http://rdf.ncbi.nlm.nih.gov/pubchem/patent/WO-2011044545-A3
Outgoing Links
| Predicate | Object |
|---|---|
| assignee | http://rdf.ncbi.nlm.nih.gov/pubchem/patentassignee/MD5_78fed085d0bc8a5ab46adaa8c24c3ebc |
| classificationCPCInventive | http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P19-02 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61K51-1224 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P29-00 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P31-04 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P31-12 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61K47-6917 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P31-00 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P35-00 http://rdf.ncbi.nlm.nih.gov/pubchem/patentcpc/A61P9-00 |
| classificationIPCInventive | http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/A61K9-48 http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/A61P35-00 http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/A61K47-36 http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/A61K47-42 http://rdf.ncbi.nlm.nih.gov/pubchem/patentipc/A61K49-04 |
| filingDate | 2010-10-10-04:00^^<http://www.w3.org/2001/XMLSchema#date> |
| inventor | http://rdf.ncbi.nlm.nih.gov/pubchem/patentinventor/MD5_eac9b9a45e7e39032e64fe4a279cb721 |
| publicationDate | 2011-09-15-04:00^^<http://www.w3.org/2001/XMLSchema#date> |
| publicationNumber | WO-2011044545-A3 |
| titleOfInvention | Methods and compositions for targeted imaging |
| abstract | Novel aspect of my invention consists of a new approach to targeting imaging agents to macrophage-rich sites of interest. Examples of such sites are tumor sites and vulnerable atherosclerotic plaques. It is of high clinical importance to diagnose vulnerable plaques using non- invasive imaging procedures. Prior art (US Pat Appl 20070243136) suggests to use reconstituted high density lipoprotein (rHDL) particles to deliver contrast agents to vulnerable atherosclerotic plaques through macrophages that represent a marker of these plaques. Despite multiple advantages of the HDL nanoparticles as delivery platform, the currently suggested HDL compositions for use as imaging agents in MRI, CT, Gamma- scintigraphy, or optical imaging techniques (US Pat Appl 20070243136) have low efficacy in terms of targeted delivery of contrast molecules such, for example, as GdBCAs, to the plaque and subsequent retention within the arterial wall. This results in low amount of contrast molecules delivered and therefore low MRI contrast enhancement which is not sufficient to significantly reduce the dosage of Gd required. In order to increase the delivery and retention of rHDL within the arterial wall, antibodies for different plaque components have been suggested to be incorporated in rHDL as targeting moieties (US Pat Appl 20070243136). However, the suggested imaging agents would share all the disadvantages of antibodies (unstable, expensive to produce, potentially immunogenic, etc.). Alternatively, an apo E-derived lipopeptide has been shown to increase efficacy of the rHDL platform for molecular MR imaging of atherosclerotic plaques in vivo (Chen et al. Contrast Media MoI Imaging 2008;3:233-42). This synthetic lipopeptide represents a dipalmitoylated version of apo E-derived highly positive peptide, which has the amino acid sequence (LRKLRKRLLR)2, and is a tandem dimer (141-15O)2 derived from the LDL receptor binding domain of apo E. Despite resulting in an improved in vivo MR imaging signal enhancement in atherosclerotic mice (90% vs. 53% enhancement within the arterial vessel 24 h after administration of a 50 umol Gd/kg dose), incorporation of this detergent-like highly positive molecule in the rHDL platform can also bring the apo E-derived tandem peptide- associated disadvantages to the platform. For example, this tandem peptide and its dipalmitoylated version are known to mediate uptake of liposomes or micelles into endothelial cells of brain microvessels (Keller et al. Angew Chem Int Ed Engl 2005; 44:5252-5; Sauer et al. Biochemistry 2005;44:2021-9; Sauer et al. Biochim Biophys Acta 2006;1758:552-61). In addition, this tandem peptide can exert neurotoxic effects (Wang et al. J Cell Physiol Novel aspect of my invention consists of a new approach to targeting imaging agents to macrophage-rich sites of interest. Examples of such sites are tumor sites and vulnerable atherosclerotic plaques. It is of high clinical importance to diagnose vulnerable plaques using non- invasive imaging procedures. Prior art (US Pat Appl 20070243136) suggests to use reconstituted high density lipoprotein (rHDL) particles to deliver contrast agents to vulnerable atherosclerotic plaques through macrophages that represent a marker of these plaques. Despite multiple advantages of the HDL nanoparticles as delivery platform, the currently suggested HDL compositions for use as imaging agents in MRI, CT, Gamma- scintigraphy, or optical imaging techniques (US Pat Appl 20070243136) have low efficacy in terms of targeted delivery of contrast molecules such, for example, as GdBCAs, to the plaque and subsequent retention within the arterial wall. This results in low amount of contrast molecules delivered and therefore low MRI contrast enhancement which is not sufficient to significantly reduce the dosage of Gd required. In order to increase the delivery and retention of rHDL within the arterial wall, antibodies for different plaque components have been suggested to be incorporated in rHDL as targeting moieties (US Pat Appl 20070243136). However, the suggested imaging agents would share all the disadvantages of antibodies (unstable, expensive to produce, potentially immunogenic, etc.). Alternatively, an apo E-derived lipopeptide has been shown to increase efficacy of the rHDL platform for molecular MR imaging of atherosclerotic plaques in vivo (Chen et al. Contrast Media MoI Imaging 2008;3:233-42). This synthetic lipopeptide represents a dipalmitoylated version of apo E-derived highly positive peptide, which has the amino acid sequence (LRKLRKRLLR)2, and is a tandem dimer (141-15O)2 derived from the LDL receptor binding domain of apo E. Despite resulting in an improved in vivo MR imaging signal enhancement in atherosclerotic mice (90% vs. 53% enhancement within the arterial vessel 24 h after administration of a 50 umol Gd/kg dose), incorporation of this detergent-like highly positive molecule in the rHDL platform can also bring the apo E-derived tandem peptide- associated disadvantages to the platform. For example, this tandem peptide and its dipalmitoylated version are known to mediate uptake of liposomes or micelles into endothelial cells of brain microvessels (Keller et al. Angew Chem Int Ed Engl 2005; 44:5252-5; Sauer et al. Biochemistry 2005;44:2021-9; Sauer et al. Biochim Biophys Acta 2006;1758:552-61). In addition, this tandem peptide can exert neurotoxic effects (Wang et al. J Cell Physiol 1997;173:73-83). Recently, Gd-containing HDL obtained by incubation of native human HDL (commercially available HDL preparations purified from human plasma; Calbiochem, San Diego, CA) with Gd-DTPA- l,2-dimyristoyl-sn-glycero-3-phosphoethanolamine (Gd-DTPA- DMPE) and Gd/6-amino-6-methylperhydro-l,4-diazepinetetraacetic acid with a 17-carbon long aliphatic chain (Gd-AAZTA-C17) have been suggested as high-relaxitivity MRI contrast agents (Briley-Saebo et al. J Phys Chem B 2009;l 13:6283-9). However, incubation of native HDL with Gd-DTPA-DMPE resulted in the uncontrolled particle fusion due to detergent perturbations whereas the composition and integrity of HDL-Gd- AAZT A-C17 adducts was not characterized. In contrast to rHDL platform, both native HDL-based agents suggested lack the control and reproducibility between batches because native HDL is a heterogeneous lipoprotein class with different subspecies that vary in apolipoprotein and lipid composition, in size and charge, and in physiological functions (Castro G.R. & Fielding CJ. Biochemistry 1988;27:25-9; Miida et al. Biochemistry 1992;31: 11112-7; Mowri et al. J Lipid Res 1992;33: 1269-79; von Eckardstein et al. Curr Opin Lipidol 1994;5:404-16). For this reason, the size, shape, protein and lipid composition, structure, properties and physiological function of native HDL purified from human plasma using ultracentrifugation vary significantly depending on donors, isolation procedure variations and storage conditions and therefore cannot be well controlled. Compositions of the invention are rHDL and HDL-like liposomal compositions, protein constituents of which, apolipoproteins A-I and/or A-II or fragments thereof are used not only as structural but also as targeting agents. This is achieved by certain controlled chemical or enzymatic modification of apolipoproteins A-I or A-II or fragments thereof. Such modification converts these apolipoproteins to substrates for macrophage scavenger receptors and results in the improvement of contrast agent- (HDL/modified apolipoprotein)-particle association with macrophages and/or absorption (uptake) by macrophages when compared to that of the contrast agent-(HDL/apolipoprotein)-particle constructed with non-modified naturally occurring apo A-I. These advantageous compositions are demonstrated by the present invention to solve numerous problems which otherwise are associated with high dosages of contrast agent required and the lack of control and reproducibility of formulations, especially in large-scale production. Compositions of the invention can be used for noninvasive optimal sensitive and specific in vivo molecular detection and localization of macrophage-rich sites of interest using imaging techniques such as computed tomography (CT), gamma- scintigraphy, positron emission tomography (PET), single photon emission computed tomography (SPECT), magnetic resonance imaging (MRI), and combined imaging techniques. Chemical or enzymatic modification of fully assembled HDL particles (without Gd) has been shown to enhance their absorption by the macrophages (Bergt et al. Biochem J 2000;346 Pt 2,345-54; Pankhurst et al. J Lipid Res 2003;44,349-55; Panzenboeck et al. J Biol Chem 1997;272:29711-20; Sue et al. J Cell Sci 2003;l 16:89-99). However, published data demonstrate that in the modified HDL particle described in (Panzenboeck et al. J Biol Chem 1997;272:29711-20) both, the protein and the lipid portion of the particle have undergone the chemical modification. The prior art (US Pat Appl 20070243136) neither suggests nor teaches one of ordinary skill in the art to investigate the performance of HDL particles in which only the apolipoprotein portion has been chemically altered. Compositions of the invention can be used for targeting macrophages in imaging of macrophage-related diseases characterized by neoplastic tissue (US Pat Appls 20010002251 and 20090004113) including the cancers: sarcoma, lymphoma, leukemia, carcinoma and melanoma, cardiovascular diseases (e.g., arteriosclerosis, atherosclerosis, intimal hyperplasia and restenosis) and other activated macrophage-related disorders including autoimmune diseases (e.g., rheumatoid arthritis, Sjogrens, scleroderma, systemic lupus erythematosus, non-specific vasculitis, Kawasaki's disease, psoriasis, Type I diabetes, pemphigus vulgaris), granulomatous diseases (e.g., tuberculosis, sarcoidosis, lymphomatoid granulomatosis, Wegener's granulomatosus), inflammatory diseases (e.g., inflammatory lung diseases such as interstitial pneumonitis and asthma, inflammatory bowel disease such as Crohn's disease, and inflammatory arthritis), and in transplant rejection (e.g., in heart/lung transplants). In addition to atherosclerosis (US Pat Appl 20070243136), examples of macrophage-related diseases are also macrophage- related pulmonary diseases such as emphysema (Marten K. and Hansell D. M. Eur Radiol 2005;15:727-41; US Pat Appl 20050281740). |
| priorityDate | 2009-10-09-04:00^^<http://www.w3.org/2001/XMLSchema#date> |
| type | http://data.epo.org/linked-data/def/patent/Publication |
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