WO1987007150A1 - Systemes d'apport de medicaments a recepteur cible - Google Patents

Systemes d'apport de medicaments a recepteur cible Download PDF

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Publication number
WO1987007150A1
WO1987007150A1 PCT/US1987/000965 US8700965W WO8707150A1 WO 1987007150 A1 WO1987007150 A1 WO 1987007150A1 US 8700965 W US8700965 W US 8700965W WO 8707150 A1 WO8707150 A1 WO 8707150A1
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Prior art keywords
receptor
drug
ligand
delivery system
drug delivery
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PCT/US1987/000965
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English (en)
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Jeffrey S. Nye
Solomon H. Snyder
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The Johns Hopkins University
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Publication of WO1987007150A1 publication Critical patent/WO1987007150A1/fr

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/542—Carboxylic acids, e.g. a fatty acid or an amino acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/543—Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • A61K47/543—Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine
    • A61K47/544—Phospholipids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6905—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion
    • A61K47/6911—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion the form being a liposome

Definitions

  • the present invention relates to the field of human diagnostics and therapeutics. Specifically, the invention relates to the targeting of drugs to particular body locations. BACKGROUND OF THE INVENTION
  • Liposomes are synthetic lipid vesicles, which can encapsulate a variety of sizes of molecules in their internal spaces. Liposomes have been widely studied as carriers for delivering substances to cells and tissues in the body. (Gregoriadis, Liposome Technology, Vol. I, II, III, CRC Press, Boca Raton, 1985.) Nanoparticles, like liposomes, also have been studied for use as drug carriers. Nanoparticles are made of synthetic polymeric substances such as polycyanoacrylate, polyanhydrides of aromatic and aliphatic dicarboxylic acids, polymethylcyanoacrylate and the like. They may also be formed of proteins such as albumin and gelatin. (Polymeric Nanoparticles and Microspheres, Boca Raton, CRC Press, 1986.) Nanoparticles may entrap or adsorb the drugs which they carry.
  • the present invention provides an alternative means of targeting drug carrying agents which does not require tissue-specific antibodies.
  • the present invention utilizes the specific interactions of therapeutic and functional pharmacological agents and their cell surface receptors.
  • the receptors for betaadrenergic ligands are predominantly found in the lung, heart and adipose tissue, whereas opiate receptors are found in the gut, spinal cord, and on lymphocytes.
  • cancerous tissues characteristically express receptors, for example, brain glioma expresses beta-adrenergic receptors (Receptor Binding Techniques, Society for Neuroscience, Washington, D.C. 1980) and bronchogenic carcinoma expresses receptors for certain biologically active peptides (Peptides, Vol. 4, pages 683-686, 1983.) SUMMARY OF THE INVENTION
  • a receptor-targeted drug delivery system comprising: a polymeric drug carrying agent selected from the group consisting of liposomes and nanoparticles; a ligand capable of binding a receptor, said ligand being covalently attached to said carrying agent and being a therapeutic and functional pharmacological agent; and a drug, said drug being associated with said drug carrying agent.
  • a therapeutic method of treating a human having a diseased organ or tissue comprising: administering an effective amount of the receptor-targeted drug delivery system of the present invention to the human to affect the metabolism of cells expressing receptors for the ligand on their surfaces or nearby cells, said cells being among those of the diseased organ or tissue.
  • a diagnostic method for determining whether a human has a diseased organ or tissue comprising: administering the receptor-targeted drug delivery system to the human; and noninvasively detecting the localization of said drug.
  • Figure 1 depicts schemes for the synthesis of ligand-lipid conjugates.
  • Figure 2 shows examples of ligands with reactive functional groups and ligand-lipid conjugates made therefrom.
  • Figure 3 shows the affinity of ligand-lipid conjugates for their receptors.
  • Figure 4 reports data demonstrating the formation of stearylpindolol-containing liposomes and the encapsulation of a fluorescent solute.
  • Figure 5 shows the stability of encapsulated solutes within liposomes composed of ligand-lipid conjugates, as measured by 45 Ca-EDTA release.
  • Figure 6 reports data showing that ligand-lipid conjugates are incorporated into the structure of the liposomes.
  • Figure 7 shows the affinity of adenosine phosphatidyl ethanolamine-bearing liposomes for adenosine receptors.
  • Figure 8 shows the affinity of stearyl-pindolol-bearing liposomes for beta-adrenergic receptors.
  • Figure 9 reports data showing the delivery of methotrexate to cells with beta-adrenergic receptors by ligand targeted liposomes containing methotrexate.
  • ligands having therapeutic and functional pharmacologic activity and capable of binding a receptor can be covalently joined to polymeric carrying agents to form ligand-polymeric carrying agent conjugates which retain their ability to bind to cell surface receptors. Drugs thus associated with these ligand-polymeric carrying agents are thereby delivered to cells bearing the corresponding cell surface receptor.
  • Carrying agents contemplated for use in the present invention are polymeric substances, although the polymers need not be covalent polymers.
  • liposomes are suitable polymeric carrying agents whose monomer molecules are generally lipids or phospholipids which are noncovalently joined.
  • nanoparticles may be used as polymeric carrying agents. Nanoparticles are covalently linked polymers of monomers such as acrylates, cyanoacrylates, aromatic and aliphatic dicarboxylic acids and the like. The nanoparticles may be either homopolymers or heteropolymers.
  • the size of the polymeric carrying agents may range from about 20 nm to about 10 u in diameter. Any size which would enable the polymeric carrying agents to circulate in the vasculature or other body compartment is suitable for most applications. However, for topical and other means of administration, even larger particles could be used.
  • Liposomes may be formed using standard methods such as the reverse evaporation method (REV) of Papahadjopolous (Proceedings of the National Academy of Sciences U.S.A., Vo. 75, pgs. 4194-4198, 1978), the dehydration-rehydration method (DRV) of Gregoriadas (U.K. Patent Application 8321012, 1983), sonication to form small unilamellar vesicles (SUV) (Biochemistry Vol. 8, pg. 344, 1967) or other suitable methods.
  • the lipids employed in such liposomes will generally be naturally occurring lipids such as phosphatidylcholine, phosphatidylserine, sphingomyelin, cholesterol, their synthetic analogs, and mixtures thereof.
  • Nanoparticles may be formed using standard procedures taught in the art. For example, Brasseur et al. European Journal of Cancer, vol. 16, pgs. 1441-1445, 1980, teaches preparation of nanoparticles from methylcyanoacrylate by means of polymerization and filtration through a fritted glass filter. (See, for other examples, Couvreur, et al. Journal of Pharmacy and Pharmacology, Vol. 31, pgs. 331-332, 1979, and Leong et al. Journal of Biomedical Materials Research, Vol. 20, pgs. 51-64, 1986)
  • the ligands which are covalently attached to the polymeric carrying agents may be any that are therapeutic and functional pharmacologic agents, and which bind to receptors on the surface of cells.
  • the terra therapeutic and functional pharmacologic agent means natural or synthetic substances which produce biological effects by stimulating or blocking specific cell surface receptors.
  • the substances may be of varied chemical structures, such as peptides, or other organic chemical structures. Desirably the avidity of such binding is K D less than 10 -5 M and preferably the binding would be even stronger, with K D less than 10 -8 M.
  • the ligands may be, for example, hormones, drugs, neurotransmitters or biologically active peptides or their chemical derivatives or analogs.
  • analogs of naturally occurring or synthetic ligands which retain the properties of specificity of binding to the ligand receptors and functionality as pharmacologic agents are used.
  • Such analogs may be designed with appropriate reactive groups for coupling to lipids or to other carrying agent monomers. See, for example, Snyder, Journal of Medicinal Chemistry, Vol. 26, pgs. 1667-1672, 1973.
  • conjugates formed by covalently joining the ligand and polymeric carrying agent retain binding and pharmacologic functionality characteristics. Covalently joined ligands can be routinely tested to insure that these properties are retained.
  • the preferred way to insure retention of receptor-binding and pharamcologic activity is to provide a ligand having a unique functional group for joining to the polymeric carrying agent.
  • Such functional groups should not be constituents of the binding or active portion of the ligand.
  • Covalent ligand-monomer conjugates of defined chemical structure, composition and purity are synthesized according to techniques known in the art.
  • the ligand should preferably have no more than about 10, and more preferably no more than about 2, identical functional groups. If there are multiple similarly reactive groups, then means must be taken to separate the reaction products. Once separated, each can be chemically characterized and tested for retention of binding to cell surface receptors. Such means of separation and testing are standard procedures which are known in the art, and certain techniques will be preferred depending on the compound. As the number of similarly reactive functional groups increases, however, such separation and testing become more difficult, and obtaining substantially pure receptor-targeted carriers becomes significantly more complicated.
  • the ligands may be covalently attached to the polymeric carrying agents either before or after polymerization, that is to say the ligand may be attached to carrying agent monomer molecules or to the subsequently prepared polymeric carrying agent. If first attached to monomers, then the ligand-monomer conjugates may be used alone or preferably are admixed with other free monomers and processed to form the polymeric carrying agent. Of course, the monomers used to prepare the conjugate need not be the same as the free monomers used when subsequently polymerizing the carrying agent. In fact, other monomers generally will be preferred in order to permit separate optimization of the preparation and properties of conjugates and polymeric carrying agents. The ratio of free monomers to ligand-monomer conjugates may vary.
  • At least one ligand-monomer will be incorporated per subsequently prepared carrying agent polymer.
  • the amount of ligand- monomer conjugates be from about 0.5 mol% to about 10 mol%.
  • a ligand bearing a carboxylic acid functional group can be coupled to a lipid bearing a primary amino group, resulting in an amide ligand-lipid conjugate; or the carboxyl group- containing ligand can be coupled to an hydroxyl-containing lipid, resulting in an ester ligand-lipid conjugate.
  • lipids which may be coupled to carboxylic acid-containing ligands include the naturally occurring stearylamine, phosphatidyl ethanolamine, sphinganine, and ceramide, as well as paraffin alcohols and other synthetic lipids.
  • an amino group-containing ligand can be coupled to a fatty acid or its active ester or acid chloride, again yielding an amide ligand-lipid conjugate; or a ligand bearing an hydroxyl group can be reacted with a fatty acid to yield an ester linked ligand-lipid conjugate.
  • Another means of coupling would involve nucleophilic substitution of electrophilic ligands, for example by thiol derivatives of lipids or phospholipids.
  • Lipids which may be coupled to nucleophilic ligands include phosphatidyl serine, fatty acids preferably having from 12 to 18 carbon atoms, and their active esters or acid chlorides (X). Standard reaction conditions are used depending upon the reactants.
  • Lipids for coupling to electrophilic ligands include thiol derivatives of phosphatidyl ethanolamine or other lipid. Such lipids have been described (Nature 288, 602-604, 1980).
  • polyalkyl cyanoacrylate or aerylamide nanoparticles may be attached to ligands by copolymerizing the acrylate monomer with a small amount (0.1 to 5%) of an active ester of acrylic acid, as described in Methods in Enzymology, vol. LXXXIII, pp. 306-310, 1982.
  • an amine containing ligand is reacted with the matrix and the ligand-polymer is purified by standard techiques.
  • a ligand-monomer conjugate is prepared using an amine containing ligand and the active acryloyl ester. This compound is then copolymerized with the acrylic acid monomer to form targeted nanoparticles.
  • the specific reactions to be employed will vary with the compounds used and are known in the art.
  • the drug which is chosen to be associated with (carried by) the carrying agent may or may not interact with the same cell surface receptor as does the ligand which is covalently bound to the outer surface of the carrying agent.
  • insulin could be used to target liposomes, by being covalently bound to the liposomes, and could also be delivered by the liposomes to the target tissue or organ.
  • Association of the drug to the carrying agent can occur, for example, by the drug filling interstitial spaces of the carrying agent, such that the carrying agent physically entraps the drug, or by covalent, ionic, or hydrogen bonding, or by means of adsorption by non-specific bonds. Whatever the mode of association, the drug must retain its therapeutic or diagnostic properties.
  • the drugs may be solid or liquid, hydrophobic, hydrophilic or both.
  • the dosages of drug associated with the carrying agent which are to be administered are those required to deliver an effective amount of the drug to the target tissue or organ. Such amounts are determined clinically. Such amounts are determined clinically.
  • the same considerations of toxicity and efficacy apply for the carrying agent- associated drug as for the free drug. In general lower dosages may suffice as compared to administration of free drug, because the carrying agent will stabilize the drug in the body, making it more resistant to degradation.
  • the enhanced delivery efficiency due to the targeting of the drug will provide the same effective concentration of a drug to a localized area of the body even when using a lower total dosage as computed per body weight.
  • two classes of drugs are contemplated for use in the present invention: bioaffecting molecules and diagnostic molecules.
  • Bioaffecting molecules are any which affect cell and body functions, either positively or negatively. This class includes cytotoxics, cytostatics, hormones, neurotransmitters, biologically active peptides and the like. Diagnostic molecules are those which can be detected in the body without recourse to invasive procedures such as surgery. Such molecules include fluorescent compounds, radiolabeled compounds, X-ray opaque dyes, ferromagnetic compounds, and the like. A compendium of drugs which may be used is found in Gilmah et al., Goodman and Gilman's The Pharmacologic Basis of Therapeutics, MacMillan, New York, 1980.
  • Administration of the receptor-targeted drug delivery system may be by any of the various means known in the art. Such means include but are not limited to: nebulizers, eye drops, topically, by implant, intraperitoneally, intramuscularly, intravenously, and orally. The following examples are not meant to limit the scope of the invention, but only to more fully illustrate the invention.
  • N 6 -(4-carboxymethyl)phen ⁇ ladenosine (la in figure 2) and distearyl phosphatidyl ethanolamine (DSPE) was performed as follows. To la (0.123 mmol) in dimethyl formamide (DMF) (10 ml) at 4°C were added sequentially with stirring hydroxybenzyltriazole and 1-ethyl-3-(3-dimethylaminopro ⁇ yl)carbodiimide (0.15 mmol of each). After 30 min the solution was warmed to 23°C and DSPE (0.125 mmol) and triethylamine (15 mmol) dissolved in CHCI 3 were added. The reaction was stirred under an argon atmosphere for 16 h.
  • DMF dimethyl formamide
  • DSPE 1-ethyl-3-(3-dimethylaminopro ⁇ yl)carbodiimide
  • the product was a ninhydrin negative, phosphate positive spot (R f 0.44) on thin-layer chromatography using silica gel developed in CHCl 3 /MeOH/water (60/30/5.) It forms a white emulsion in aqueous solutions.
  • SUV small unilamellar vesicles
  • 9.5 umol phosphatidyl choline labeleled with tritium
  • 10 umol cholesterol and 0.5 umol of conjugate 1b
  • Figure 2. The resulting lipsomes were purified by chromatography over SephadexTM G25. Fractions containing 3 H-phos ⁇ hatidyl choline were extracted with CHCl 3 /MeOH (2/1) and water. The organic layer was dried and resuspended in 95% ethanol and the UV spectrum was obtained. It revealed a peak at 303 nm corresponding to quantitative recovery of (1b.)
  • the affinity of ligand-carrying agent monomers conjugates for membrane receptors was determined by comparing their ability to inhibit radiolabeled ligands from binding to their specific receptors.
  • Stearyl-pindolol (3b) shows an IC 50 (concentration which produces 50% inhibition) for the beta-adrenergic receptor of about 500 nM and in the presence of the solubilizer HPBCD about 20nM.
  • the adenosine-lipid conjugate shows an IC 50 of ahout 50 nM for adenosine (A 1 ) receptors.
  • Standard receptor binding assays were performed with 125 I- cyanopindolol (50 pM) (compound A) and rat lung membrane homogenates and with 3 H-1-PIA phenyl isopropyl adenosine (compound B) (2 nM) and calf cortex membrane homogenates. The results are shown in Figures 3A and 3B, respectively. Varying concentrations of ligand-lipid conjugates or other compounds were mixed with the radio-ligand before the addition of membranes. Specific binding is defined by the binding inhibited by the addition of 1uM pindolol in assays of compound A and 10uM 1-PIA (phenylisopropyl adenosine) in assays of compound B. Percent binding is defined as the binding at a given concentration of inhibitor compared to specific binding.
  • Small unilamellar vesicles as described above were prepared using distearyl phosphatidyl choline (20 umol) and stearyl pindolol (0.2 umol) with cholesterol (20 umol). Trace quantities of 3 H- phosphatidyl choline were used as a marker of the lipid membranes. Carboxyfluorescein (0.15 M) was included in the aqueous phase. Equal quanities of liposomes were loaded on a molecular sieve column (Sephadex G25, 1.5 x 30 cm). Fractions were assayed for 3 H and fluorescence. The fluorescence measurements plotted in Figure 4 were obtained after releasing encapsulated dye with Triton X-100 (1%). Over 90% of the fluorescence was quenched for both types of liposomes.
  • Phosphatidyl choline cholesterol REV liposomes (as described by Papahadjopolous, Proceedings of the National Academy of Science, USA. 75, pp. 4194-4198, 1978) with or without 1 mol% stearyl pindolol were prepared containing 45 Ca-EDTA.
  • the liposomes were purified by repeated centrifugation and then dialyzed to remove unencapsulated 45 Ca-EDTA. Aliquots of the liposomes were placed into dialysis bags at 4°C or 37°C and transferred to new dialysate at the intervals plotted in Figure 5. Released 45 Ca is defined as the radioactivity measured in the dialysate.
  • SUV liposomes prepared as described above composed of distearyl phosphatidyl choline and cholesterol and supplemented with either adenosine-phosphtidyl ethanolamine (adenosine-PE) 1b, biotin-PE or stearylpindolol (3b) at 1 mol% were prepared and purified.
  • the liposomes were added to standard receptor binding assays using 3 H-1-PIA (phenyl isopropyl adenosine) and calf cortex membranes with 1-PIA (10 mM) used as blank.
  • Figure 7 shows the inhibition of receptor binding to 3 H-1-PIA which is caused by the targeted liposomes.
  • Liposomes containing adenosine-PE but not stearyl-pindolol or biotin-PE compete effectively for adenosine A 1 receptors.
  • Example 10 Liposomes containing adenosine-PE but not stearyl-pindolol or biotin-PE compete effectively for adenosine A 1 receptors.
  • SUV liposomes were prepared as described above with egg PC (phosphatidyl choline) and cholesterol and varying concentrations of stearyl-pindolol (0-10 mol%) as indicated. Varying quantities of liposomes were added to standard receptor binding assays using 125 I- cyanopindolol and rat lung membranes. Liposomes containing stearylpindolol inhibit binding in a dose-dependent manner whereas liposomes lacking stearyl-pindolol do not. Maximal inhibition obtained by the liposomes was only approximately 50% of specific 125 I-cyanopindolol binding, perhaps due to geometric constraints on the accessibility of liposomes to membrane receptors. Example 11.
  • Distearyl phosphatidyl choline (DSPC) and cholesterol liposomes containing methotrexate supplemented with nothing, stearyl-pindolol or adenosine-PE at 1 mol% were added to N18 tg2 mouse neuroblastoma for 48 h. In control experiments free methotrexate was used. In two experiments, before addition of methotrexate targeted stearyl-pindolol liposomes, either free pindolol (10 mM) or empty stearyl-pindolol liposomes were added. Figure 9 shows the results.

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Abstract

Des agents porteurs de médicaments tels que des liposomes et des nanoparticules peuvent être dirigés sur des tissus ou organes spécifiques du corps par liaison covalente de ligands thérapeutiques et pharmacologiques qui gardent une grande affinité pour leurs récepteurs ainsi qu'une activité pharmacologique. Les ligants peuvent être conjugués à des monomères avant qu'ils soient transformés dans leur structure de type liposome ou nanoparticule. Les médicaments pouvant être véhiculés par ces agents porteurs peuvent avoir une fonction thérapeutique ou diagnostique.
PCT/US1987/000965 1986-05-30 1987-04-28 Systemes d'apport de medicaments a recepteur cible WO1987007150A1 (fr)

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0409690A1 (fr) * 1989-07-18 1991-01-23 Exsymol S.A.M. Produits pour application cutanées, à effets cosmétiques et/ou thérapeutiques
US5258499A (en) * 1988-05-16 1993-11-02 Vestar, Inc. Liposome targeting using receptor specific ligands
US5342607A (en) * 1986-07-03 1994-08-30 Advanced Magnetics, Inc. Receptor mediated endocytosis type magnetic resonance imaging contrast agents
US5352432A (en) * 1986-07-03 1994-10-04 Advanced Magnetics, Inc. Hepatocyte specific composition and their use as diagnostic imaging agents
US5490991A (en) * 1986-07-03 1996-02-13 Advanced Magnetics, Inc. Directed delivery of radioprotectants using a receptor specific carrier
US5679323A (en) * 1986-07-03 1997-10-21 Advanced Magnetics, Inc. Hepatocyte-specific receptor-mediated endocytosis-type compositions
EP0861667A2 (fr) * 1990-09-14 1998-09-02 Syngenix Limited Agents particulaires
EP1266032A1 (fr) * 2000-02-18 2002-12-18 Biocrystal Limited Nanocristaux fluorescents encapsules fonctionnalises
EP2106806A1 (fr) 2008-03-31 2009-10-07 Fraunhofer-Gesellschaft zur Förderung der Angewandten Forschung e.V. Nanoparticules pour la livraison ciblée d'agents actifs vers les poumons
JP2014523924A (ja) * 2011-07-28 2014-09-18 セダーズ−シナイ メディカル センター 両親媒性スペーサーまたは両親媒性ポリマー上に治療薬を含む抗酸化、神経保護、および抗腫瘍ナノ粒子
WO2015192149A3 (fr) * 2014-06-13 2016-01-28 The Regents Of The University Of California Supports nanostructurés pour administration de substance guidée et ciblée à la demande

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3857931A (en) * 1971-02-01 1974-12-31 Hoffmann La Roche Latex polymer reagents for diagnostic tests
US4140662A (en) * 1977-03-25 1979-02-20 Ortho Diagnostics, Inc. Attachment of proteins to inert particles
US4283382A (en) * 1977-12-28 1981-08-11 Eastman Kodak Company Fluorescent labels comprising rare earth chelates
US4377567A (en) * 1978-10-02 1983-03-22 The Procter & Gamble Company Lipid membrane drug delivery
US4429008A (en) * 1981-12-10 1984-01-31 The Regents Of The University Of California Thiol reactive liposomes
US4460560A (en) * 1982-06-18 1984-07-17 University Of Southern California Drug delivery by polymeric carriers
US4544545A (en) * 1983-06-20 1985-10-01 Trustees University Of Massachusetts Liposomes containing modified cholesterol for organ targeting
US4565696A (en) * 1983-08-03 1986-01-21 The Regents Of The University Of California Production of immunogens by antigen conjugation to liposomes

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3857931A (en) * 1971-02-01 1974-12-31 Hoffmann La Roche Latex polymer reagents for diagnostic tests
US4140662A (en) * 1977-03-25 1979-02-20 Ortho Diagnostics, Inc. Attachment of proteins to inert particles
US4283382A (en) * 1977-12-28 1981-08-11 Eastman Kodak Company Fluorescent labels comprising rare earth chelates
US4377567A (en) * 1978-10-02 1983-03-22 The Procter & Gamble Company Lipid membrane drug delivery
US4429008A (en) * 1981-12-10 1984-01-31 The Regents Of The University Of California Thiol reactive liposomes
US4429008B1 (en) * 1981-12-10 1995-05-16 Univ California Thiol reactive liposomes
US4460560A (en) * 1982-06-18 1984-07-17 University Of Southern California Drug delivery by polymeric carriers
US4544545A (en) * 1983-06-20 1985-10-01 Trustees University Of Massachusetts Liposomes containing modified cholesterol for organ targeting
US4565696A (en) * 1983-08-03 1986-01-21 The Regents Of The University Of California Production of immunogens by antigen conjugation to liposomes

Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5342607A (en) * 1986-07-03 1994-08-30 Advanced Magnetics, Inc. Receptor mediated endocytosis type magnetic resonance imaging contrast agents
US5352432A (en) * 1986-07-03 1994-10-04 Advanced Magnetics, Inc. Hepatocyte specific composition and their use as diagnostic imaging agents
US5490991A (en) * 1986-07-03 1996-02-13 Advanced Magnetics, Inc. Directed delivery of radioprotectants using a receptor specific carrier
US5679323A (en) * 1986-07-03 1997-10-21 Advanced Magnetics, Inc. Hepatocyte-specific receptor-mediated endocytosis-type compositions
US5258499A (en) * 1988-05-16 1993-11-02 Vestar, Inc. Liposome targeting using receptor specific ligands
EP0409690A1 (fr) * 1989-07-18 1991-01-23 Exsymol S.A.M. Produits pour application cutanées, à effets cosmétiques et/ou thérapeutiques
FR2649888A1 (fr) * 1989-07-18 1991-01-25 Exsymol Sa Produits pour applications cutanees, a effets cosmetiques ou/et therapeutiques
EP0861667A3 (fr) * 1990-09-14 2001-08-08 Syngenix Limited Agents particulaires
EP0861667A2 (fr) * 1990-09-14 1998-09-02 Syngenix Limited Agents particulaires
EP1266032A1 (fr) * 2000-02-18 2002-12-18 Biocrystal Limited Nanocristaux fluorescents encapsules fonctionnalises
EP1266032A4 (fr) * 2000-02-18 2005-01-19 Biocrystal Ltd Nanocristaux fluorescents encapsules fonctionnalises
EP2106806A1 (fr) 2008-03-31 2009-10-07 Fraunhofer-Gesellschaft zur Förderung der Angewandten Forschung e.V. Nanoparticules pour la livraison ciblée d'agents actifs vers les poumons
JP2014523924A (ja) * 2011-07-28 2014-09-18 セダーズ−シナイ メディカル センター 両親媒性スペーサーまたは両親媒性ポリマー上に治療薬を含む抗酸化、神経保護、および抗腫瘍ナノ粒子
WO2015192149A3 (fr) * 2014-06-13 2016-01-28 The Regents Of The University Of California Supports nanostructurés pour administration de substance guidée et ciblée à la demande
US10245322B2 (en) 2014-06-13 2019-04-02 The Regents Of The University Of California Nanostructured carriers for guided and targeted on-demand substance delivery
US10864270B2 (en) 2014-06-13 2020-12-15 The Regents Of The University Of California Nanostructured carriers for guided and targeted on-demand substance delivery

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