WO2017213328A1 - Liposome comprenant un conjugué récepteur synthétique-phospholipide, et composition pour le transfert d'un matériau fonctionnel qui peut se lier au récepteur synthétique et qui comprend, en tant que principe actif, un ligand auquel est lié le matériau fonctionnel - Google Patents

Liposome comprenant un conjugué récepteur synthétique-phospholipide, et composition pour le transfert d'un matériau fonctionnel qui peut se lier au récepteur synthétique et qui comprend, en tant que principe actif, un ligand auquel est lié le matériau fonctionnel Download PDF

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WO2017213328A1
WO2017213328A1 PCT/KR2017/002204 KR2017002204W WO2017213328A1 WO 2017213328 A1 WO2017213328 A1 WO 2017213328A1 KR 2017002204 W KR2017002204 W KR 2017002204W WO 2017213328 A1 WO2017213328 A1 WO 2017213328A1
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synthetic receptor
cell membrane
phospholipid
conjugate
biotin
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Korean (ko)
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박지호
김희곤
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한국과학기술원
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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
    • 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
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7068—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines having oxo groups directly attached to the pyrimidine ring, e.g. cytidine, cytidylic 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/001—Preparation for luminescence or biological staining
    • A61K49/0013—Luminescence
    • A61K49/0017—Fluorescence in vivo
    • A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations

Definitions

  • the present invention consists of a method for producing a cell membrane vesicle comprising a conjugate of synthetic receptor-phospholipids, consisting of a double lipid membrane comprising a conjugate of synthetic receptor-phospholipids, fused to a cell membrane to allow cells to make the conjugate
  • the present invention relates to a liposome for releasing cell membrane vesicles, and a composition for delivering functional substances containing a ligand capable of binding to the synthetic receptor and having a functional substance bound thereto as an active ingredient.
  • Molecules and nanoparticles targeting various tumors have been developed to reduce the side effects of anticancer drugs and to increase tumor targeting effects.
  • active target molecules such as monoclonal antibodies, peptides, oligonucleotides and the like have been bound to the surface of the nanoparticles.
  • physiological barriers such as abnormal vasculature structures and dense intercellular matrix, diffuse nanoparticles accumulated through enhanced enhanced permeability and retention (EPR) effects.
  • EPR enhanced permeability and retention
  • the therapeutic effect on the cells is limited to only the perivascular area (Jain, RK & Stylianopoulos, Nature reviews. Clinical oncology 7, 653-664 (2010)).
  • the lack of binding sites and heterogeneity for the target molecules results in an uneven distribution of therapeutic drugs in the tumor, which can undermine the effectiveness of the active-target strategy.
  • Two-step therapy significantly increases the tumor target inducing effect of nanoparticles by creating binding sites for the nanoparticles.
  • a two-stage treatment strategy is to induce a biological or artificial binding site in a tumor with the first dose of the drug, change the microenvironment of the tumor, and then a second dose drug with a therapeutic effect on the tumor with the microenvironment changed. By targeting it.
  • Extracellular vesicles are known to mediate intracellular signal transduction by delivering lipids, cytoplasmic proteins and RNA through direct contact with the cell surface, endocytosis of the endoplasmic reticulum, and endoplasmic-cell membrane fusion.
  • EV Extracellular vesicles
  • MFL membrane fusogenic liposomes
  • the present inventors primarily introduce synthetic receptor-phospholipids into MFL to treat tumors, and the synthetic receptor-phospholipids treated on tumors spread throughout the tumor through intracellular tumor membranes, resulting in synthetic receptors.
  • the present invention was completed by clarifying that the therapeutic effect of the drug is significantly increased when the therapeutic drug is bound to a substance targeting phospholipid.
  • An object of the present invention is a method of producing a membrane membrane vesicle comprising a conjugate of synthetic receptor-phospholipids, consisting of a double lipid membrane comprising a conjugate of synthetic receptor-phospholipids, fused to a cell membrane to allow cells to
  • the present invention provides a liposome for releasing cell membrane vesicles including a conjugate, and a functional substance delivery composition containing a ligand capable of binding to the synthetic receptor and having a functional substance bound thereto as an active ingredient.
  • step 2) providing a method for producing a cell membrane vesicle comprising a synthetic receptor-phospholipid conjugate comprising the step of treating the cells of the liposome of step 1) to produce a cell membrane vesicle comprising a conjugate of the synthetic receptor-phospholipid.
  • the present invention also provides a cell membrane vesicle comprising a conjugate of synthetic receptor-phospholipid prepared by the above method.
  • the present invention also provides a liposome consisting of a double lipid membrane comprising a conjugate of synthetic receptor-phospholipids, which fuses to the cell membrane to allow cells to release a cell membrane vesicle comprising the conjugate.
  • the present invention provides a functional substance delivery composition
  • a functional substance delivery composition comprising a conjugate of the cell membrane vesicles or the liposomes, including a conjugate of a synthetic receptor-phospholipid, and a ligand capable of binding to the synthetic receptor and a functional substance bound as an active ingredient. to provide.
  • the present invention is a pharmaceutical for the prevention or treatment of cancer, comprising a conjugate of the synthetic receptor-phospholipids, the cell membrane vesicles or the liposomes, and a ligand capable of binding to the synthetic receptor, the anticancer agent bound as an active ingredient To provide a composition.
  • the synthetic receptor-phospholipid when a liposome comprising a conjugate of synthetic receptor-phospholipids is prepared and processed in a cell, the synthetic receptor-phospholipid is efficiently removed by the cell membrane vesicles secreted from the cell to the periphery of the treated cell. It was found that the drug could be delivered and exhibited a significant drug effect when treated by binding the therapeutic drug to a substance targeting the synthetic receptor-phospholipid.
  • liposomes including the synthetic receptor-phospholipids and substances targeting the synthetic receptor-phospholipids can be usefully used in drug delivery compositions for the prevention or treatment of various diseases.
  • 1 is a schematic of two-step targeted cancer therapy:
  • MFL membrane fusogenic liposomes
  • SR-L synthetic receptor-lipid conjugates (red);
  • FIG. 2 shows cancer-specific cell membrane delivery and intracellular migration of synthetic receptor-lipid conjugates:
  • Figure 2a Confocal fluorescence micrographs of cancer cells (HeLa and 4T1) and macrophages (Raw264.7 and J774A.1) to which fluorescent lipids (red) were delivered by MFL. Lysosomes were stained with Lyso Tracker (green);
  • FIG. 2 d shows the change in time-dependent Alexa594-SA fluorescence of the cells in the transwell filter and the lower chamber.
  • the lower figure shows the cells indicated by the arrows in the upper figure
  • Fluorescent lipids red
  • FIG. 5 is a diagram showing dose-dependent cellular delivery and survival of synthetic receptor-lipid conjugates:
  • Figure 6 shows extracellular vesicle-mediated intercellular migration of synthetic receptor-lipid conjugates:
  • FIG. 7 is a diagram showing cell membrane-specific phototoxicity in tumor cells to which synthetic receptor-lipid conjugates are delivered:
  • Fig. 7a Confocal fluorescence microscopy of HeLa cells in which Ce6-SA is located in the cell membrane. Biotin-lipid-bound MFL-treated cells were treated with Ce6-SA for 1 or 5 hours. The standard is 20 ⁇ m;
  • FIG. 7B is a diagram showing radiation dose-dependent cell death after photodynamic therapy. Biotin-lipid-bound MFL-treated HeLa cells were treated with Ce6-SA for 1 hour, washed and irradiated;
  • Fig. 7c shows incubation time-dependent cell death after PDT.
  • Biotin-lipid-bound MFL-treated HeLa cells were treated with Ce6-SA for 1 or 5 hours, washed and irradiated for PDT;
  • FIG. 7 d shows biotin-lipid-bound MFL-dependent cell death after PDT.
  • Biotin-lipid-bound MFL-treated or untreated cells were treated with Ce6-SA for 1 or 5 hours, washed and irradiated for PDT;
  • Figure 7 e is a diagram showing the phototoxic effect of unbound Ce6-SA in the culture. Biotin-lipid-bound MFL-treated or untreated cells were treated with Ce6-SA for 1 hour and irradiated for PDT without washing;
  • FIG. 7 is a diagram showing reactive oxygen species-dependent cell death after PDT.
  • Biotin-lipid-bound MFL-treated cells were treated with Ce6-SA for 1 hour and then washed. It was then treated with different concentrations of sodium azide (NaN 3 ) and irradiated for PDT;
  • FIG. 9b Treatment of cells of the upper filter with Cetin-SA after 4 hours after treatment with biotin-lipid-bound MFL or treatment with Ce6-MFL directly with cells of the upper filter after 4 hours Transwell.
  • FIG. 10 relates to a two stage target photodynamic therapy:
  • 10A Fluorescence image of 4T1 tumor sections after intravenous injection of BMFL or BPL containing fluorescent lipids (red). Nuclei were Hoechst (blue) blood vessels stained with CD31 (green). Scale bar is 100 ⁇ m.
  • 10B Fluorescence and quantification of 4T1 tumor sections after two stage target delivery. Mice with 4T1 tumors were injected intravenously with BMFL or PBS before intravenous Alexa594-SA. Tumors were collected 2 days after SA injection. Nuclei were Hoechst (blue) blood vessels stained with CD31 (green). Data are mean ⁇ s.e.m. (n ⁇ 29 vessels in each group, *** p ⁇ 0.001, Student's t test). Scale bar is 100 ⁇ m.
  • 10C Histological observation of 4T1 tumors visualized using H & E staining 2 days after PDT. Scale bar is 500 ⁇ m.
  • 10 d and 10 e tumor growth inhibition by stage 2 PDT in 4T1 (d) and MDA-MB-231 (e) tumors.
  • Arrowheads indicate laser irradiation after two stages of target delivery. Data are mean ⁇ s.e.m. (n ⁇ 6 in each group, *** p ⁇ 0.001 for treatment compared to the other groups using a one-way ANOVA with Tukey post test).
  • Cy7-SA was injected intravenously into mice with 4T1 tumors 1 day after BMFL or PBS injection, and organs were harvested for 2 days after Cy7-SA injection. Biodistribution of Cy7-SA was visualized and quantified in vitro using an NIR fluorescence imaging system. Data are mean ⁇ s.e.m. (n> 4, *** p ⁇ 0.001, Student's t test).
  • FIG. 13 shows complete regression of representative MDA-MB-231 tumors after stage 2 target PDT.
  • the present invention is a.
  • step 2) providing a method for producing a cell membrane vesicle comprising a synthetic receptor-phospholipid conjugate comprising the step of treating the cells of the liposome of step 1) to produce a cell membrane vesicle comprising a conjugate of the synthetic receptor-phospholipid.
  • the synthetic receptor is preferably one selected from the group consisting of biotin, azide, nitrilotriacetic acid (NTA), cyclodextrin, and embodiments of the present invention. It is more preferable that it is biotin.
  • Phospholipids include Phosphoatidylcholine, DDPC (l, 2-dimyristoylamido-l, 2-deoxyphosphatidylcholine), DLPC (dilauroylphosphatidylcholine), DMPC (dipalmitoyl phosphatidylcholine), DSPC (DOCs, DOCatid, PhD) di-oleoyl-sn-glycero-3-phosphocholine ), Dermatan sulfate proteoglycan (DSPG), 1-palmitoyl-2-oleoyl-phosphatidylglycerol (POPG), phosphatidylethanolamine, bis (1, 2-dimethylphosphino) ethane (DMPE), DPPE (1,2) -Bis (diphenylphosphino) ethane), DSPE (1,2-Distearoyl-sn-glycero-3-phosphoethanolamine), DOPE (dioleoylphosphat
  • the present invention also provides a cell membrane vesicle comprising a conjugate of synthetic receptor-phospholipid prepared by the above method.
  • the present invention also provides a liposome consisting of a double lipid membrane comprising a conjugate of synthetic receptor-phospholipids, which fuses to the cell membrane to allow cells to release a cell membrane vesicle comprising the conjugate.
  • the synthetic receptor is preferably one selected from the group consisting of biotin, azide, nitrilotriacetic acid (NTA), cyclodextrin, and embodiments of the present invention. It is more preferable that it is biotin.
  • the phospholipids include phosphatidylcholine (Phosphoatidylcholine, DDPC (l, 2-dimyristoylamido-l, 2-deoxyphosphatidylcholine), DLPC (dilauroylphosphatidylcholine), DMPC (dimyristoylphosphatidylcholine), and DPPC (dipalmitoyl phosphatidylcholine) 2-di-oleoyl-sn-glycero-3-phosphocholine), POPC (1-palmitoyl-2-oleoylphosphatidylcholine), DEPC (diethyl phosphorocyanidate), phosphatidylglycerol (Phosphotidylglycerol, dimyristoyl phosphatidylglycerol), DPPG (dipalmitoyl- phosphatidylglycerol (DPS) (dermatan sulfate proteoglycan), POPG (1
  • the liposomes of the present invention may capture phospholipids conjugated with functional substances, such as hydrophilic drugs, and secrete cell membrane vesicles fused to cell membranes to capture phospholipids bound to the functional substances, and the cell membrane vesicles are secreted from the cell membranes. It is composed of a double lipid layer of the cell membrane.
  • the bilipid membrane of liposomes is composed of components similar to the bilipid membrane of cells, specifically, basic phospholipids, functional phospholipids conjugated with various functional substances, cationic phospholipids and PEG (polyethylene) It is preferred that the glycol is composed of a lipid bound to polyethylene glycol), but is not limited thereto.
  • biotinylated MFL (BMFL) was prepared using DMPC, DSPE-PEG, DOPAP and biotinylated PE, and biotin-lipid-bound It was confirmed that MFL binds to cancer cell membranes more effectively than BNFL (biotinylated non-fusogenic liposomes) and BPL (biotinylated pegylated liposomes) through cell membrane fusion process, and through extracellular vesicles (EV) secreted from the cancer cells It was confirmed to deliver the conjugate of synthetic receptor-phospholipid conjugates (SRL) to other cells around (see FIG. 2C).
  • SRL synthetic receptor-phospholipid conjugates
  • the present invention is a functional substance delivery containing a ligand (ligand) that is capable of binding to the cell membrane vesicles or the liposomes, and the synthetic receptor, including a synthetic receptor-phospholipid conjugate, the functional material is bound as an active ingredient. It provides a composition for.
  • a ligand ligand
  • the synthetic receptor including a synthetic receptor-phospholipid conjugate
  • the functional material is any one selected from the group consisting of hydrophilic drugs, fluorescent materials, MRI contrast agents, and compounds attachable using click chemistry
  • the ligand is streptavidin, cyclooctyne.
  • cyclooctyne polyhistidine
  • polyhistidine is preferably any one selected from the group consisting of cholesterol (cholesterol), according to an embodiment of the present invention is more preferably streptavidin.
  • the drug is preferably a cell membrane dye, a photosensitive agent, an anticancer agent, an antibiotic.
  • the anticancer agent is gemcitabine, busulfan, chlororambucil, cyclophosphamide, cyclophosphamide, melphalan, cisplatin, ifosfamide, cytarabine Cytarabine, 5-Fluorouracil (5-FU), Methotrexate (MTX), Daunorubicin, Adriamycin, Vinblastine, Vincristine, Bindecine (Vindesine), Procarbazine, Tamoxifen, Tamoxifen, Megesterolacetate, Flutamide, and Goserelin Acetate (Gosereline acetate, Zoladex) are preferably any one selected from the group consisting of However, the present invention is not limited thereto.
  • the antibiotics include penicillin antibiotics, cephalosporine antibiotics, macrolide antibiotics, tetracycline antibiotics, quinolone antibiotics, antihistamines, antibacterial agents, and clindamycin. (clindamycin), metronidazole, chloramphenicol, actinomycin-D, bleomycin, and mitomycin-C. Preferred but not limited thereto.
  • compositions of the present invention include, for example, one or more of water, saline, phosphate buffered saline, dextrin, glycerol, ethanol, as well as combinations thereof. Such compositions may be formulated to provide fast release, or sustained or delayed release of the active ingredient after administration.
  • Pharmaceutically acceptable carriers can be prepared according to a variety of factors well known to those of skill in the art, including, for example, the particular bioactive agent used, its concentration, stability, and intended bioavailability; Diseases and conditions or conditions to be treated with the cell membrane binding liposomes of the present invention; The subject to be treated, age, size and general condition; Factors such as, but not limited to, the route used to administer the composition, such as nasal, oral, ocular, topical, transdermal and muscular, should be considered.
  • Pharmaceutically available carriers which are generally used for the administration of physiologically active substances other than the oral route of administration include aqueous solutions comprising D5W, dextrose and physiological salts within 5% of the volume. Pharmaceutically available carriers may also include additional ingredients that can enhance the stability of the active ingredients such as preservatives and antioxidants.
  • the dosage of the functional substance delivery composition of the present invention is administered at a dose effective for the intended treatment.
  • Therapeutically effective amounts required to treat or inhibit the progress of a particular medical disease can be readily determined by one skilled in the art using preclinical and clinical studies known in the medical arts.
  • the therapeutically effective amount refers to the amount of active ingredient which elicits a biological or medical response of a particular tissue, system, and animal or human, which is desired by a clinician or researcher.
  • any suitable route of administration may be used as the route of administration of the functional substance delivery composition of the present invention.
  • the present invention is a cancer prevention comprising a cell membrane membrane vesicle of claim 4 or a liposome of claim 5, including a conjugate of a synthetic receptor-phospholipid, and a ligand capable of binding to the synthetic receptor, the anticancer agent is bound as an active ingredient or Provided is a therapeutic pharmaceutical composition.
  • the anticancer agent is gemcitabine, busulfan, chlororambucil, cyclophosphamide, cyclophosphamide, melphalan, cisplatin, ifosfamide, cytarabine Cytarabine, 5-Fluorouracil (5-FU), Methotrexate (MTX), Daunorubicin, Adriamycin, Vinblastine, Vincristine, Bindecine (Vindesine), Procarbazine, Tamoxifen, Tamoxifen, Megesterolacetate, Flutamide, and Goserelin Acetate (Gosereline acetate, Zoladex) are preferably any one selected from the group consisting of However, the present invention is not limited thereto.
  • the cancer is preferably selected from the group consisting of lung cancer, testicular cancer, bladder cancer, prostate cancer, breast cancer, ovarian cancer, cervical cancer, pancreatic cancer, skin cancer, stomach cancer and liver cancer, but is not limited thereto.
  • biotin-lipid-bound MFL BMFL
  • Ce6-SA biotin-lipid-bound MFL Lipids delivered were found to reach far from blood vessels (see FIG. 10A), and mice pretreated with biotin-lipid-bound MFL were compared with mice injected with SA only, both in the peripheral and internal parts of the tumor.
  • pretreatment of biotin-lipid-bound MFL enables increased homogeneous delivery of SA and homogeneous delivery through generating binding sites in the tumor microenvironment. It was confirmed to make it.
  • pretreatment of biotin-lipid-bound MFL includes the synthetic receptor-phospholipids of the present invention, as it creates a binding site in the tumor, enhancing the accumulation and distribution of Ce6-SA, thereby significantly increasing the efficacy of PDT.
  • the liposomes and the substance targeting the synthetic receptor-phospholipid can be usefully used in the composition for drug delivery for the prevention or treatment of various diseases.
  • HeLa cells B16-F10 cells were cultured in DMEM (Hyclone), 4T1 cells were cultured in RPMI (Hyclone). The culture was added with 10% FBS (Hyclone) and 1% penicillin-streptomycin (Hyclone), all cells in a tissue culture flask in a 37 ° C. incubator in an atmosphere of 95% air and 5% carbon dioxide. Incubated.
  • 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC, Avanti Polar Lipids), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N- [methoxy (polyethylene glycol) -2000] (DSPE-PEG, Avanti Polar Lipids), 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP, Avanti Polar Lipids), and 1,2-dipalmitoyl-sn-glycero-3-phosphoethanolamine-N -(biotinyl) (Biotinyl PE, Avanti Polar Lipids) was used.
  • DMPC 1,2-dimyristoyl-sn-glycero-3-phosphocholine
  • DSPE-PEG Avanti Polar Lipids
  • DOTAP 1,2-dioleoyl-3-trimethylammonium-propane
  • Biotinyl PE Biotinyl PE, Avanti Polar Lipids
  • the molar ratios of DMPC, DSPE-PEG, DOPAP and biotinylated PE used for each liposome were 71.2: 3.8: 20: 5 (BMFL), 75: 0: 20: 5 (BNFL) and 91.2: 3.8 : 0: 5 (BPL).
  • BMFL BMFL
  • BNFL BNFL
  • BPL biotinylated PE
  • the above-mentioned lipids were dissolved in chloroform and mixed at an appropriate ratio. The mixture was completely dried for one day, and the remaining fat film was hydrated using phosphate buffered saline (PBS), and then extruded with 100 nm membrane filter paper (Whatman).
  • PBS phosphate buffered saline
  • the size of the liposomes (hydrodynamic size) and zeta potential were measured using a dynamic light scattering (Zetasizer Nano ZS90, Malvern Instruments).
  • Model synthetic receptor delivery using liposomes is 1,2-dipalmitoylsn-glycero-3-phosphoethanolamine-N- (lissamine rhodamine B sulfonyl) (Liss Rhod PE, Avanti polar instead of biotinylated PE). lipids) was added in an appropriate amount.
  • Biotin Lipids Combined MFL ( biotinylated MFL ; BMFL ) Confirms that the binding of cancer cells is higher than that of phagocytes.
  • biotin-lipid-bound MFL can specifically deliver synthetic receptor-phospholipids to cancer cells compared to macrophages, where they are compared to macrophages because they are mononuclear cells. This is because it contributes to the formation of a monouclear phagocyte system and to the elimination of nanoparticles injected into our bodies.
  • biotin-lipid-bound MFL containing fluorescent lipids were treated with cancer cells and macrophages of Example ⁇ 1-1> for 1 hour to track liposome lipids delivered to cells.
  • the cells were stained with lysosomes.
  • biotin-lipid-bound MFL can fuse better with cancer cells than phagocytes with predominant phagocytosis.
  • Biotin-lipid-bound MFL by macrophages, such as macrophages because biotin-lipid-bound MFL must fuse with the cell membrane to deliver synthetic receptor-phospholipids to the cell surface and provide a binding site for SA Phagocytosis of may decrease the efficiency of presenting biotin on the cell surface. Therefore, we hypothesized that biotin-lipid-bound MFL can generate cancer-specific binding sites and increase the target of therapeutic molecules.
  • HeLa cells were treated with each of the liposomes for 1 hour, and the extra unbound liposomes were completely washed off. The cells were then incubated with SA bound to the fluorophores to detect biotin present on the cell membrane.
  • FIG. 2C As measured by confocal microscopy, as shown in FIG. 2C, it was found that biotin-lipid-bound MFL delivered biotinylated lipids to the cell membrane most effectively.
  • Cells treated with BNFL were unevenly distributed on the cell surface, and it was confirmed that BPL hardly delivered biotinylated lipids to the cell membrane (FIG. 2C, upper left).
  • FIG. 2C When the fluorescence intensity was measured for quantification, cells treated with biotin-lipid-bound MFL or BNFL had comparable amounts of surface biotin, whereas cells treated with BPL could neglect the amount of biotin on the cell surface. It was confirmed that the degree (Fig. 2c, upper right).
  • the present inventors performed the following experiment to determine whether biotinylated lipids preferentially delivered to the cell surface by liposomes can be delivered to other cells in the form of extracellular vesicles (extracellular vesicles).
  • transwell assay in which cell membrane vesicles secreted by the cells were allowed to move, but not the cells themselves.
  • cell cultures containing EVs were prepared from cells pretreated with biotin-lipid-bound MFL. Then, when EV was removed from the culture, it was examined whether biotin delivery decreased. First, to obtain an EV-containing culture, centrifugation was performed at 10,000 ⁇ g to remove dead cells and cell impurities. The EV-containing culture solution was subjected to ultracentrifugation at 100,000 ⁇ g for 2 hours to obtain supernatant, which was a culture solution in which EV was removed after precipitation of EV. Intact cells were then treated with each culture and surface biotin was detected.
  • biotin-lipid-bound MFL delivers biotinylated lipids to the cell surface, which is delivered to other cells via EV.
  • FIG. 6 when treated with cells by increasing the amount of biotin-lipid-bound MFL, it showed amplification of the dose-dependent surface biotin signal, which showed cell viability. ), It was confirmed that there is no effect (Fig. 6).
  • Phototoxicity analysis was performed by irradiation, the phototoxicity of CE6-SA was measured by LIVE / DEAD analysis. Specifically, HeLa cells were treated with biotin-lipid-bound MFL for 1 hour, and then unbound biotin-lipid-bound MFL was removed from the culture, and the cells were treated with Ce6-SA for 1 hour, followed by radiation. The cells were treated with 5 ⁇ M Ethidium homodier-1 (Invitrogen) at room temperature for 1 hour. Thereafter, Ce6-SA binding to surface biotin was visualized using a confocal fluorescence microscope (Nikon), and red fluorescence from cells with damaged cell membranes was measured.
  • Ethidium homodier-1 Invitrogen
  • the inventors examined whether Ce6-SA bound to the cell membrane killed tumor cells by photothermal or photodynamic effects.
  • the phototoxicity of Ce6-SA was measured by measuring the phototoxicity of Ce6-SA in the presence of sodium azide, a redox quencher and singlet oxygen scavenger. The photodynamic effect was measured.
  • Tumor xenograft models were prepared by injecting 5 ⁇ 10 5 4T1 cells into Balb / c mice. When the tumor volume reached a certain size, the mice were divided into any five groups and treated as follows: (i) One day before injecting Ce6-SA (Ce6 at a concentration of 1.5 mg / kg) to the mice. 200 ⁇ l of 10 mM biotin-lipid-bound MFL solution was injected. On day 2, the tumors were irradiated with light (660 nm, ⁇ 100 mW / cm 2 , 30 minutes). (ii) One day prior to injecting Ce6-SA into mice, 200 ⁇ l of 10 mM biotin-lipid-bound MFL solution was injected.
  • Tissue samples obtained from the sacrificed mice were immediately immersed in liquid nitrogen and stored at -80 ° C.
  • the tissue was then sectioned (10 ⁇ m), transferred to room temperature, dried for 1 hour and fixed with acetone or 4% formaldehyde.
  • the fractions fixed with blocking solution were treated for 20 minutes prior to treatment with rat anti-mouse CD31 (Invitrogen) diluted in blocking solution.
  • tissue fractions were washed thoroughly and treated with Alexa Fluor 488 bound goat anti-rat IgG (Invitrogen) for 1 hour. After washing thoroughly, the tissue fraction was encapsulated in a mounting medium (Sigma). Tissue fractions were then observed by confocal microscopy (Nikon).
  • mice were injected with biotin-lipid-bound MFL containing fluorescent lipids and tumors were obtained at 2 hours, 8 hours and 24 hours. Confocal microscopy showed that the distribution of fluorescent lipids delivered by biotin-lipid-bound MFL was restricted to the vascular area at 2 hours after infusion, but at a long time after administration (8 hours and 24 hours), it was confirmed that the lipid appears throughout the tumor tissue.
  • delivery by BPEG was highly concentrated in the perivascular region, whereas biotin-lipid-bound MFL It was confirmed that the lipid delivered reached far away from the blood vessel (FIG. 10A).
  • a xenograft 4T1 tumor model was used to determine how pretreatment of biotin-lipid-bound MFL affects SA accumulation and distribution in tumors.
  • mice were injected intravenously with 5 ⁇ M biotin-lipid-bound MFL or PBS 200 ⁇ l, and on day 1 post treatment, Alexa 647 fluorescent dye bound 500 ⁇ g of SA was injected. Then, on day 2, histological analysis of the mice was performed.
  • Alexa 647 dyes are used both in the periphery of highly vascularized tumors and in the interior of tumors that have collapsed due to high IFP, with relatively low interstitial fluid pressure (IFF). Fluorescence intensity was measured using NIS-elements BR software (Nikon).
  • mice pretreated with biotin-lipid-bound MFL confirmed significantly increased accumulation of SA in both the peripheral and the inner part of the tumor compared to mice injected with SA only.
  • tumors pretreated with biotin-lipid-bound MFL showed significantly increased SA signals compared to controls (FIG. 10B).
  • tumors show high IFP, which causes blood vessels to collapse and redirect blood vessels from the center to the periphery.
  • the lack of lymphatic vessels and poor convection resulting in this makes delivery of the drug to the tumor difficult. Therefore, the results indicate that pretreatment of biotin-lipid-bound MFL overcomes these physiological barriers by enabling the accumulation of SA and enabling homogeneous delivery through the generation of binding sites in the tumor microenvironment. Indicates that it can.
  • biotin-lipid-bound MFL accumulated in the spleen and liver, the main mononuclear phagocyte system (FIG. 11A). This contributes to very short half-life in blood resulting from active uptake by phagocytes and from the surface of slightly positively charged biotin-lipid-bound MFL.
  • FIG. 11B normal tissue shows little difference in the accumulation of SA in the organ after biotin-lipid-bound MFL treatment.
  • mice were injected with biotin-lipid-bound MFL, BNFL, BPL or saline, and Ce6-SA (1.5). Ce6) at a concentration of mg / kg was administered after 24 hours.
  • Tumors were irradiated with a single dose of light (660 nm, ⁇ 100 mW / cm 2 , 30 min) 2 days after Ce6-SA injection.
  • the irradiated tumors had an average volume of ⁇ 60 mm 3 , and their volumes did not differ significantly from each other. Tumor volume was measured over two weeks after light irradiation. As a result, as shown in FIG.
  • MDA-MB-231 tumors which are one of the triple negative breast tumor cell types, which are the three most common target receptors. (Estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 / neu) are lacking, making targeted therapy difficult.
  • the inventors have determined whether pretreatment of biotin-lipid-bound MFL for delivery of synthetic receptors allows for targeted treatment of MDA-MB-231 tumors.

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Abstract

La présente invention concerne un liposome comprenant un conjugué récepteur synthétique-phospholipide, et une composition pour le transfert d'un matériau fonctionnel qui peut se lier au récepteur synthétique, et qui comprend, en tant que principe actif, un ligand auquel est lié le matériau fonctionnel, et spécifiquement, en préparant un liposome comprenant un conjugué récepteur synthétique-phospholipide, lors du traitement d'une cellule avec ce dernier, le récepteur synthétique-phospholipide peut efficacement être transporté à la surface de la cellule traitée via une vésicule de membrane cellulaire sécrétée par la cellule, et en combinant un médicament thérapeutique avec un matériau ciblant le récepteur synthétique-phospholipide et en effectuant un traitement, un effet thérapeutique marqué est mis en évidence, et ainsi le liposome comprenant le récepteur synthétique-phospholipide et le matériau ciblant le récepteur synthétique-phospholipide peut être efficacement utilisé dans une composition permettant le transfert de médicament pour le traitement ou la prévention de diverses maladies.
PCT/KR2017/002204 2016-06-07 2017-02-28 Liposome comprenant un conjugué récepteur synthétique-phospholipide, et composition pour le transfert d'un matériau fonctionnel qui peut se lier au récepteur synthétique et qui comprend, en tant que principe actif, un ligand auquel est lié le matériau fonctionnel WO2017213328A1 (fr)

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CN117100719A (zh) * 2023-09-26 2023-11-24 重庆大学 一种靶向肝癌的纳米颗粒的制备方法和应用

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