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WO2017078609A1 - Synthèse monotope de structures organométalliques avec des molécules cibles encapsulées et leur utilisation - Google Patents

Synthèse monotope de structures organométalliques avec des molécules cibles encapsulées et leur utilisation Download PDF

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Publication number
WO2017078609A1
WO2017078609A1 PCT/SE2016/051092 SE2016051092W WO2017078609A1 WO 2017078609 A1 WO2017078609 A1 WO 2017078609A1 SE 2016051092 W SE2016051092 W SE 2016051092W WO 2017078609 A1 WO2017078609 A1 WO 2017078609A1
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molecule
target
metal
mof
dox
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Haoquan ZHENG
Hani Nasser Abdelhamid
Leifeng LIU
Wei Wan
Peng Guo
Xiaodong Zou
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SU HOLDING AB
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C07D233/58—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring nitrogen atoms
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/22—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material
    • B01J20/223—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof comprising organic material containing metals, e.g. organo-metallic compounds, coordination complexes
    • B01J20/226—Coordination polymers, e.g. metal-organic frameworks [MOF], zeolitic imidazolate frameworks [ZIF]
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/28—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties
    • B01J20/28014—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof characterised by their form or physical properties characterised by their form
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/30—Processes for preparing, regenerating, or reactivating
    • B01J20/3085—Chemical treatments not covered by groups B01J20/3007 - B01J20/3078
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/30—Processes for preparing, regenerating, or reactivating
    • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
    • B01J20/3202—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the carrier, support or substrate used for impregnation or coating
    • B01J20/3206—Organic carriers, supports or substrates
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/30—Processes for preparing, regenerating, or reactivating
    • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
    • B01J20/3231—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating characterised by the coating or impregnating layer
    • B01J20/3242—Layers with a functional group, e.g. an affinity material, a ligand, a reactant or a complexing group
    • B01J20/3244—Non-macromolecular compounds
    • B01J20/3246—Non-macromolecular compounds having a well defined chemical structure
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J20/00—Solid sorbent compositions or filter aid compositions; Sorbents for chromatography; Processes for preparing, regenerating or reactivating thereof
    • B01J20/30—Processes for preparing, regenerating, or reactivating
    • B01J20/32—Impregnating or coating ; Solid sorbent compositions obtained from processes involving impregnating or coating
    • B01J20/3291—Characterised by the shape of the carrier, the coating or the obtained coated product
    • B01J20/3293—Coatings on a core, the core being particle or fiber shaped, e.g. encapsulated particles, coated fibers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
    • C07F3/06—Zinc compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
    • C07H15/20—Carbocyclic rings
    • C07H15/24—Condensed ring systems having three or more rings
    • C07H15/244—Anthraquinone radicals, e.g. sennosides

Definitions

  • the present invention relates to a metal-organic framework with encapsulated target- molecule, a process for the preparation of a metal-organic framework with encapsulated target-molecule, as well as the metal-organic framework with encapsulated target-molecule obtained by the process, and the use of the metal-organic framework with encapsulated target-molecule.
  • Metal-organic frameworks are coordination networks consisting of metal ions and organic linkers that are coordinated to the metal ions. MOFs have high porosity, large surface areas and tuneable functionality, and have great promise for applications in sorption and separation, catalysis, sensing and drug delivery. MOFs have been used as carriers of metal nanoparticles for catalysis (Jiang, et a I, J. Am. Chem. Soc. 131, 11302- 11303 (2009); and Dhakshinamoorthy, et al., Chem. Soc. Rev. 41, 5262-5284 (2012)) and of organic molecules such as drugs (US 2015/0150981; Horcajada, P., et al. Chem. Rev.
  • WO 2012/020214 discloses a material possessing antimicrobial properties wherein both the framework itself as well as incorporated guest molecules are active against microbes.
  • the potential applications of MOFs can be developed and extended by the introduction of hierarchical structures containing both micropores and mesopores.
  • post- functionalisation strategies involve multiple steps, which are both costly and produce large amount of waste.
  • MOFs small pore window that limits their potential to encapsulate large molecules.
  • inorganic carriers for example mesoporous silica
  • the current loading capacity of large molecules in MOFs is rather low.
  • One strategy to overcome these drawbacks is to combine MOF synthesis and molecule encapsulation into a one-pot process (Lyu, et al., Nano Lett. 14, 5761-5765 (2014); and Liang et al., Nature Communications 6, Article number 7240, (2015); Abstracts presented at International Conference on Nanospace Materials (Taipei, Taiwan; 23-25 June 2015) and Gordon Research Conference (Biddeford, ME, USA; June 28-July 3, 2015)).
  • the present invention relates to a metal-organic framework with encapsulated target- molecule, characterized in that the MOF has a core-shell structure, wherein the core comprises the MOF and the encapsulated target-molecule, and the shell comprises the MOF and is substantially free of target-molecules.
  • the present invention further relates to a process for the preparation of a metal-organic framework (MOF) with encapsulated target-molecule, comprising the steps of:
  • the present invention also provides a metal-organic framework with encapsulated target-molecule obtained by the process according to the present invention. Further, the present invention provides use of a metal-organic framework with an encapsulated target-molecule obtained by the process according the present invention in separation, catalysis, for gas separation, removal of organic pollutants, bio-imaging, drug delivery, and sensing.
  • Figure 1 shows pH-induced one-pot synthesis of MOFs with encapsulated target- molecules.
  • Figure 2 shows a SEM image of DOX@ZIF-8 with 20% DOX loadings (a), and powder X- ray diffraction pattern (PXRD, b), colour (c) and TEM images (d) of the DOX@ZIF-8 crystals intensifying with higher DOX loading (0, 4, 14 and 20% DOX loadings).
  • Figure 3 shows UV-Vis spectra of a DOX solution, the mixed solution of DOX molecule and zinc nitrate and solid-state UV-Vis spectra of DOX@ZIF-8.
  • Figure 4 shows the TEM image and the electron diffraction (ED) pattern (inset) of a single DOX@ZIF-8 crystal.
  • Figure 5 shows the distribution of mesopores in DOX@ZIF-8 crystals (with 20% DOX loading) illustrated by electron tomography, (a) TEM image of a DOX@ZIF-8 single crystal, (b) Cross-section of the electron tomogram with the mesopores marked by dark- grey areas, (c) 3D distribution of the mesopores in the DOX@ZIF-8 crystal.
  • the DOX molecules are present in the mesopores.
  • a mesopore-free shell is clearly seen, indicating that the shell is substantially free of the DOX molecules.
  • Figure 6 shows the particle size distribution of the DOX@ZIF-8 crystals with different DOX loadings, 0% (a), 4% (b), 14% (c), and 20% (d), obtained by dynamic light scattering (DLS).
  • Figure 7 shows the UV-Vis absorbance spectra of organic dye target molecular solution and the mixed solution of target-molecule and zinc nitrate.
  • Figure 8 shows PXRD patterns of hierarchical micro-/meso-structured ZIF-8 crystals in which different type of organic dyes have been encapsulated.
  • Figure 9 shows PXRD pattern (a), SEM image (b) and TEM image (c) of ZIF-67 crystals (synthesized using Co as the metal instead of Zn in ZIF-8) in which DOX has been encapsulated.
  • Figure 10 shows a TEM image of (Pd&DOX)@ZIF-8.
  • Figure 11 shows in (a) the N 2 adsorption/desorption isotherm, (b) pore size distribution of the DOX@ZIF-8 crystals after treatment.
  • Figure 12 shows the pH-responsive release of DOX from DOX@ZIF-8 crystals (a) and (b) and time dependent dissolving profiles of free DOX at different pH values (c) as determined by UV-Vis spectrophotometry.
  • pH 6.5-7.4
  • ⁇ 1% At high pH (6.5-7.4), there is virtually no release ( ⁇ 1%).
  • 5.0-6.0 At low pH (5.0-6.0), > 95% of DOX is released during 7-9 days.
  • Figure 13 shows a comparison of mitochondrial functions of macrophages and breast cancer cells exposed to DOX@ZIF-8, a mixture of ZIF-8 and DOX (ZIF-8+DOX), pure ZIF-8 and free DOX.
  • the present invention provides a metal-organic framework (MOF) with an encapsulated target-molecule, characterized in that the MOF has a core-shell structure, wherein the core comprises the MOF and the encapsulated target-molecule, and the shell comprises the MOF and is substantially free of target-molecules.
  • MOF metal-organic framework
  • the term "shell” is used for the peripheral shell that surrounds the core in a core-shell structure.
  • both the core and the shell contain the MOF.
  • the core of the MOF further comprises one or more target molecules.
  • target-molecule denotes a molecule, material or a particle that is encapsulated in a MOF.
  • the target-molecule for encapsulation in a MOF in the process according to the present invention may be a small organic molecule, such as: a drug, for example an anti-cancer drug; a dye, such as rhodamine B, methyl orange, methylene blue, or a mixture thereof; a vitamin; or a flavour.
  • the target-molecule may also be a biomacromolecule, such as: a protein or DNA; an organometallic catalyst; a magnetic particle; an inorganic material, such as graphene or carbon nanotube; or a metal nanoparticle.
  • the target-molecule is an organic molecule, such as small organic molecule or a biomacromolecule.
  • MOFs can be porous and may contain intrinsic pores.
  • the shell of the MOF according to the present invention is substantially free from pores equal to or larger than the encapsulated target-molecules, or pores larger than 1 nm.
  • the shell does not contain pores in the range 1-100 nm. More preferably, the shell does not contain pores in the range 1-50 nm, or 2-50 nm.
  • the term "substantially free of target-molecules" intends to mean that ⁇ 2 % of the total weight of the encapsulated target-molecules are encapsulated in the shell of the MOF according to the present invention.
  • a MOF with a shell enables the safe storage of the encapsulated target-molecule under physiological conditions and an induction release period in acidic media.
  • the release of the encapsulated target-molecules is associated with the decomposition of the MOF at low pH, and especially by first decomposition of the shell.
  • the shell preferably has a thickness that is at least twice the size of intrinsic pores of the MOF.
  • the shell has a thickness of at least 1 nm, at least 2 nm, at least 5 nm, at least 10 nm, or at least 15 nm. If the thickness is smaller than the intrinsic pores, the encapsulated molecules may diffuse out through the pores.
  • the upper limit for the thickness of the shell depends on the size of the encapsulated target-molecule.
  • the thickness of the shell may be up to 20% of the diameter of the MOF crystal.
  • Crystals of MOF with encapsulated target-molecules according to the present invention may have a diameter in the range of 30-2000 nm, 30-500 nm, 50-500 nm, or 70-300 nm.
  • the specific surface area (BET area) may be at least 500 m 2 /g, or at least 1000 m 2 /g-
  • the present invention also provides a process for the preparation of a metal-organic framework (MOF) with encapsulated target-molecule, comprising the steps of: a) mixing a target-molecule with a metal salt in a suitable solvent and adjusting the pH of the solution to a value between 6 and 12;
  • a MOF comprising a core comprising the MOF and the encapsulated target-molecule and a shell comprising the MOF and that is substantially free of the target-molecules.
  • the preparation is made as a one-pot process, which permits for less use of solvents and less amounts of waste.
  • the target molecule and metal salt are both soluble in the suitable solvent used for mixing in step (a).
  • suitable solvents may be water, methanol, dimethylformamide (DMF), ethyl acetate, diethyl ether, acetone acetonitrile, dimethyl sulfoxide (DMSO), and tetrahydrofuran (THF), or a mixture of one or more of these.
  • the solvent is preferably selected from water and methanol, more preferably water.
  • Performing step (a) at a pH of 6-12, or preferably a pH of 7-11, or a pH of 8-11 promotes the interaction between the target-molecules and the metal ions prior to the formation of the MOF crystals.
  • the pH may be adjusted by a suitable base; such as NaOH, triethylamine (TEA), piperidine, ethanolamine, and sodium formate; preferably NaOH or triethylamine.
  • Step (a) is preferably performed for at least 1 minute, at least 2, at least 5, or at least 10 minutes. Further, the time for step (a) is preferably not longer than 30 minutes, or 1 hour. The time allowed for the reaction of target- molecule, the metal salt and the organic linker in step (b) affects the thickness of the shell.
  • the target-molecule, metal salt and organic linkers should be allowed to react for at least 1 minute, or at least 2, at least 5, at least 10, or at least 15 minutes, in step (b).
  • the reaction time provides a possibility to adjust the thickness of the shell of the resulting MOF crystal. This enables control of the release of the encapsulated target- molecule.
  • the time for step (b) is preferably not longer than 45 minutes, or 30 minutes.
  • the metal ions and organic linkers may be present in excess amount so that the crystallisation of the MOF can still occur even after the target-molecules have been depleted and a shell can continue to be formed.
  • the encapsulated target-molecules are expected to be homogeneously distributed within the core of the MOF, while the shell is substantially free from target- molecules.
  • An advantage with a shell that is substantially free from target-molecules is that the initial release of the target-molecules can be delayed, such that an induction period may be obtained even though the surrounding conditions are kept constant, for example without changing the pH. This is because the shell, which surrounds the core, should decompose before the encapsulated target-molecules may be released from the core.
  • the process according to the present invention provides for an easy preparation and enables easy control of the process as well as loading of target-molecules into the framework.
  • the loading amount can be tuned by the concentration of the target- molecules in the solution used in the process.
  • the loading of the target-molecule may be at least 1%, at least 2%, at least 3%, at least 4%, at least 5%, at least 10 %, or at least 15%, of the total weight of the metal-organic framework with the encapsulated target- molecule.
  • the loading of a target-molecule is suitably not more than 50% of the total weight of the metal-organic framework with encapsulated target-molecule.
  • the loading of an organic target-molecule is suitably not more than 35% of the total weight of the metal-organic framework with encapsulated target-molecule.
  • High loadings, for example at least 5 wt%, or at least 10 wt%, of the target-molecule enables homogeneous distribution of the target-molecules within the core of the MOF.
  • Another advantage with the method according to the present invention is that it facilitates encapsulation of large molecules in metal-organic frameworks. Further, the process according to the present invention also makes it possible to obtain multi-functionalized materials by encapsulation of two or more target-molecules in a one-pot process.
  • target-molecules may be chosen to have an activity that is either complementary to or is different from each other, which enables the production of a material with tailored properties.
  • the target- molecules that may be encapsulated in a MOF according to the present invention may have different functionalities and may be selected from organic molecules, magnetic nanoparticles, quantum dots, metal oxides, biomolecules and enzymes.
  • the process according to the present invention enables construction of multi-functional delivery systems for a wide range of applications by adding target-molecules with different functionalities in step (a). This opens new opportunities in developing multifunctional materials.
  • the materials obtained by the process according to the present invention may be used for controlled and targeted release of drugs and other molecules; as heterogeneous catalysts; for gas separation, for example C0 2 separations; removal of organic pollutants; bio-imaging; sensing, such as in biosensors, etc.
  • the synthesis is simple, green and scalable, and has strong potential for industrial applications.
  • the process according to the present invention also enables control of the mesoporosity of the final products.
  • Mesopores typically have a diameter of from 2 to 50 nm.
  • Removal of encapsulated target-molecules from a metal-organic framework prepared according to the present invention provides for the introduction of homogeneously distributed mesopores in the MOF.
  • the mesopores thus induced may be homogeneously distributed within said core.
  • Removal of encapsulated target-molecules can be made after step (c) in the process according to the present invention, for example by dispersing MOF with encapsulated target-molecules in ethanol solution, and reflux for 0.5-2 h.
  • one embodiment of the present invention is a metal-organic framework with hierarchical porosity prepared by the process for preparing a MOF with an encapsulated molecule according to the present invention, and further comprising a step of removing the encapsulated target-molecules from the obtained MOF crystals.
  • hierarchical porosity denotes a porous system comprising i) pores that are intrinsic in a MOF, and ii) pores that are induced in the MOF by the target- molecule or by a subsequent removal of the target-molecule.
  • the induced pores may occur only in the core of the MOF, while the shell is substantially free from induced pores.
  • Intrinsic pores of MOFs are ordered and typically have a diameter in the range of 0.3 - 2.0 nm.
  • the size of the induced pores that are introduced in the MOF can be tuned by the loading amount of encapsulated target-molecule. Removal of an encapsulated target-molecule in a process according to the present invention may induce pores with a diameter of 1-100 nm, 1-50 nm, 2-50 nm, or 10-20 nm.
  • the core may have pores induced by the target-molecules, which pores may have a diameter of 1-100 nm, 1-50 nm, 2-50 nm, or 10-20 nm while the shell is substantially free from such pores.
  • ⁇ 1 % of the amount of the pores with a diameter of 1-100 nm, 1-50 nm, 2- 50 nm, or 10-20 nm occur in the shell.
  • the induced pores may be interconnected. Further, the induced pores can be accessible for other molecules.
  • the collection of the MOF crystals in step (c) of the process according to the present invention may be performed by conventional methods, such as centrifugal separation, filtration and freeze-drying.
  • the present invention further provides a metal-organic framework with encapsulated target-molecule, obtained by the process according to the present invention.
  • Suitable metal salts for use in the process according to the present invention comprises metal ions selected from the group consisting of lUPAC Groups 3 and 6-15, and combinations thereof.
  • the metal ions are selected from tetrahedrally- coordinated transition metal ions, such as iron, cobalt, copper and zinc, and their metal complexes; more preferably cobalt or zinc.
  • Typical salt-forming anions are selected from the group consisting of acetate, sulphate, nitrate, phosphate, sulphide, halides, sulphite, carbonate and citrate.
  • suitable metal salts are selected from ZnCI 2 , Zn(CH 3 COO) 2 , ZnS0 4 , Zn(N0 3 ) 2 , Zn 3 (P0 4 ) 2 or CoCI 2 , Co(CH 3 COO) 2 , CoS0 4 , Co(N0 3 ) 2 ; nitrate salts of cobalt and zinc are preferred.
  • the organic linker may be selected from a compound of formula (I), (II), (III), or any combination of the connection structure:
  • a 1 , A 2 , A 3 and A 4 are each independently selected from C, N, P and B, and
  • a 5 , A 6 and A 7 are each independently selected from C and N, and
  • R 1 , and R 4 and R 9 each individually comprise an electron withdrawing, or weakly electron donating, and non-sterically hindering group that does not interfere with transition metals that may become linked to any or both of the nitrogen atoms adjacent to the carbon atom in the ring to which R 1 , and R 4 or R 9 , respectively, is attached;
  • R 2 , R 3 , R 6 , and R 7 are each independently selected from electron withdrawing or weakly electron donating groups, such as hydrogen, Ci-6 alkyl, halo, cyano and nitro;
  • R 10 is an electron withdrawing or a weakly electron donating group, such as a hydrogen, Ci-6 alkyl, halo, cyano or nitro;
  • R 5 and R 8 are each independently selected from hydrogen, Ci-6 alkyl, halo, cyano and nitro;
  • R 11 is an electron withdrawing or a weakly electron donating group, such as a hydrogen, Ci-6 alkyl, halo, cyano or nitro;
  • R 12 is an electron withdrawing or a weakly electron donating group, such as a hydrogen, Ci-6 alkyl, halo, cyano or nitro.
  • a 1 , A 2 , A 3 - A 4 , A 5 , A 6 and A 7 are each independently selected from C and N, and
  • R 1 , R 4 , and R 9 each individually are selected from hydrogen, Ci-6 alkyl, formyl, halo, cyano and nitro;
  • R 2 , R 3 , R 6 , and R 7 are each independently selected from hydrogen, Ci-6 alkyl, halo, cyano and nitro;
  • R 5 and R 8 are each independently selected from hydrogen, Ci-6 alkyl, halo, cyano and nitro;
  • R 10 is hydrogen, Ci-6 alkyl, halo, cyano or nitro;
  • R 11 is hydrogen, Ci-6 alkyl, halo, cyano or nitro
  • R 12 is hydrogen, Ci-6 alkyl, halo, cyano or nitro.
  • organic linker may be selected from a compound of formula (I) or (II), wherein
  • a 1 , A 2 , A 3 and A 4 are C;
  • R 1 is hydrogen, methyl or formyl
  • R 2 and R 3 are hydrogen; R 4 is hydrogen or amino; and
  • R 5 , R 6 , R 7 , and R 8 are hydrogen.
  • the organic linker is selected from the group consisting of 2-methylimidazole, imidazole, 2-aminobenzimidazole, benzimidazole and carboxyaldehyde-2-imidazole.
  • the MOF prepared with the process according to the present invention may be a zeolitic imidazolate framework (ZIF), HKUST-1, MOF-5, MIL-53, MIL-101, UIO-66, NOTT-400, ZnBT or MOP-1.
  • the MOF is a ZIF.
  • Zeolitic imidazolate frameworks (ZIFs) have the advantage that they possess high thermal and hydrothermal stabilities.
  • zeolitic imidazolate frameworks are ZIF-1, ZIF-2, ZIF-3, ZIF-4, ZIF-5, ZIF-6, ZIF-7, ZIF-8, ZIF- 9, ZIF-10, ZIF-11, ZIF-12, ZIF-14, ZIF-20, ZIF-21, ZIF-22, ZIF-23, ZIF-60, ZIF-61, ZIF-62, ZIF- 64, ZIF-65, ZIF-67, ZIF-68.
  • the ZIFs are selected from ZIF-8, ZIF-67 and ZIF-70.
  • ZIFs may be used in applications for gas separation, and as carriers for metal nanoparticles and drugs.
  • the metal-organic framework in the present invention is ZIF-8.
  • ZIF-8 built from zinc ion and 2-methylimidazolate, has the further advantage that it is non-toxic and biocompatible.
  • the present invention provides use of a metal-organic framework (MOF) with encapsulated target-molecule the materials according to the present invention, for controlled and targeted release of drugs and other molecules, as heterogeneous catalysts, for gas separation, removal of organic pollutants, bio imaging, or sensing. More specific, the present invention provides use of a metal-organic framework (MOF) with encapsulated target-molecule for drug delivery in cancer therapy via pH responsive release. The present invention thus provides for a method for drug delivery in cancer therapy by using a metal-organic framework (MOF) with encapsulated target-molecule.
  • a pH-responsive drug delivery system enables a drug delivery system with no release of drugs under physiological condition in circulation.
  • a specific example of a target-molecule for encapsulation in a MOF according to the present invention is an anti-cancer drug, such as anti-cancer drugs selected from the group consisting of doxorubicin (DOX), daunorubicin, mitoxantrone, methotrexate, idarubicin, 5-fluorouracil, epirubicin, aclarubicin, pirarubicin, duazomycin, duazomycin, mitomycin, medorubicin, rodorubicin and bleomycin.
  • Preferred anti-cancer drugs are selected from the group consisting of DOX, daunorubicin, mitoxantrone, methotrexate, and 5-fluorouracil.
  • a more preferred anti-cancer drug for use in the present invention is DOX.
  • DOX, daunorubicin, mitoxantrone, methotrexate, and 5-fluorouracil molecules have functional groups that form weak coordination bonds with Zn 2+ ions in aqueous medium.
  • a metal-organic framework with encapsulated target-molecules according to the present invention is DOX@ZIF-8.
  • DOX@ZIF-8 according to the present invention may have a DOX loading of at least 1 wt%, at least 2%, at least 3%, at least 4%, at least 5%, at least 10 %, or at least 15 wt%, based on the total weight of the loaded MOF.
  • DOX@ZIF-8 ZIF-8 with encapsulated doxorubicin
  • DOX@ZIF-8 can be utilised as an efficient drug delivery vehicle in cancer therapy via pH responsive release.
  • DOX@ZIF-8 according to the present invention shows a higher efficacy on three different breast cancer cell lines compared to (non-encapsulated) doxorubicin.
  • Another important advantage with metal-organic frameworks with encapsulated target- molecules prepared according to the present invention is that there is virtually no release of the encapsulated target-molecules at high pH and a slower release of the target-molecules at low pH compared with other metal-organic frameworks with encapsulated target-molecules.
  • the drug release for DOX@ZIF-8 is associated with the decomposition of ZIF-8 at low pH values.
  • DOX molecules are safely stored in DOX@ZIF-8 carriers prepared according to the present invention. After 15 days at a pH > 6.5, DOX@ZIF-8 prepared with the method according to the present invention only releases ⁇ 1% doxorubicin of the total amount of encapsulated doxorubicin.
  • Decomposition of the drug-free shell of ZIF-8 which acts as a protective capsule for the drug, provides for an induction period during which the DOX release may be very low ( ⁇ 1%).
  • This unique release property of DOX@ZIF-8 may be used in a pH-responsive drug delivery system in cancer therapy.
  • organic dyes undergo photo-bleaching or fading due to the photochemical alteration of the dye molecules. This process leads to that the light emission capacity of the dye molecules decreases with time.
  • An advantage with encapsulation of dyes in a MOF according to the present invention is that it increases the rigidity of the dye which significantly increases the lifetime of the dye molecules.
  • the increase of the long lifetime by encapsulation of dye molecules in a MOF is important for tissue and biological applications involving fluorescence energy transfer, for example fluorescence lifetime imaging microscopy (FILM) and lifetime biosensors, where auto-fluorescence precludes the imaging.
  • the dye molecules encapsulated in a MOF according to the present invention are protected by the MOF and may be insensitive to surrounding environment such as water vapor, oxygen, C0 2 , and others gases. It may also be less sensitive to the viscosity and polarity of solvents.
  • Dye molecules encapsulated in a MOF according to the present invention may be used in solid state dyes (SSD), laser dyes, and as a probe for sensors.
  • SSD solid state dyes
  • the synthesis used in the process according to the present invention is schematically shown in Figure 1.
  • Metal ions and target-molecules (a) self-assemble into coordination polymers (b) in an aqueous solution with a pH value between 6 and 12.
  • Organic linkers disassemble the metal ions from target-molecules and assemble the metal ions with the linkers into hierarchical MOFs (c).
  • the resulting crystals consist of a core with isolated and homogeneously distributed target-molecules within a MOF, and a shell comprising MOF and that is substantially free of target-molecules.
  • the loading amount, the thickness of the shell, and the hierarchical porosity of the crystals can be controlled by the concentration of the target-molecules in the solution.
  • the tested organic linker is 2-methylimidazole, and the metal ions are Zn 2+ and Co 2+ resulting in ZIF-8 and ZIF-67, respectively.
  • Four different target-molecules are used: doxorubicin (DOX), rhodamine B (RhB), methyl orange (MO), and methylene blue (MB).
  • reagents were purchased and used without purification: water, fetal bovine serum (FBS), phosphate- buffered saline (PBS), sodium dodecyl sulphate (SDS), polyvinylpyrrolidone (PVP), L-ascorbic acid, rhodamine B, methyl orange, methylene blue, 3-(4,5-dimethylthiazol-2-yl))-2,5-diphenyl tetrazolium bromide (MTT, Sigma- Aldrich), 4',6-diamidino-2-phenylindole (DAPI, Eugene, OR), DOX (Yinghuan Chempharm), ⁇ ( ⁇ 3)2 ⁇ 6 ⁇ 2 ⁇ responsibly Co(N03)2-6H20, 2-methylimidazole (2-mim), and triethylamine (TEA), were purchased from Sigma Aldrich (Germany).
  • FBS fetal bovine serum
  • PBS phosphate- buffered saline
  • the morphology of DOX@ZIF-8 was observed by SEM (JEOL JSM-7401F) at an accelerating voltage of 2.0 kV.
  • the HRTEM images were taken on a JEOL JEM-2100LaB6 microscope operating at 200 kV.
  • the particle size distribution of DOX@ZIF-8 was determined by dynamic light scattering (DLS, Malvern Zetasizer Nano Series). The N2 adsorption- desorption isotherm was recorded at 77 K on a Micromeritics ASAP2020 analyzer.
  • the MTT results, fluorescence intensity and protein quantification were obtained using a BioTek SynergyTM MX multi-mode micro plate reader operated by the Gen5TM software.
  • the 570 nm wavelength was set in the UV/Vis absorbance model to determine the MTT reading, and 562 nm was set for the protein quantification.
  • the fluorescence intensity was measured at excitation/emission wavelengths of 494/516 nm.
  • the localizations of DOX and DOX@Z!F-8 were observed by confocal laser scanning microscopy (CLSM, Olympus FV1000) at an excitation/emission wavelengths of 405/461 nm for DAPI and 559/572 nm for DOX.
  • DOX@ZIF-8 crystals were collected by centrifugal separation (13000 rmp, 30 min) and washed at least three times with a mixture of ethanol and water.
  • the powder product was dried at room temperature under vacuum.
  • the loading amount of DOX was tuned by changing the concentration of the DOX stock solution.
  • a DOX-free ZIF-8 was synthesised in a similar way, using 4 ml of deionised H 2 0. See Table 1 for detailed descriptions. DOX@ZIF-8 crystals with 0, 4, 14 and 20 wt% loadings were achieved ( Figure 2a-d), per weight of MOF with encapsulated target-molecule DOX.
  • DOX molecules were coordinated with Zn 2+ ions by examining the red shift of the UV-Vis spectrum, and comparing it with that of a free DOX solution, while the solid state UV- Vis spectrum of DOX@ZIF-8 showed that there was no coordination bond between DOX and Zn 2+ ions in DOX@ZIF-8 ( Figure 3).
  • Table 1 Synthesis conditions of ZIF-8 encapsulated with different target-molecules.
  • the DOX@ZIF-8 materials prepared according Example 1 consisted of isolated crack-free crystals of diameter 70-300 nm as shown with scanning electron microscopy (SEM) ( Figure 2(a)). Powder X-ray diffraction (PXRD) showed that the DOX@ZIF-8 nanocrystals were of high crystallinity with sharp diffraction peaks ( Figure 2(b)). The DOX molecules were well dispersed, as there were no diffraction peaks from the free DOX molecules. Target-molecules were successfully loaded into the ZIF nanocrystals, as indicated by the colour of the DOX@ZIF-8 nanocrystals becoming more intense with higher DOX concentration ( Figure 2(c)).
  • TEM Transmission electron microscopy
  • Each ZIF-8 nanocrystal consisted of a core with isolated and homogeneously distributed mesopores and a mesopore-free shell as shown by electron tomography ( Figure 5).
  • the diameter of the mesopores, in which the DOX molecules were located was 5-15 nm.
  • the mesopore-free shell was approximately 20 nm thick, which was substantially free of DOX molecules.
  • the particle size increases and the size distribution broadened (from 100 ⁇ 30 nm to 230 ⁇ 150 nm, respectively) with increased loading of DOX, as shown by dynamic light scattering (DLS, Figure 6, 0% DOX (a), 4% DOX (b), 14% DOX (c), and 20% DOX (d)).
  • the target- molecules@ZIF-8 nanocrystals were dissolved in a nitric acid solution, and the concentration of the target-molecules was determined by UV-Vis spectrophotometry (Perkin Elmer Lambda 19 UV-Vis-NIR spectrometer).
  • the loading amount was determined from the UV-Vis absorbance at 479 nm for DOX, 554 nm for rhodamine B, 460 nm for methyl orange and 665 nm for methylene blue.
  • the loadings of rhodamine B, methyl orange and methylene blue were 15, 14 and 17%, respectively (Table 1, Figures 7 and 8).
  • the cobalt nitrate aqueous solution was then added to the 2-methylimidazole solution, and the mixture immediately became a milky suspension.
  • the precipitate was collected by centrifugation (13000 rmp, 30 min) and washed at least three times with a mixture of ethanol and H 2 0.
  • the powder product was dried at room temperature under vacuum.
  • PVP polyvinylpyrrolidone
  • the product was collected by centrifugation, washed three times with water and dispersed in 10 ml of water. Typically, a solution of 0.2 g of (0.66 mmol) ⁇ ( ⁇ 0 3 ) 2 ⁇ 6 ⁇ 2 0, 4 ml of (10 mg/ml) DOX/rhodamine B solution and 1 ml stock solution of Pd nanoparticles was prepared. The pH was adjusted to 8 using a NaOH solution. After a short time of stirring (1 min), a 10 g solution containing 2 g (24.36 mmol) 2-mim and 8 g deionized H 2 0 was added dropwise. The reaction mixture was stirred for 15 minutes.
  • the precipitate was collected by centrifugal separation and washed at least three times with a mixture of ethanol and H 2 0.
  • the powder product was dried at room temperature under vacuum.
  • the samples in which DOX and rhodamine B are the target-molecules are denoted as (Pd&DOX)@ZIF-8 and (Pd&rhodamine B)@ZIF- 8, respectively. Both mesopores and Pd nanoparticles were observed in the same ZIF nanoparticle ( Figure 10).
  • the fluorescence lifetime of the rhodamine B after encapsulation was measured using a Varian Cary Eclipse Fluorescence spectrophotometer at room temperature with an excitation wavelength of 500 nm and observing the fluorescence emission at 750, 620, 620, 600 nm.
  • the lifetime ( ⁇ ) of a fluorophore represents an average value of time spent at the excited state.
  • the lifetime of the Rhodamine B after encapsulation increased 2-27 folds compared to free Rhodamine B.
  • DOX@ZI F-8 as a drug delivery system for ca ncer therapy was studied.
  • DOX@ZI F-8 nanoparticles were tested in a stepped release experiment. 10 mg of DOX@ZI F-8 was added into 20.0 ml of 7.4 buffer solutions with 10% (v/v) FBS and kept at 37 °C for 7 days. The pH of the solution was then adjusted to 6.5 with dilute HCI (0.6 M) and kept for another 7 days. The pH was again adjusted stepwise over 3 days to 6.0, 5.5 and 5.0 by adding dilute HCI (0.6 M). The adding time of acid is indicated by a rrows in Figure 12(b). The amount of loading was determined from the UV-Vis absorbance at 479 nm for DOX.
  • the cytotoxicities of DOX@ZI F-8, free DOX, pure ZI F-8, and a mixture of free DOX and ZI F-8 were evaluated by determining the cellular viability using an MTT ((3-(4,5,- dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay, which measures the mitochondrial function of the cells. The comparison was made with the same concentrations of DOX and ZI F-8.
  • DOX@ZI F-8 contains 0.8 ⁇ g of ZI F-8 and 0.2 ⁇ g of DOX, and is compared with 0.8 ⁇ g/ml ZI F-8, 0.2 ⁇ g/ml DOX, and a solution containing 0.8 ⁇ g/ml ZI F-8 and 0.2 ⁇ g/ml DOX.
  • ZnO 100 ⁇ g/ml was used as a positive control for cell death in the primary macrophage experiments.
  • Human Cell lines Human breast cancer cell lines, MCF-7, MDA-MB-231, and MDA-MB- 468 were purchased from the American Type Culture Collection (ATCC) and cultured in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% (v/v) fetal bovine serum (FBS), 100 U m l penicillin and 100 mg/ml streptomycin at 37 °C with 5% C0 2 in the atmosphere. The medium was changed twice a week. The cells were harvested with trypsin.
  • DMEM Dulbecco's Modified Eagle Medium
  • FBS fetal bovine serum
  • Apoptosis/Necrosis analysis Apoptosis/Necrosis analysis. Apoptosis/necrosis of the cells was analysed by fluorescence activated cell sorting (FACS) with fluorescein isothiocyanate (FITC) Annexin V/Dead cell apoptosis kit staining.
  • FACS fluorescence activated cell sorting
  • FITC fluorescein isothiocyanate
  • the macrophages and breast cancer cells were seeded onto 96 well plates at a concentration of lxlO 6 cells/well a nd treated with PBS (control), 0.5 ⁇ g/ml DOX@ZIF-8, 0.4 ⁇ g/ml ZIF, 0.1 ⁇ g/ml DOX or a mixture of 0.4 ⁇ g/ml ZI F and 0.1 ⁇ g/ml DOX respectively for the desired time period (12 and 24 h for the macrophages, 24 and 48 h for the cell lines). Both the medium and the ha rvested cells were collected by centrifugation at 2000 rpm for 5 min and washed twice.
  • the cells were suspended in a 100 ⁇ lx annexin-binding buffer and stained with 5 ⁇ of FITC-labeled Annexin V and 1 ⁇ of 100 ⁇ g/ml propidium iodide (PI) at room temperature for 15 min. Then 400 ⁇ of lx annexin-binding buffer was added, and the cells were analysed using a BD LSRFortessa flow cytometer with FITC and PETexas Red channel (detect PI). The data was analysed with the FCS Express 4 software.
  • the cells were fixed in 2.5% glutaraldehyde in a 0.1 M phosphate buffer (pH 7.4) at room temperature and transferred to an Eppendorf tube to be further fixed overnight in a refrigerator. After the fixation, the cells were rinsed with a 0.1 M phosphate buffer and centrifuged. The cell pellets were postfixed in 2% osmium tetroxide in a 0.1 M phosphate buffer (pH 7.4) at 4 °C for 2 h, dehydrated in ethanol followed by acetone and embedded in LX-112 (Ladd, Burlington, Vermont, USA).
  • Ultrathin sections (of thickness 50-60 nm) were cut by a Leica Ultracut UCT (Leica, Wien, Austria). Sections were contrasted with uranyl acetate followed by lead citrate and examined in a Tecnai 12 Spirit Bio TWIN transmission electron microscope (FEI Company, Eindhoven, Netherlands) at 100 kV. Digital images were recorded by using a Veleta camera (Olympus Soft Imaging Solutions, GmbH Munster, Germany).
  • the cells were then washed twice and lysed in 280 ⁇ of cell lysis buffer for 30 min.
  • Cell lysates from each well were transferred into 96 well black plates to measure the fluorescence intensity (100 ⁇ of cell lysates) and quantify the protein concentration with a bicinchoninic acid (BCA) protein assay (25 ⁇ cell lysates) respectively.
  • the fluorescence intensity was determined at excitation/emission wavelengths of 494/516 nm, and the protein concentration was measured by the absorbance at 562 nm.
  • the relative cellular Zn 2+ fluorescence intensity was calculated as:
  • Relative Zn 2+ level Sample's (Fluorescence Intensity/ Protein Mass)] xlOO/ Control's (Fluorescence Intensit / Protein Mass) (1) Statistical analysis. The MTT assays, relative cellular Zn 2+ level and apoptosis/necrosis analysis are presented as mean values with standard deviations (s.d.). Statistical data analysis was performed by ANOVA, followed by a post hoc test (Tukey HSD, alpha 0.05) using KaleidaGraph v4.1. The significance level was set to be ***p ⁇ 0.001.
  • ZI F-8 nanocrystals The effect of ZI F-8 nanocrystals on mitochondrial function of breast cancer cell lines MCF-7, MDA-MB-231, and MDA-MB-468 was tested.

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Abstract

La présente invention concerne une structure organométallique avec des molécules cibles encapsulées, un procédé de préparation de celle-ci, ainsi que celle obtenue par le procédé, et son utilisation.
PCT/SE2016/051092 2015-11-05 2016-11-07 Synthèse monotope de structures organométalliques avec des molécules cibles encapsulées et leur utilisation Ceased WO2017078609A1 (fr)

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