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WO2024133949A1 - Polymersomes comprenant des copolymères séquencés peg-b-pcl - Google Patents

Polymersomes comprenant des copolymères séquencés peg-b-pcl Download PDF

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Publication number
WO2024133949A1
WO2024133949A1 PCT/EP2023/087760 EP2023087760W WO2024133949A1 WO 2024133949 A1 WO2024133949 A1 WO 2024133949A1 EP 2023087760 W EP2023087760 W EP 2023087760W WO 2024133949 A1 WO2024133949 A1 WO 2024133949A1
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Prior art keywords
peg
pcl
poly
mpeg
ethylene glycol
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Karolis NORINKEVICIUS
Anders Egede DAUGAARD
Torsten Høybye Bak REGUEIRA
Peter Jeppe MADSEN
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Aquaporin AS
Danmarks Tekniske Universitet
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Aquaporin AS
Danmarks Tekniske Universitet
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    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/66—Polyesters containing oxygen in the form of ether groups
    • C08G63/664—Polyesters containing oxygen in the form of ether groups derived from hydroxy carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
    • B01D69/12—Composite membranes; Ultra-thin membranes
    • B01D69/125—In situ manufacturing by polymerisation, polycondensation, cross-linking or chemical reaction
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
    • B01D69/14—Dynamic membranes
    • B01D69/141—Heterogeneous membranes, e.g. containing dispersed material; Mixed matrix membranes
    • B01D69/142—Heterogeneous membranes, e.g. containing dispersed material; Mixed matrix membranes with "carriers"
    • B01D69/144—Heterogeneous membranes, e.g. containing dispersed material; Mixed matrix membranes with "carriers" containing embedded or bound biomolecules
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
    • B01D71/06—Organic material
    • B01D71/48—Polyesters
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
    • B01D71/06—Organic material
    • B01D71/52—Polyethers
    • B01D71/521—Aliphatic polyethers
    • B01D71/5211—Polyethylene glycol or polyethyleneoxide
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D71/00—Semi-permeable membranes for separation processes or apparatus characterised by the material; Manufacturing processes specially adapted therefor
    • B01D71/06—Organic material
    • B01D71/76—Macromolecular material not specifically provided for in a single one of groups B01D71/08 - B01D71/74
    • B01D71/80—Block polymers
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/68—Polyesters containing atoms other than carbon, hydrogen and oxygen
    • C08G63/685—Polyesters containing atoms other than carbon, hydrogen and oxygen containing nitrogen
    • C08G63/6852—Polyesters containing atoms other than carbon, hydrogen and oxygen containing nitrogen derived from hydroxy carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G63/00—Macromolecular compounds obtained by reactions forming a carboxylic ester link in the main chain of the macromolecule
    • C08G63/91—Polymers modified by chemical after-treatment
    • C08G63/912—Polymers modified by chemical after-treatment derived from hydroxycarboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/32—Polymers modified by chemical after-treatment
    • C08G65/329—Polymers modified by chemical after-treatment with organic compounds
    • C08G65/331—Polymers modified by chemical after-treatment with organic compounds containing oxygen
    • C08G65/332—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof
    • C08G65/3324—Polymers modified by chemical after-treatment with organic compounds containing oxygen containing carboxyl groups, or halides, or esters thereof cyclic
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D2325/00—Details relating to properties of membranes
    • B01D2325/39—Amphiphilic membranes
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G2650/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G2650/28—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule characterised by the polymer type
    • C08G2650/58—Ethylene oxide or propylene oxide copolymers, e.g. pluronics

Definitions

  • the disclosure relates to polymersomes comprising PEG-b-PCL block copolymers, methods of making the same and semi- permeable separation membranes comprising the same.
  • Amphiphilic block copolymer materials can be used for forming a wide range of self-assemblies, such as micelles, vesicles, or rods both in organic solvents and in aqueous media. Applications range from encapsulation of drugs or vitamins for stabilization and/or delivery to serving as templates for nanometer scale patterning.
  • Systems based on poly (ethylene glycol ) -block-poly ( caprolactone ) copolymers (PEG-b-PCL) may be useful due to their ability to form polymersome structures.
  • PEG-b-PCL poly (ethylene glycol) -block-poly ( caprolactone ) copolymers
  • a ring-opening polymerization reaction of s- caprolactone is utilized, where the growth of the monomer chain is promoted by a poly (ethylene glycol) methyl ether macroinitiator.
  • stannous octoate Sn(0ct) 2
  • calcium, or aluminum complexes may be used in this ring-opening polymerization method.
  • Alternative synthesis routes using biocatalysts, e.g. , enzymes such as Candida antarctica lipase B are also possible, Huang et al. , 2015. Shuai et al. 2004 explores the synthesis of diblock copolymers of poly ( s-caprolactone ) (PCL) and monomethoxy poly ( ethylene glycol) (mPEG) with various compositions.
  • PCL poly ( s-caprolactone )
  • mPEG monomethoxy poly ( ethylene glycol)
  • thermo- sensitive PEG- PCL-PEG behaviour in a three-component biomimetic hydrogel composite for drug delivery (Fu et al. , 2012) and preventing postoperative adhesion (Yang et al. , 2012)
  • thermo-sensitive PEG-PCL-PEG behaviour in a three-component biomimetic hydrogel composite for drug delivery (Fu et al. , 2012) and preventing postoperative adhesion (Yang et al. , 2012)
  • development of a reactive oxygen species-sensitive degradable PEG-PCL-PEG micellar thermogel (Jung et al. , 2019) .
  • amphiphilic lipids and block copolymers for forming self-assembled vesicles having bilayer or bilayer-like structures is well known in the art, in particular for immobilising amphiphilic membrane proteins, such as aquaporin water channels (AQPs) .
  • AQPs aquaporin water channels
  • Vesicles comprising AQPs can then be used to make membranes having reconstituted AQPs for applications such as the purification of water ( WO2006/ 122566 ) or the generation of salinity power (WQ2007/033675 ) , in general by depositing the vesicles as a layer or in a film on a supporting substrate, which allows the selective passage of water molecules through the membranes by nanofiltration, reverse osmosis, forward osmosis or pressure retarded osmosis.
  • WQ2013/043118 discloses thin film composite (TEC) membranes in which aquaporin water channels (AQPs) are incorporated in the active layer of the membrane. In addition, it discloses a method of producing thin film composite membranes and their uses in filtration processes, such as nanofiltration and osmotic filtration processes.
  • the TFC membranes comprise lipid-AQP/copolymer-AQP vesicles that are incorporated in the TFC active layer.
  • W02010/146365 describes preparation of TFC-aquaporin-Z (AqpZ) filtration membranes that use an amphiphile triblock copolymer as a vesicle forming substance for incorporating immobilised AQPs .
  • WO2014 / 108827 discloses a hollow fiber (HF) module having fibers modified with a thin film composite (TFC) layer comprising aquaporin water channels in which the aquaporin water channels are incorporated in vesicles before incorporation into the TFC layer .
  • HF hollow fiber
  • TFC thin film composite
  • a method for making a liquid composition comprising self-assembled polymer somes , wherein said polymersomes comprise an amphiphilic triblock copolymer of the poly (ethylene glycol) - b-poly ( caprolactone ) -b- poly (ethylene glycol) ( PEG-b-PCL-b- PEG) type, which is defined by PEG a -b-PCLb-b-PEG c where a, b and c each represent the number of repeating block monomers and b is greater than 15, and where a fraction f is set to be comprised between 15% - 45%, where f is the fraction of the total hydrophilic Mn fraction in relation to the total Mn of the resulting triblock copolymer chain.
  • the amphiphilic triblock copolymer obtained in the method is defined by PEG a -b-PCLb-b-PEG c where a, b and c each represent the number of repeating block monomers and b is greater than 15, such as equal to 18 or greater, such as equal to 19 or greater, PEG a and PEG C being polymers exhibiting predominantly hydrophilic behaviour and PCLb being a polymer exhibiting predominantly hydrophobic behavior and fraction f is comprised between 15 % and 45%, wherein f is calculated as the fraction of predominantly hydrophillic polymer Mn over total polymer Mn.
  • b is strictly greater than 18.
  • the efficiency of vesicle formation may be advantageously increased, in particular when fraction f is comprised between 0.2 and 0.4, such as between 0.26 and 0.32.
  • the hydrophilic Mn fraction in relation to the total Mn of the polymer chain maintained between these ranges may advantageously allow to obtain an optimal efficiency of vesicle formation across an array of triblock copolymer lengths .
  • said PEG-b-PCL copolymers are synthesized by the ring-opening polymerization of s-caprolactone where poly (ethylene glycol) (PEG) is used as an initiator.
  • PEG poly (ethylene glycol)
  • a coupling agent is added to the reaction and the reaction is continued for obtaining PEG-b-PCL-b-PEG triblock copolymers.
  • the Mn of, e.g. , PEG or mPEG when the Mn of, e.g. , PEG or mPEG is below 1500 gutiob 1 at least 90% of s-caprolactone conversion is achieved within 9 hours. In a further possible implementation form of the first aspect when the Mn of, e.g. , PEG or mPEG is between 1500 gutiob 1 and 2500 gutiob 1 at least 90% of s-caprolactone conversion is achieved within 17 hours.
  • the PEG-b-PCL copolymers advantageously comprise copolymers of the methoxy poly ( ethylene glycol ) -b-poly ( caprolactone ) (mPEG- b-PCL) type by methoxy poly ( ethylene glycol) (mPEG) being used as initiator for the ring-opening polymerization of s- caprolactone .
  • the PEG-b-PCL block copolymers advantageously comprise vinyl-PEG- b-PCL or vinyl -mPEG-b-PCL block copolymers by vinyl-PEG or vinyl-mPEG, or a allyloxy (polyethylene glycol) of the form being used as initiator for the ring-opening polymerization of s-caprolactone .
  • poly ( ethylene glycol) molecules having the same -OH functionality but different termination may be used, such as: Poly ( ethylene glycol) monomethacrylate of the form: poly (ethylene glycol) (alpha-azide, omega-hydroxy) - terminated, which can be utilized for azide-alkyne cyclo- addition reactions) : or other poly ( ethylene glycol) s, which are amine, or carboxylic acid terminated.
  • the reaction is carried out at between approximately 60°C and 110°C.
  • the reaction is carried out at between 80°C and 90°C.
  • low polydispersity block copolymers with very well-defined chain lengths may be advantageously obtained.
  • Narrow polydispersity materials may produce a significantly higher amount of vesicles/polymersomes compared to high polydispersity materials.
  • another positive effect of low PDI materials is thinner and more homogeneous vesicle bilayer thickness.
  • cryogenic transmission electron microscopy (Cryo-TEM) .
  • a method for vesicle formation with a greater efficiency via obtaining a greater ratio of vesicle to non-desireable structures, such as worm structures and rods is provided.
  • a coupling agent may be added to the reaction.
  • PEG-b-PCL- b-PEG triblock copolymers may be advantageously obtained.
  • the coupling agent may advantageously generate a PEG-b-PCL-b-PEG triblock copolymer by being covalently linked to a PEG-b-PCL diblock copolymer on each end.
  • the coupling agent may be diisocyanate, dicarboxylic acids, divinyl adipate, and/or divinyladipate or any combination thereof.
  • the coupling agent is divinyladipate and an enzyme, such as NZ435 is used for catalizing the coupling.
  • the enzyme NZ435 is particularly well suited for catalizing the coupling.
  • amounts of PEG and/or PCL components for preparation of the PEG-PCL-PEG triblocks are adjusted such that the Mn of the hydrophilic fraction in the triblock copolymer chains is between 15% and 45% of the total Mn of the triblock copolymer chains, such as between 20% and 40% of the total Mnof the triblock copolymer chains.
  • the ratio between the hydrophilic part of the PEG and the hydrophobic part of PCL may be advantageously controlled.
  • the morphology of selfassembled nanostructures correlates to the packing parameter and thus by the Mn ratio of hydrophilic to hydrophobic blocks.
  • a fraction f is set to be comprised between 26% - 32%, where f is the fraction of the total hydrophilic Mn fraction in relation to the total Mn of the resulting triblock copolymer chain .
  • fraction f is set to be comprised between 15% - 45%, such as between 20% - 40%, such as between 26% - 32%, such as 26.3 where the triblock copolymer is defined by PEGi2-b-PCL26-b- PEG12, 27.8, where the triblock copolymer is defined by PEG15- b-PCLao-b-PEGis , 31.3, where the triblock copolymer is defined by PEG23-b-PCL39-b-PEG23. Maintaining the percent hydrophilic fraction in relation to the total Mn of the polymer chain may advantageously allow to obtain an optimal efficiency of vesicle formation across a range of triblock copolymer lengths .
  • a solubilized transmembrane protein is added to the liquid composition.
  • Copolymers may interact via the end functional groups with the amino acid residues of the transmembrane protein.
  • amino acid negative charge may be established under certain conditions (pH, pKs etc. ) used to produce the liquid composition and/or the membranes comprising the polymersomes .
  • the method further comprises steps for producing a thin film composite (TFC) separation membrane, the method comprising the step of applying the liquid composition to a porous support membrane.
  • TFC thin film composite
  • the method comprises producing the TFC membrane by interfacial polymerisation .
  • a polymersome comprising an amphiphilic triblock copolymer of the poly (ethylene glycol ) -b-poly ( caprolactone ) -b- poly ( ethylene glycol) (PEG-b-PCL-b-PEG) type.
  • the amphiphilic triblock copolymer is defined by PEG a -b-PCLb-b- PEG C where a, b and c each represent the number of repeating block monomers and b is greater than 15, such as equal to 18 or greater, such as equal to 19 or greater, PEG a and PEG C are polymers exhibiting predominantly hydrophilic behaviour and PCLb is a polymer exhibiting predominantly hydrophobic behavior and fraction f is comprised between 15 % and 45%, wherein f is calculated as the fraction of predominantly hydrophillic polymer Mn over total polymer Mn.
  • b is strictly greater than 18.
  • the efficiency of vesicle formation may be advantageously increased, in particular when fraction f is comprised between 0.2 and 0.4, such as between 0.26 and 0.32.
  • the hydrophilic Mn fraction in relation to the total Mn of the polymer chain maintained between these ranges may advantageously allow to obtain an optimal efficiency of vesicle formation across an array of triblock copolymer lengths.
  • the triblock copolymer is defined by PEGi2-b-PCL26-b-PEGi2, or 27.8, where the triblock copolymer is defined by PEGis-b-PCLso-b-PEGis, or 31.3, where the triblock copolymer is defined by PEG23-b-PCL39-b-PEG23.
  • PEG a and/or PEG C further comprise a vinyl group.
  • the polymersome further comprises a transmembrane protein in the membrane of the self assembled polymersome.
  • a separation membrane comprising the polymersome according to the present disclosure .
  • Fig. 1 represents the synthesis of mPEG-PCL diblock copolymers by using Novozym 435® (CALB) as a catalyst.
  • CALB Novozym 435®
  • Fig. 2 represents the synthesis of mPEG-PCL-mPEG triblock copolymers by using tin (II) 2-ethylhexanoate Sn(Oct) 2 as a catalyst .
  • Fig. 3a and 3b are a collection of size exclusion chromatograms of different mPEG-PCL-mPEG triblock variants.
  • Fig. 4 is a plot of s-caprolactone conversion over time for tin (II) and enzyme catalyzed fractions as part of time- resolved 13 C-NMR measurements.
  • Fig. 5 illustrates a method of mPEG-b-PCL diblock/ triblock polymersome preparation.
  • Fig. 6 shows Cryo-TEM images of mPEG-PCL diblock and triblock vesicle solutions.
  • Fig. 7 shows Cryo-TEM images of mPEG-PCL diblock and triblock vesicles representing differences in bilayer thicknesses.
  • Fig. 8 shows size distribution of the different vesicular mixtures .
  • the invention relates to a method for making a liquid composition comprising self-assembled polymer somes , wherein said polymersomes comprise amphiphilic block copolymers of the poly (ethylene glycol) -b- poly ( caprolactone ) (PEG-b-PCL) type.
  • a synthesis method typically comprises the step of synthesizing said PEG-b-PCL copolymers by a tin (II) 2-ethylhexanoate Sn(Oct) 2 catalysed reaction and a poly (ethylene glycol) (PEG) is used as an initiator for the ring-opening polymerization of s- caprolactone . Said reaction is carried out as described in Example 1 herein below.
  • the invention further relates to vesicles and a method for obtaining said vesicles as disclosed herein, which vesicles comprise an amphiphilic triblock copolymer of the PEG a -b-PCLb- PEGc type as vesicle membrane forming material and further optionally comprising a transmembrane protein.
  • PEG blocks forming the copolymer may in some instances be end-functionalized.
  • end-functionalized PEG are, e.g. bis (amino alkyl) or bis (hydroxyalkyl ) terminated PEG a or PEG C , where a and c represent any positive natural number value from 5 to 50, such as 9, 12, 15 or 23.
  • transmembrane proteins examples include aquaporin water channels, i.e. , aquaporins and aquaglyceroporins , such as those listed in the definitions below.
  • the invention relates to a method of making the liquid composition as disclosed, in which a solution of an amphiphilic triblock copolymer of the PEG a -b-PCLb-PEG c type as vesicle membrane forming material is mixed with a transmembrane protein.
  • the liquid composition may be applied to a support membrane or an active layer of a separation membrane.
  • the active layer may be a thin film composite (TEC) layer formed on the support membrane.
  • TEC membrane may be formed using alternative reaction components, e.g. , as described by Zhou et al. in Journal of Membrane Science, Volume 471, 1 December 2014, Pages 381-391 "Thin-film composite membranes formed by interfacial polymerization with natural material sericin and trimesoyl chloride for nanofiltration".
  • a highly selective active layer may also be formed on the substrate by the layer-by-layer method (see Wang et al. , Membranes, 5 (3) : 369-384, 2015) .
  • the filtration membrane according to the invention may be prepared by adding a liquid composition comprising said diblock and/or triblock copolymer vesicles, e.g. , also comprising aquaporin water channel proteins as the transmembrane protein, during the membrane fabrication process, such as adding the liquid composition to an aqueous MPD solution when forming a TFC layer.
  • a liquid composition comprising said diblock and/or triblock copolymer vesicles, e.g. , also comprising aquaporin water channel proteins as the transmembrane protein
  • Producing a thin film composite (TFC) separation membrane comprising the polymersomes according to this disclosure may be achieved by applying the liquid composition to a porous support membrane.
  • a thin film composite (TFC) layer which comprises aquaporin water channels
  • said method comprises the steps of: a) obtaining an aquaporin vesicles suspension, wherein said vesicles are polymersomes comprising amphiphilic triblock copolymers according to any one of the possible implementation forms of the present disclosure, such as disclosed in Examples 1 or 2 herein below, b) preparing an aqueous solution of a di- or triamine, c) dissolving a di- or triacyl halide in an apolar organic solvent , d) preparing a mixture of amine and aquaporin vesicle by dissolving/mixing the vesicles preparation from step a) with the solution from step b) , e) applying the mixture from step d) onto a porous support membrane
  • Coupled agent is a molecule that reacts with the OH- group of two PEG a -b-PCLb diblock copolymers to produce a triblock copolymer of the type PEG a - b-PCLb-PEGc.
  • Families of coupling agents include, but are not limited to diisocyanates, dicarboxylic acids, acyl halides, sulfinyl halides and anhydrides. In specific enabling embodiments disclosed herein, the following components are used: Hexamethylene diisocyanate and divinyl adipate, in the case of enzyme/lipase catalyzed coupling of diblocks mediated by Novozym 435.
  • transmembrane protein is a type of membrane protein spanning the entire thickness of the biological membrane to which it is permanently attached in nature. That is, in nature, transmembrane proteins span from one side of a membrane through to the other side of the membrane.
  • Non-exhaus five examples of transmembrane proteins are ammonia transporters, urea transporters, chloride channels, and aquaporin water channels.
  • aquaporin water channel includes a functional natural or synthetic aquaporin or aquaglyceroporin water channel, such as aquaporin Z (AqpZ) , GIPf, SoPIP2;l, aquaporin 1 and/or aquaporin 2.
  • Aquaporin water channels include bacterial aquaporins and eukaryotic aquaporins, such as yeast aquaporins, plant aquaporins and mammalian aquaporins, as well as related channel proteins, such as aquaglyceroporins .
  • aquaporins and aquaglyceroporins include: Prokaryotic aquaporins such as AqpZ; mammalian aquaporins, such as Aqpl and Aqp2 ; plant aquaporins, such as plasma intrinsic proteins (PIP) , tonoplast intrinsic proteins (TIP) , nodulin intrinsic proteins (NIP) and small intrinsic proteins (SIP) , e.g. SoPIP2;l, PttPIP2;5 and PtPIP2;2; yeast aquaporins, such as AQY1 and AQY2; and aquaglyceroporins, such as GlpF and Yfl054.
  • Prokaryotic aquaporins such as AqpZ
  • mammalian aquaporins such as Aqpl and Aqp2
  • plant aquaporins such as plasma intrinsic proteins (PIP) , tonoplast intrinsic proteins (TIP) , nodulin intrinsic proteins (NI
  • Aquaporin water channel proteins may be prepared according to the methods as set out in Karlsson et al. (FEES Letters 537: 68-72, 2003) or as described in Jensen et al. US 2012/0080377 ( see Example 6 ) .
  • the transmembrane protein may be an anion channel protein, such as a voltage-dependent anion channel, which is useful in preparation of ion exchange membranes for reverse electrodialysis, cf. Dlugolecki et al. (Journal of Membrane Science, 319 214-222, 2008) .
  • separation membrane includes membranes useful for separating water and, optionally, certain small size solutes including anions and cations, from other solutes, particles, colloids and macromolecules.
  • separation membranes are "filtration membranes” such as nanofiltration (NF) membranes, forward osmosis (FO) membranes and reverse osmosis (RO) membranes.
  • NF nanofiltration
  • FO forward osmosis
  • RO reverse osmosis
  • TFC membrane thin film composite
  • TFC membranes are typically made by depositing a polyamide layer on top of a polyethersulfone or polysulfone porous layer on top of a non-woven or woven fabric support.
  • the polyamide rejection layer is formed through interfacial polymerization of an aqueous solution of an amine with a solution of an acid chloride in an organic solvent.
  • TFC membranes may be produced as described in WO 2013/043118 (Nanyang Technological University & Aquaporin A/ S ) .
  • Other types of filtration membranes are those formed by the layer- by-layer (LbL) deposition method, such as described in Gribova et al. (Chem. Mater. , 24: 854-869, 2012) and Wang et al. (Membranes, 5 (3) : 369-384, 2015) .
  • the selfassembled polymersome may be embedded or incorporated in the polyelectrolyte multilayer (PEM) films, as outlined in Figure 4 of Gribova et al.
  • PEM polyelectrolyte multilayer
  • Thin-film-composite or (TFC) membranes as used herein may be prepared using an amine reactant, preferably an aromatic amine, such as a diamine or triamine, e.g. , 1 , 3-diaminobenzene (m-Phenylenediamine , > 99%, e.g. , as purchased from Sigma- Aldrich) in an aqueous solution, and an acyl halide reactant, such as a di- or triacid chloride, preferably an aromatic acyl halide, e.g. , benzene- 1,3, 5 -tricarbonyl chloride (CAS No.
  • an aromatic amine such as a diamine or triamine, e.g. , 1
  • 3-diaminobenzene m-Phenylenediamine , > 99%, e.g. , as purchased from Sigma- Aldrich
  • an acyl halide reactant such as a di- or triacid
  • trimesoyl chloride (TMC) , 98%, e.g. as purchased from Sigma-Aldrich) dissolved in an organic solvent where said reactants combine in an interfacial condensation polymerization reaction, cf. Khorshidi et al. (2016) Y1
  • IsoparTM G Fluid which is produced from petroleum-based raw materials treated with hydrogen in the presence of a catalyst to produce a low odour fluid the major components of which include isoalkanes.
  • IsoparTM G Fluid Chemical Name: Hydrocarbons, C10-C12, isoalkanes, ⁇ 2% aromatics; CAS No: 64742-48-9, chemical name: Naphtha (petroleum) , hydrotreated heavy (from ExxonMobil Chemical) .
  • Alternatives to the reactant 1 , 3-diaminobenzene include diamines such as hexamethylenediamine etc.
  • alternatives to the reactant benzene-1 , 3 , 5-tricarbonyl chloride include a diacyl chloride, adipoyl chloride, cyanuric acid etc. as known in the art.
  • diblock copolymer as used herein means a polymer consisting of two types of monomers, A and B. The monomers are arranged such that there is a chain of each monomer, and those two chains are covalently bound together to form a single copolymer chain.
  • triblock copolymer as used herein means a polymer consisting of two or three types of monomers, A, B and/or C. The monomers are arranged such that there is a chain of each monomer, and those chains are covalently bound together to form a single copolymer chain, such as triblock copolymers of the form ABA or ABC.
  • M n means number average molecular weight. It means the total weight of polymer divided by the number of polymer molecules. Thus, M n is the molecular weight weighted according to number fractions.
  • M w means weight average molecular weight. The molecular weight weighted according to weight fractions. Molecular mass may be measured by gel permeation chromatography (GPC) in tetrahydrofuran. Polydispersity index defined as Mn/Mw will be determined from the elution curves obtained in GPC.
  • the vesicles of the present invention have a particle size of between about 10 nm diameter up to 200 nm diameter depending on the precise components of the vesicles and the conditions used for their formation. It will be clear to those skilled in the art that a particle size refers to a range of sizes and the number quoted herein refers to the average diameter, most commonly mean diameter of that range of particles.
  • the vesicle compositions of the present invention comprise vesicles having mean hydrodynamic diameters of 300 nm or less, in some cases mean diameters that are less than 400 nm such as less than 50 nm.
  • Polydispersity as used herein refers to variations in chain length of the block copolymer material.
  • the vesicles of the present invention have a membrane thickness of between about 6 nm diameter up to 18 nm diameter depending on the precise components of the vesicles and the conditions used for their formation. It will be clear to those skilled in the art that membrane thickness refers to a range of thicknesses and the number quoted herein refers to the average diameter when referring to a solution of vesicles, most commonly mean thickness .
  • Examples of molar ratios of transmembrane protein to block copolymer is dependent on the transmembrane protein used, the types of copolymers used, and the desired size of the vesicle.
  • the molar ratio of transmembrane protein to block copolymer may be between 1:200 to 1:2000, such as 1:400 to 1 :1500, such as 1: 600 to 1:1000.
  • self-assembled refers to the process by which vesicles are formed through hydrophilic and hydrophobic interaction of amphiphilic substances, such as the diblock copolymers described herein having a relatively hydrophilic PEG moiety and a relatively hydrophobic PCL moiety.
  • Hydrodynamic diameter represents the hydrodynamic size of nanoparticles in aqueous media measured by dynamic light scattering (DLS) defined as the size of a hypothetical hard sphere that diffuses in the same fashion as that of the particle being measured.
  • DLS dynamic light scattering
  • Forward osmosis is an osmotic process that uses a selectively permeable membrane to effect separation of water from dissolved solutes.
  • the driving force for this separation is an osmotic pressure gradient between a solution of high concentration, herein referred to as the draw and a solution of lower concentration, referred to as the feed.
  • the osmotic pressure gradient induces a net flow of water through the membrane into the draw, thus effectively concentrating the feed.
  • the draw solution can consist of a single or multiple simple salts or can be a substance specifically tailored for forward osmosis applications.
  • the feed solution can be a dilute product stream, such as a beverage, a waste stream or seawater, cf. IFOA, http : // forwardosmosis .biz/ educat ion/what-is-forward-osmosis/
  • PAFO pressure assisted forward osmosis process
  • PRO pressure retarded osmosis which is useful in the generation of osmotic power.
  • Membranes of the present invention are useful in all types of forward osmosis processes and may be specifically adapted for each FO type.
  • RO reverse osmosis
  • Reverse osmosis refers to when an applied feed water pressure on a selectively permeable membrane is used to overcome osmotic pressure. Reverse osmosis typically removes many types of dissolved and suspended substances from feed water, including bacteria, and is used in both industrial processes and in the production of potable water. During the RO process, the solute is retained on the pressurized side of the membrane and the pure solvent, the permeate, passes to the other side. Selectivity specifies that the membrane does not allow larger molecules or ions through its pores (holes) , while allowing smaller components of the solution (such as solvent molecules) to pass freely.
  • LPRO membranes typically operate at a feed water pressure of from about ⁇ 5 bar and up to a maximum operating pressure of about 25 bar 15 specific flux LMH/bar. LPRO performed at the lower feed pressure ranges, e.g. , 2 to 5 bar is sometimes designated ultra-low pressure reverse osmosis. LPRO membranes known in the art have typical operating limits for feed water temperature of about 45 °C, feed water pH in the range of 2 to 11, and chemical cleaning in the range of pH 1 to 12.
  • ring opening polymerization (ROP) reaction was done in toluene or neat (without any solvent) conditions at 60 °C, thereby reproducing the method disclosed in the prior art.
  • Novozym 435® lipase immobilized on polymer resin particles
  • Prepolymer of poly ethylene glycol
  • PEG-b-PCL copolymers are synthesized said by a tin (II) 2-ethylhexanoate Sn(Oct) 2 catalyzed reaction and wherein poly ( ethylene glycol) (PEG) is used as an initiator for the ring-opening polymerization of s-caprolactone .
  • tin (II) 2-ethylhexanoate Sn(Oct) 2 catalyzed reaction and wherein poly ( ethylene glycol) (PEG) is used as an initiator for the ring-opening polymerization of s-caprolactone .
  • PEG poly ( ethylene glycol)
  • PEGa-b-PCLb-b-PEGc variants obtained include but were not limited to PEGg-b-PCLig-b-PEGg, PEGi 2 -b-PCL 23 -b-PEGi 2 , PEGis-b- PCL 27 -b-PEGi5, and PEG 2O -b-PCL 4 o-b-PEG 2 o .
  • Diblock PEG a -b-PCL b variants included PEG 2 o-b-PCLb 2 o, PEG43-b-PCL3 2 , and PEG 4 3-b- PCL47.
  • a collection of size exclusion chromatograms of different mPEG-PCL-mPEG triblock variants is disclosed in Fig. 3.
  • a kinetic 13 C NMR study of the mPEG-PCL diblock synthesis by using Novozym 435® and Sn(Oct) 2 as catalysts was caried out as described in Example 1.3 herein below,
  • Vesicle formation of the different variants of the mPEG-PCL diblock and triblock copolymers is represented in Fig. 5 and the process is detailed in Example 1.4 herein below.
  • Fig. 6 Resulting Cryo-TEM images of mPEG-PCL diblock and triblock vesicle solutions are shown in Fig. 6.
  • PEGi 2 -b-PCL 23 -b-PEGi 2 , PEGi5-b-PCL 27 -b-PEGi5, and PEG 20 - b-PCL4o-b-PEG 2 o yield good amounts of vesicles but PEGg-b-PCLig- b-PEGg does not, thereby setting a lower threshold for copolymer length.
  • Methoxypoly ( ethylene glycol) (mPEG) prepolymer (1H NMR 1810 g mol-1, 0.994 mmol, 1.80 g) was first dissolved in dry toluene (30 mL) and the solvent removed by rotary evaporation, followed by 35 °C in vacuo overnight. The dry mPEG was then added to a 100 mL Schlenk flask. The flask was backfilled with N2 three times. Then, caprolactone (s-CL, distilled, 36.8 mmol, 4.1 mL) was injected to the flask, followed by dilution with dry toluene (10 mL) . The mixture was stirred and heated up to 60 °C.
  • HMDI hexamethylene diisocyanate
  • Proton nuclear magnetic resonance H-NMR was used to confirm the structure of the methoxy poly(ethyleneglycol) - block-poly ( s -caprolactone ) (mPEG-PCL) diblock and triblock copolymers.
  • the spectrum was recorded on a 300 MHz NMR Spectrometer (Bruker, MA, USA) , using deuterated chloroform (CDCI3) as the solvent at 25 °C, which was used to reference the spectrum.
  • Size-exclusion chromatography was performed on a chromatographic system, which consists of a Viscotek VE 2001 Gel permeation chromatography (GPC) solvent / sample module connected to a Viscotek TriSEC Model 302 Triple Detector Array (refractive index, light scattering, viscometer) , see Fig. 3.
  • the column set consisted of a PL Guard and two PL gel mixed D columns (Polymer Laboratories, UK) connected in series. Tetrahydrofuran (THE) (Merck, Germany) was used as a mobile phase.
  • TEE Tetrahydrofuran
  • the samples were measured at a flow rate of 1 mL -min -1 . Molar masses were determined using a calibration based on narrow polystyrene (PS) standards (PSS, Mainz, Germany) . Samples were analyzed by using OmniSEC 5.10 software.
  • the kinetic study for the different synthetic routes were performed by conducting a time series of one-dimensional 13 C NMR spectra, which were acquired with a spectral width of 240 ppm. Most of the samples were prepared in toluene-d8 but also in solventless conditions. The reaction catalyzed by the enzyme was performed at 60 °C and the tin catalyzed at 90 °C for the evaluation of s-CL conversion over time. mPEG prepolymers (1000 and 2000 g -mol -1 ) were used to investigate the differences in reaction kinetics.
  • Spectra were acquired by sampling the free induction decay (FID) with 16348 complex data points during and acquisition time of 451 milliseconds. For the time series, up to 400 time points were acquired by summing 64 transients with an inter-scan relaxation delay of 4 seconds between the individual transient.
  • 1 H- 13 C Heteronuclear Single Quantum Coherence (HSQC) and 1 H- 13 C Heteronuclear Multiple Bond Correlation (HMBC) spectra were used to conduct and validate assignments in post-reaction material.
  • NMR spectra were acquired on a 600 MHz Bruker Avance III HD NMR spectrometer equipped with a BBFO Smartprobe probehead on an 800 MHz Bruker Avance III HD NMR spectrometer equipped with a cryogenically cooled probehead (TCI probe) .
  • NMR tubes were equipped with glass capillaries in order to ensure sufficient stirring and therefore homogenization of the sample during the measurement.
  • Polymersomes were prepared by direct hydration as previously reported by Gorecki et al. , 2021, and Sui et al. , 2015.
  • mPEG-PCL 100 mg was mixed with mPEG (Mn ⁇ 550 g mol- 1 , 1.0 g) in order to promote the hydration of the block copolymer.
  • the polymer mixture was heated to 60 °C and stirred at 300 rpm for 30 min. Subsequently, the temperature was lowered to 40 °C, and pre-heated PBS buffer (pH 7.4, 136 mN NaCl, 2.6 mN KC1, 10 mL) was injected in multiple steps.
  • the obtained vesicle solution was stored at room temperature prior further use.
  • Samples for the Cyogenic transmission electron microscopy were vitrified on a glow-discharged lacey formvar film enforced by silicon monoxide coating and supported by a copper mesh grid (Ted Pella Inc. , USA) .
  • the samples were vitrified in liquid ethane with the use of Vitrobot Mark IV (FEI, USA) and subsequently mounted in a Gatan cryoholder (FEI, USA) .
  • the images were acquired in cryogenic mode using a Tecnai G2 20 TWIN 200 kV TEM equipped with a FEI High- Sensitive 4k x 4k Eagle camera.
  • Figure 6 shows that the mPEG43-b-PCL37 diblock material, which was prepared by enzymatic reaction leads to lesser number of vesicles on the Cryo-TEM grid, with many small micelle-like structures visible. Contrary to that, mPEG43-b-PCL42 prepared by tin catalyzed reaction produced many vesicle species, which were ranging from 100-200 nm to 1.0-2.0 pm. The later also possess a much more homogeneous and thinner bilayer thickness.
  • mPEGg- b-PCLig-b-mPEGg is the lower limit of the chain length of such polymers, where no vesicle formation is observed.
  • mPEGg-b-PCLig-b-mPEGg is the lower limit of the chain length of such polymers, where no vesicle formation is observed.
  • rapid precipitation of the material was also observed for mPEGg-b-PCLig-b-mPEGg .
  • Some vesicle structure formation was visible for the mPEGi2-b-PCL23- b-mPEGi2 triblock; however, the coverage of the grid was rather low.
  • mPEGi5-b-PCL27-b-mPEGi5 and mPEG2Q-b-PCL4o-b-mPEG2o have formed the most vesicles with high Cryo-TEM grid coverage. Both triblock copolymers seemed to produce vesicles of very homogeneous sizes ranging from 100 to 200 nm.
  • Fig. 8 shows size distribution of the different vesicular mixtures. Graphs were generated by using ImageJ (Fiji) editing tool .
  • vinyl terminated poly ( ethylene glycol) (1.8 g, 0.94 mmol, 1921 g mol -1 , VPEG) was added after which the flask was backfilled with N2.
  • Prior-usage VPEG was dispersed in toluene and the solvent removed at reduced pressure in order to remove traces of water.
  • N2 s-caprolactone (4.6 mL, 41.36 mmol) was injected together with toluene (10 mL, dry) .
  • the reaction temperature was raised to 85 °C.
  • tin (II) 2-ethylhexanoate (0.01 mL, 0.26 wt %/0.074 mol % relative to s-caprolactone, distilled) was injected. The reaction was carried for 20 hr, afterwhich it was exposed to precipitation in cold diethyl ether and then precipitation in cold heptane. The solvent was removed in vacuo overnight, obtaining white, fine powder. Yield: 84 %, 5.49 g .
  • thiol-ene chemistry Other methods for carrying out thiol-ene chemistry include photochemical initiation, thermal initiation and electrochemical initiation among others.

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Abstract

L'invention concerne un polymersome comprenant un copolymère triséquencé amphiphile du type poly(éthylène glycol)-b-poly(caprolactone)-b-poly(éthylène glycol) (PEG-b-PCL-b-PEG).
PCT/EP2023/087760 2022-12-23 2023-12-22 Polymersomes comprenant des copolymères séquencés peg-b-pcl Ceased WO2024133949A1 (fr)

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