Health Research, Inc.

University of California

Other

Thomas J Dougherty

Ravindra Kumar Pandey

William R Potter

Kenneth R Weishaupt

Peter Kanter

Zachary Grossman

Kevin M Smith

Andrei N Kozyrev

Alexander J Pallenberg

Samuel Korman

Charles Sheer

Isabelle Meunier

David A Bellnier

Nadine Jagerovic

Thomas C Dougherty

Joseph M Ryan

Fuu-Yau Shiau

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 comprising a chemical combination of a photodynamic tetra-pyrrolic compound with a plurality of radionuclide element atoms such that the compound may be used to enhance MR imaging and also be used as a photodynamic compound for use in photodynamic therapy to treat hyperproliferative tissue. The preferred compounds have the structural formula: where R, R, RR, RR, R, RR, R, R, and Rcumulatively contain at least two functional groups that will complex or combine with an MR imaging enhancing element or ion. The compound is intended to include such complexes and combinations and includes the use of such compounds for MR imaging and photodynamic therapy treatment of tumors and other hyperproliferative tissue.

[object Object]

A method for MR imaging that comprises conducting the MR imaging after injecting compositions that are chemical combination of porphyrins, chlorins, bacteriochlorins, and related tetra-pyrrolic compounds with radioactive elements such as Technetium, Gadolinium, Indiumand 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 method uses 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, Inor Gd(III) complexes of compounds of the formula: 

A process for the preparation of pyropheophorbide a and its derivatives, including 3-devinyl-3-(1'-hexyloxy)ethyl-pyropheophorbide-a, otherwise known as HPPH, is provided. The process involves treating chlorin e, in the form of its trimethyl ester, with a base, followed by heating to give pyropheophorbide a, which is converted to HPPH by treatment with acid, followed by hexyl alcohol under basic conditions.

Efficient synthesis of pyropheophorbide a and its derivatives

Pyropheophorbide compounds are injected into a host and accumulate in tumor tissue to a higher degree than surrounding normal tissues. When the pyropheophorbide compounds are exposed to a particular wavelength of light the compounds become cytotoxic and destroy the tumor or diseased tissue without causing irreversible normal tissue damage. The pyropheophorbide compounds have shown improved results as compared to drugs currently used in photodynamic therapy. Further, they absorb light further in the red, optimizing tissue penetration mad are retained in the skin for short time periods relative to other drugs used in photodynamic therapy.

Pyropheophorbides and their use in photodynamic therapy

Conjugate are formed by covalently linking a target-specific compound to pyropheophorbide compound which conjugated are injected into a host and accumulate in tumor tissue to a higher degree than surrounding normal tissues. When the pyropheophorbide compound component of the conjugate is exposed to a particular wavelength of light the compound becomes cytotoxic destroying the tumor or diseased tissue without causing irreversible normal tissue damage. The pyropheophorbide compounds have been shown to have a variety of characteristics when used in photodynamic therapy. These characteristics are further improved when the compounds are bound to a target specific component such as a ligand capable of binding to a specific cellular receptor (e.g. growth hormones and growth factors) or an antibody capable of binding to a particular antigen.

Pyropheophorbides conjugates and their use in photodynamic therapy

Purpurin-carbohydrate conjugates and their method of preparation and use for treatment of cancer cells. The conjugates have the general formula:wherein Rand Rtaken together are &#x2550;NRor are independently &#x2014;OR, where at least one Ris preferably a mono or polysaccharide moiety and R-Rare various groups formed from carbon and hydrogen and optionally oxygen and nitrogen where Rand Rmay together from a covalent bond.

Galectin recognized photosensitizers for photodynamic therapy

Long wave length absorbing bacteriochlorin alkyl ether analogs

Compositions that are a chemical combination of porphyrins, chlorins, bacteriochlorins, and related tetra-pyrrolic compounds with radioactive elements such as Technetium , Gadolinium, Indium 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 , In or Gd(III) complexes of compounds of the formula:

Chlorin and bacteriochlorin-based aminophenyl DTPA and N2S2 conjugates for MR contrast media and radiopharmaceuticals

A novel method for treating undesired hyperproliferative tissue in a mammal. The method includes the steps of: injecting the mammal with a photodynamic compound having a selective uptake in the hyperproliferative tissue and which is activated at a particular light frequency; injecting the mammal with a xanthenone-4-acetic acid or a Group I metal, Group II metal or quaternary salt thereof near the time of maximum uptake of the photodynamic compound in the hyperproliferative tissue; and exposing the hyperproliferative tissue to light at the particular frequency that activates the photodynamic compound. The method of the invention causes necrosis of the hyperproliferative tissue to an extent greater than can be obtained by either the photodynamic compound or xanthenone-4-acetic acid alone. Further and surprisingly the method enhances immune response of the mammal to the hyperproliferative tissue even after the photodynamic compound and xanthenone-4-acetic acid are no longer present in the mammal.

Method for treating hyperproliferative tissue in a mammal

A method and apparatus for injection molding of high quality thermoplastic parts is such that a conventional movable mold half is mounted on a movable platen of the injection molding machine, and a special stationary mold half is mounted on the stationary platen. The stationary mold half includes a stationary plate secured to the stationary platen, with the stationary plate including stationary mold inserts. Each stationary mold insert has a stationary mold insert surface. An A-half parting line plate is movably attached to the stationary plate, with the A-half parting line plate being movable with respect to the stationary plate and the stationary mold inserts. A driving device, such as a hydraulic cylinder, is disposed between the stationary plate and the A-half parting line plate, with the driving device driving the A-half parting line plate toward and away from the stationary plate. A control circuit is provided for controlling the driving device to control a movement of the A-half parting line plate with respect to the stationary plate.

Method for injection molding of high quality parts

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

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.

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Grand Island, NY, United States of America

Thomas J Dougherty