Fluorochemical targeted therapies

Abstract

The present invention is directed to compositions and methods targeting cells in a subject harboring conditions or at risk for conditions that would benefit from gas-based diagnostic and therapy. The present invention relates to the use of fluorochemical compositions and methods of delivery that result in retention of the fluorochemical composition and any bioactive agent, including gaseous substances, delivered in combination with the fluorochemical composition.

What is claimed is: 
     
         1 . A theranostic composition comprising a fluorocarbon, a fluorophore, and a biological molecule. 
     
     
         2 . The theranostic composition of  claim 1  further comprising an emulsifying agent. 
     
     
         3 . The theranostic composition of  claim 1  or  2  further comprising oxygen. 
     
     
         4 . The theranostic composition of any one of  claims 1 - 3 , wherein said fluorocarbon is perfluorooctyl bromide. 
     
     
         5 . The theranostic composition of any one of  claims 1 - 4 , wherein said fluorophore is a phthalocyanine dye with an absorbance maximum of about 680 nm to about 776 nm and an emission maximum of about 685 nm to about 792 nm. 
     
     
         6 . The theranostic composition of  claim 5 , wherein said phthalocyanine dye is IRDye® 700DX or IRDye® 800CW. 
     
     
         7 . The theranotic composition of any one of  claims 1 - 6 , wherein said biological molecule is selected from the group consisting of a protein with an Arg-Gly-Asp tripeptide motif (RGD), an antibody, antibody fragment, a soluble receptor, a receptor fusion protein, a receptor-Fc-fusion protein, and tyrosine kinase inhibitor. 
     
     
         8 . The theranostic composition of  claim 7 , wherein said biological molecule is nintedanib or afatinib. 
     
     
         9 . The theranostic composition of  claim 7 , wherein said biological molecule is panitumumab, cituximab or an RGD-containing polypeptide. 
     
     
         10 . The theranostic composition of any one of  claims 2 - 9 , wherein said emulsifying agent is lecithin or egg yolk phospholipids. 
     
     
         11 . The theranostic composition of any one of  claims 1 - 10 , wherein said biological molecule is covalently bound to said fluorophore. 
     
     
         12 . A theranostic composition comprising:
 a. oxygenated perfluorooctyl bromide;   b. IRDye® 700DX or IRDye® 800CW; and   c. an RGD peptide,   
       wherein said RGD peptide is covalently bound to said IRDye® 700DX or IRDye® 800CW. 
     
     
         13 . A theranostic composition comprising:
 a. oxygenated perfluorooctyl bromide;   b. IRDye® 700DX or IRDye® 800CW; and   c. cituximab,   
       wherein said cituximab is covalently bound to said IRDye® 700DX or IRDye® 800CW. 
     
     
         14 . The theranostic composition of  claim 12  or  claim 13 , wherein said theranostic composition is a liquid, aerosol or emulsion. 
     
     
         15 . A theranostic composition of any one of  claims 1 - 14  for use in the treatment of cancer. 
     
     
         16 . A theranostic composition of any one of  claims 1 - 14  for use in the treatment of a fibrosis. 
     
     
         17 . A method of imaging or killing a cell comprising administering an amount of a fluorochemical composition, wherein the fluorochemical composition comprises a perfluorocarbon, wherein said cell is ex vivo or in vivo. 
     
     
         18 . The method of  claim 16 , wherein the cell is an epithelial cell, a mesodermal or mesenchymal cell, a cancer cell, a stroma cell, a fibroblast, a macrophage, or a myofibroblast. 
     
     
         19 . The method of  claim 16 , wherein the fluorochemical composition comprises a gas therapeutic. 
     
     
         20 . The method of  claim 16 , wherein the fluorochemical composition comprises a biological molecule. 
     
     
         21 . The method of  claim 20 , wherein a label is covalently linked to the biological molecule. 
     
     
         22 . The method of  claim 16 , wherein the fluorochemical composition comprises an emulsion agent. 
     
     
         23 . The method of  claim 19 , wherein the gas therapeutic is selected from the group consisting of oxygen, carbon dioxide, nitrogen, helium, nitric oxide, hydrogen sulphide, neon, argon, krypton, xenon, radon, sulfur hexafluoride, carbon monoxide, hydrogen, chlorine, fluorine, ethane, and combinations thereof. 
     
     
         24 . The method of  claim 21 , wherein the biological molecule is selected from the group consisting of antibody, an antibody fragment, a receptor fusion protein, a trap molecule, a ligand, a fragment of a ligand, a ligand fusion protein, a soluble receptor, a small molecule, a tyrosine kinase inhibitor, and a peptide. 
     
     
         25 . The method of  claim 21 , wherein the label is selected from the group consisting of a quantum dot, a lanthanide series chelate, a fluorescein derivative, a rhodamine derivative, a coumarin derivative, a cyanine derivative, a near infra-red probes, an IRDye® 800CW, an IRDye® 700DX, an IRDye® 680LT, and an IRDye® 680RD. 
     
     
         26 . The method of  claim 24 , wherein the tyrosine kinase inhibitor is selected from the group consisting of afatinib, axitinib, bafetinib, bosutinib, cediranib, crizotinib, dasatinib, erlotinib hydrochloride, gefitinib, imatinib, lapatinib, lestaurtinib, neratinib, nilotinib, nintedanib, ponatinib, quizartinib, regorafenib, ruxolitinib, sunitibin, tofacitinib, vandetanib, N-acetylcysteine, vatalanib, and combinations thereof. 
     
     
         27 . The method of  claim 24 , wherein the antibody is selected from the group consisting of alemtuzumab, bevacizumab, cetuximab, gemtuzumab ozogamicin, ibritumomab tiuxetan, ofatumumab, panitumumab, rituximab, simtuzumab, tositumomab, trastuzumab, trastuzumab DM1, and combinations thereof. 
     
     
         28 . The method of  claim 24 , wherein the biological molecule comprises an integrin-binding moiety. 
     
     
         29 . The method of  claim 28 , wherein the biological molecule comprises an RGD tripeptide sequence. 
     
     
         30 . The method of  claim 17 , wherein the perflurocarbon is selected from the group consisting of bis(F-alkyl) ethanes, cyclic fluorocarbons, perfluorinated amines, brominated perfluorocarbons, perfluorooctyl chloride, perfluorooctyl hydride, perfluoroalkylated ethers, perfluoroalkylated polyethers, fluorocarbon-hydrocarbon compounds, and combinations thereof. 
     
     
         31 . The method of  claim 22 , wherein the emulsion agent is selected from the group consisting of phospholipids, nonionic surfactants, fluorinated surfactants, and combinations thereof. 
     
     
         32 . The method of  claim 31 , wherein the phospholipid is selected from the group consisting of lecithin, egg yolk phospholipids, and combinations thereof. 
     
     
         33 . The method of  claim 31 , wherein the fluorinated surfactant is selected from the group consisting of triperfluoroalkylcholate, perfluoroalkylcholestanol, perfluoroalkyloxymethylcholate, C 3 F 7 O(CF 2 ) 3 C(═O)NH(CH 2 ) 3 N(O)(CH 3 ) 2  (XMO-10), fluorinated polyhydroxylated surfactants, and combinations thereof. 
     
     
         34 . The method of  claim 31 , wherein the nonionic surfactant is selected from the group consisting of polyoxyethylene-polyoxypropylene copolymers, pluronic, and combinations thereof. 
     
     
         35 . The method of any one of  claims 17 - 34  comprising the step of administering laser energy to the cell after administering the fluorochemical composition. 
     
     
         36 . The method of  claim 35 , wherein the laser energy is administered through an optical wave guide. 
     
     
         37 . The method of any one of  claims 17 - 36 , wherein the cell is in a patient. 
     
     
         38 . The method of  claim 17 , wherein the patient is a human patient or a veterinary patient. 
     
     
         39 . The use of perflubron or perflubron emulsion and Raman spectroscopy to identify fibroblasts or macrophages associated with cancer, pre-cancer, or dysplastic cells. 
     
     
         40 . The use of topically applied or instilled neat perflubron or perflubron emulsion to improve the visualization of tumors with probe confocal endomicroscopy, Raman spectroscopy, OCT, near band imaging, or stimulated Raman spectroscopy. 
     
     
         41 . The use of perflubron or perflubron emulsion to carry O 2  or CO 2  with a near infrared dye and another agent to a target tissue to enhance PDT. 
     
     
         42 . The use according to  claim 41 , wherein the other agent is a biological molecule. 
     
     
         43 . A method of treating cancer in a patient comprising:
 a. administering a composition comprising perflubron and a photosensitizer to a patient;   b. treating the patient with photodynamic therapy prior to, during, and after surgery to kill or inhibit the function of tumor associated fibroblasts or macrophages.   
     
     
         44 . A method of treating cancer in a patient comprising:
 a. administering a composition comprising perflubron and a photosensitizer to a patient prior to surgery;   b. treating the patient with photodynamic therapy prior to surgery to kill or inhibit, during, and after surgery to kill or inhibit the function of tumor associated tumor associated fibroblasts or macrophages fibroblasts or macrophages, or cancer cells in or about the lymphatic system.   
     
     
         45 . The method of  claim 43  or  44 , wherein the photosensitizer comprises a near infrared dye coupled to a biological molecule. 
     
     
         46 . The method of  claim 45 , wherein the near infrared dye is an IR800 dye. 
     
     
         47 . A method of treating cancer in a patient comprising sequentially the steps of:
 a. administering a composition comprising perflubron, and a first gas, to a tumor;   b. administering a metabolic inhibitor to the tumor; and   c. administering a second gas to the tumor,   wherein the tumor stromal cells and the cancer cells are inhibited or killed.   
     
     
         48 . The method of  claim 45 , wherein:
 a. the first gas is oxygen;   b. the metabolic inhibitor is a glycolysis inhibitor selected from the group consisting of 2-deoxyglucose, 2-deoxy-D-glucose, 2-deoxy-2-[18f]fluoro-D-glucose, glucose transport inhibitors, phosphofructokinase 2 inhibitors, phosphoglycerate mutase inhibitors, pyruvate kinase M2 inhibitors, lactate dehydrogenase A inhibitors, and lactate excretion inhibitors; and   c. the second gas is carbon dioxide.   
     
     
         49 . A method of controlling the microenvironment of a tumor comprising sequentially the steps of:
 a. administering a composition comprising perflubron, and a first gas, to a tumor;   b. administering a metabolic inhibitor to the tumor; and   c. administering a second gas to the tumor,   wherein the tumor stromal cells and the cancer cells are inhibited or killed.   
     
     
         50 . The method of any one of  claims 47 - 49  further comprising the step of surgically removing the tumor. 
     
     
         51 . The method of  claim 50 , wherein the step of surgically removing the tumor is performed after the second gas is administered to the tumor.