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Patent Application Titled "Use of Fusarochromanone and Its Derivatives in the Diagnosis and Treatment of Cancer and Other Diseases" Published Online

February 19, 2014



By a News Reporter-Staff News Editor at Biotech Week -- According to news reporting originating from Washington, D.C., by NewsRx journalists, a patent application by the inventors Furmanski, Brian (Memphis, TN); Wuthier, Roy E. (Columbia, SC); Fuseler, JR., John W. (Columbia, SC), filed on December 27, 2012, was made available online on February 6, 2014 (see also University of South Carolina).

The assignee for this patent application is University of South Carolina.

Reporters obtained the following quote from the background information supplied by the inventors: "The use of light in the treatment of various skin diseases has been around for centuries. This field termed phototherapy uses a combination of small molecules that can absorb light in the visible, UV-A, and near-infrared range. Phototherapy is comparable to radiotherapy in its efficacy. However unlike radiotherapy and chemotherapy, phototherapy lacks the nonspecific toxicity seen in radiotherapy and chemotherapy and because of this, phototherapy can be given on more regular intervals.

"Photodiagnostic therapy (PDT) is an experimental technology that relies on the ability of fluorescent small molecules to preferentially accumulate in diseased tissues. Due to this preferential retention, it is possible to distinguish between normal and diseased tissue. It is thought that these small molecules in tumorgenic tissues may accumulate due to a decrease in intracellular pH, an increase in low density lipoproteins, and abnormal membrane composition.sup.1.

"It is generally accepted that small nonpolar molecules can pass through the plasma membrane of a cell by simple diffusion.sup.3. Evidence for this has been described in the uptake of adriamycin, quinone, and rhodamine 123 in unilamellar and transbilayer vesicles.sup.4, 5. Simple diffusion has also been used to describe the uptake of doxorubicin, daunorubicin, and rhodamine 123 in cultured transformed and normal cells.sup.1, 6, 7.

"Photodynamic therapy (PDT) is an emerging minimally invasive therapy for the treatment of cancer, age-related macular degeneration, psoriasis and a host of other chronic diseases. PDT employs the use of photosensitizing agents in combination with light to disrupt cellular functions, which ultimately leads to cell death. The intracellular location of photosensitizing agents also plays critical role in the mode of action in cellular toxicity. Most photosensitizers used in clinical, and experimental treatment of cancer are localize in cytoplasmic organelles of a cell..sup.8 Photosensitizing agents are compounds that absorb a specific wavelength of light which then reacts with molecular oxygen to generate a reactive oxygen species. These reactive oxygen species such as H.sub.20.sub.2, NO, and .sup.-OH are the true perpetrators of the cellular toxicity seen in PDT.

"Psoralen is commonly used in PDT to treat skin diseases (e.g., Eczema, Psoriasis and Vitiligo, and mycosis fungoides). However, psoralen is not a chemotherapeutic agent by itself, and therefore is not effective without the application of energy in the form of light.

"Although great strides have been made in photodynamic therapy, a need exists for a photosensitizing agent that will selectively accumulate in diseased cells and act as a chemotherapeutic agent (even without the application of light)."

In addition to obtaining background information on this patent application, NewsRx editors also obtained the inventors' summary information for this patent application: "Objects and advantages of the invention will be set forth in part in the following description, or may be obvious from the description, or may be learned through practice of the invention.

"In general, the present disclosure is directed toward a method of photodynamic therapy to treat diseased cells in an animal. According to the method, 5-amino-2,2-dimethyl-6-[3'-(R,S)amino-4'-hydroxy-butan-1-one]-2,3-dihydro- -4H-1-benzopyran-4-one or an analog thereof is administered to the animal such that the 5-amino-2,2-dimethyl-6-[3'-(R,S)amino-4'-hydroxy-butan-1-one]-2,3-dihydro- -4H-1-benzopyran-4-one or an analog thereof accumulates in the diseased cells. Then, the diseased cells containing 5-amino-2,2-dimethyl-6-[3'-(R,S)amino-4'-hydroxy-butan-1-one]-2,3-dihydro- -4H-1-benzopyran-4-one or an analog thereof is exposed to light energy (e.g., ultraviolet light).

"Other features and aspects of the present invention are discussed in greater detail below.

BRIEF DESCRIPTION OF THE DRAWINGS

"A full and enabling disclosure of the present invention, including the best mode thereof to one skilled in the art, is set forth more particularly in the remainder of the specification, which includes reference to the accompanying figures, in which:

"FIG. 1 shows a co-culture monochrome image of B16 melanoma and cardiac myocytes.

"FIG. 2 shows confocal Imaging of FC101 Uptake of B16 Melanoma Cells and normal cardiac fibroblasts:

"For B16 Melanoma Cells:

"A--Time 0 (before exposure to FC101). All Cells express weak auto-fluorescence localized predominantly in the perinuclear cytoplasm.

"B--Time -10 sec following addition of FC101 (400 nM). The drug has immediately entered the cells and is accumulating in the perinuclear cytoplasm. Accumulation of the drug in the perinuclear region appears asymmetrical, suggesting it may be preferentially localized in the Golgi complex.

"C--Time -4 min following addition of FC101. FC101 fluorescence remains largely localized in the perinuclear region and does not appear to spread out into the peripheral and marginal cytoplasm. The cells exhibit little or no morphological changes at this time.

"D--Time -20 min following addition of FC101. The distribution and fluorescence of FC101 appears stable with no decrease in intracellular drug fluorescence. The cells also exhibit little or no morphological changes at this time.

"For Normal Cardiac Fibroblasts:

"E--Time 0. All cells express a minimal auto-fluorescence predominately localized in the perinuclear cytoplasm.

"F--Time -10 sec flowing addition of FC101 (400 nM). The cells exhibit no uptake of FC101 with the cytoplasmic fluorescence remaining essentially the same as that seen before exposure to FC101 (E).

"G--Time -4 min following addition of FC101. Some of the cells exhibit a minimal increase in cytoplasmic fluorescence due to limited uptake of the drug.

"H--Time -20 min following additional of FC101. All cells exhibit a significant increase in intracellular fluorescence due to continued slow uptake of the drug. FC101 appears predominantly localized in the perinuclear cytoplasm. Scale bar=20 .mu.m.

"FIG. 2A shows the linear uptake of FC101 in B16 cells.

"FIG. 2B shows the exponential uptake in normal cardiac fibroblasts.

"FIG. 3a shows a comparison of the Uptake and Steady-State

"Concentrations of FC101 in the Cytoplasm of B16 Melanoma Cells. Images of the B16 melanoma were collected at 1 second intervals. FC101 was added to cells at 20 seconds following initiation of the experiment with the capture of image 2. Total cellular integrated optical density was measured for each of the indicated FC101 levels.

"FIG. 3b shows the relationship between Drug Dosage and Steady-State Intracellular Concentration of FC101 in B16 Melanoma Cells. Steady-state IOD levels of FC101 were measured at drug level after 2 min incubation. Note the linear correlation between the initial extracellular concentration of the drug and the cytoplasmic IOD of FC101. These kinetic data suggest the uptake of FC101 in B16 melanoma cells is dependent only the initial concentration of the drug applied to cells, and that uptake appears to be governed by zero-order kinetics.

"FIG. 4a shows the comparison of the Uptake and Steady-State Concentrations of FC101 in the Cytoplasm of Normal Cardiac Fibroblasts. FC101 was added to cells at 30 seconds following initiation of the experiment with the capture of image 1. Images of the Cardiac Fibroblasts were collected at 10 sec intervals. Total cellular integrated optical density was measured for each of the indicated FC101 levels. Note that the scale is shown in minutes, not in seconds as seen in FIG. 7.

"FIG. 4b shows the relationship between Drug Dosage and Steady-State Intracellular Concentration of FC101 in Normal Cardiac Fibroblasts. Steady-state IOD levels of FC101 were measured at drug level after 10 min incubation. The Y-axis is expressed in exponential terms; note the close correlation between the initial extracellular concentration of the drug and the Log.sub.10 IOD of cytoplasmic FC101. Thus, the intracellular concentration of FC101 follows a non-linear logarithmic correlation with the initial extracellular concentration of the drug. These data suggest that uptake of FC101 in cardiac fibroblasts may be carrier-mediated, in addition to being dependent on the initial concentration of the drug applied to cells.

"FIG. 5 shows the comparison of Experimentally Measured and ACD-Predicted Log D Values for FC101 at Various pH's. Log D properties of FC101 were predicted using ACD/labs 11.0 software. Experimentally measured Log D was done by the shaken-flask method using n-octanol/phosphate buffer to determine the experimental ionized partition coefficient for FC101 (For details, see Methods). Note that while the two methods agree closely at pH 7.0-7.6, the partition coefficients diverge at either higher or lower pH values.

"FIGS. 5A and 5B show FC101 uptake in MCF7 cells at 0 seconds and at 10 seconds, respectfully.

"FIG. 6 is shown to scale comparison of cardiac and B16 cells.

"FIG. 7 shows 500,000 cells/ml at various FC101 doses."

For more information, see this patent application: Furmanski, Brian; Wuthier, Roy E.; Fuseler, JR., John W. Use of Fusarochromanone and Its Derivatives in the Diagnosis and Treatment of Cancer and Other Diseases. Filed December 27, 2012 and posted February 6, 2014. Patent URL: http://appft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=1649&p=33&f=G&l=50&d=PG01&S1=20140130.PD.&OS=PD/20140130&RS=PD/20140130

Keywords for this news article include: Biotechnology, Therapy, Cytoplasm, Treatment, Chalcogens, Fibroblasts, Photomedicine, Intracellular Space, University of South Carolina.

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Source: Biotech Week


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