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    CHARGE TRIGGERING OF SELF-ORGANIZED NANOPARTICLES
    1.
    发明申请
    CHARGE TRIGGERING OF SELF-ORGANIZED NANOPARTICLES 审中-公开
    自组织纳米粒子的充电触发

    公开(公告)号：WO2012155920A1

    公开(公告)日：2012-11-22

    申请号：PCT/DK2012/050174

    申请日：2012-05-16

    申请人： DANMARKS TEKNISKE UNIVERSITET ,  JØLCK, Rasmus Irming ,  HENRIKSEN, Jonas, Rosager ,  GJETTING, Torben ,  ANDRESEN, Thomas, Lars

    发明人： JØLCK, Rasmus Irming ,  HENRIKSEN, Jonas, Rosager ,  GJETTING, Torben ,  ANDRESEN, Thomas, Lars

    IPC分类号： A61K9/10 ,  A61K9/127 ,  A61K47/00

    CPC分类号： A61K47/48838 ,  A61K9/1272 ,  A61K9/145 ,  A61K31/282 ,  A61K31/7088 ,  A61K47/544 ,  A61K47/60 ,  A61K47/62 ,  A61K47/6455 ,  A61K47/65 ,  A61K47/6911 ,  A61K47/6917 ,  A61K47/6921 ,  Y10S977/80 ,  Y10S977/801 ,  Y10S977/907

    摘要： The present application discloses a nanoparticle comprising compounds of the formula A-B- C(-D), wherein A designates an anchoring moiety having self-organizing properties in relation to the nanoparticle; B designates a cleavable linker; C designates an anionic moiety having a net charge of at least -2 at p H 6.0; and D, which is optional, designates a polymer moiety which induces long circulating properties of the nanoparticle in mammalian tissue; and wherein the average net charge of the compounds is at least -1 at p H 6.0. The application also discloses the individual compounds of the formula A-B-C(-D) as well as a drug delivery system comprising the self-organized nanoparticle having included in the interior thereof one or more pharmaceutically active agents and/or diagnostically relevant species, and a method of treating a cancerous or inflammatory condition in a mammal, involving the administration of the drug delivery system to the mammal.

    摘要翻译： 本申请公开了包含式A-B-C（-D）的化合物的纳米颗粒，其中A表示具有相对于纳米颗粒的自组织性质的锚定部分; B表示可切割接头; C表示在p H 6.0下净电荷至少为-2的阴离子部分; 和D是任选的，表示在哺乳动物组织中诱导纳米颗粒的长循环性质的聚合物部分; 并且其中化合物的平均净电荷在p H 6.0下至少为-1。 本申请还公开了式ABC（-D）的各种化合物以及包含其内部含有一种或多种药物活性剂和/或诊断相关物种的自组织纳米颗粒的药物递送系统，以及方法 在哺乳动物中治疗癌症或炎性疾病，涉及向哺乳动物施用药物递送系统。

    METHODS AND COMPOSITIONS FOR TARGETED IMAGING
    3.
    发明申请
    METHODS AND COMPOSITIONS FOR TARGETED IMAGING 审中-公开

    公开(公告)号：WO2011044545A2

    公开(公告)日：2011-04-14

    申请号：PCT/US2010/052117

    申请日：2010-10-10

    申请人： SIGALOV, Alexander, B.

    发明人： SIGALOV, Alexander, B.

    IPC分类号： A61K47/42 ,  A61K47/36 ,  A61K9/48 ,  A61K49/04 ,  A61P35/00

    CPC分类号： A61K51/1224 ,  A61K47/6917

    摘要： 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).

    SALIPRO PARTICLES
    8.
    发明申请
    SALIPRO PARTICLES 审中-公开
    SALIPRO颗粒

    公开(公告)号：WO2014095576A1

    公开(公告)日：2014-06-26

    申请号：PCT/EP2013/076404

    申请日：2013-12-12

    申请人： FRAUENFELD, Jens

    发明人： FRAUENFELD, Jens

    IPC分类号： A61K9/127 ,  A61K9/51

    CPC分类号： A61K47/6917 ,  A61K9/1274 ,  A61K9/1275 ,  A61K9/145 ,  A61K9/146 ,  A61K38/164 ,  A61K39/00 ,  A61K47/24 ,  A61K47/42 ,  A61K47/543 ,  A61K47/544 ,  A61K47/62 ,  A61K47/64 ,  A61K47/6929

    摘要： The invention provides a nanoscale particle comprising a lipid binding polypeptide, lipids and a hydrophobic agent, wherein the hydrophobic agent is different from the lipids, and wherein the lipid binding polypeptide is a saposin-like protein or a derivative or truncated form thereof. The invention further provides a process for preparing a particle comprising a saposin-like protein or a derivative or truncated form thereof and lipids comprising the step of (a) contacting the saposin-like protein or a derivative or truncated form thereof with solubilized lipids in a liquid environment and (b) allowing for the self-assembly of the particle at a pH of from 5.0 to 10.0. In addition, the invention provides a pharmaceutical composition comprising the particle of the invention for delivering a hydrophobic agent to an individual in need thereof and includes the use of the particle of the invention in preventing, treating or lessening the severity of a disease or its use in a diagnostic method, a cosmetic treatment, as hydrophobic agent delivery particle, as a tool for drug development, drug screening, membrane protein research or as vaccination formulation.

    摘要翻译： 本发明提供包含脂质结合多肽，脂质和疏水剂的纳米级粒子，其中所述疏水剂不同于所述脂质，并且其中所述脂质结合多肽是类似于类似蛋白质的蛋白质或其衍生物或截短形式。 本发明还提供了一种制备包含类似于类似蛋白质的蛋白质或其衍生物或截短形式的颗粒和脂质的方法，所述方法包括以下步骤：（a）将类似于类似蛋白质的蛋白质或其衍生物或截短形式与溶解的脂质接触 液体环境和（b）允许在5.0至10.0的pH下自组装颗粒。 此外，本发明提供了包含本发明的颗粒的药物组合物，用于将疏水剂递送至有需要的个体，并且包括使用本发明的颗粒来预防，治疗或减轻疾病的严重性或其用途 在诊断方法中，作为疏水剂递送颗粒的美容处理，作为药物开发，药物筛选，膜蛋白研究或疫苗制剂的工具。

    TRUNCATED APOLIPOPROTEIN B-CONTAINING LIPOPROTEIN PARTICLES FOR DELIVERY OF COMPONENTS TO TISSUES OR CELLS
    10.
    发明申请
    TRUNCATED APOLIPOPROTEIN B-CONTAINING LIPOPROTEIN PARTICLES FOR DELIVERY OF COMPONENTS TO TISSUES OR CELLS 审中-公开
    截短的载脂蛋白B的脂蛋白颗粒用于将组分递送至组织或细胞

    公开(公告)号：WO03000184A2

    公开(公告)日：2003-01-03

    申请号：PCT/US0219512

    申请日：2002-06-20

    申请人： UNIV WAKE FOREST ,  SHELNESS GREGORY

    发明人： SHELNESS GREGORY

    IPC分类号： A61K9/127 ,  A61K47/48 ,  A61K

    CPC分类号： A61K9/1275 ,  A61K47/6849 ,  A61K47/6917

    摘要： A lipoprotein compound delivery particle comprises: (a) a lipophilic or amphipathic compound to be delivered (e.g. paclitaxel); (b) at least one polar lipid (this ingredient being optional when the lipophilic or amphipathic compound serves itself as a polar lipid); (c) optionally, at least one neutral lipid; and (d) a truncated apolipoprotein B (apoB) protein having a deleted LDL receptor binding region. Conjugates useful for making such particles, pharmaceutical formulations containing such particles, and methods of using such particles are also described.

    摘要翻译： 脂蛋白化合物递送颗粒包含：（a）待递送的亲脂性或两亲性化合物（例如紫杉醇）; （b）至少一种极性脂质（当亲脂性或两亲性化合物自身用作极性脂质时，该成分是任选的）; （c）任选地，至少一种中性脂质; 和（d）具有缺失的LDL受体结合区的截短的载脂蛋白B（apoB）蛋白。 还描述了可用于制造这种颗粒的缀合物，含有这些颗粒的药物制剂以及使用这些颗粒的方法。