WO2018000043A1 - Matériau de revêtement pour cellules - Google Patents

Matériau de revêtement pour cellules Download PDF

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Publication number
WO2018000043A1
WO2018000043A1 PCT/AU2017/050673 AU2017050673W WO2018000043A1 WO 2018000043 A1 WO2018000043 A1 WO 2018000043A1 AU 2017050673 W AU2017050673 W AU 2017050673W WO 2018000043 A1 WO2018000043 A1 WO 2018000043A1
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WIPO (PCT)
Prior art keywords
cell
mof
zif
cells
layer
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PCT/AU2017/050673
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English (en)
Inventor
Kang LIANG
Joseph J. Richardson
Paolo Falcaro
Frank Caruso
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Commonwealth Scientific And Industrial Research Organisation
The University Of Melbourne
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Priority claimed from AU2016902550A external-priority patent/AU2016902550A0/en
Application filed by Commonwealth Scientific And Industrial Research Organisation, The University Of Melbourne filed Critical Commonwealth Scientific And Industrial Research Organisation
Publication of WO2018000043A1 publication Critical patent/WO2018000043A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/04—Preserving or maintaining viable microorganisms
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/02—Preservation of living parts
    • A01N1/0205—Chemical aspects
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/02—Preservation of living parts
    • A01N1/0205—Chemical aspects
    • A01N1/0231—Chemically defined matrices, e.g. alginate gels, for immobilising, holding or storing cells, tissue or organs for preservation purposes; Chemically altering or fixing cells, tissue or organs, e.g. by cross-linking, for preservation purposes

Definitions

  • the invention relates in general to coating materials for cells.
  • the invention relates to cells coated with non-biological material and to a method for preparing the same.
  • the lipid bi-layer membrane encasing a single cell offers limited, if any, protection from environmental stresses. As a result, strategies for providing artificial long- term protection and preservation of the cells are often employed.
  • Prolonged cell viability and protection from environmental stresses may be afforded by the deposition of durable, synthetic coatings on a cell.
  • a number of protective coating materials for cells have been proposed. For example, microencapsulation of whole population of cells in polymer membranes has been studied since the 1930s, and remains an important technological development in the field of tissue engineering and regenerative medicine.
  • conventional cell coatings preclude the possibility to recover the cell in a viable state after it is coated, for example by removing the coating. Removal of conventional cell coatings typically requires noxious chemicals and harsh conditions, inevitably leading to cell death. In the cases of tissue engineering and regenerative medicine removal of the coating from the population of cells is not even necessary contemplated. Also, conventional cell coating materials are often not ideal in that they provide for an indiscriminate barrier against diffusion of cytotoxic molecules and cell nutrients equally. This in turn limits long-term preservation of cell viability.
  • the present invention provides a cell coated with a layer of crystalline Metal Organic Framework (MOF).
  • MOF Metal Organic Framework
  • the unique porosity of crystalline MOF provides for a coating layer that preserves cell viability by acting as a size-selective permeable physical barrier.
  • the layer of crystalline MOF allows diffusion of nutrients into the cytoplasm while protecting the cell from the attack of cytotoxic agents.
  • the present invention further provides a method of coating a cell with a layer of crystalline Metal Organic Framework (MOF), the method comprising combining in a solution the cell and MOF precursor compounds, wherein the cell promotes formation of the layer of crystalline MOF.
  • MOF Metal Organic Framework
  • MOF precursor compounds when in a solution with MOF precursor compounds, cells can promote formation of MOF in crystalline form. By being crystalline and forming around the cell, the MOF provides for a coating that is selectively permeable to nutrients, thus supporting cell viability while protecting the cell from cytotoxic agents.
  • MOFs are hybrid coordination structures formed by metal clusters comprising metal ions, e.g. metal ions or metal oxides, coordinated by multi-functional organic ligands. This results in the formation of one-, two- or three-dimensional structures that can be highly porous.
  • the crystalline nature of a MOF arises from a regular and spatially ordered distribution of intrinsic cavities within the framework.
  • the size of the intrinsic cavities is characteristic of each specific crystalline MOF and may range from 5 to 500 angstroms (A).
  • A angstroms
  • the size distribution of the intrinsic cavities is extremely narrow, lending such materials to applications that require, for example, precise size selectivity of filtered or absorbed matter.
  • the layer of crystalline MOF is selectively permeable. Specifically, since the size distribution of a crystalline MOF's intrinsic cavities is narrow, the layer of crystalline MOF allows diffusion of cell nutrients from the external environment into the cell cytoplasm while protecting the cell from multiple external cytotoxic aggressors. This can significantly improve cell viability and reduce malnutrition of the coated cells.
  • the present invention can advantageously make use of a variety of different MOFs and a diverse range of cells.
  • the crystalline MOF may be a meso- or micro- MOF
  • the cell may be a eukaryotic or a prokaryotic cell.
  • the cell is one that has been isolated from a living organism (e.g. an animal, including a human, or plant).
  • the cell is isolated from a line of cells grown in an in vitro culture.
  • the cell is an artificial cell.
  • the layer of crystalline MOF around the cell can be removed on-demand under physiochemical conditions that do not adversely affect cell viability. It will be appreciated that the programmed breaking-up of the cytoprotective coating is pivotal for the practical use of cells in sensors, drug delivery systems, cell therapy, or regenerative medicine.
  • the invention further provides for use of Metal Organic Framework (MOF) precursor compounds in coating a cell, wherein the MOF precursor compounds form a layer of crystalline MOF around the cell.
  • MOF Metal Organic Framework
  • Figure 1 shows a schematic cross-section of a cell coated with a layer of crystalline ZIF-8
  • Figure 2 shows a schematic illustration of a cyclic procedure involving the coating of a cell with a layer of MOF and cell separation from the crystalline MOF;
  • Figure 3 shows synchrotron small-angle X-ray scattering (SAXS) diffraction patterns of standard ZIF-8 crystals (black) and Saccharomyces cerevisiae yeast cells coated with ZIF- 8 (grey).
  • SAXS synchrotron small-angle X-ray scattering
  • Figure 3 shows the 2D SAXS pattern recorded for the cells coated with ZIF-8 (measured using a 0.5 mm capillary as a sample holder)
  • Figure 4 shows SEM images of Saccharomyces cerevisiae yeast cells after incubation in solution with ZIF-8 precursor compounds for (a) 1 minutes, (b) 5 minutes, (c) 10 minutes, and (d) 20 minutes;
  • Figure 4(e) shows an SEM image of a fragment of a layer of ZIF-8;
  • Figure 5 shows (a) differential interference contrast (DIC) and (b) fluorescent microscopy images of Saccharomyces cerevisiae yeast cells coated with a layer of ZIF-8 using FDA as a fluorescent and viability
  • ZIF-8 patterned dark grey
  • Figure 8 shows cell viability data relative to non-coated Saccharomyces cerevisiae yeast cells and Saccharomyces cerevisiae yeast cells coated with a layer of ZIF-8 after 24 h exposure to filipin, an anti-fungal drug
  • Figure 9 shows data relative to Saccharomyces cerevisiae yeast cells growth measurement (OD 6 oo) for non-coated Saccharomyces cerevisiae yeast cells (black circles) and Saccharomyces cerevisiae yeast cells coated with a layer of ZIF-8 (grey circles) before and after dissolution of the layer of MOF by EDTA
  • Figure 10 shows SEM images of a cracked ZIF-8 layer from coated yeast cells obtained after (a) 1, (b) 2, (c) 3 and (d) 4 coating cycles, and (e) thickness values of the corresponding coating layer plotted against the cycle number; and
  • Figure 11 shows (a) an SEM image of Micrococcus Luteus coated with a layer of ZIF-8, (b) SAXS diffraction patterns of standard ZIF-8 crystals (bottom line, black), native Micrococcus Luteus (middle line, light grey), and Micrococcus Luteus coated with ZIF-8 (top line, dark grey), and in the inset of (b) a 2D representation of SAXS patterns generated by the ZIF-8 coated bacteria, (c) a fluorescent microscopy image of Micrococcus Luteus coated with a layer of ZIF-8, obtained using FDA as a fluorescent cell viability indicator, and (d) FDA cell viability assay on uncoated Micrococcus Luteus (naked) and Micrococcus Luteus coated with a layer of ZIF-8.
  • the present invention provides a cell coated with a layer of crystalline Metal Organic Framework (MOF).
  • MOF Metal Organic Framework
  • the layer of MOF is provided around the entire cell such that, as a result of the cell being coated, a continuous layer (i.e. a continuous coating) of MOF exists around the cell. Accordingly, for an external molecule to enter into the cytoplasm of the coated cell it would have to first diffuse through the intrinsic cavities of crystalline MOF forming the coating layer.
  • the invention provides a cell encapsulated (e.g. encased, or enclosed) within a layer of crystalline MOF.
  • MOFs are porous materials.
  • the porosity of a MOF can be visualised as a spatial arrangement of cavities in the form of cages connected by channels.
  • MOFs according to the present invention include those having at least two metal clusters coordinated by at least one organic ligand. Depending on the particular choice of metal ions and organic ligands, MOFs having cavities in the form of open micro- and mesopores are available.
  • the expression 'metal cluster' is intended to mean a chemical moiety that contains at least one atom or ion of at least one metal or metalloid. This definition embraces single atoms or ions and groups of atoms or ions that optionally include organic ligands or covalently bonded groups. Accordingly, the expression 'metal ion' includes, for example, metal ions, metalloid ions and metal oxides.
  • Suitable metal ions that form part of a MOF structure can be selected from Group 1 through 16 metals of the IUPAC Periodic Table of the Elements including actinides, and lanthanides, and combinations thereof.
  • the metal ion may be selected from Li + , Na + , K + Rb + , Be 2+ , Mg 2+ , Ca 2+ , Sr 2+ , Ba 2+ , Sc 3+ , Y 3+ , Ti 4+ , Zr 4+ , Hf 4 *, V 5+ , V 4+ , V 3+ , V 2+ , Nb 3+ Nb 5+ , Ta 5+ , Cr 6+ , Cr 3+ , Mo 6+ , Mo 3+ , W 6+ , W 3+ , Mn 4+ , Mn 3+ , Mn 2+ , Re 7+ , Re 2+ , Fe 3+ , Fe 2+ Ru 4+ , Ru 3+ , Ru 2+ , Os 3+ , O
  • Suitable metal ion coordinating organic ligands can be derived from oxalic acid, malonic acid, succinic acid, glutaric acid, phtalic acid, isophtalic acid, terephthalic acid, citric acid, trimesic acid, 1,2,3-triazole, pyrrodiazole, or squaric acid.
  • Organic ligands suitable for the purpose of the invention comprise organic ligands listed in WO 2010/075610 and Filipe A. Almeida Paz, Jacek Klinowski, Sergio M. F. Vilela, Joao P. C. Tome, Jose A. S. Cavaleiro, Joao Rocha, 'Ligand design for functional metal-organic frameworks', Chemical Society Reviews, 2012, Volume 41, pages 1088-1110, the contents of which are included herein in their entirety.
  • Ln lanthanide
  • the MOF is selected from mixed component MOFs, known as MC- MOFs.
  • MC-MOFs have a structure that is characterised by more than one kind of organic ligand and/or metal.
  • MC-MOFs can be obtained by using different organic ligands and/or metals directly in the solution into which MOF precursor compounds and the cell are combined, or by post-synthesis substitution of organic ligands and/or metals species of formed MOFs. Specific examples of MC-MOFs can be found in A.D. Burrows, CrystEngComm 2011, Volume 13, pages 3623-3642, which content is included herein in its entirety.
  • the MOF is a zinc imidazolate framework (ZIF).
  • ZIFs are a sub-class of MOFs that are particularly suited to biologic applications because of (i) their prolonged stability in physiological conditions, (ii) the pH responsive nature of their metal- organic ligand bonds, which can be used as a trigger for pH-induced drug delivery applications, and (iii) negligible cytotoxicity.
  • ZIFs can be synthesized in water and are chemically stable in water even at high temperatures (e.g. at boiling point) for prolonged periods of time (e.g. several weeks). The stability of ZIFs in water makes them preferred matrices for providing a layer for cells.
  • ZIFs feature tetrahedrally-coordinated transition metal ions (e.g. Fe, Co, Cu, or Zn) connected by organic imidazolate organic ligands, resulting in three-dimensional porous solids. Similarly to zeolites, ZIFs have great thermal and chemical stability. Depending on the choice of ligand and metal ions, provided by the precursor compounds, many ZIF topologies can be synthesized.
  • transition metal ions e.g. Fe, Co, Cu, or Zn
  • a MOF that may be made in accordance with the invention may be a carboxylate -based MOF, a heterocyclic azolate-based MOF, or a metal-cyanide MOF.
  • MOFs that may be made according to the present invention include those commonly known in the art as CD-MOF-1, CD-MOF-2, CD-MOF-3, CPM-13, FJI- 1, FMOF-1, HKUST-1, IRMOF-1, IRMOF-2, IRMOF-3, IRMOF-6, IRMOF-8, IRMOF-9, IRMOF-13, IRMOF-20, JUC-48, JUC-62, MIL-101, MIL-100, MIL-125, MIL-53, MIL-88 (including MIL-88A, MIL-88B, MIL-88C, MIL-88D series), MOF-5, MOF-74, MOF-177, MOF-210, MOF-200, MOF-205, MOF-505,
  • the MOF is selected from ZIF-8, HKUST-1, IRMOF-1, MIL-53, MIL-88,MIL-88A, MIL-88B, MIL-88C, MIL-88D, MOF-5, MOF-74, NOTT- 100, Ln-bdc, ZIF-67, ZIF-90, ZIF-67, and a combination thereof.
  • the MOF according to the invention is crystalline.
  • any reference made herein to a 'MOF' is therefore to be intended as reference to a 'crystalline MOF' .
  • the metal clusters are coordinated by the organic ligands to form a geometrically regular network made of repeating units of cluster/organic ligand arrangements.
  • the crystalline nature of a MOF arises from regular and spatially ordered distribution of intrinsic cavities forming the MOF framework.
  • the expression 'intrinsic cavities' is intended to mean the ordered network of interconnected voids that is specific to a crystalline MOF by the very nature of the MOF.
  • the intrinsic cavity network of a MOF results from the specific spatial arrangement of the MOF's metal clusters and organic ligands and is unique to any pristine crystalline MOF.
  • the intrinsic cavities of a crystalline MOF can be visualised as being formed by regularly distributed cages interconnected by windows or channels.
  • the specific shape of cages and window/channels in a crystalline MOF is determined by the spatial arrangement of the chemical species forming the MOF framework. Accordingly, the expression 'intrinsic cavities' specifically identifies the overall ordered network of cages and window/channels of the native MOF framework.
  • a crystalline MOF generates diffraction patterns when characterized by commonly known crystallographic characterization techniques. These include, for example, X-ray powder diffraction (XPD), grazing incidence X-ray diffraction, small angle X-ray scattering (SAXS), single crystal X-Ray diffraction, electron diffraction, neutron diffraction and other techniques that would be known to the skilled person in the field of crystallography of materials.
  • XPD X-ray powder diffraction
  • SAXS small angle X-ray scattering
  • the present invention provides a cell coated with a permeable layer of crystalline Metal Organic Framework (MOF). Accordingly, the present invention also provides a method of coating a cell with a permeable layer of crystalline Metal Organic Framework (MOF), the method comprising combining in a solution the cell and MOF precursor compounds, wherein the cell promotes formation of the permeable layer of crystalline MOF. Similarly, the present invention provides use of Metal Organic Framework (MOF) precursor compounds in coating a cell, wherein the MOF precursor compounds form a permeable layer of crystalline MOF around the cell.
  • MOF Metal Organic Framework
  • a layer of crystalline MOF coats a cell.
  • the term 'cell' means a biological unit comprising a membrane-bound cytoplasm.
  • a cell suitable for use in the invention is a cell provided with all structural features of a living cell, i.e. a whole cell.
  • the present invention provides a whole cell coated with a layer of crystalline Metal Organic Framework (MOF).
  • MOF crystalline Metal Organic Framework
  • the present invention may therefore be described as providing a method of coating a whole cell with a layer of crystalline Metal Organic Framework (MOF), the method comprising combining in a solution the cell and MOF precursor compounds, wherein the cell promotes formation of the layer of crystalline MOF.
  • MOF Metal Organic Framework
  • the invention further provides use of Metal Organic Framework (MOF) precursor compounds in coating a whole cell, wherein the MOF precursor compounds form a layer of crystalline MOF around the cell.
  • MOF Metal Organic Framework
  • the cell will be understood as being provided in a viable state.
  • the cell being 'viable' is meant that the cell is a living cell as opposed to a dead cell.
  • the present invention provides a viable cell coated with a layer of crystalline Metal Organic Framework (MOF).
  • the present invention may therefore be described as providing a method of coating a viable cell with a layer of crystalline Metal Organic Framework (MOF), the method comprising combining in a solution the cell and MOF precursor compounds, wherein the cell promotes formation of the layer of crystalline MOF.
  • the invention further provides use of Metal Organic Framework (MOF) precursor compounds in coating a viable cell, wherein the MOF precursor compounds form a layer of crystalline MOF around the cell.
  • MOF Metal Organic Framework
  • Cell viability can be determined by any means known to persons skilled in the art.
  • a cell suitable for the purposes of the present invention may be any type of cell, whether modified or not, and derived from any source.
  • a cell may be, for example, a eukaryotic cell or a prokaryotic cell, including a genetically-modified cell, a cell containing the same genetic material as a naturally-occurring cell, a cell from a line of cells, or one isolated from an organism.
  • the cell is a eukaryotic cell.
  • a eukaryotic cell comprises genetic material that is enclosed within a nuclear envelope (also known as nuclear membrane, nucleolemma or karyotheca). Multiple eukaryotic cells can organise into complex structures and are the characteristic cells of animals (including humans), plants, fungi, and Protista.
  • the cell is a eukaryotic cell belonging to kingdom Animalia, for example an animal cell or a human cell.
  • a eukaryotic cell belonging to kingdom Animalia, for example an animal cell or a human cell.
  • Such a cell has characteristically no cell wall or chloroplasts.
  • eukaryotic cells belonging to kingdom Animalia include exocrine secretory epithelial cells, hormone-secreting cells, keratinizing epithelial cells, wet stratified barrier epithelial cells, neurons (e.g. sensory transducer cells, autonomic neuron cells, sense organ and peripheral neuron supporting cells, central nervous system neurons, glial cells, or lens cells), metabolism and storage cells, barrier function cells, extracellular matrix cells, contractile cells (e.g.
  • skeletal muscle cells red skeletal muscle cells, white skeletal muscle cells, intermediate skeletal muscle cells, nuclear bag cells of muscle spindle, nuclear chain cells of muscle spindle, satellite cells such as stem cells, heart muscle cells, ordinary heart muscle cells, nodal heart muscle cells, purkinje fiber cells, smooth muscle cells, myoepithelial cells of iris, myoepithelial cell of exocrine glands), blood and immune system cells (e.g.
  • erythrocytes erythrocytes, leukocytes, platelets, megakaryocytes, monocytes, connective tissue macrophage cells, epidermal Langerhans cells, osteoclast cells, dendritic cells of lymphoid tissues, microglial cells of central nervous system, neutrophil granulocytes, eosinophil granulocytes, basophil granulocytes, hybridoma cells, mast cells, helper T cells, suppressor T cells, cytotoxic T cells, natural Killer T cells, B cells, natural killer cells, reticulocytes), stem cells (e.g.
  • the cell is not derived from a human embryo.
  • the present invention therefore provides a cell coated with a layer of crystalline Metal Organic Framework (MOF), the cell being one that is not derived from a human embryo.
  • MOF crystalline Metal Organic Framework
  • the invention also provides a method of coating a cell with a layer of crystalline Metal Organic Framework (MOF), the cell being one that is not derived from a human embryo, and the method comprising combining in a solution the cell and MOF precursor compounds, wherein the cell promotes formation of the layer of crystalline MOF.
  • the invention also provides for use of Metal Organic Framework (MOF) precursor compounds in coating a cell, wherein the cell is not derived from a human embryo, and the MOF precursor compounds form a layer of crystalline MOF around the cell.
  • the invention therefore provides a whole cell coated with a layer of crystalline Metal Organic Framework (MOF), the cell being one that is not derived from a human embryo.
  • the invention provides a method of coating a whole cell with a layer of crystalline Metal Organic Framework (MOF), the cell being one that is not derived from a human embryo, and the method comprising combining in a solution the cell and MOF precursor compounds, wherein the cell promotes formation of the layer of crystalline MOF.
  • MOF Metal Organic Framework
  • the present invention provides a viable cell coated with a layer of crystalline Metal Organic Framework (MOF), the cell being one that is not derived from a human embryo.
  • the invention also provides a method of coating a viable cell with a layer of crystalline Metal Organic Framework (MOF), the cell being one that is not derived from a human embryo, and the method comprising combining in a solution the cell and MOF precursor compounds, wherein the cell promotes formation of the layer of crystalline MOF.
  • the invention also provides for use of Metal Organic Framework (MOF) precursor compounds in coating a viable cell, wherein the cell is not derived from a human embryo, and the MOF precursor compounds form a layer of crystalline MOF around the cell.
  • MOF Metal Organic Framework
  • the cell is an anchorage-independent cell such as a hepatocyte.
  • a hepatocyte is particularly environmentally sensitive.
  • the cell is a hormone producing cell.
  • a hormone inducing cell include a cell of the anterior pituitary gland, which can be harnessed to provide artificial organs.
  • the cell is an insulin-producing cell.
  • an insulin-producing cell examples include a mammalian pancreatic alpha cell, beta cell and intact islet. Those cells may be used to provide artificial pancreas.
  • the cell is a tumor cell.
  • a tumor cell for use in accordance to the invention may be a cell associated with any type of cancer.
  • a tumor cell suitable for use in the invention may be a modified cytokine secreting cell, such as a myoblast or a xenogenic cell.
  • Examples of a tumor cell suitable for use in the invention also include a cell associated with a cancer such as bladder cancer, bone cancer, bowel cancer, brain cancer, breast cancer, kidney cancer, leukaemia, liver cancer, lung cancer, lymphoma, mesothelioma, myeloma, ovarian cancer, pancreatic cancer, prostate cancer, skin cancer, stomach cancer, testicular cancer, thyroid cancer, or uterine cancer.
  • the cell is a eukaryotic cell belonging to kingdom Plantae.
  • Such cells have chloroplasts, cellulose cell walls, and large central vacuoles.
  • Examples of eukaryotic cells belonging to kingdom Plantae include plant cells such as parenchyma cells, collenchyma cells, sclerenchyma cells, meristematic cells, xylem cells, plant epidermal cells, and plant stem cells (e.g. cambium cells and callus cells).
  • the cell is a eukaryotic cell belonging to kingdom Fungi (i.e. eukaryotic Fungal hypha cells).
  • eukaryotic cells belonging to kingdom Fungi include yeast cells (e.g. yeast cells of the species Saccharomyces cerevisiae, Cryptococcus, and Candida).
  • the cell is a eukaryotic cell belonging to kingdom Protista.
  • Such cells include all eukaryotic cells that do not belong to kingdom Animalia, Plantae or Fungi.
  • kingdom Protista includes all organisms which are unicellular or unicellular-colonial and which form no tissues.
  • the cell is a prokaryotic cell.
  • a prokaryotic cell Unlike eukaryotic cells, a prokaryotic cell lacks a nuclear envelope separating genetic material from the cytoplasm.
  • prokaryotic cells include bacterial cells (i.e. unicellular microorganisms belonging to the Domain Bacteria), and Archea cells (i.e. unicellular microorganisms belonging to the Domain Archea).
  • the cell is an artificial cell.
  • artificial cell is meant an engineered particle that mimics one or many functions of a naturally-occurring eukaryotic or prokaryotic cell.
  • the cell is a genetically-modified cell.
  • genetically-modified cell By the expression 'genetically-modified cell' is meant a cell containing genetic material that has been altered in a way that does not occur naturally. Methods for genetically-modifying a cell would be known to the skilled person, and include methods based on the alteration of the genetic material of the cell by removing heritable material or by introducing exogenous DNA.
  • the cell is one that has been isolated from a living organism, such as a human, an animal or a plant.
  • a living organism such as a human, an animal or a plant.
  • subsequent to isolation the cell is subjected to ex vivo manipulation (e.g. activation, genetic modification, culture, expansion etc.) before being coated with a layer of crystalline MOF.
  • ex vivo manipulation e.g. activation, genetic modification, culture, expansion etc.
  • a skilled person would be aware of available techniques and procedures to isolate a living cell from a living organism and optionally to manipulate the cell.
  • the cell is isolated from a line of cells grown in an in vitro culture.
  • a skilled person would be aware of available techniques and procedures to isolate a cell from an in vitro line of cells.
  • the invention also provides a method of coating a cell with a layer of crystalline Metal Organic Framework (MOF). Specifically, the method of the invention comprises combining in a solution the cell and MOF precursor compounds.
  • MOF crystalline Metal Organic Framework
  • MOF precursor compounds include those compounds known in the art that provide the metal ions listed herein in the solution within a suitable solvent. Those compounds may be salts of the relevant metal ions, including metal-chlorides, -nitrates, -acetates -sulphates, - hydrogen sulphates, -bromides, -carbonates, -phosphates, and derivatives thereof, including mono- and poly- hydrate derivatives.
  • suitable metal salt precursor compounds include, but are not limited to, cobalt nitrate (Co(N03)2 xH20), zinc nitrate ( ⁇ ( ⁇ 3)2 ⁇ ⁇ 2 ⁇ ), iron(III) nitrate (Fe(N03)3 xH20), aluminium nitrate ( ⁇ 1( ⁇ 3)3 ⁇ ⁇ 2 ⁇ ), magnesium nitrate (Mg(N03)2-xH20), calcium nitrate (Ca(N03)2-xH20), beryllium nitrate (Be(N03)2-xH20), europium nitrate (Eu(N03)3-xH20), terbium nitrate (Tb(N03)3-xH20), ytterbium nitrate (Yb(N03)3-xH20), dysprosium nitrate (Dy(N03)3-xH20), erbium nitrate (Er(N03)3 xH20), gallium nitrate
  • MOF precursor compounds also include organic ligands of the kind described herein that coordinate the metal ion clusters in the MOF framework.
  • the organic ligands include molecules that have at least two chemical moieties capable of coordinating a metal ion. In some embodiments, these groups comprise carboxylates, phosphonates, sulphonates, N- heterocyclic groups, and combinations thereof.
  • Suitable organic ligands include those ligands listed in WO 2010/075610 and Filipe A. Almeida Paz, Jacek Klinowski, Sergio M. F. Vilela, Joao P. C. Tome, Jose A. S. Cavaleiro, Joao Rocha, Ligand design for functional metal-organic frameworks, Chemical Society Reviews, 2012, Volume 41, pages 1088-1110, the contents of which are included herein in their entirety.
  • organic ligand precursor compounds include, but are not limited to, 4,4',4"- [benzene-l,3,5-triyl-tris(ethyne-2,l-diyl)]tribenzoate, biphenyl-4,4'-dicarboxylate, 4,4',4"- [benzene-l,3,5-triyl-tris(benzene-4,l-diyl)]tribenzoate, 1,3,5-benzenetribenzoate, 1,4- benzenedicarboxylate, benzene-l,3,5-tris(lH-tetrazole), 1,3,5-benzenetricarboxylic acid, terephthalic acid, imidazole, benzimidazole, 2-nitroimidazole, 2-methylimidazole (Hmlm), 2-ethylimidazole, 5-chloro benzimidazole, purine, fumaric acid, a-cyclodextrin, ⁇ -
  • Benzenetricarboxylate 2,5-Dihydroxy- 1 ,4-benzenedicarboxylate, 2,5-Dihydroxy- 1 ,4- benzenedicarboxylic acid, 2,5-Dimethoxy-l,4-benzenedicarboxylate, 2,5-Dimethoxy-l,4- benzenedicarboxylic acid, 1,4-Naphthalenedicarboxylate, 1,4-Naphthalenedicarboxylic acid, 1,3-Naphthalenedicarboxylate, 1,3-Naphthalenedicarboxylic acid, 1,7- Naphthalenedicarboxylate, 1,7-Naphthalenedicarboxylic acid, 2,6-
  • Naphthalenedicarboxylate 1,5-Naphthalenedicarboxylic acid, 2,7- Naphthalenedicarboxylate, 2,7-Naphthalenedicarboxylic acid, 4,4',4"-Nitrilotrisbenzoate, 4,4',4"-Nitrilotrisbenzoic acid, 2,4,6-Tris(2,5-dicarboxylphenylamino)-l,3,5-triazine, 2,4,6-Tris(2,5-dicarboxylatephenylamino)-l,3,5-triazine, 1,3,6,8-Tetrakis(4- carboxyphenyl)pyrene, l,3,6,8-Tetrakis(4-carboxylatephenyl)pyrene, 1,2,4,5-Tetrakis(4- carboxyphenyl)benzene, l,2,4,5-Tetrakis(4-carboxylatephenyl)benzene, 5,10,15,20- Tetrakis(
  • the organic ligands can also be functionalised organic ligands.
  • any one of the organic ligands listed herein may be additionally functionalised by amino-, such as 2-aminoterephthalic acid, urethane-, acetamide-, or amide-.
  • the organic ligand can be functionalised before being used as precursor for MOF formation, or alternatively the assembled MOF itself can be chemically treated to functionalise its bridging organic ligands.
  • suitable chemical protocols that allow functionalizing a MOF with functional groups, either by pre-functionalizing organic ligands used to synthesize the MOF or by post-functionalizing a pre-formed MOF.
  • Suitable functional groups that may be provided on the MOF include -NHR, -N(R) 2 , -NH 2 , -N0 2 , -NH(aryl), halides, aryl, aralkyl, alkenyl, alkynyl, pyridyl, bipyridyl, terpyridyl, anilino, -O(alkyl), cycloalkyl, cycloalkenyl, cycloalkynyl, sulfonamido, hydroxyl, cyano, - (CO)R, -(S0 2 )R, -(C0 2 )R, -SH, -S(alkyl), -S0 3 H, -S0 3" M + , -COOH, COO " M + , -P0 3 H 2 , - P0 3 H " M + , -P03 2" M 2+ , -C0 2 H,
  • the solvent that can be used to prepare the solution in which MOF precursor compounds and a cell are combined, provided that (i) the MOF precursor compounds are soluble in the solvent, and (ii) the cell is compatible with the solvent. That is, the solvent will typically be one that does not adversely affect the cell viability.
  • solvent examples include dimethylformamide, tetrahydrofuran, methanol, ethanol, dimethyl sulfoxide (DMSO), acetone, water and mixtures thereof.
  • the solution into which the cell and MOF precursor compounds are combined is an aqueous solution, for example a deionised water solution, or a physiological buffered solution (i.e. water comprising one or more salts such as KH 2 P0 4 , NaH 2 P0 4 , K 2 HP0 4 , Na 2 HP0 4 , Na 3 P0 4 , K 3 P0 4 , NaCl, KC1, MgCl 2 , CaCl 2 , etc.).
  • aqueous solution for example a deionised water solution, or a physiological buffered solution (i.e. water comprising one or more salts such as KH 2 P0 4 , NaH 2 P0 4 , K 2 HP0 4 , Na 2 HP0 4 , Na 3 P0 4 , K 3 P0 4 , NaCl, KC1, MgCl 2 , CaCl 2 , etc.).
  • the layer of MOF forms there is no particular limitation regarding the concentration of MOF precursor compounds present in the solution.
  • Concentrations of MOF precursor compounds in the solution can include a range between about 0.001 M and 10 M, between about 0.01 M and 5 M, between about 0.01 M and 5 M, between about 0.02 M and 1 M, between about 0.02 M and 0.5 M, between about 0.05 M and 0.25 M, or between about 0.08 M and 0.16 M.
  • the values refer to concentration of organic ligand as well as concentration of metal salt, relative to the total volume of the solution containing the MOF precursor compounds and the cell.
  • the ratio between the concentration of organic ligands and the concentration of metal salts is not limited, provided the ratio is adequate for the formation of a layer of MOF promoted by the combination with the cell in accordance to the invention.
  • the organic ligand to metal salt ratio may range from about 1000: 1 to about 1:1000 (mohmol), from about 500: 1 to about 1:500, from about 100:1 to about 1: 100, from about 70: 1 to about 1:70, from about 30: 1 to about 1:30, from about 10: 1 to about 1: 10, from about 5: 1 to about 1:5, from about 2.5: 1 to about 1:2.5, from about 2: 1 to about 1:2, or from about 1.5: 1 to about 1: 1.5.
  • the cell promotes formation of a layer of crystalline MOF.
  • the cell per se causes, induces or triggers formation of the crystalline MOF upon combination with the MOF precursor compounds in a solution.
  • the MOF grows around the cell to eventually coat it entirely.
  • the ionic species-rich environment of a cell membrane acts to locally concentrate MOF precursor compounds thanks to the chelating ability of membrane species. It is believed that formation of a crystalline MOF is facilitated by membrane species affinity towards MOF precursor compounds arising, for example, from intermolecular hydrogen bonding and hydrophobic interactions. This in turn favours localised formation of the MOF leading to the growth of a porous exoskeleton encasing the cell.
  • the resulting increase in the local concentration (i.e. in the immediate surroundings of the cell) of both metal cations (deriving from the dissolution of the metal salt precursor) and organic ligands would facilitate pre-nucleation clusters of the MOF framework.
  • hydrophilic molecules and molecules having negatively charged domains or moieties show improved ability to nucleate a MOF over molecules with more hydrophobic character and positively charged moieties. It may therefore be postulated that negatively charged domains in the cell membrane attract the positive metal ions provided by the MOF metal precursor in solution and contribute to stabilize the metal-organic ligand clusters at the early stages of MOF formation.
  • negatively charged domains in the cell membrane attract the positive metal ions provided by the MOF metal precursor in solution and contribute to stabilize the metal-organic ligand clusters at the early stages of MOF formation.
  • Provided crystalline MOF forms there is no particular limitation regarding the amount of cells present in the solution with the MOF precursor compounds.
  • the solution contains a number of cells between about 1 and about lOxlO 10 per ml of solution, between about 1 and about 10x10 s per ml of solution, between about 1 and about lOxlO 6 per ml of solution, between about 1 and about lOxlO 4 per ml of solution, between about 1 and about 10x10 per ml of solution, between about 1 and about 100 per ml of solution, between about 1 and about 50 per ml of solution, between about 1 and about 25 per ml of solution, or between about 1 and about 10 per ml of solution.
  • Combining the MOF precursor compounds in solution with the cell is surprisingly sufficient to cause formation of the MOF framework. There is no need to apply other factors or reagents to trigger formation of the MOF. For example, it is not necessary to apply heat to the solution as conventionally done in traditional solvothermal MOF synthesis methods (which typically require use of a heat source such as an oven, for example a microwave oven, a hot plate, or a heating mantel).
  • a heat source such as an oven, for example a microwave oven, a hot plate, or a heating mantel.
  • formation of the layer of crystalline MOF is effected at a solution temperature that is lower than 100°C, 90°C, 75°C, 50°C, or 35°C.
  • the solution temperature may be between about -50°C and about 75°C, between about -50°C and about 50°C, or between about -50°C and about 30°C.
  • formation of the layer of crystalline MOF is effected at a solution temperature between about 0°C and about 10°C, between about 0°C and about 8°C, or between about 2°C and about 6°C.
  • formation of the layer of crystalline MOF is effected at a solution temperature of about 4°C.
  • the method is performed at room temperature.
  • room temperature will be understood as encompassing a range of temperatures between about 20°C and 25°C, with an average of about 23°C. Performing the method at these lower temperatures is advantageous for heat sensitive cells.
  • a solution containing a metal precursor may be first mixed with a solution containing an organic ligand, and a separate solution containing a cell is subsequently introduced into the solution containing the metal salt and the organic ligand.
  • a solution containing a cell and an organic ligand may be first prepared, and subsequently introduced into a separate solution containing a metal precursor.
  • a solution containing a cell and a metal precursor may be first prepared, and subsequently introduced into a separate solution containing an organic ligand. Still further, separate solutions each individually containing a metal precursor, an organic ligand and a cell, respectively, may be mixed together at the same time.
  • Formation of the MOF according to the method of the invention is advantageously fast.
  • the layer of crystalline MOF may form within about 1 second, 10 seconds, 1 minute, 10 minutes, 30 minutes, 60 minutes or 2 hours.
  • the cell promotes formation of the layer of crystalline MOF in less than about 1 minute, less than about 5 minutes, less than about 10 minutes, less than about 15 minutes, less than about 30 minutes, less than about 60 minutes, or less than about 120 minutes.
  • temperature and concentration of MOF precursor compounds it was found in a solution containing only MOF precursor compounds (i.e.
  • the MOF would not form.
  • the cell per se has been found to promote formation of the MOF.
  • Coating a cell with a layer of crystalline MOF advantageously hinders cell proliferation, yet maintaining cell viability.
  • the coating layer of crystalline MOF prevents cell division by inducing an artificial hibernation state of the cell, while at the same time allowing transport of nutrients or chemical stimulants necessary for cell viability.
  • the layer of MOF acts as a physical restriction suppressing cells from budding. Accordingly, a cell coated with a layer of crystalline MOF does not self-reproduce, and can be advantageously stored in a coated form over days, weeks, months or years without adversely affecting its viability.
  • the coated cell is stored at a temperature of between about 0°C and about 10°C, between about 0°C and about 8°C, or between about 2°C and about 6°C.
  • the coated cell may be stored at storage temperature for a period of time of at least a week, at least a month or at least a year, for example a week, a month or a year. In an embodiment, the coated cell is stored for about 2 months at about 4°C.
  • the layer of MOF can advantageously act as a selectively permeable physical barrier that allows diffusion of nutrients and substrates into the cytoplasm, that is, one can control the microenvironment for optimal cellular function. Simultaneously, the layer can also protect the cell from the attack of cytotoxic agents, macrophages or immunoglobulins. Since the layer of MOF can impede diffusion of molecules that are larger than the MOF intrinsic cavities, large cytotoxic bio-molecules (e.g. cytotoxic enzymes) cannot diffuse through the layer to attack the cell. This is schematically represented in Figure 2, showing a cell being coated with a layer of MOF that allows diffusion of nutrients while acting as physical barrier for large molecules.
  • cell self-reproduction i.e. cell proliferation
  • cell self-reproduction i.e. cell proliferation
  • the cell in a viable state separates from the crystalline MOF as a resolute of the MOF dissolving, degrading, disintegrating, rupturing, or deteriorating.
  • all biological functions of the cell prior to being coated are reinstated.
  • the cell recuperates its ability to self-replicate.
  • the cell in a viable state separates from the MOF as a result of the layer of MOF dissolving. This may be achieved, for example, by inducing a variation of the pH of the solvent or by adding into the dispersion medium a compound that dissolves the layer of MOF.
  • the MOF may be stable above a threshold pH value. In that case there is no detectable release of the cell into the dispersion medium. However, the MOF may dissolve when the pH drops below the threshold, resulting in the release of the cell into the dispersion medium.
  • certain MOFs can be stable at pH higher than physiological pH (about 7.4), but dissolve when the pH drops to physiological pH. This can result in the release of the cell into the dispersion medium.
  • the cell separates from the crystalline MOF as a result of the layer of MOF being dissolved by a compound that is added to the dispersion medium.
  • a compound that is added to the dispersion medium examples include ethylenediamine tetra-acetic acid (EDTA), Diethylenetriaminepentaacetic acid (DTPA), N,N-bis(carboxymethyl)glycine; Triglycollamic acid (NT A), and phosphate buffer.
  • the compound may be added in an amount sufficient to bring its concentration in the dispersion medium to between about 0.001 mol/L and about 10 mol/L, between about 0.01 mol/L and about 10 mol/L, between about 0.1 mol/L and about 10 mol/L, between about 0.5 mol/L and about 10 mol/L, between about 1 mol/L and about 10 mol/L, between about 1 mol/L and about 8 mol/L, between about 1 mol/L and about 5 mol/L, or between about 1 mol/L and about 2 mol/L.
  • the layer of crystalline MOF coats the cell and that the cell can subsequently separate in a viable state from the crystalline MOF
  • the largest thickness of the layer of crystalline MOF there is no limitation as to the largest thickness of the layer of crystalline MOF.
  • the 'largest thickness' of the layer of crystalline MOF is meant the maximum thickness of the layer measured by SEM along a radial direction perpendicular to the cell external membrane.
  • the largest thickness of the layer of crystalline MOF ranges from about 10 nm to about 500 ⁇ , from about 25 nm to about 250 ⁇ , from about 50 nm to about 200 ⁇ , from about 50 nm to about 100 ⁇ , from about 100 nm to about 250 nm from about 50 nm to about 25 ⁇ , from about 50 nm to about 10 ⁇ , from about 50 nm to about 5 ⁇ , from about 50 nm to about 2.5 ⁇ , from about 50 nm to about 1 ⁇ , or from about 50 nm to about 0.5 ⁇ .
  • Specific embodiments of the invention will now be described with reference to the following non-limiting examples.
  • Optical micrographs were obtained using an Olympus BX60M microscope.
  • Scanning electron microscope (SEM) images of samples were taken on a Zeiss MERLIN SEM at an accelerating voltage of 5.0 kV.
  • Confocal microscopy images were acquired via a Nikon AIR confocal laser scanning microscope.
  • Synchrotron SAXS data were collected at the SAXS/WAXS beamline at the Australian Synchrotron. 5 Diffraction patterns were collected using a Pilatus 1M detector.
  • Encapsulation of yeast cells and bacteria cells with a layer of ZIF-8 2 mg dry yeast cells were cultured in the yeast culture media containing Saccharomyces cerevisiae yeast cells extract (10 mg mL "1 ) and glucose (20 mg mL "1 ) with continuous shaking at 30 °C for 18 h.
  • the yeast cells (were washed with deionized (DI) water three times and finally suspended in 5 mL aqueous solution of Hmlm (160 mM). 5 mL aqueous solution of zinc acetate dihydrate (40 mM) was then added into the Hmlm solution containing the yeast cells.
  • the mixture was placed on a shaking stage (300 rpm) for 10 min for the formation of the layer of ZIF-8.
  • the coated cells were washed with DI water three times to remove the excess ZIF-8 precursor compounds, and finally suspended in DI water.
  • the micro structure of the layer of MOF was analysed by synchrotron small-angle X-ray scattering (SAXS).
  • SAXS synchrotron small-angle X-ray scattering
  • the resulting scattering pattern was comprised of peaks that were analogous in position and relative intensity to pure ZIF-8 ( Figure 3), thus confirming the nature, structure and crystallinity of the layer.
  • the morphology and elemental distribution of the ZIF-8 layer was also assessed by scanning electron microscopy (SEM) and Energy-dispersive X-ray spectroscopy (EDS), respectively.
  • SEM imaging of c.a. 500 yeast cells coated within a layer of ZIF-8 revealed that each individual cells was coated with a homogeneous layer of ZIF-8. That is, SEM images showed that each discrete cell was individually and entirely coated with a layer of ZIF-8.
  • the analysis did not reveal, for example, aggregates of cells coated within the same layer of ZIF-8, or partially non-coated cells.
  • Elemental analysis performed using high-magnification SEM was consistent with a homogeneous distribution of Zn, O and C (the main components of ZIF-8) on the cell surface. This strongly supports the formation of a continuous layer of ZIF-8 on individual yeast cells.
  • the thickness of the ZIF-8 coatings could be tuned in the 100-250 nm range by carrying out sequential ZIF-8 coating steps (Figure 10).
  • Figure 10 shows SEM images of cracked ZIF-8 coating layer which were used to measure the thickness of ZIF-8 coatings on yeast cells after 1 to 4 coating cycles.
  • (a) relates to 1 coating cycle, resulting in a coating layer thickness of 104nm
  • (b) relates to 2 coating cycles, resulting in a thickness of the coating layer of 148nm
  • (c) relates to 3 coating cycles, resulting in a thickness of the coating layer of 210nm
  • (d) relates to 4 coating cycles, resulting in a thickness of the coating layer of 257nm.
  • Figure 10 (e) shows a plot of the ZIF-8 coating thickness against the number of subsequent coating cycles.
  • CSM Confocal scanning laser microscopy
  • Micrococcus Luteus that possess a peptidoglycans-based outer membrane.
  • Micrococcus Luteus can survive in oligotrophic (nutrient deficient) environments and is of interest for biotechnological applications (e.g. terpenes biosynthesis).
  • biotechnological applications e.g. terpenes biosynthesis
  • Figure 11 shows (a) an SEM image of Micrococcus Luteus coated with a layer of ZIF-8, (b) SAXS diffraction patterns of standard ZIF-8 crystals (bottom line, black), native Micrococcus Luteus (middle line, dark grey), and Micrococcus Luteus coated with ZIF-8 (top line, grey), and in the inset of (b) a 2D representation of SAXS patterns generated by the ZIF-8 coated bacteria, (c) a fluorescent microscopy image of Micrococcus Luteus coated with a layer of ZIF-8, obtained using FDA as a fluorescent cell viability indicator, and (d) FDA cell viability assay on uncoated Micrococcus Luteus (naked) and Micrococcus Luteus coated with a layer of ZIF-8.
  • the cells were then washed three times with DI water to remove free dyes in the solution.
  • resazurin assay 20 ⁇ . resazurin solution (0.15 mg mL "1 in DPBS) was added into each 0.2 mL yeast suspension and incubated at 30 °C for 2 h. The cells were then washed three times with DI water to remove free dyes in the solution.
  • OD 6 oo optical density at 600 nm
  • the OD 6 oo data also showed that the growth rate and final cell number of the yeast, after the removal of the ZIF-8 layer, reached a similar level to non-coated yeast.
  • the ZIF-8 coatings have no measurably adverse impact on the yeast cells.
  • our results show that a ZIF-8 layer can extend the cell's lifetime, by artificially supressing cell division, without significantly affecting the activity of cells in the growth state.

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Abstract

La présente invention concerne une cellule revêtue d'une couche de réseau organométallique cristallin (MOF).
PCT/AU2017/050673 2016-06-29 2017-06-29 Matériau de revêtement pour cellules WO2018000043A1 (fr)

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Cited By (13)

* Cited by examiner, † Cited by third party
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US11672866B2 (en) 2016-01-08 2023-06-13 Paul N. DURFEE Osteotropic nanoparticles for prevention or treatment of bone metastases
US11344629B2 (en) 2017-03-01 2022-05-31 Charles Jeffrey Brinker Active targeting of cells by monosized protocells
US11744894B2 (en) * 2018-01-17 2023-09-05 Nankai University Composite biological agent based on porous frame materials
US20200397902A1 (en) * 2018-01-17 2020-12-24 Nankai University Novel composite biological agent based on porous frame materials
WO2020068798A1 (fr) * 2018-09-24 2020-04-02 Guo Jimin Cellules de mammifère vivant modifiées avec des nanoparticules modulaires fonctionnelles
US20220033768A1 (en) * 2018-09-24 2022-02-03 Jimin Guo Living mammalian cells modified with functional modular nanoparticles
US20210386055A1 (en) * 2018-10-30 2021-12-16 Unm Rainforest Innovations Metal-organic Framework-Assisted Cryopreservation of Red Blood-Cells
CN110960889A (zh) * 2019-12-25 2020-04-07 中国石油大学(华东) 一种具有花状结构的含油污水分离膜及其制备方法
CN114441458B (zh) * 2021-05-24 2023-06-09 中国科学院海洋研究所 一种zif材料在抑制模拟酶中的应用
CN114441458A (zh) * 2021-05-24 2022-05-06 中国科学院海洋研究所 一种zif材料在抑制模拟酶中的应用
WO2023021241A1 (fr) 2021-08-16 2023-02-23 Åbo Akademi Biomolécules encapsulées pour administration intracellulaire
WO2023021242A1 (fr) 2021-08-16 2023-02-23 Åbo Akademi Mitochondries bioactives encapsulées dans une structure organométallique
WO2023019978A1 (fr) * 2021-08-18 2023-02-23 深圳职业技术学院 Procédé de préparation d'une structure noyau-enveloppe de cellule myocardique revêtue de mof

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