This patent application is assigned to
The following quote was obtained by the news editors from the background information supplied by the inventors: "Inefficient delivery and poor uptake of therapeutic drugs to solid tumors hamper the efficacy of cancer treatments. Therefore, the 'enhanced permeability and retention' (EPR) effect of solid tumors has been explored extensively as a target in the design of drug delivery systems. Solid tumors behave differently from normal tissues, having several abnormalities, such as leaky blood vessels and a poor lymph system. It is an important feature that nanosized particles can extravasate from the vasculature and passively accumulate in tumors. Inorganic nanoparticles, especially gold nanoparticles (Au NPs) with good biocompatibility, versatile surfaces, tunable sizes, and unique optical properties have received significant attention as drug delivery systems to improve targeting effect and efficacy for cancer treatments."
In addition to the background information obtained for this patent application, NewsRx journalists also obtained the inventors' summary information for this patent application: "This application relates to compositions that include targeted nanoparticle conjugates and to the use of the targeted nanoparticle conjugates for treating a disorder in a subject. In an aspect of the application, the targeted nanoparticle conjugate can include a polyethylene glycolylated (PEGylated) nanoparticle; at least one hydrophobic therapeutic agent coupled to the surface of the nanoparticle; and at least one targeting moiety coupled to polyethylene glycol of the nanoparticle for targeting the composition to a cell associated with a disorder.
"In some aspects, the disorder is cancer and the at least one targeting moiety targets the composition to a cancer cell. The hydrophobic therapeutic agent can be an anti-cancer agent that has a logP value of about 1 to about 3. In one example, the anti-cancer agent is Phthalocyanine 4.
"In other aspects, the at least one targeting moiety includes a polypeptide that binds to EGFR. The polypeptide can include an EGF peptide having the amino acid sequence of SEQ ID NO: 1.
"Another aspect of the application relates to a composition for treating brain cancer. The composition includes a PEGylated gold nanoparticle; Phthalocyanine 4 conjugated to the PEGylated gold nanoparticle; and a polypeptide coupled to polyethylene glycol of the nanoparticle, the polypeptide binding EGFR. The polypeptide can consist of the amino acid sequence of SEQ ID NO: 1.
"In some aspects, the composition upon systemic administration to the subject readily crosses the blood brain barrier and targets the brain cancer cells. The Phthalocyanine 4 can be readily up taken by the brain cancer cells upon targeting and upon uptake can be activated by light to cause cancer death or suppress cancer growth.
"The application further relates to a method for treating brain cancer. The method includes administering systemically to a subject with brain cancer a therapeutically effective amount of a composition comprising PEGylated gold nanoparticles; Phthalocyanine 4 conjugated to the PEGylated gold nanoparticles; and EGF peptides consisting of the amino acid sequence of SEQ ID NO: 1 coupled to polyethylene glycol of the nanoparticles. The cancer cell administered the composition is then exposed to light, thereby inducing the cytotoxic effects of Phthalocyanine 4.
BRIEF DESCRIPTION OF THE DRAWINGS
"FIG. 1 is a schematic illustration of two-way synthesis of EGF.sub.pep-Au nanoparticles. Dark circles stand for the resin; Light circles stand for gold nanoparticles; Lines stand for monofunctional PEG5K or for bifunctional PEG3K/7.5K/12K; Arrows stands for EGF peptide.
"FIG. 2 is a schematic of: (A) a diagram of the construction of EGF.sub.pep-Au NP-Pc 4; and (B) a procedure for photodynamic.
"FIG. 3 illustrates (A) epi-fluorescent images of in vitro uptake and increasing accumulation of EGF.sub.pep-Au NP-Pc 4 9L.E29 cells incubated with either EGFpep-Au NP-Pc 4, or Au NP-Pc 4 at 1.times.10.sup.-6 mol/L of Pc 4 taken over time at 40.times. magnification; (B) a graph showing quantification of Pc 4 (mols) per Au NP (mols) in 9L.E29 cells over time; and (C) a graph showing quantification of Au (.mu.g) per 9L.E29 cell over time.
"FIG. 4 illustrates: (A) confocal imaging of 9L.E29 cells seeded on coverslips and incubated with EGF.sub.pep-Au NP-Pc 4 or free Pc 4 at 1.times.10.sup.-6 mol/L of Pc 4, and either LysoTracker (for lysosomes), MitoTracker (for mitochondria), or EEA1 antibodies (for early endosomes); (B) a graph of an MTT assay showing cytotoxicity associated with EGF.sub.pep-Au NP-Pc 4 and Pc 4 in the dark and under different light exposures on 9L.E29 cells; and (C) a viability assay (Trypan blue staining) showing cytotoxicity associated with EGF.sub.pep-Au NP-Pc 4 and free Pc 4 under different light exposures and concentrations of Pc 4 on 9L.E29 cells.
"FIG. 5 illustrates: (A) evenly scaled fluorescent images of ex vivo organs overlayed on corresponding black and white pictures of biodistribution of EGF.sub.pep-Au NP-Pc 4 Mice injected with Au NP-Pc 4 or EGF.sub.pep-Au NP-Pc 4 (at a concentration of 1 mgkg.sup.-1 of Pc 4), euthanized at 4 hours, 24 hours, or 7 days post-injection; (B) silver enhanced staining of ex vivo organs for visualization of Au NPs; (C) a graph of fluorescence biodistribution for Pc 4 content (in average RFUs) of ex vivo organs of all mice injected with EGF.sub.pep-Au NP-Pc 4, for each time point n.gtoreq.3; and (d) Au NP biodistribution for Au NP content (in .mu.g of Au) of ex vivo organs of all mice injected with EGF.sub.pep-Au NP-Pc 4, for each time point n.gtoreq.3.
"FIG. 6 illustrates: (A) fluorescence images of an EGF.sub.pep-Au NP-Pc 4 injected mouse showing accumulation of Pc 4 and its subsequent drop in intensity after being activated by laser light; (B) photographs of an EGF.sub.pep-Au NP-Pc 4 injected and PDT treated mouse (The left tumor was not treated with light); (C) Hematoxylin and Eosin staining of Paraffin fixed tumor sections from animals sacrificed at 4 hours after injection of either Au NP-Pc 4, or EGF.sub.pep-Au NP-Pc 4 and either treated or not treated with laser light, visualized at 40.times. magnification; and (D) a graph showing Pc 4 fluorescence (RFU) per .mu.g of Au in 9L.E29 tumors over time in mice injected intravenously with either EGF.sub.pep-Au NP-Pc 4 or Au NP-Pc 4 complexes at a dosage of 1 mgkg.sup.-1 of Pc 4 and ex vivo tumor tissues.
"FIG. 7 is a schematic illustration of a model of redistribution showing the difference in Pc 4 uptake when delivered by EGF.sub.pep-Au NP-Pc 4 that may account for differences in cell death pathways.
"FIG. 8 is a schematic illustration of the design of targeted nanoparticle conjugates that include the PDT drug Pc 4 conjugated to EGF-conjugated Au NP.
"FIG. 9 illustrates: (A) a plot showing absorbance spectra of COOH-functionalized Au NPs, EGF-Au NPs and EGF-Au NP-Pc 4 conjugates in water; (B) a plot showing the fluorescence spectrum of EGF-Au NP-Pc 4 conjugate; (C) an image of 1% agarose gel at 120 V for 4 h in TAE (tris acetate EDTA) buffer of COOH-functionalized Au NP, EGF-Au NPs and EGF-Au NP-Pc 4 conjugates; and (D) a TEM image of the conjugates.
"FIG. 10 illustrates: (A) a graph showing PDT effect of the EGF-Au NP-Pc 4 conjugates on toxicity in light and dark after 4 h incubation measured with an MTT assay; bright-field images of the conjugate-incubated cancer cells before (B) and after (C) light exposure.
"FIG. 11 illustrates: (A) a plot of time dependent drug release in the water-toluene system for in vitro studies of the PDT drug release from EGF-Au NPs; (B) a confocal image of live glioma cancer cells after 4 h incubation with the conjugates; and (C) confocal fluorescence images of fixed glioma cells after incubation for 24 h with EGF-Au NP-Pc 4, [Pc 4]=1 .mu.M.
"FIG. 12 illustrates fluorescence imaging of extracted brains with (A) tumors targeted with EGF-Au NP-Pc 4 conjugates compared to (B) untargeted Au NP-Pc 4 conjugates in brain tumor-bearing mice and the overlay of fluorescence and monochromatic images."
URL and more information on this patent application, see: Basilion, James; Burda, Clemens. Targeted Nanoparticle Conjugates. Filed
Keywords for this news article include: Alkenes, Therapy, Oncology, Peptides, Polyenes, Proteins, Amino Acids, Hydrocarbons, Solid Cancers, Nanotechnology, Organic Chemicals, Gold Nanoparticles, Polyethylene Glycols, Drug Delivery Systems, Emerging Technologies,
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