Health Research, Inc.

William R Potter

Thomas J Dougherty

Kenneth R Weishaupt

Ravindra Kumar Pandey

Leroy M Wood

Allan R Oseroff

Amy L Gryshuk

Lalit Goswami

Donn Boyle

Yihui Chen

Chao Liu

Mahabeer Dobhal

Janet Morgan

Tetrapyrrolic photosensitizers and imaging agent compounds having A, B, C, and D rings and having a reduced B ring and an oxidized D ring. The compounds preferably have a purity of at least 95 percent and preferably have a fused system connected at an unsaturated carbon atom of the C ring nearest the D ring and at the unsaturated carbon atom between the C and D rings. The invention also includes a method of making the compounds at over 95 percent yield by starting with a B and D ring oxidized tetrapyrollic compound and dissolving it in a halogenated hydrocarbon solvent and treating it with sufficient nitroalkane solution of FeCl6HO to oxidize the D ring and separating the resulting organic layer and drying.

B ring reduced-D ring oxidized tetrapyrrolic photosensitizers for photodynamic therapy and tumor imaging

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.

Fluorinated photosensitizers related to chlorins and bacteriochlorins for photodynamic therapy

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.

Adduct of fluorescent dye and tumor avid tetrapyrrole

A tetrapyrollic photosensitizer compound having at least one pendant &#x2014;CHCHCON(CHCON(CHCOOH))or &#x2014;N(CHCOOH)group or esters thereof said tetrapyrollic compound being a chlorin, bacteriochlorin, porphyrin, pyropheophorbide, purpurinimide, or bacteriopurpurinimide. Desirably the compound has the formula: or a pharmaceutically acceptable derivative thereof, wherein R-Rand Rare various substituents and Ris substituted or unsubstituted &#x2014;CHCHCON(CHCON(CHCOOH)); or &#x2014;N(CHCOOH). The invention also includes a method of treatment by photodynamic therapy by treatment with light after injecting the compound and a method of imaging by fluorescence after injection of the compound.

Water soluble tetrapyrollic photosensitizers for photodynamic therapy

A tetrapyrollic photosensitizer compound having at least one pendant &#x2014;CHCHCON(CHCON(CHCOOH))or &#x2014;N(CHCOOH)group or esters thereof said tetrapyrollic compound being a chlorin, bacteriochlorin, porphyrin, pyropheophorbide, purpurinimide, or bacteriopurpurinimide. Desirably the compound has the formula: or a phamaceutically acceptable derivative thereof, wherein R-Rand Rare various substituents and Ris substituted or unsubstituted &#x2014;CHCHCON(CHCON(CHCOOH)); or &#x2014;N(CHCOOH). The invention also includes a method of treatment by photodynamic therapy by treatment with light after injecting the compound and a method of imaging by fluorescence after injection of the compound.

The present invention relates to an apparatus which includes a polypod support which includes a fiber optic supporting platform. The fiber optic supporting platform includes an opening. The apparatus further includes at least three legs forming a tripod, each of the legs having two ends, a first end being secured to the fiber optic supporting platform and the second end being adapted for attachment to the skin of the patient, a first tube having an outer diameter, a second tube having an outer diameter and an inner diameter, where the inner diameter of the second tube surrounds the outer diameter of the first tube and where the outer diameter of the second tube is slidably mounted within the opening of the fiber optic surrounding platform and a fiber optic.

Fiber optic positioner

An apparatus that efficiently and accurately directs or splits a non-polarized light beam input from a fiber optic into one, two, four or eight output beams wherein the light beam input is passed through a collimator, the apparatus uses non-polarizing beam splitters and the output beams are coupled to fiber optics using a lens matched to divergence of the beam to direct the beam into the fiber optic and uses an iris diaphragm attenuator to adjust the energy of the output beam prior to its entry into the fiber optic.

Light beam splitter

Long wave length absorbing bacteriochlorin alkyl ether analogs

A carotene conjugate of the formula: ##STR1## where R.sup.1 is hydrogen or methyl; R.sup.2 is: ##STR2## R.sup.3, R.sup.4 and R.sup.5 are independently, hydrogen, methyl or ethyl; R.sup.6 and R.sup.7 are independently --R.sup.13, --OR , --C(R.sup.6)(O), --C(R.sup.16).sub.2 OR.sup.13, --CH.dbd.CHR.sup.13, or --(CH.sub.2)R.sup.14 ; R.sup.8 is --R.sup.13, --OR.sup.13, --C(R.sup.16)(O), --C(R.sup.16).sub.2 OR.sup.13, --CH.dbd.CHR.sup.13, or --(CH.sub.2)R.sup.14 or taken with R.sup.10 is .dbd.O; R.sup.9 is --R.sup.13, --OR.sup.13, --C(R.sup.16)(O), --C(R.sup.16).sub.2 OR.sup.13, --CH.dbd.CHR.sup.13, or --(CH.sub.2)R.sup.14 or taken with R.sup.10 is a chemical bond; R.sup.10 is --R.sup.13, --OR.sup.13, --C(R.sup.16)(O) , --C(R.sup.16).sub.2 OR.sup.13, --CH.dbd.CHR.sup.13, or --(CH.sub.2)R.sup.14 or taken together with R.sup.9 is a chemical bond or taken with R.sup.8 is .dbd.O; R.sup.11 is R.sup.13, or --OR.sup.13 ; R.sup.12 is --C(R.sup.13).sub.2 C(Y)--, --C(O)O(O)C--, --C(NR.sup.13)O(O)C--, or --C(O)N(R.sup.15)--C(O)--; R.sup.13 is, independently at each occurrence, hydrogen or lower alkyl of from 1 through about 10 carbon atoms; R.sup.14 is an amino acid residue, R.sup.15 is --R.sup.13, --R.sup.14, or --C(O)NHR.sup.13 ; R.sup.16 is, independently at each occurrence, hydrogen or lower alkyl of 1 to about 4 carbon atoms and Y is .dbd.O, .dbd.S, or 2H--.

Carotene analogs of porphyrins, chlorins and bacteriochlorins as

An apparatus that efficiently and accurately splits a laser beam input into eight or more outputs where the beam energies of the output beams are within ten and preferably within five percent of each other. The apparatus includes an arrangement of at least seven beam splitters each of which can split an incident laser beam into two exit beams of equal energy at a particular incident angle. At least some of the splitters have different particular incident angles but the particular incident angle of the first splitter is used as the incident angle for all splitters. The exit beams of the first splitter are directed to second and third splitters that have particular incident angles relatively close to the particular incident angle of the first splitter when compared with the relationship of the particular incident angle of the first splitter to the particular incident angles of the remaining splitters.

Laser beam splitter

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.

Alkyl ether analogs of chlorins having an N-substituted imide ring

Method and apparatus for stabilizing a fiber optic relative to the skin surface of a patient so that radiation from the fiber optic strikes a defined surface area on the skin independently of patient movement. The apparatus comprises a polypod support having a fiber optic supporting platform and at least three legs to form a tripod. Each of the legs has two ends, a first of which is secured to the fiber optic supporting platform and the second of which is securely attached to the skin of the patient, either directly or by means of a foot attached to the second end. The method of the present invention comprises attaching a polypod, as above described, to the skin of a patient and irradiating a defined surface area by means of an end of a fiber optic held by the polypod support.

A submersible lens fiberoptic assembly for PDT treatment includes an optical fiber, a fiber jacket, a ball lens made of zirconia and a housing. This fiberoptic assembly is simple and inexpensive to manufacture, and has a high quality of output light beam. A submersible lens fiberoptic assembly for PDT treatments is also disclosed which uses a hemisphere ball lens for treatment of areas inaccessible to a normal 'forward looking' lens.

Submersible lens fiberoptic assembly for use in PDT treatment

To obtain tumor-selective, photosensitizing drugs useful in the localization of neoplastic tissue and treatment of abnormal neoplastic tissue such as tumors, one of two methods is used. In the first method, a hydrolyzed mixture of the products of reaction of hematoporphyrin with acetic acid and sulfuric acid is cycled through a microporous membrane system to exclude low molecular weight products. In the second method, drugs are synthesized or derived from other pyrrole compounds. The drugs: (1) include two covalently bound groups, each with four rings, some of which are pyrroles such as phlorins, porphyrins, chlorins, substituted pyrroles, substituted chlorins or substituted phlorins, each group being arranged in a ring structure, connected covalently to another group and have a triplet energy state above 37.5 kilocalories per mole; (2) are soluble in water, forming an aggregate of over 10,000 molecular weight in water and have an affinity for each other compared to serum protein such that 10 to 100 per cent remain self aggregated in serum protein; and (3) are lipophyllic and able to disaggregate and attach to cell plasma, nuclear membrane, mitochondria, lysosomes and tissue. The drug obtained by the first method has an empirical formula of approximately C.sub.68 H.sub.70 N.sub.8 O.sub.11 or C.sub.68 H.sub.66 N.sub.8 O.sub.11 Na.sub.4. Neoplastic tissue retains the drug after it has cleared normal tissues and illumination results in necrosis. Moreover, other photosensitizing materials may be combined with a carrier that enters undesirable tissues and cells of the reticular endothelial system such as macrophages. These photosensitizing materials: (1) must have a triplet energy state above 3.5 kilocalories per mole; (2) cannot be easily oxidized; and (3) not physically quench any required energy state. Preferably, this photosensitizing material should be li

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Grand Island, NY, United States of America

William R Potter