WO1991004014A1 - Procede de transport de compositions a travers la barriere hemato-encephalique - Google Patents

Procede de transport de compositions a travers la barriere hemato-encephalique Download PDF

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Publication number
WO1991004014A1
WO1991004014A1 PCT/US1990/005349 US9005349W WO9104014A1 WO 1991004014 A1 WO1991004014 A1 WO 1991004014A1 US 9005349 W US9005349 W US 9005349W WO 9104014 A1 WO9104014 A1 WO 9104014A1
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Prior art keywords
brain
transferrin
liposomes
insulin
blood
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Application number
PCT/US1990/005349
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English (en)
Inventor
Franklin D. Collins
Robert C. Thompson
Michael J. Yarus
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Synergen, Inc.
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Publication of WO1991004014A1 publication Critical patent/WO1991004014A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
    • A—HUMAN NECESSITIES
    • A63—SPORTS; GAMES; AMUSEMENTS
    • A63F—CARD, BOARD, OR ROULETTE GAMES; INDOOR GAMES USING SMALL MOVING PLAYING BODIES; VIDEO GAMES; GAMES NOT OTHERWISE PROVIDED FOR
    • A63F3/00—Board games; Raffle games
    • A63F3/06—Lottos or bingo games; Systems, apparatus or devices for checking such games
    • A63F3/065—Tickets or accessories for use therewith
    • A63F3/0685—Tickets or accessories for use therewith having a message becoming legible after a chemical reaction or physical action has taken place, e.g. applying pressure, heat treatment, spraying with a substance, breaking microcapsules

Definitions

  • This barrier consists of uniform, tight junctions between adjacent endothelial cells lining brain capillaries. These junctions prevent the penetration into the brain of many water-soluble molecules. In addition, there is a relative absence of the intracellular bulk transport vesicles that shuttle molecules across endothelial cells in other organs. These barriers prevent the entry into the brain of a wide variety of potentially therapeutic compounds administered to the systemic circulation.
  • the blood-brain barrier prevents certain nerotransmitters, such as dopamine, and most macromolecules, such as nerve growth factors, from entering the brain from the circulation.
  • nerotransmitters such as dopamine
  • macromolecules such as nerve growth factors
  • One method proposed for delivering non-penetrating drugs to the brain is to chemically link the drug to a carrier compound that is capable of penetrating the blood-brain barrier.
  • the penetrating compounds that have been proposed for use as carriers include small, lipid soluble molecules, such as modified dihydropyridines (Bodor, 1987, Ann. N.Y. Acad. Sci. 507: 289-306), or compounds that enter the brain through a specific transport system in brain endothelial cells, such as the transport systems for transferrin, insulin, and insulin ⁇ like growth factors I and II (Pardridge, 1988, Ann. N.Y. Acad. Sci. 529: 50-60).
  • This proposed method is subject to two serious drawbacks the may prevent delivery to the brain of a wide range of therapeutic agents.
  • the drug must retain its activity when chemically coupled to the carrier or there must be an endogenous and accessible brain enzyme able to uncouple the drug and carrier once they are inside the brain.
  • large drugs for example macromolecules such as nerve growth factors, are very likely to dominate the chemical properties of the drug-carrier combination and prevent penetration of the combination into the brain.
  • liposomes targeted to endogenous brain transport systems that will be used to encapsulate and deliver normally non-penetrating therapeutic agents to the brain. Since the therapeutic agents will be encapsulated in liposomes, they will be protected from enzymatic inactivation in the blood. Moreover, there will be no need to chemically couple these therapeutic agents to the carrier and chemically uncouple them in the brain. In addition, liposomes are capable of delivering large macromolecules, such as nerve growth factors, that would be unlikely to penetrate the brain when chemically coupled to a carrier molecule.
  • the liposomes of the invention are targeted by the addition to the outside layer of the liposome of one or more molecules that are normally transported across the blood- brain barrier.
  • transported molecules include, but are not limited to, transferrin, insulin, and insulin-like growth factors I and II as described by Fishman et al., 1987, J. Neurosci. Res. 18:299-304; and Frank et al., 1986, Diabetes 35:654-661, each of which is specifically incorporated herein by reference.
  • Each endogenous transport system consists of specific membrane receptors on the endothelial cell surface to which the transported molecule binds, followed by mechanisms for internationalization of the molecule into an intracellular vesicle, and expulsion of the contents of the vesicle into the brain as described by Deutry-Varsat et al., 1987, J. Neurosci. Res. 18:299-304; Klausner et al., 1983, J. Biol. Chem. 258: 4715-4724; and Duffy et al., 1987, each of which is specifically incorporated by reference herein.
  • the liposomes are attached to the transport systems by coupling to their external surface either one of the transported molecules mentioned above (transferrin, insulin, or insulin ⁇ like growth factors) or antibodies directed to the specific brain endothelial cell receptors for these transported molecules.
  • Such coupling methods are described, for example, by Schneider et al., 1984, Nature 311: 675-678 specifically incorporated herein by reference.
  • the invention consists of methods for delivering therapeutic and diagnostic agents to the brain across the blood brain barrier.
  • agents are delivered to the brain by encapsulating them in liposomes targeted to any of a number of endogenous brain transport systems that transport specific ligands across the blood brain barrier.
  • the liposomes are targeted to such endogenous transport systems by coupling to their outer surface either the specifically- transported ligand or antibodies to the brain endothelial cell receptor for the ligand.
  • Examples of such liposome- targeting molecules are the speci.fically-transported proteins transferrin, insulin, or insulin-like growth factors I and II and antibodies to the receptors for transferrin, insulin, or embodiments of this invention and, together with the descrip serves to explain the principles of the invention.
  • Figure 1 illustrates the results of a competition bindi experiment described in Example 1.
  • the present invention relates to t of targeted liposomes to deliver therapeutic and/or diagnost agents across the blood-brain barrier.
  • the liposomes may be prepared by any of a wide variety of standard methods for producing stable, unilamellar liposomes of uniform internal diameter.
  • liposomes are composed saturated phospholipids and cholesterol in relative proporti suitable to produce stable liposomes.
  • the liposomes also co a modified lipid that is capable of covalently linking a var of targeting molecules to the external liposome surface.
  • the covalent-linker lipid is MPB-PE.
  • the liposomes are composed of distearo phosphatidylcholine, cholesterol, and MPB-PE (N-[4-(p aleimidophenyl) butryl] phosphatidylethanolamine) in the ra molar of 1:1:0.068, assuming the final composition reflects initial reaction mixture.
  • liposomes are generated by passage either through a micropore membrane or through a microfluidizer generate unilamellar liposomes of uniform diameter. Examples of these methods may be found in Klimchak and Lank, 1988 Biopharmaceutics FEB:18-21: and Olsen et al., 1979, Bioche . Biophvs. Acts 557:9-23. each of which is specifically incorporated herein by reference.
  • the liposomes are targeted for passage through the blood-brain barrier by the coupling, to the outside of the liposome, of molecules which are actively transported across the blood-brain barrier. These transported molecules are added to the outside of intact liposomes and become covalently linked under appropriate reaction conditions to a suitably modified lipid incorporated into the liposome.
  • suitable transport substances include, but are not limited to, transferrin, insulin, insulin-like growth factor 1 (IGF-I), insulin-like growth factor II (IGF-II), and antibodies against specific brain endothelial cell receptors for transferrin, insulin, IGF-I, and IGF-II.
  • liposomes are covalently coupled through the modified lipid N-[4-p-maleimidophenyl) butyrl] phosphatidylethanolamine (MPB-PE) to iron-saturated transferrin on the surface.
  • MPB-PE modified lipid N-[4-p-maleimidophenyl) butyrl] phosphatidylethanolamine
  • transferrin-coated liposomes competed effectively with free transferrin for the transferrin receptors on human cells (Example 1, Figure 1).
  • transferrin-coated liposomes were also able to increase the penetration into the brain of a radiolabeled tracer (Example 2, Table 1) .
  • a wide variety of therapeutic agents are envisioned for encapsulation within the liposomes of this invention. These include: protein neurotrophic factors (for example, nerve growth factor) to treat brain injury and neurodegenerative diseases; enzymes to replace enzymatic activities lost through genetic defects where the loss causes severe metabolic storage diseases such as Tay-Sachs disease;
  • SUBSTIT neurotransmitters and neuromodulators such as dopamine and jg-endorphin, that would be useful for treating Parkinson's disease and intractable pain, respectively, or conditions including disorders of movement, cognition, and behavior.
  • antibiotics for treating infectious diseases such as neurosyphilis or AIDS, where Penetration into the brain of systemically administered antibiotics is presently a block to treatment; chemotherapeutic agents for treating brain tumors with agents that do not reach the tumor in sufficient amounts when tolerable doses are administered systemically; and diagnostic agents. such as specific contrast media for brain imaging, that are currently not used because of poor penetration into the brain upon systemic administration.
  • Example 1 Method for Producing Liposomes
  • the following lipids are dissolved in 25ml chloroform and evaporated to dryness as a thin film in the bottom of a round-bottomed flask: 300mmol disearoyl phosphatidylcholine, 300mmol cholesterol, and 20.4 mmol N-[4-(p-maleimidophenyl) butyrl] phosphatidylethanolamine (MPB-PE).
  • MPB-PE contains a reactive group capable of coupling to a wide variety of proteins. (Martin and Papahadjopoulos, 1982, J. Biol. Chem. 257:286-288).
  • the material to be encapsulated is dissolved in Buffer I consisting of 108mM NaCl, 35mM Na 2 HP0 4 , 20mM citric acid, ImM EDTA, pH 4.5.
  • Buffer I consisting of 108mM NaCl, 35mM Na 2 HP0 4 , 20mM citric acid, ImM EDTA, pH 4.5.
  • the low pH prevents premature hydrolysis of the covalent linking group on MPB-PE.
  • Lipids are swollen in this solution for 3 hours, then the solution is passed seven times through a microfluidizer MHO as described by Teagarden et al. in Pharmaceutical Res. 5.: 482-487 (1988) at a final nitrogen pressure of 10,000 psi to create unilamellar liposomes in a narrow size range with an average diameter of approximately lOOnm.
  • the unilamellar nature of the liposomes was confirmed by X-ray diffraction and the size distribution determined by light scattering.
  • the mixture is passed over a Sephadex G150 column equilibrated with buffer I.
  • the liposomes emerge from the column in the void volume.
  • the liposomes are deaerated under argon for 2 hours.
  • Ten mg of iron-saturated transferrin is added dissolved in Ringer's salt solution.
  • the pH is raised to 7.0 at which pH the coupling group on MPB-PE is activated, and the reaction allowed to stand under argon overnight at 4°C.
  • Reactive groups on MPB-PE that do not couple to transferrin during this step including those molecules of MPB-PE whose reactive groups face the interior of the liposome, are hydrolyzed and inactivated when oxygen is reintroduced during subsequent processing.
  • Transferrin- coupled liposomes are separated from free, unreacted transferrin by a second passage of the reaction mixture through a G-150 column equilibrated with Ringer's salt solution. The amount of transferrin is measured in each fraction emerging from the column by standard protein assay in order to calculate the amount of unincorporated transferrin and the number of coupled transferrin molecules per liposome.
  • an aliquot of each liposome preparation can be stored at 4°C for various lengths of time, then passed over a G-150 sizing column to determine what proportion of the transferrin and encapsulated drug emerge in the liposome vs. the non-liposome fractions.
  • a competition assay can be run comparing the ability of transferrin-coupled liposomes to .compete with free transferrin for the transferrin receptor.
  • Figure 1 illustrates the results of one such competition assay. The experiment consists of introducing a fixed amount (InM) of
  • Test wells also contain increasing concentrations of one of the following: free unlabeled transferrin, transferrin-coupled liposomes, or liposomes without transferrin coupled to their outer surface.
  • the reduction in the amount of 125I-labeled transferrin bound was measured in triplicate tubes.
  • Figure 1 plots the 125I-labeled transferrin bound in each tube (average +. standard deviation) vs. the log of the final molar concentration of either liposomes or unlabeled transferrin. The results indicate that transferrin-coupled liposomes can bind well to the transferrin receptor.
  • Sprague-Dawley rate are anaestetized with Nembutal and cleared of blood by perfusion through an aortic cannula with
  • Buffer II consisting of Ringer's salt solution containing
  • bovine serum albumin 0.2% bovine serum albumin.
  • the subclavian arteries are tied off and the perfusion continued to the remainder of the upper half of the body.
  • the perfusate is circulated at 6-8ml/min.
  • the p0 2 is maintained at 210 ⁇ 20 and 165 ⁇ 2mm Hg in the infusate and exfusate, respectively.
  • the pC0 2 typically ranges from approximately 12 +.12 in the infusate to 22 +.4mm
  • Transferrin-coupled liposomes are prepared with either a radiolabeled tracer, such as an 125I-labeled peptide, or a histochemical tracer, such as a biotinylated peptide, encapsulated inside them.
  • a radiolabeled tracer such as an 125I-labeled peptide
  • a histochemical tracer such as a biotinylated peptide
  • Buffer II After the blood is cleared from an animal, typically lOmin after perfusion has begun, the liposomes are added and perfusion continued for various times up to 60min.
  • the brain microvasculature is isolated by the method of Brandel
  • brains are removed and homogenized.
  • the homogenate is passed through nylon meshes of decreasing pore diameter.
  • the material captured on the final nylon filter consists solely of thin brain vascular elements, devoid of smooth muscle cells (Fishman et al., 1987, J.
  • the amount of liposome encapsulated radiolabeled tracer that appears in this vascular fraction is multiplied by a predetermined correction factor in order to calculate the total amount of encapsulated radiolabeled tracer in the brain vasculature.
  • the correction factor corresponds to the percentage of the total brain vasculature typically recovered in the final fraction retained on nylon mesh and is determined as described in Fishman et al., 1987
  • the fraction of the brain homogenate that is not retained on the final passage through nylon mesh is the brain parenchymal fraction.
  • the total amount of liposome- encapsulated radiolabeled tracer in this fraction measures the amount delivered to the brain.
  • the transport of liposome-encapsulated material into the brain is also demonstrated by direct localization of transported material in brain sections using histochemistry.
  • transferrin-coupled liposomes containing a biotinylated peptide La Rochelle and Froehner, 1986, J. Biol. Chem. 261:5270-5274
  • the brain is fixed by continued perfusion with 4% paraformaldehyde for light microscopy or 4% paraformaldehyde and 0.25% glutaraldehyde for electron microscopy.
  • Various brain regions are dissected, embedded in Epon-Araldite and sectioned on an ultramicrotome for electron microscopy.

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Abstract

Procédés d'acheminement d'agents thérapeutiques et diagnostiques au cerveau à travers la barrière hémato-encéphalique. Lesdits agents sont acheminés au cerveau par encapsulage dans des liposomes ciblés sur des systèmes de transport endogène du cerveau, lesquels transportent des ligands spécifiques à travers la barrière hémato-encéphalique. On peut citer à titre d'exemples de ladite molécule ciblant les liposomes, les protéines spécifiquement transportées telles que la transferrine, l'insuline, ou les facteurs I et II de croissance analogues à l'insuline, ainsi que des anticorps contre les récepteurs pour la transferrine, l'insuline, ou les facteurs I et II de croissance analogues à l'insuline.
PCT/US1990/005349 1989-09-21 1990-09-21 Procede de transport de compositions a travers la barriere hemato-encephalique WO1991004014A1 (fr)

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US410,319 1989-09-21

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