbonate or sodium hydroxide/THF solution. The dicarboxylic acid 9 obtained by the cleavage of the fused anhydride ring system was converted into the corresponding methyl ester 10 upon reacting with diazomethane. Reaction of 10 with sodium borohydride and subsequent treatment with HBr/acetic acid and various alkyl alcohols will generate the desired alkyl ether derivatives 11 (FIG. 3). The regiospecific hydrolysis of the propionic ester functionality into the corresponding carboxylic acid and subsequent conversion into various amides could generate a series of amide analogs. The following examples serve to illustrate and not limit the present invention; melting points are uncorrected and were measured on a Fisher Johns melting point apparatus. Electronic absorption spectra were measured on a Genesis 5 spectrophotometer. Mass spectra were measured at the Department of Molecular and Cellular Biophysics, RPCI, Buffalo. NMR spectra were obtained with a 400 MHz Bruker instrument at the NMR facility of the institute. Samples were dissolved in CDCl.sub.3 and the chemical shifts are expressed in .delta. ppm relative to CHCl.sub.3 at 7.258 ppm. Analytical thin layer chromatography was used to monitor the reactions and to check the purity of the desired compounds on cut strips of Merck or Whatman silica gel 60F254 precoated (0.25 mm thickness) plastic backed sheets. For column chromatography Silica gel (70- 230 mesh) was used for normal gravity column. Tetrahydrofuran (THF) was distilled over sodium, and dichloromethane over calcium hydride before use. The phrase "dried, filtered and evaporated" means drying over sodium sulfate, filtering through glass wool, and then evaporating off the solvent using a Buchi rotary evaporator under house vacuum or high vacuum achieved with an oil pump.

Alkyl Ether Analogs of Chlorins Having an N-substituted Imide Ring

Patent(s): Issued
U.S. Patent Number: 5,952,366
Date Issued: September 14, 1999
International Issued Patents: CA
International Pending Applications: JP

Summary: Compounds having the generic formula: ##STR1## where R.sup.1, R.sup.2 and R.sup.3 are independently alkyl of 3 through about 10 carbon atoms; provided that, R.sup.1 and R.sup.2 together contain at least six carbon atoms. The compounds have utility in photodynamic therapy in treatment of tumors and other diseases. The invention includes a method of treatment by contacting a tumor with the compound and then exposing the tumor to light.

Detail: In accordance with the invention, a new series of compounds is therefore provided, which have good antitumor activity and which absorb at relatively long wave lengths of light. More particularly, the compounds have the generic formula: ##STR2## Where R.sup.1, R.sup.2, and R.sup.3 are independently alkyl of 3 through about 10 carbon atoms; provided that, R.sup.1 and R.sup.2 together contain at least six carbon atoms. R.sup.3 is preferably methyl or ethyl and R.sup.2 and R.sup.3 are preferably alkyl of 3 through 8 carbon atoms.

Multimodality Agents for Tumor Imaging and Therapy

Patent(s): Pending
U.S. Patent Application Number: PCT/US2008/010609

Summary: A compound that is a conjugate of an antagonist to an integrin expressed by a tumor cell and at least one of a tumor avid tetrapyrollic photosensitizer, a fluorescent dye, and a radioisotope labeled moiety wherein the radioisotope is 11C, 18F, 64Cu, 124I, 99Tc, 111In or GdIII and its method of use for diagnosing, imaging and/or treating hyperproliferative tissue such as tumors. Preferably the photosensitizer is a tumor avid tetrapyrollic photosensitizer, e.g. a porphyrin, chlorin or bacteriochlorin, e.g. pheophorbides and pyropheophorbides. Such conjugates have extreme tumor avidity and can be used to inhibit or completely destroy the tumor by light absoption. The integrin is usually αvβ3, α5βl, αvβ5, α4βl, or α2βl. Preferably, the antagonist is an RGD peptide or another antagonist that may be synthetic such as a 4-{2-(3,4,5,6-tetra-hydropyrimidin- 2-ylamino) ethyloxy}-benzoyl]amino-2-(S)-amino- ethyl-sulfonylamino group. Such compounds provide tumor avidity and imaging ability thus permitting selective and clear tumor imaging.

Detail: The invention is a compound that is a conjugate of an antagonist to an integrin expressed by a tumor cell and at least one of a fluorescent dye, or a tumor avid tetrapyrollic photosensitizer, that may be complexed with an element X where X is a metal selected from the group consisting of Zn, In, Ga, Al, or Cu or a radioisotope labeled moiety wherein the radioisotope is selected from the group consisting of 11C, 18F, 64Cu, 124I, 99Tc, 111In and GdIII and its method of use for diagnosing, imaging and/or treating hyperproliferative tissue such as tumors and other uncontrolled growth tissues such as found in macular degeneration. In a preferred embodiment, the compound is a tumor avid tetrapyrollic photosensitizer compound conjugated with an antagonist for an integrin expressed by a tumor cell. Such compounds have extreme tumor avidity and can be used to inhibit or completely destroy the tumor by light absoption. The tetrapyrollic photosensitizer is usually a porphyrin, chlorin or bacteriochlorin including pheophorbides and pyropheophorbides and the integrin is usually an αvβ3, α5βl, αvβ5, α4βl, or α2βl integrin. In a preferred embodiment, the antagonist is an RGD peptide or another antagonist that may be synthetic such as a 4-{2-(3,4,5,6- tetra-hydropyrimidin-2- ylamino)ethyloxy}-benzoyl]amino-2-(S)-aminoethyl-sulfony- lamino group. The integrin is most commonly αvβ3. The antagonist may be combined with an imaging compound such as a fluorescent dye or a structure including an ele- ment X where X is a metal selected from the group consisting of Zn, In, Ga, Al, or Cu or a radioisotope labeled moiety wherein the radioisotope is selected from the group consisting of 11C, 18F, 64Cu, 124I, 99Tc, 111In. Such compounds provide tumor avidity and imaging ability thus permitting selective and clear tumor imaging. Objects of this invention include:1. Efficient synthetic methodologies for the preparation of αvβ3 target-specific photosensitizers.(a) RGD conjugated photosensitizers(b) Integrin- antagonist conjugated photosensitizers.2. Multimodality agents (photosensitizer-cyanine dye conjugates) with and without RGD peptide. 3. Target-specific PET/fluorescence imaging agent.

Silica Nanoparticles Postloaded with Photosensitizers for Drug Delivery in Photodynamic Therapy

Patent(s): Pending
U.S. Patent Application Number: PCT/US2009/001029

Summary: A nanoparticle including a polysiloxane base having an exterior surface and having a photosensitizer at least partly exposed at its exterior surface, said photosensitizer being secured to the exterior surface by loading the photosensitizer onto the surface after for- mation of the ploysiloxane base of the nanoparticle. The nanoparticle may have tumor targeting moieties and may be post loaded with cyanine dye. The nanoparticle preferably includes post loaded moieties providing at least two of tumor specificity, photodynamic properties and imaging capabilities and the photosensitizer is tagged with a radioisotope. A method for preparation of the nanoparticle is also provided.

Detail: In accordance with the invention, nanoparticles postloaded with photosensitizer molecules are provided to overcome the drawback of their premature release and thus enhance the outcome of PDT. In accordance with the invention, silica sol-gel based nanoparticles are provided containing at least one post-loaded photosensitizer. The photosensitizer is preferably a tetrapyrrole-based compound related to porphyrins, chlorins, bacteriochlorins, benzochlorins, benzoporphyrin derivatives, pheophorbides including pyropheophorbides, and phthalocyanines, naphthanocyanines with and without fused ring systems and derivatives of all the above. The nanoparticle may also include imaging agents, e.g. radionuclides, magnetic resonance (MR) and fluorescence imaging agents, either post-loaded or chemically bonded. The imaging agents and photosensitizers may be at a periphery (surface) of the nanoparticles to increase efficiency. Target-specific nanoparticles may be provided by incorporating biotargeting molecules such as specific antibodies at the surface that react with particular ligands to obtain target specificity. Diagnostic agents may be present in the antibody in addition to imaging agents and tumor specific photosensitizers as previously and subsequently discussed. In general, the nanoparticle of the invention has the structural formula:where the ring represents a siloxane polymer matrix. R4 is (Ri)n-(R^)n where Ri may be a labeled photosensitizer (IP) or unlabeled photosensitizer (P), cyanine dye, SPECT (single proton emission computed tomography) imaging agent, PET (positron emission tomography) imaging agent, MR imaging agent or fluorescent imaging agent at least partially available at a surface of the siloxane polymer matrix. At least one Ri or R2 group is a photosensizer, preferably a tetrapyrollic photosensitizer, e.g. porphyrins, chlorins, bacteriochlorins, benzochlorins, benzoporphyrins, pheophorbides including pyropheophorbides, and derivatives thereof. n is 0 or 1 ; provided that at least one n is 1 ; R2 is cyanine dye, SPECT, PET, MR or fluorescent imaging agent, linked targeting agent RGD, F3 peptide, carbohydrate or folic acid or labeled photosensitizer (IP) or unlabeled photosensitizer (P) post loaded so as to be at least partially embedded in the siloxane polymer matrix. RGD is a peptide that contains the Arg-Gly-Asp attachment site that recog- nizes v3 and v5 integrin receptors that play a role in angiogenesis, vascular intima thickening and proliferation of malignant tumors. At least one labeled photosensitizer (IP) or unlabeled photosensitizer (P) is present in Rj or R2 that is sufficiently embedded in the siloxane polymer matrix by postloading to prevent leaching to an extent greater than 40% upon 24 hour continuous washing in 1% bovine serum albumin (BSA).