No assignee for this patent application has been made.
News editors obtained the following quote from the background information supplied by the inventors: "Cancer is a group of heterogeneous diseases that arise from increased cellular replication and decreased cell death. The key to finding successful treatments for cancer is to exploit differences that arise from normal and cancer cells to increase preferential cell killing. Many current chemotherapies and radiation therapy target rapidly growing cells. However, since there are normal cells that frequently divide, there are many side effects associated with the non-specificity of the treatments, such as myelosuppression, immunosuppression, and gastrointestinal complications. To minimize side effects, present strategies being investigated for cancer treatment are targeting deregulated proteins, gene therapy, or targeting differences in the microenvironment such as angiogenesis, pH, temperature, or hypoxia.
"Hypoxia arises in tumors or metastases greater than 1 mm in diameter, due to inadequate vasculature. Hypoxia alters the tumor biology by increasing receptor tyrosine kinase activity, angiogenesis, invasiveness, metastasis, generation of reactive oxygen species, and suppression of immune reactivity. Hypoxia is generally regarded as a barrier to overcome, since it leads to resistance in many chemotherapies and radiation therapy. Currently, new approaches exploit hypoxia in tumors as a means of selective treatment, as disclosed by
"There are a variety of compounds that selectively target and react within a hypoxic environment, including nitroaromatics, aromatic N-oxides, and aliphatic N-oxides. In U.S. Pat. Nos. 7,405,317 B2 and 7,550,496 B2 there is taught hypoxia targeting moieties for use as triggers in prodrug therapy.
"Hypoxia targeting moieties have a high redox potential in which they may be reduced by any cellular environment. However, in the presence of oxygen the reaction is reversed. When hypoxia targeting moieties undergo reduction in hypoxic environments, they form covalent adducts with macromolecules such as DNA, proteins, or lipids, resulting in accumulation within the hypoxic environment. Reduction may be catalyzed by a specific enzyme or combination of enzymes such as cytochrome P-450, cytochrome P-450 reductase, xanthine oxidase, aldehyde oxidase, and DT-diaphorase see inter alia Workman (1992) Int J Radiat Oncol 22: 631-637.
"As is known to those skilled in the art, nanocarriers are becoming increasingly popular in cancer treatments. Nanocarriers are nanoscale delivery vehicles (10-1000 nm diameter) in which molecules, such as drugs or imaging agents, may be encapsulated within or covalently linked to the exterior of the delivery vehicle. Examples include liposomes, micelles, dendrimers, and nanoemulsions. Nanocarriers can reduce many side effects of chemotherapies by limiting interactions with non-specific tissues. Nanocarriers are also useful in stabilizing, solubilizing, increasing circulation times, and improving biodistribution of drugs. They passively target tumors through the leaky vasculature, known as the enhanced permeability retention effect (EPR). They can also actively target tumors via surface modifications. EPR is based on the pathophysiological characteristics of tumors including hypervascularity, insufficient vessel maturation, secretion of vascular permeability factors, and inefficient lymphatic drainage, see inter alia Petros&DeSimone (2010) Nat Rev Drug Discov, 9:615-627.
"Polymeric micelles (PMC) are supramolecular nanoparticles, which are useful agents in solubilizing and transporting hydrophobic drugs in vivo. PMCs comprise amphiphilic copolymers which are very stable in aqueous environments due to low critical micelle concentrations. A major advantage of PMCs is hydrophobic drugs can be encapsulated spontaneously, eliminating the need to alter the drug with potentially detrimental modifications. Effective PMCs can be optimized for biocompatibility, stability, drug loading capacity and release kinetics, size (10-100 nm), and an appropriate clearance mechanism. These characteristics are optimized through selection of core forming units (hydrophobic) and the corona forming units (hydrophilic), the arrangement of the monomers into the polymer, and the methods of polymerization and micellization. PMCs can also be produced in large quantities with reproducible results and are tunable for size and composition. As drug delivery systems, PMCs can lower drug toxicity by limiting interactions with nonspecific cells, increase drug circulation time, increase drug stability and solubility, and can be modified with targeting moieties, as reported by Torchilin (2001) J Control Release, 73:137-172. Several chemotherapeutic agents have been successfully encapsulated with high efficiency in PMCs, some of which are currently in clinical trials. See, inter alia, Rios-Doria et al. 2012, Drug Deliv, 2012:1-8;
"Photodynamic therapy (PDT) has been shown to be a very effective treatment of certain cancers with limited side effects (Dolmans et al. (2003) Nat Rev Cancer, 3:380-387). The principle of PDT is to initially sensitize cells with a photosensitizer, and then introduce light to the targeted area in the presence of oxygen to generate reactive oxygen species (ROS), thereby inducing cell death. PDT has a low toxicity compared to other cancer therapies since the photosensitizer is non-toxic under dark conditions and may be triggered by specific light wavelengths, and both the sensitizer and light may be preferentially directed to the target area sparing non-specific tissues. Light sources for PDT typically are in the higher wavelength range for enhanced tissue penetration and may be administered by optic fiber to maximize the amount of tissue that can be treated with light. However, PDT is still only efficacious for superficial tumors. By creating a light supply that can illuminate deeply embedded tumors and penetrate throughout the surrounding areas, the applications of PDT can be broadened significantly. Light can be generated throughout the tumor by utilizing a chemiluminescent producing system (CLS), or the generation of light by chemical reactions. Laptev et al. (2006) Br
"In U.S. Pat. No. 7,416,898 B2, the disclosure of which hereby incorporated by reference, there is disclosed highly sensitive chemiluminescent substrates that can be modified to be triggered by different mechanisms, such as by enzymatic reactions, temperature and pH differentials, and others. The 1,2-dioxetane chemiluminescent chemical reaction may be enhanced by methods in U.S. Pat. No. 7,300,766 B2 the disclosure of which is hereby incorporated by reference, or by utilization of organic molecules such as diphenylanthracene and fluorescein.
"Enhancing the chemiluminescent reaction facilitates more effective PDT by increasing the ability to activate the photosensitizers. For example, fluorescein can enhance the 1,2-dioxetane chemiluminescence and then transfer energy to a photosensitizer, such as Rose Bengal. Another benefit of PDT as a therapy is the ability to track the location of the effective treatment area due to fluorescence emission of the photosensitizers."
As a supplement to the background information on this patent application, NewsRx correspondents also obtained the inventors' summary information for this patent application: "The present invention as detailed below, improves upon the prior art by providing compositions and methods for treatment and detection of hypoxic areas of cancers with a targeted polymeric micelle (PMC).
"The present invention provides a hypoxia targeting moiety attached to a PMC, which is capable of encapsulating a chemotherapeutic agent, a light producing system, a sensitizing system, a radioactive system, and the like.
"Accordingly, the present invention provides a compound of the following formula:
"where E is an encapsulated agent within a PMC in which E is selected from the group consisting of an imaging agent, a therapeutic agent, a therapeutic adjuvant, a light producing system, a radioactive system, a sensitizing agent, and the like. The encapsulated agent may or may not be conjugated to a hypoxia targeting moiety; R.sub.1 is a hypoxia targeting moiety including an aromatic N-oxide, an aliphatic N-oxide, nitroazole, nitroimidazole, nitrothiophene, nitrothiazole, nitrooxazole, nitrofuran, nitropyrrole, transition metal moieties and the like; R.sub.2 maybe an imaging agent, a targeting moiety, a therapeutic agent, a sensitizing agent, or any combination thereof. R.sub.2 may be the same as the encapsulated compound or a different compound, and R.sub.3 is a polar biocompatible moiety for improving solubility, stability, and biodistribution of the PMC.
"The present invention also provides a method for treating tumors and for generating light using the above compound.
"For a more complete understanding of the present invention reference is made to the following detailed description and accompanying examples.
BRIEF DESCRIPTION OF THE DRAWING
"FIG. 1 is a graph showing the efficacy of the present invention."
For additional information on this patent application, see:
Keywords for this news article include: Biotechnology, Patents, Oncology, Treatment, Chalcogens, Bioengineering, Cancer Gene Therapy.
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