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WO2008038291A1 - Combinaison de médicaments liposomiaux anti-cancer et d'agents augmentant le ph du système lysosome/endosome pour une thérapie - Google Patents

Combinaison de médicaments liposomiaux anti-cancer et d'agents augmentant le ph du système lysosome/endosome pour une thérapie Download PDF

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Publication number
WO2008038291A1
WO2008038291A1 PCT/IL2007/001214 IL2007001214W WO2008038291A1 WO 2008038291 A1 WO2008038291 A1 WO 2008038291A1 IL 2007001214 W IL2007001214 W IL 2007001214W WO 2008038291 A1 WO2008038291 A1 WO 2008038291A1
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drug
lysosome
endosome
liposome
encapsulated
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PCT/IL2007/001214
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English (en)
Inventor
Alberto A. Gabizon
Hilary Shmeeda
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Yissum Research Development Company Of The Hebrew University Of Jerusalem
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Publication of WO2008038291A1 publication Critical patent/WO2008038291A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
    • A61K31/704—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers

Definitions

  • This invention relates to the use of liposome-encapsulated drugs for therapy, in particular for delivery of anti-cancer drugs.
  • Liposomes have the advantage of improved circulation times in the blood, protection of the drug within the lipid particle or portion thereof, avoidance of general tissue penetration due to size considerations etc.
  • PEG polyethylene glycol
  • pegylation was found to protect the liposomes from detection by mononuclear phagocyte system (MPS), thereby to provide the liposome with a relatively long half-life in blood circulation.
  • MPS mononuclear phagocyte system
  • surface-bound methoxypolyethylene glycol (MPEG) liposomes such as STEALTH ® liposomes used in DOXIL ®
  • blood circulation was found to be approximately 55 hours in humans.
  • Pegylated liposomes were also found to exhibit a limited tissue distribution and direct measurement of DOXIL ® showed that at least 90% of the drug, doxorubicin, remained liposome-encapsulated during circulation.
  • PEG-coated liposomes have shown to localize in tumors as a result of increased vascular permeability and local retention. This is due to the fact that tumor blood vessels are disorganized or 'leaky 1 . It is hypothesized that because of their small size ( ⁇ 100 run) and persistence in the circulation, the STEALTH ® liposomes are able to extravasate from the altered and often compromised vasculature of tumors and penetrate the tumor itself. This hypothesis is supported by studies using colloidal gold- containing STEALTH ® liposomes, which can be visualized microscopically.
  • Stable liposomal drug formulations generally show reduced in vitro cytotoxicity when compared to free drug [Horowitz AT, Barenholz Y, and Gabizon AA: "In Vitro Cytotoxicity of Liposome-Encapsulated Doxorubicin: Dependence on Liposome Composition and Drug Release.” Biochimica et Biophysica Acta, 1109:203-209, 1992]. This is because stable liposomes, such as STEALTH ® used in DOXIL ® , leak minute amounts of encapsulated doxorubicin during in vitro incubation.
  • One strategy to enhance cytotoxicity is to increase the uptake of liposomes by cells and the intracellular release of drug.
  • liposomes For Stealth liposomes, cell uptake is a slow process which can be accelerated by targeting liposomes with ligands binding to internalizing cell receptors.
  • liposomes tend to accumulate in intracellular acidic vesicles, such as endosomes and lysosomes, as is the fate for most nanoparticles ingested by cells.
  • acidic vesicles such as endosomes and lysosomes
  • Liposomes are degraded in lysosomes by digestive enzymes (acid hydrolases), namely, lipases, and the contents of liposomes including any encapsulated drug are released in the interior medium of the lysosomes.
  • the interior of the lysosomes is more acidic (pH 4.8), than the cytosol (pH 7).
  • the lysosome's single membrane stabilizes the low pH by pumping in protons (H + ) from the cytosol and Cl " ion channels, and also protects the cytosol, and therefore the rest of the cell, from the digestive enzymes within the lysosome.
  • Lysosomotropic agents are compounds that tend to accumulate in the lysosome and are usually weak bases. These agents generally tend to inhibit liposome breakdown in lysosomes, and, as a result, interfere with endocytosis of liposomes and other nanoparticles [Dijkstra J, Van Galen M, and Scherphof GL: "Effects of ammonium chloride and chloroquine on endocytic uptake of liposomes by Kupffer cells in vitro.” Biochim Biophys Acta, 804:58-67, 1984]. Therefore there was an existing prejudice against the use of such lysosomotropic agents, concomitant with liposomes as vehicles for drug delivery.
  • CQ Chloroquine
  • CQ has been extensively used as an antimalarial agent.
  • the mechanism of entry of free drugs into cells involves generally diffusion (for example, doxorubicin) or transport (for example, methotrexate) following in any case a pathway that does not involve endocytosis and is by definition not lysosomotropic.
  • lipophilic and amphipathic drugs enter cells by diffusion given their ability to cross biological membranes.
  • Water- soluble drugs generally require a transport system to enter cells (see for instance, Pharmacology, Edited by H.P. Rang, M.M. Dale, and J.M. Ritter, Churchill- Livingstone, New York, 1995 (page 67).
  • the present invention is based on the finding that Chloroquine (CQ) enhanced the cytotoxicity and/or growth inhibiting effect of a liposome encapsulated chemotherapeutic drug, the Stealth ® encapsulated doxorubicin (DOXIL ® ). This enhancing effect was exhibited when tumor cells were exposed to CQ concomitantly or shortly after exposure to DOXIL ® .
  • CQ Chloroquine
  • a pharmaceutical composition comprising a liposome encapsulating a cationic amphiphilic drug, and at least one lysosome/endosome pH increasing agent, and a physiologically acceptable carrier.
  • the cationic amphiphilic drug in accordance with the present invention, is selected from antibacterial agents, antifungal agents, cytotoxic agents, antineoplastic agents, antiproliferative agents, immunosuppressants, disinfectants, antiseptic agents, antipsychotic agents and agents used in the treatment of cardiovascular diseases.
  • a cationic amphiphilic drug in accordance with the present invention are mitoxantrone, anthracycline-based drugs (e.g. daunorubicin, idarubicin, epirubicin, doxorubicin); camptothecin analogs (e.g. topotecan, irinotecan) inhibiting DNA Topoisomerase I enzyme; psychotropic drugs such as the desipramine piperidine and piperazine-type neuroleptics, promazine, imipramine, amitriptyline, fluoxetine, sertraline; cardiovascular agents (e.g. verapamil or a calcium cannel blocker).
  • mitoxantrone anthracycline-based drugs
  • anthracycline-based drugs e.g. daunorubicin, idarubicin, epirubicin, doxorubicin
  • camptothecin analogs e.g. topotecan, irinotecan
  • the pharmaceutical composition of the invention comprises the cationic amphiphilic drug doxorubicin.
  • the lysosome/endosome pH increasing agent is a basic lysosomotropic agent.
  • the basic lysosomotropic agent in accordance with the invention is selected from the group consisting of Quinine, Chloroquine (CQ), Hydroxychloroquine, Primaquine, Mefloquine and Halofantrine
  • the pharmaceutical composition of the invention comprises the basic lysosomotropic agent CQ.
  • the lysosome/endosome pH increasing agent is an inhibitor of a proton pump.
  • the liposome encapsulating the cationic amphiphilic drug comprises polyethylene gly col-coated lipids.
  • the liposome encapsulating the cationic amphiphilic drug comprises on its surface an agent for targeting said liposome to a selected cell population or a selected target tissue.
  • the target cell population comprises cancer cells.
  • the agent for targeting in accordance with the invention is selected from the group consisting of folate, transferrin, Epidermal Growth Factor (EGF), tumor specific antibodies (e.g. EGF-r, Her2, folate receptor, transferrin receptor) or fragments of tumor specific antibodies, and an agent that leads to internalization of the liposome into an acidic vesicle compartment.
  • EGF Epidermal Growth Factor
  • tumor specific antibodies e.g. EGF-r, Her2, folate receptor, transferrin receptor
  • fragments of tumor specific antibodies e.g. EGF-r, Her2, folate receptor, transferrin receptor
  • the cationic amphiphilic drug and the at least one lysosome/endosome pH increasing agent are encapsulated in the same liposome.
  • the cationic amphiphilic drug is encapsulated in one liposome population and the least one lysosome/endosome pH increasing agent is encapsulated in another liposome population.
  • the cationic amphiphilic drug is encapsulated in liposomes and the least one lysosome/endosome pH increasing agent is in a free, non-encapsulated form.
  • the pharmaceutical composition of the invention is used for the treatment of cancer.
  • a use of at least one lysosome/endosome pH increasing agent for the preparation of a medicament for enhancing the therapeutic effect of a liposome encapsulated cationic amphiphilic drug is provided.
  • a use of at least one lysosome/endosome pH increasing agent for the preparation of a medicament for the treatment of a condition which is to be treated with a liposome encapsulated cationic amphiphilic drug is provided.
  • the cationic amphiphilic drug is doxorubicin.
  • the liposomal cationic amphiphilic drug is DOXIL ® .
  • the lysosome/endosome pH increasing agent is a basic lysosomotropic agent.
  • the basic lysosotropic agent may be selected from the group consisting of Quinine, Chloroquine (CQ), Hydroxychloroquine (known as Plaquenil when in sulfate form), Primaquine, Mefloquine and Halofantrine
  • the agent is CQ in a free or encapsulated form.
  • an article of manufacture comprising two separate dosage forms, a first dosage form comprising a cationic amphiphilic drug encapsulated in liposomes, and a second dosage form comprising at least one lysosome/endosome pH increasing agent together with instructions for the simultaneous or within a time interval administration of said first and second dosage forms.
  • the at least one lysosome/endosome pH increasing agent may be in free or liposome encapsulated form.
  • the first dosage form is adapted for parenteral administration and the second dosage form is adapted for parenteral administration or for oral administration.
  • the time interval for administration is no more than 7 days.
  • a method for improving the therapeutic activity of a cationic amphiphilic drug being encapsulated in liposomes comprising administering to a subject in need of such treatment the liposome encapsulated cationic amphiphlic drug in combination with at least one lysosome/endosome pH increasing agent.
  • a method for improving the cytotoxic activity of a cationic amphiphilic drug being encapsulated in liposomes comprising administering to a subject in need of such treatment the liposome encapsulated cationic amphiphlic drug in combination with at least one lysosome/endosome pH increasing agent.
  • the liposome encapsulated cationic amphiphilic drug is administered simultaneously with the at least one lysosome/endosome pH increasing agent or within a time interval that is no longer than 7 days.
  • the liposome encapsulated cationic amphiphilic drug is DOXIL ® .
  • the lysosome/endosome pH increasing agent is chloroquine in a free or encapsulated form.
  • Fig. 1 is a graph showing the effect of 3 hours CQ exposure on in vitro growth of KB human head & neck carcinoma cells followed by 72 hours incubation.
  • Fig. 2 is a graph showing KB human head & neck carcinoma cells expressing high levels of folate receptor (KB-FR) after incubation for 72 hr in the presence of the identified concentrations of free doxorubicin (free Dox), liposomal Stealth ® doxorubicin (DOXIL), and folate targeted DOXIL ® (FT- DOXIL), in the presence or absence of chloroquine (CQ) 100 ⁇ M.
  • free Dox free doxorubicin
  • DOXIL liposomal Stealth ® doxorubicin
  • FT- DOXIL folate targeted DOXIL ®
  • Figs. 3A-3D are graphs showing KB human head & neck carcinoma cells following various incubations with DOXIL ® and CQ, including incubation for 3 hours with DOXIL ® followed by incubation with CQ for 72 hours (Fig. 3A); incubation for 3 hours with CQ followed by incubation with DOXIL ® for 72 hours (Fig. 3B); exposure for 3 hours with DOXIL ® and CQ and additional incubation for 72 hours (Fig. 3C) and incubation for 72 hours with DOXIL ® and CQ (Fig. 3D).
  • Figs. 4A-4B are graphs showing M 109 (BALB/c mouse lung carcinoma, Fig. 4A), and J6456 (BALB/c mouse T-cell lymphocytic lymphoma, Fig. 4B) cell lines following exposure to DOXIL ® and different concentrations of CQ and incubation for 72h.
  • Figs. 5A-5B are graphs showing the in vitro growth of KB-folate receptor (KB-FR) cells after 3 hours exposure to DOXIL ® (Fig. 5A) or FT- DOXIL ® (Fig. 5B) and incubation for 72 hours, in the absence or in combination with CQ at different concentrations.
  • Fig. 6 is a graph showing the effect of increasing concentrations of CQ on the cytotoxicity of DOXIL ® in KB-cells following exposure for 3 hours to DOXIL ® and CQ and an additional incubation for 72 hours.
  • Figs. 7A-7B are survival curves of BALB/c female mice bearing mouse J6456 lymphoma, and mouse J6456-FR lymphoma (Figs. 7A and 7B, respectively) and being injected (i.p) with a single dose of DOXIL ® (10 mg/kg body weight), and in combination with CQ (i.p injection) or a total of 5 consecutive days at a daily dose of 1 mg/mouse, beginning 3 hours after DOXIL ® injection.
  • DOXIL ® 10 mg/kg body weight
  • CQ i.p injection
  • Chloroquine was found to enhance the growth inhibitory effect of DOXIL ® when given in vitro or in vivo together or shortly after exposure of the cell culture or animal model to DOXIL ® .
  • This effect was found to be more potent when using folate receptor-targeted liposomes [Gabizon A, Shmeeda H, Horowitz AT, and Zalipsky S: "Tumor cell targeting of liposome-entrapped drugs with phospholipid-anchored folic acid-PEG conjugates.” Advanced Drug Delivery Reviews, 56:1177-1192, 2004].
  • chloroquine affects the movement of drug molecules deposited by liposomes in the lysosomes, and enhances their transfer to the cytosol and possibly from there to other cellular organelles such as the nucleolus thereby improving drug access to the target intracellular molecules and structures.
  • some of these targets are microtubules, mitochondria, DNA, and various enzymes.
  • doxorubicin in the presence of CQ, or any other pH increasing agent, capable of decreasing the acidification of endosomes/lysosomes, doxorubicin will be unprotonated, losing its positive charge, and due to its amphiphilic nature will be able to cross lysosomal membranes in uncharged form, diffuse into the cytosol, and reach the nucleus and/or mitochondria where the target molecules for doxorubicin are present.
  • the present invention thus concerns the enhancing effect of pH increasing agents such as CQ on cationic amphiphilic drugs that need in order to manifest their therapeutic activity, to diffuse into the cytosol and reach the nucleus and/or other intracellular target molecules and structures.
  • a first aspect of the invention provides a pharmaceutical composition comprising a liposome encapsulating a cationic amphiphilic drug, and at least one lysosome/endosome pH increasing agent.
  • the pharmaceutical composition comprises a pharmaceutically acceptable carrier, the cationic amphiphilic drug encapsulated in liposomes and the endosome/lysosome pH increasing agent in a free, non- encapsulated (non-liposome associated) fo ⁇ n.
  • the pharmaceutical composition comprises a pharmaceutically acceptable carrier, a liposome-encapsulated cationic amphiphilic drug, and a liposome-encapsulated endosome/lysosome pH increasing agent.
  • the drug and the pH increasing agent may be provided in separate liposomes, so that the pharmaceutical composition comprises two groups of liposomes; one consisting of the liposome-encapsulated endosome/lysosome pH increasing agent, and one consisting of the liposome-encapsulated cationic amphiphilic drug.
  • the at least one lysosome/endosome pH increasing agent is encapsulated in the same liposomes encapsulating the cationic amphiphilic drug. Encapsulation in a single liposome may assure that the drug and the pH increasing agent will reach the target cells/tissue simultaneously, when such simultaneous effect is desired.
  • the pharmaceutical composition according to a preferred embodiment is a cytotoxic agent used for the treatment of cancer.
  • the invention provides the use of at least one lysosome/endosome pH-increasing agent for the preparation of a medicament for enhancing the therapeutic effect of a liposome encapsulated cationic amphiphilic drug.
  • the use of at least one lysosome/endosome pH-increasing agent for the preparation of a medicament for the treatment of a condition which is to be treated with a liposome encapsulated cationic amphiphilic drug is further provided.
  • the present invention provides the use of a liposome encapsulated cationic amphiphilic drug together with lysosome/endosome pH-increasing agent for the preparation of a medicament.
  • the medicament is for the treatment of cancer.
  • cationic amphiphilic drug denotes any organic molecule which when in the cell, biochemically affects at least one cellular process which results in a therapeutic effect.
  • the drug may be any organic small molecule, nucleic or amino acid based molecule, or other molecule that is beneficial in a disease-healing process and that is membrane permeable in neutral form but relatively membrane-impermeable when protonated in the acidic pH of the lysosome/endosome (pH substantially lower than that of the cytosol and typically between 4.0 to 5.0).
  • pH substantially lower than that of the cytosol and typically between 4.0 to 5.0.
  • the cationic amphiphilic drug has a pKa greater than about 5.0.
  • cationic amphiphilic drugs there are various cationic amphiphilic molecules that may be used in the context of the present invention as cationic amphiphilic drugs.
  • the cationic amphiphilic drugs may be antibacterials, antifungals, cytotoxic agents, antineoplastic agents, antiproliferative agents, immunosuppressants, disinfectants, or antiseptics agents, as well as agents used in psychiatry and in the treatment of cardiovascular diseases.
  • the cationic amphiphilic drug is a cytotoxic drug.
  • cytotoxic drugs comprise mitoxantrone, anthracycline-based drugs such as daunorubicin, idarubicin, epirubicin, doxorubicin; camptothecin analogs inhibiting DNA Topoisomerase I enzyme such as topotecan, irinotecan; Vinca " alkaloids and synthetic derivatives such as vincristine, vinblastine, vinorelbine; quinolone-derived antibacterial agents such as ciprofloxacin, ofloxacin, norfloxacin; psychotropic compounds such as desipramine, piperidine and piperazine-type neuroleptics, promazine, imipramine, amitriptyline, fluoxetine, sertraline, cardiovascular agents such as verapamil and other calcium-channel blockers.
  • doxorubicin as the cationic amphiphilic drug.
  • the pharmaceutical composition further comprises a "lysosome/endosome pH-increasing agent", and this term refers to any low molecular weight agent that is capable of increasing the pH inside lysosomes/endosomes to a pH above 4.0, preferably above 5.0 (i.e. above the endosome's/lysosome's natural pH).
  • pH-increasing agents typically fall under two groups.
  • One group is basic lysosomotropic agents, namely, those that preferably enter endosomes/lysosomes and due to their basic nature raise their internal pH. Examples of such agents are, without being limited thereto, quinine, chloroquine, hydroxy-chloroquine, primaquine, mefloquine, halofantrine.
  • chloroquine (herein at times referred to by the abbreviation CQ), which is exemplified hereinbelow. It should be noted that chloroquine has a weak cytotoxic effect in some cell lines at the concentrations tested. To neutralize this effect, the following data were calculated taking as baseline the growth observed with chloroquine alone, and therefore reflect a true, net combined effect of enhancement of cytotoxicity. As will be discussed further below, the combined effect is a synergistic effect, i.e. an effect being greater than the sum of effects of the drug and agent, when given independently.
  • free drugs are not taken up by endocytosis and are by definition not lysosomotropic.
  • Free doxorubicin enters cells rapidly by diffusion - within minutes of in vitro exposure the drug reaches its maximal concentration in cells.
  • the enhancement of the effect of doxorubicin by chloroquin in accordance with the present invention is largely dependent on its liposomal form. This appears to be due to the unique intracellular route of liposomal doxorubicin, as opposed to free doxorubicin. In support of this view is the finding that improved drug retention is observed with chloroquine only in cells treated with the liposomal drug but not with the free drug.
  • liposomes as other nanoparticles, cannot diffuse through intact cell membranes because of their size, nor can they be taken up through transporter-controlled membrane channels designed to facilitate uptake of individual molecules.
  • liposome delivery of drugs and other agents to the cell interior across cellular membrane involves an endocytic process, either receptor-mediated endocytosis or fluid-phase endocytosis (pinocytosis).
  • Vacuolar proton ATPase belongs to a special class of ATPases (V-type) composed of two multi-subunit sectors.
  • the two sectors include a peripheral detachable sector (V 1 ) containing the catalytic ATPase domain and an integral membrane sector (Vo) responsible for proton translocation across membranes.
  • V 1 peripheral detachable sector
  • Vo integral membrane sector
  • the V-H + -ATPaSe is responsible for acidification of cellular organelles such as endosomes, lysosomes, secretory granules and in some cells the trans-golgi cisternae. Studies with specific inhibitors of the enzyme have shown that maintaining low pH in the acidic compartments is essential for proper vesicular traffic and protein sorting within the cells.
  • AVOs acidic vesicular organelles
  • inhibitors of V-H + - ATPase such as, but not limited to, macrolides such as bafilomycin Al and concanamycin, and benzolactone enamides such as salicilyhalamide A, lobatamide A and oximidine II.
  • Lysosomotropic agents are also candidate modulators of AVO function as well as antisense molecules designed to prevent AVO formation and/or the expression of V-H + -ATPase subunits within the cell.
  • the cationic amphiphilic drug is encapsulated in a liposome.
  • liposome denotes any bilayered vesicle stable during storage, as well as after administration to the subject in need thereof. In terms of storage, stability includes chemical as well as physical stability under storage conditions (2-8 0 C) and in biological fluids (37°C) for at least six months. Stability also refers to the integrity and composition of the lipid assembly being substantially unaltered during storage and if loaded with a drug, the later has a low leakage from the liposome. To this end, the lipid assembly may be combined with stabilizers.
  • stabilizers include cholesterol and similar membrane active sterols, lipopolymers such as PEGylated lipids, the latter further discussed below.
  • liposomes may be employed in the context of the present invention, including, without being limited thereto, multilamellar vesicles (MLV), small unilamellar vesicles (SUV), large unilamellar vesicles (LUV), sterically stabilized liposomes (SSL), multivesicular vesicles (MW), and large multivesicular vesicles (LMW) as well as in other bilayered forms known in the art.
  • MLV multilamellar vesicles
  • SUV small unilamellar vesicles
  • LUV large unilamellar vesicles
  • SSL sterically stabilized liposomes
  • MW multivesicular vesicles
  • LMW large multivesicular vesicles
  • LMW large multivesicular vesicles
  • preferred injectable liposomes are those in the size range of 50-150nm in diameter (LUV or SUV [Gabizon A. et al. Cancer Res. 54:987-992 (1994)]); for local treatment larger liposomes, such as MLV or MW, can also be used [Grant G. et al. Anesthesiology 101:133-137 (2004)].
  • the lipids forming the liposomes typically include one or two hydrophobic acyl chains, which may be combined with a steroid group, and may contain a chemically reactive group, (such as an amine, acid, ester, aldehyde or alcohol) at the polar head group.
  • a chemically reactive group such as an amine, acid, ester, aldehyde or alcohol
  • One group of lipids forming the liposomes are typically those having a glycerol backbone wherein at least two of the hydroxyl groups is substituted with acyl chains and a third hydroxyl group is replaced with a phosphate group to which reactive groups may be attached, a combination or derivatives of same and may contain a chemically reactive group as defined above at the headgroup.
  • the acyl chain(s) is between 14 to about 24 carbon atoms in length, and has varying degrees of saturation being fully, partially or non- hydrogenated lipids.
  • the lipid matrix may be of natural source, semisynthetic or folly synthetic lipid, and neutral, negatively or positively charged.
  • the liposomes comprise phospholipids.
  • the phospholipids may be a glycerophospholipid.
  • glycerophospholipid include, without being limited thereto, three types of lipids: (i) zwiterionic phospholipids, which include, for example, phosphatidylcholine (PC), egg yolk phosphatidylcholine, soybean-derived PC in natural, partially hydrogenated or fully hydrogenated form, dimyristoyl phosphatidylcholine (DMPC) sphingomyelin (SM); (ii) negatively charged phospholipids: which include, for example, phosphatidylserine (PS), phosphatidylinositol (PI), phosphatidic acid (PA), phosphatidylglycerol (PG) dipalmipoyl PG, dimyristoyl phosphatidylglycerol (DMPG); synthetic derivatives in which the conjugate renders a zwitterionic phospholipid
  • a specific phospholipid employed in accordance with the invention is hydrogenated soybean-derived PC, mPEG-DSPE, and cholesterol.
  • Loading of the drug within the liposome may be achieved by any known method of encapsulation available, including, passive as well as active (remote) loading [Haran, G., Cohen, R., Bar, L. K. & Barenholz, Y. "Transmembrane Ammonium sulfate gradients in liposomes produce efficient and stable entrapment ofamphipatic weak base". Biochimica et Biophysica Acta 1151:201- 215, 1993; Barenholz Y. J liposome Res. 13:1-8, 2003, U.S. patent Nos. 5,136,771 and 5,939,096].
  • At least the liposomes encapsulating the cationic amphiphilic drug comprises lipids derivatized with hydrophilic polymers.
  • Preparation of and derivatization of lipids with hydrophilic polymers (thereby forming lipopolymers) has been described, for example by Tirosh et al. [Tirosh et al., Biopys. J., 74(3): 1371-1379 1998] and in U.S. Patent Nos. 5,013,556; 5,395,619; 5,817,856; 6,043,094, 6,165,501, incorporated herein by reference and in WO 98/07409.
  • the lipopolymers may be non-ionic lipopolymers (also referred to at times as neutral lipopolymers or uncharged lipopolymers) or lipopolymers having a net negative or a net positive charge.
  • polymers which may be attached to lipids so as to form derivatized lipids.
  • Such polymers include, without being limited thereto, polyethylene glycol (PEG), polysialic acid, polylactic (also termed polylactide), polyglycolic acid (also termed polyglycolide), apolylactic-polyglycolic acid, polyvinyl alcohol, polyvinylpyrrolidone, polymethoxazoline, polyethyloxazoline, polyhydroxyethyloxazoline, polyhydroxypropyloxazoline, polyaspartamide, polyhydroxypropyl methacrylamide, polymethacrylamide, polydimethylacrylamide, polyvinylmethylether, polyhydroxyethyl acrylate, derivatized celluloses such as hydroxymethylcellulose or hydroxyethylcellulose.
  • the polymers may be employed as homopolymers or as block or random copolymers.
  • a specific family of lipopolymers employed by the invention include monomethylated PEG attached to DSPE (with different lengths of PEG chains, the methylated PEG referred to herein by the abbreviation mPEG) in which the PEG polymer is linked to the lipid via a carbamate linkage resulting in a negatively charged lipopolymer.
  • Other lipopolymers are the neutral methyl polyethyleneglycol distearoylglycerol (mPEG-DSG) and the neutral methyl poly ethylenegly col oxycarbony 1-3 -amino- 1 ,2-propanediol distearoylester (mPEG-DS) [Garbuzenko O. et al., Langmuir. 21 :2560-2568 (2005)].
  • the PEG moiety preferably has a molecular weight of the head group is from about 750Da to about 20,000 Da. More preferably, the molecular weight is from about 750 Da to about 12,000 Da and most preferably between about 1,000 Da to about 5,000 Da.
  • One specific PEG-DSPE employed herein is that wherein PEG has a molecular weight of 2000Da, designated herein 2000 PEG- DSPE or 2k PEG-DSPE.
  • liposomes including such derivatized lipids have also been described, whereby typically between 1-20 mole percent of such a derivatized lipid is included in the liposome formulation.
  • STEALTH ® liposomes comprise a polyethylene glycol (PEG) coating. It was found that this coating helps evade the potential impact of the immune system and enables delivery of drugs to disease specific areas of the body. It has been found that Stealth ® liposomes target the leaky vasculature associated with tumor and diseased tissue, there by increasing drug concentration at these sites.
  • PEG polyethylene glycol
  • DOXIL ® is doxorubicin HCl encapsulated in long-circulating, sterically stabilized, STEALTH ® liposomes, with surface-bound methoxypolyethylene glycol (MPEG) to protect liposomes from detection by the mononuclear phagocyte system (MPS) and to increase blood circulation time.
  • DOXIL ® is an anti-cancer drug for the treatment of refractory ovarian cancer and AIDS-related Kaposi's sarcoma and other tumors, and is the first marketed product to incorporate STEALTH ® technology.
  • the mechanism of action of doxorubicin HCl is thought to be related to its ability to bind DNA and inhibit nucleic acid synthesis. Studies have demonstrated rapid cell penetration of doxorubicin and perinuclear chromatin binding followed by rapid inhibition of mitotic activity and nucleic acid synthesis, and induction of mutagenesis and chromosomal aberrations.
  • STEALTH ® liposomes have a half-life of approximately 55 hours in humans. They are stable in blood, and direct measurement of liposomal doxorubicin shows that at least 90% of the drug (the assay used cannot quantify less than 5-10% free doxorubicin) remains liposome-encapsulated during circulation.
  • the lipopolymer may be introduced into the liposome by two different ways: (a) either by adding the lipopolymer to a lipid mixture forming the liposome.
  • the lipopolymer will be incorporated and exposed at the inner and outer leaflets of the liposome bilayer [Uster P.S. et al. FEBBS Letters 386:243 (1996)]; (b) or by firstly prepare the liposome and then incorporate the lipopolymers to the external leaflet of the pre- formed liposome either by incubation at temperature above the Tm of the lipopolymer and liposome-forming lipids, or by short term exposure to microwave irradiation.
  • the liposomes comprise on its outer surface a targeting agent which can selectively or preferably deliver the liposomes to a target cell population, or to a target tissue.
  • a targeting agent which can selectively or preferably deliver the liposomes to a target cell population, or to a target tissue.
  • STEALTH ® liposomes bearing ligands can target receptors expressed on diseased cells. This ligand-binding promotes efficient drug uptake into cells and enhances efficacy.
  • the targeting agent should be an agent capable of specifically binding to a marker, receptor or antigen present more abundantly on cancer cells.
  • targeting agents are: folate, transferrin, Epidermal Growth Factor (EGF), antibodies or fragments of antibodies binding specifically to receptors such as EGF-r, Her2, folate receptor, transferrin receptor, and other that lead to internalization of the liposome into an acidic vesicle compartment.
  • EGF Epidermal Growth Factor
  • components suitable for stabilization of the liposomes may include, without being limited thereto, sterols and sterol derivatives, such as cholesterol, cholesteryl hemisuccinate, cholesteryl sulfate.
  • the mole% of each component in the liposome may be determined and selected to achieve a specified degree of fluidity or rigidity, to control the stability of the assembly during storage as well as after delivery, e.g. in serum and to control the rate of release of the cationic amphiphilic drug carried thereby.
  • Liposomes having a more rigid structure e.g.
  • liposomes in the gel (solid ordered) phase or in a liquid crystalline fluid (liquid disordered) state may be achieved by reducing or eliminating sterols from the lipid composition and by using a relatively rigid lipid, for example, a lipid having a relatively high solid ordered to liquid disordered phase transition temperature, such as, above room temperature.
  • a relatively rigid lipid for example, a lipid having a relatively high solid ordered to liquid disordered phase transition temperature, such as, above room temperature.
  • Rigid, i.e., saturated, lipids having long acyl chains contribute to greater membrane rigidity in the assembly.
  • a good example for such a lipid is HSPC or DSPC.
  • Lipid components, such as cholesterol are also known to contribute to rigidity in lipid assemblies based on fluid lipids. Such a sterol reduces free volume thereby reducing permeability.
  • high lipid fluidity is achieved by incorporation of a relatively fluid lipid, typically one having a relatively low liquid to liquid-crystalline phase transition temperature, for example, at or below room temperature, more preferably, at or below the target body temperature.
  • a relatively fluid lipid typically one having a relatively low liquid to liquid-crystalline phase transition temperature, for example, at or below room temperature, more preferably, at or below the target body temperature.
  • a good example for such a phospholipid is egg PC.
  • the endosome/lysosome pH-increasing agent may be in a free form or encapsulated in a liposome.
  • the cationic amphiphilc drug and the endosome/lysosome pH-increasing agent may be incorporated in the same liposome or in two separate populations of liposomes.
  • a method for improving the therapeutic activity of a liposomal encapsulated cationic amphiphilic drug comprising administering to a subject in need of such treatment liposomes encapsulating a cationic amphiphilic drug in combination with at least one lysosome/endosome pH increasing agent.
  • a liposomal encapsulated cationic amphiphilic cytotoxic drug comprising administering to a subject in need of such treatment liposome encapsulating a cationic amphiphilic drug in combination with at least one lysosome/endosome pH increasing agent.
  • the term “improving” denotes an effect that is greater than the effect of the liposomal cationic amphiphilc drug when given alone and preferably, improving denotes a synergistic effect achieved by a treatment comprising the administration of liposomal cationic amphiphilc drug and the at least one lysosome/endosome pH increasing agent together ("in combination") with the drug or shortly (up to several days, for example, up to about 7 days, preferably, up to 3 days) before or after the administration of the pH increasing agent.
  • the synergistic effect refers to an effect that is greater than the sum of effects achieved by the administration of each component individually.
  • the liposomal cationic amphiphilic drug and the endosome/lysosome pH increasing agent should be administered close in time to each other.
  • the liposome encapsulating a cationic amphiphilic cytotoxic drug is administered simultaneously with the at least one lysosome/endosome pH increasing agent. Alternatively it may be administered a short period before or after it. Because of the long circulation time (2-3 days) of some liposome formulations of cytotoxic drugs, the lysosome/endosome pH increasing agent may also be administered several days after administration of the liposomal drug.
  • One embodiment of the invention provides doxorubicin encapsulated in MPEG liposomes (namely, the commercially available DOXIL ® ) and the endosome/lysosome pH increasing agent being free or liposome encapsulated CQ.
  • the endosome/lysosome pH increasing agent and the liposomal cationic amphiphilic drug are present in two separate dosage forms provided as an article of manufacture for example present in two separate containers, and the article of manufacture further comprises instructions for simultaneous or subsequent administration of the two separate dosage forms (the administration of the endosome/lysosome pH increasing agent being either with or shortly before/after administration of the liposomal cationic amphiphilic drug.
  • the separate dosage forms may be applicable where a time interval between administrations is desired or where the administration routes, or the pharmaceutically acceptable carriers of the two components is different.
  • the article of manufacture may be applicable when one component (e.g.
  • liposomal cationic amphiphilic drug such as DOXIL ®
  • DOXIL ® the other component
  • the other component e.g. the endosome/lysosome pH increasing agent such as chloroquine
  • various routes of administration are possible in accordance with the invention and the exemplified routes should not be construed as limiting the invention
  • the time interval from administration of the cationic amphiphilc drug, e.g. an anti cancer agent, to the administration of the lysosome/endosome pH increasing agent should not exceed a maximum of seven days.
  • the in vitro experiments included cytotoxicity assays in 96 multi- well plates where the cells were incubated at 37 0 C in the presence of indicated drugs for indicated periods of time. Growth rate was always calculated after a total incubation time of 72h. Exposure times to the indicated drugs were either short (3h) or long (72h). The viability of cells and growth rate curves were based on colorimetric readings in a plate O. D. reader after methylene blue cell staining or using the Promega MTS kit. A negative growth rate indicates that OD values were lower at end of incubation lower than at baseline.
  • concentration refers to the concentration of doxorubicin in free or liposome-associated form. Cytotoxicity was quantified by standard colorimetric assays in 96-multiwell plates using the methods reported in Horowitz AT, Barenholz Y, and Gabizon AA: "In Vitro Cytotoxicity of Liposome- Encapsulated Doxorubicin: Dependence on Liposome Composition and Drug Re/e ⁇ se.” Biochimica et Biophysica Acta, 1109:203-209, 1992.
  • CQ chloroquine diphosphate
  • Doxorubicin from Teva-Abic (Natanya, Israel)
  • PLD PLD
  • DOXIL PLD
  • FT- PLD prepared from DOXIL and folate-PEG-DSPE conjugate as reported (Shmeeda H, Mak L, Tzemach D, Astrahan P, Tarshish M, and Gabizon A: "Intracellular uptake and intracavitary targeting of folate-conjugated liposomes in a mouse lymphoma model with upregulated folate receptors.” Molecular Cancer Therapeutics 5:818-824, 2006).
  • Lipids DPPG: dipalmitoyl phosphoglycerol (Lipoid, Ludwigshafen, Germany), Cholesterol (Sigma); HSPC hydrogenated soybean phosphatidylcholine (Lipoid); PEG-DSPE (Avanti, Birmingham, AL)
  • Tumors mouse J6456 lymphoma, and mouse J6456-FR lymphoma
  • mice were injected with 1 million tumor cells i.p.7 days post inoculation the mice were split into groups of 6-10 mice:
  • Group B was injected i.p. DOXIL ® at a single dose of 10 mg/kg body weight;
  • Group C was injected with DOXIL ® i.p. at a single dose of 10 mg/kg body weight. Chloroquine diphosphate (CQ) was injected i.p. for a total of 5 consecutive days at a daily dose of 1 mg/mouse, beginning 3 hours after DOXIL ® injection.
  • CQ Chloroquine diphosphate
  • Group D was injected with CQ i.p. at 1 mg/mouse for a total of 5 consecutive days in parallel to Group C. No DOXIL in this group.
  • mice were followed up for survival.
  • Figure 1 shows that when KB human head & neck carcinoma cells are exposed to CQ alone for three hours, followed by 72 hours of incubation at 37°C, CQ had no inhibitory/cytotoxic effect on the growth rate of these carcinoma cells, even at high concentrations, up to 200 ⁇ M.
  • Figure 2A presents the effect of various concentrations of doxorubicin, either in a free form (Free Dox) or in the form of liposomal doxorubicin, namely DOXIL ® (the commercial Stealth ® liposomes encapsulating doxorubicin), or folate-targeted DOXIL ® (FT-Doxil), in the absence or presence of CQ (100 ⁇ M) on the percent of growth rate of KB human head & neck carcinoma cells.
  • DOXIL ® the commercial Stealth ® liposomes encapsulating doxorubicin
  • F-Doxil folate-targeted DOXIL ®
  • the results show a strong enhancement effect of CQ on the cytotoxicity of DOXIL ® , which is more marked in the case of the folate-targeted liposomal formulation (FT-Doxil).
  • the cytotoxic activity of free doxorubicin was minimally affected by CQ.
  • Figures 3A to 3D show the effect of different treatment protocols on the growth rate of KB cells, after a total of 72 hours of incubation, in the absence or presence of CQ (100 ⁇ M). Free Doxorubicin is also presented as control.
  • Fig. 3 A shows the effect of exposure of the cells to the indicated drug for 3 hours only, with exposure to CQ for a total of 72 hours thereafter;
  • Fig. 3B shows the effect of incubation of the cells with CQ for three hours only, followed by incubation with the indicated drugs for 72 hours;
  • Fig. 3C shows the effect of incubation of the cells with the indicated drug and CQ for 3 hours only followed by 72 hours of incubation; and
  • Fig. 3 A shows the effect of exposure of the cells to the indicated drug for 3 hours only, with exposure to CQ for a total of 72 hours thereafter;
  • Fig. 3B shows the effect of incubation of the cells with CQ for three hours only, followed by incubation with the indicated drugs for 72 hours;
  • 3D shows the effect of simultaneous and continuous exposure of the cells to the indicated drug and CQ for the total incubation time, being 72 hours. The results point out that CQ is most effective when administered concomitantly with DOXIL ® or within several hours thereafter, but not prior to exposure of the cells to DOXIL ® .
  • Figures 4A and 4B show the cytotoxicity-enhancing effect of CQ on DOXIL ® , as manifested in two other tumor cell lines (other than the KB cells), namely, the M 109 cell line (BALB/c mouse lung carcinoma), and J6456 cell line (BALB/c mouse T-cell lymphocytic lymphoma). These cell lines were continuously exposed to DOXIL ® and CQ for 72h. Free Doxorubicin was used as a positive control. The results show that the growth of M109 cells was inhibited by DOXIL ® and that the effect of the drug was much more significant in the presence of CQ with a clear concentration-dependent effect going from 25 to lOO ⁇ M. The J6456 cells were also more significantly affected by DOXIL in the presence of CQ, although it should be noted that J6456 cells are highly sensitive to concentrations of CQ higher than 25 ⁇ M.
  • Figures 5A and 5B show the effect of CQ on the cytotoxicity of the indicated drugs (DOXIL ® in Figure 5A or FT- DOXIL ® in Figure 5B), after three hours exposure of KB cells to the drug.
  • the results show that CQ induced a significant enhancement of the cytotoxicity of Folate-targeted DOXIL ® in the KB, folate receptor-expressing cells.
  • the degree' of enhancement of FT- DOXIL ® cytotoxicity is shown to be related to the concentration of CQ ( Figure 5B).
  • Figure 6 shows the effect of continuous exposure of KB cells for a period of 72 hours, to free doxorubicin or DOXIL ® , in the presence or absence of CQ. Similarly, it is evident that the enhancing effect of CQ is dose dependent.
  • mice death of mice was caused by tumor growth in the abdomen and spread to other tissues.

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Abstract

La présente invention concerne l'utilisation d'un agent augmentant le pH du système lysosome/endosome (par exemple, la Chloroquine (CQ)) pour augmenter la cytotoxicité et/ou l'effet inhibiteur de croissance d'un médicament chimiothérapeutique encapsulé dans des liposomes, par exemple la doxorubicine encapsulée dans le Stealth® (DOXIL®). Cet effet d'augmentation peut être obtenu par l'administration simultanée ou séquentielle de l'agent et du médicament. L'invention concerne en outre des procédés et des compositions pharmaceutiques comportant des liposomes encapsulant un médicament amphiphile cationique, et au moins un agent augmentant le pH du système lysosome/endosome, pour le traitement de diverses maladies, particulièrement du cancer.
PCT/IL2007/001214 2006-09-27 2007-10-07 Combinaison de médicaments liposomiaux anti-cancer et d'agents augmentant le ph du système lysosome/endosome pour une thérapie WO2008038291A1 (fr)

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WO2011092708A3 (fr) * 2010-02-01 2011-09-29 Yissum Research Development Company Of The Hebrew University Of Jerusalem, Ltd. Liposomes comprenant des médicaments amphipathiques et procédé pour leur préparation
CN102716084A (zh) * 2012-06-29 2012-10-10 海南美大制药有限公司 盐酸氟西汀脂质体固体制剂
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CN104971062A (zh) * 2015-06-10 2015-10-14 浙江大学 伊立替康类药物和氯喹类药物组合及其共载脂质体和制备
US10519175B2 (en) 2017-10-09 2019-12-31 Compass Pathways Limited Preparation of psilocybin, different polymorphic forms, intermediates, formulations and their use
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WO2011036557A1 (fr) * 2009-09-22 2011-03-31 The University Of British Columbia Compositions et procédés pour améliorer la capture cellulaire et la délivrance intracellulaire de particules lipidiques
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US20130189352A1 (en) * 2011-01-27 2013-07-25 Zhejiang University Liposome comprising combination of chloroquine and adriamycin and preparation method thereof
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