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  Blood clot-targeted nanoparticlesUSPTO Application #: 20070202040Title: Blood clot-targeted nanoparticles Abstract: Emulsions comprising nanoparticles formed from high boiling perfluorochemical substances, said particles coated with a lipid/surfactant coating are made target-specific by directly coupling said nanoparticles to a targeting ligand. The nanoparticles may further include biologically active agents, radionuclides, and/or other imaging agents. (end of abstract)
Agent: Morrison & Foerster LLP - San Diego, CA, US Inventors: Gregory Lanza, Samuel A. Wickline USPTO Applicaton #: 20070202040 - Class: 424001330 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Radionuclide Or Intended Radionuclide Containing; Adjuvant Or Carrier Compositions; Intermediate Or Preparatory Compositions, Coated, Impregnated, Or Colloidal Particulate (e.g., Microcapsule, Micro-sphere, Micro-aggregate, Macro-aggregate), Delivery To Active Site Involves Particle Dissolving, Degrading, Or Otherwise Releasing Of Radionuclide The Patent Description & Claims data below is from USPTO Patent Application 20070202040. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This is a divisional of U.S. Ser. No. 10/225,024 filed 20 Aug. 2002 and now allowed, which is a continuation-in-part of U.S. Ser. No. 09/404,963 filed 24 Sep. 1999, now U.S. Pat. No. 6,548,046. The contents of these applications are incorporated herein by reference. FIELD OF THE INVENTION [0002] The invention is directed to nanoparticles which home to specific blood clots and which carry to these targets substances useful in diagnosis or treatment. More specifically, the invention concerns nanoparticles to which ligands specific for thromboses are directly bound and which further contain imaging agents and/or bioactive materials. BACKGROUND ART [0003] U.S. Pat. Nos. 5,690,907, 5,780,010 and 5,958,371, the disclosures of which are incorporated herein by reference, describe biotinylated lipid-encapsulated perfluorocarbon nanoparticles which are useful for the delivery of radionuclides, and magnetic resonance imaging agents to specific locations through a biotin-avidin system. Bioactive agents may also be included. In this approach, the target location is coupled to a target-specific ligand which is also coupled to biotin. Avidin is then employed to bridge the now biotinylated target with biotin derivatized nanoparticles contained in an emulsion. Included among the targets are blood clots; however, these blood clots are first labeled with antifibrin antibodies to which biotin is then bound. No direct targeting of blood clots with ligands specific for such clots is disclosed. [0004] This is in contrast to the compositions of the present invention wherein a ligand specific for thromboses is directly coupled, initially, to the nanoparticles in the emulsion. Thus, the emulsion, when administered, is target-specific by virtue of bearing the target-specific ligand at its surface. [0005] Fluorochemical emulsions with specification binding moieties have been described in U.S. Pat. No. 5,401,634 for use as labels in in vitro analytical procedures. However, in vivo uses, for example, for acoustic imaging, drug delivery or delivery of imaging agents or nuclides is not contemplated. In addition, consistent with the failure to envision in vivo use, no modification of these particles for binding to thromboses is mentioned. [0006] Others have described drug delivery using particulate supports which differ from the nanoparticles of the present invention. For example, PCT publication WO 95/03829 describes oil emulsions where the drug is dispersed or solubilized inside an oil droplet and the oil droplet is targeted to a specific location by means of a ligand. U.S. Pat. No. 5,542,935 describes site-specific drug delivery using gas-filled perfluorocarbon microspheres. The drug delivery is accomplished by permitting the microspheres to home to the target and then effecting their rupture. Low boiling perfluoro compounds are used to form the particles so that the gas bubbles can form. [0007] In contrast to the compositions described above, the compositions of the invention are ligand-bearing liquid emulsions based on high boiling perfluorocarbon liquids. The compositions of the invention provide facile means to deliver materials contained in their surface to blood clots. [0008] An article reporting the work of the present inventors, Flacke, S., et al., Circulation (2001) 104:1280-1285 appeared in September of 2001 and described molecular imaging of thrombus using nanoparticles formulated with GD-DTPA-BOA. The particles were covalently coupled to antifibrin monoclonal antibody and used to obtain magnetic resonance images of blood clots. [0009] The present invention expands the concept set forth in this article and provides nanoparticles which target blood clots specifically and which may provide, in addition to magnetic resonance imaging agents, means for acoustic imaging, therapeutic agents, and radionuclides. DISCLOSURE OF THE INVENTION [0010] The invention provides compositions which are liquid emulsions. The liquid emulsions contain nanoparticles comprised of liquid, relatively high boiling perfluorocarbons surrounded by a coating which is composed of a lipid and/or surfactant. The surrounding coating is able to couple directly to a moiety that targets blood clots or can entrap an intermediate component which is covalently coupled to the said moiety, optionally through a linker. Alternatively, the coating may be cationic so that negatively charged blood clot targeting agents such as nucleic acids, in general or aptamers, in particular, can be adsorbed to the surface. [0011] In addition to the targeting agent or ligand, the nanoparticles may contain at their surface a radionuclide, a contrast agent for magnetic resonance imaging (MRI) and/or a biologically active compound. The nanoparticles themselves can serve as contrast agents for ultrasound imaging. [0012] As the emulsions of the invention are intended to target blood clots or thromboses, especially in vivo, components of these clots are used as suitable targets. Among these markers or targets are fibrin, tissue factor, gpIIb/IIIa, tissue factor/VIIA complex, activated clotting factor Xa, activated clotting factor IXa, and the fibrin condensation product, d-dimer. Tissue factor is present but not preferred as it is relatively nonspecific. [0013] Thus, in one aspect, the invention is directed to a composition comprising an emulsion of liquid, high boiling perfluorocarbon-based nanoparticles, said nanoparticles further comprising a coating of a lipid/surfactant in which is embedded, or to which is directly covalently bound at least one ligand that targets blood clots, and optionally at least one biologically active compound, at least one radionuclide, and/or at least one imaging agent. [0014] In other aspects, the invention is directed to methods to administer drugs to, and to obtain images of blood clots, especially in vivo, using the compositions of the invention. BRIEF DESCRIPTION OF THE DRAWINGS [0015] FIGS. 1A and 1B show acoustic images obtained with fibrin-specific and non-fibrin-specific paramagnetic nanoparticles respectively. FIG. 1C shows similar images but with fat suppression. MODES FOR CARRYING OUT THE INVENTION [0016] The carrier system that is the basis for the present invention is a nanoparticulate system containing a high boiling perfluorocarbon as a core and an outer coating that is a lipid/surfactant mixture which provides a vehicle for binding a multiplicity of copies of one or more desired components to the nanoparticle. The construction of the basic particles and the formation of emulsions containing them, regardless of the components bound to the outer surface is described in the above-cited patents to the present applicants, U.S. Pat. Nos. 5,690,907; 5,780,010; and patents issued on daughter applications U.S. Pat. Nos. 5,989,520 and 5,958,371 and incorporated herein by reference. [0017] The high boiling fluorochemical liquid is such that the boiling point is higher than that of body temperature--i.e., 37.degree. C. Thus, fluorochemical liquids which have boiling points at least 30.degree. C. are preferred, more preferably 37.degree. C., more preferably above 50.degree. C., and most preferably above about 90.degree. C. The "fluorochemical liquids" useful in the invention include straight and branched chain and cyclic perfluorocarbons including perfluorinated compounds which have other functional groups. Perfluorinated compounds are preferred. Particularly preferred are compounds which will remain in the liquid state when they serve their function in the subject; for example, when used to obtain an acoustic image. [0018] Useful perfluorocarbon emulsions are disclosed in U.S. Pat. Nos. 4,927,623, 5,077,036, 5,114,703, 5,171,755, 5,304,325, 5,350,571, 5,393,524, and 5,403,575 and include those in which the perfluorocarbon compound is perfluorodecalin, perfluorooctane, perfluorodichlorooctane, perfluoro-n-octyl bromide, perfluoroheptane, perfluorodecane, perfluorocyclohexane, perfluoromorpholine, perfluorotripropylamine, perfluortributylamine, perfluorodimethylcyclohexane, perfluorotrimethylcyclohexane, perfluorodicyclohexyl ether, perfluoro-n-butyltetrahydrofuran, and compounds that are structurally similar to these compounds and are partially or fully halogenated (including at least some fluorine substituents) or partially or fully perfluorinated including perfluoroalkylated ether, polyether or crown ether. Continue reading... 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