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WO2010148653A1 - Vésicules polymères de membrane asymétrique - Google Patents

Vésicules polymères de membrane asymétrique Download PDF

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Publication number
WO2010148653A1
WO2010148653A1 PCT/CN2010/000968 CN2010000968W WO2010148653A1 WO 2010148653 A1 WO2010148653 A1 WO 2010148653A1 CN 2010000968 W CN2010000968 W CN 2010000968W WO 2010148653 A1 WO2010148653 A1 WO 2010148653A1
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hydrophilic
phase
block
peg
dextran
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Tuo Jin
Yulong Zhang
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Shanghai Jiao Tong University
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Shanghai Jiao Tong University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
    • A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers
    • A61K9/1273—Polymersomes; Liposomes with polymerisable or polymerised bilayer-forming substances
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
    • C08J3/00—Processes of treating or compounding macromolecular substances
    • C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
    • C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
    • C08J3/07—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media from polymer solutions

Definitions

  • the present invention demonstrates a new particulate system called polymersomes of asymmetric bilayer membrane for which the vesicle membrane is formed from two types of diblock copolymers, one forming the inner leaflet and the other forming the outer leaflet.
  • Polymer vesicles also called as polymersomes, possess the similar structure of lipid vesicles (or called liposomes), except that the membrane enclosing the aqueous core is formed from amphiphilic block copolymers instead of lipids. Polymersomes have attracted great attention due to their superior mechanical stabilities over liposomes and the flexibility regarding chemical modification of the membrane forming copolymers.
  • a number of different amphiphilic block copolymers including poly(ethylene oxide)- ⁇ b/oc/c-poly(butadiene) (PEO-b-PBD), polyethylene oxide)-6/oc/c-poly(ethylethylene) (PEO-6-PEE), polyethylene oxide) -jb/oc/c-poly(lactic acid) (PEO-6-PLA), poly(ethylene oxide)-b/oc/c-poly(caprolactone) (PEO-ib-PCL), poly(ethylene oxide)-Woc/(-polystyrene (PEO-6-PS), have been used to form polymersomes.
  • PEO-b-PBD poly(ethylene oxide)- ⁇ b/oc/c-poly(butadiene)
  • PEO-6-PEE polyethylene oxide)-6/oc/c-poly(ethylethylene)
  • PEO-6-PEE polyethylene oxide) -jb/oc/c-poly(lactic acid
  • polymersomes are unique in having the aqueous interior to which delicate biological therapeutics such as protein drugs, nucleotides, vaccines can be encapsulated with preserved native state. These natures make polymersome to be a promising system for delivery of biological therapeutics.
  • microorganisms can effectively deliver their nucleotide or peptide cargos into host cells.
  • Most microorganisms are composed of a hydrophilic interior isolated by in a stable and functional shell, allowing them to perform various bio-functions.
  • the membrane of polymersomes possess a liquid crystalline structure alike many microorganisms as well the flexibility to be modified to simulate these functions.
  • lipid compositions of the inner and outer leaflets of cell membranes are different from each other.
  • 112'141 In the plasma membranes of eukaryotic cells, phosphatidylcholine and sphingomyelin predominate in the outer leaflet while aminophospholipids are primarily in the cytosolic leaflet.
  • 1121 The asymmetric structure of the cell membrane maintains the different composition and environment of intracellular and extracellular fluid.
  • the asymmetric membrane of the biological cell membrane inspired us to develop polymersome of structure. With an asymmetric membrane, the chemical environment of a vesicle could be significantly different from that of the continuous phase, so that therapeutic molecules can be encapsulated in the vesicle by thermodynamic partition.
  • a method able to guide two different amphiphilic di-block copolymers to aform each leaflet of the vesicle bilayer is necessary.
  • the method should also be able to guide tri-block copolymers to form a monolayer with defined orientation. Therefore, creating/utilizing a guiding system becomes a key factor for assembling vesicles of asymmetric membrane.
  • the present invention addresses the above-discussed technical issues by a polymersome of asymmetric bilayer membrane and by a phase-guided self-assembly method. It combines the art of polymersome with the aqueous two-phase system to offer a polymersome with protein-friendly interior of dextran polymer.
  • two amphiphilic di-block copolymers having polysaccharide and polyethylene glycol (PEG) as the hydrophilic blocks, respectively, are added into an aqueous two-phase system consisting of polysaccharide dispersed phase and a PEG continuous phase.
  • the block copolymers having polysaccharide block align at the interface of the aqueous two-phase system with its hydrophilic block facing the polysaccharide dispersed phase, while the one with PEG block align at the interface with its hydrophilic block facing the PEG continuous phase.
  • the polymersome will be assembled in such a way surrounded by functional groups.
  • these agents can easily be encapsulated are into the polysaccharide dispersed-phase by thermodynamic partition when being added in this system. Encapsulation by thermodynamically favored partition will greatly improve loading efficiency and stability of the agents to be packed. For protein encapsulation, the loading efficiency was reached 90% in experiment.
  • the polysaccharide core of the new polymersome offers numerical functions. In addition to the preferential partition of biological cargos, it may greatly improve mechanic stability of the polymersomes if the polysaccharide core is cross-linked through conjugated groups
  • conjugation linkage can be designed to be pH-sensitive so that the cross-linked polysaccharide core may degrade and dissociate inside the endosome of target cells. This nature is useful to design a delivery system facilitating its cargo's endosomal escape.
  • the materials used in this invention can be any biocompatible copolymer yielding self-assembled fully-biodegradable polymersomes necessary for human in vivo applications.
  • the hydrophobic block of aliphatic polyester such as polylactic acid (PLA), polyglycolic acid (PGA), polylactic-co-glycolic acid (PLGA) and poly ⁇ -caprolactone (PCL), or polymers of similar structures are used.
  • the bioactive agents feasible to load into polymersome of asymmetric bilayer membrane can be protein, DNA, siRNA, etc.
  • Figure 1 Schematic description of the preparation procedure and structure of polymersomes of asymmetrical bilayer membrane, a) Preparation procedure by adding two block copolymers, DEX 2 2-PCL 66 and PEG 45 -PCL 30 , into a dextran/PEG aqueous two-phase system, b) Polymersome structure consisting of a dextran core in which bio-macromolecules are packed by preferential partition and an asymmetric block copolymer bilayer shell with the dextran block facing the core and PEG block facing the PEG continuous phase.
  • the two A-B types of diblock copolymer (DEX-PCL and PEG-PCL) may be replaced by a A-B-C type tri-block copolymer (DEX-PCL-PEG), and the dextran dispersed phase of the aqueous two-phase system may be replaced by solid particles such as polyplex.
  • FIG. 1 Photo and microscopic images indicating formation of polymersomes of asymmetric bilayer.
  • FIG. 4 Laser confocal microscopic images of polymersomes of asymmetric bilayer membrane and lateral mobility of the membrane, a) Polymersomes labeled with Nile red and FITC-dextran scanned with a 559 nm laser beam for the single color image (i) and scanned with 559 nm and 488 nm beams in sequence for the combined image (ii).
  • FIG. 1 Microcopic images of polymersomes with and without core cross-linking, a) Fluorescent microscopic images of polymersomes without core cross-linking upon dilution of continuous phase by 0, 3 and 6 times, b) Microscopic images of polymersomes with cross-linked core, c) Microscopic (i) and fluorescent microscopic images (ii and iii) of the polymersomes in b) diluted by 10 times, d) Molecular structure of GMA-Dextran for forming cross-linked core. Scale bars: 10 ⁇ m.
  • Figure 6 a) Profile of cumulative EPO released from polymersomes of asymmetric bilayer membrane in vitro, b) Profile of cumulative bioactivity of released EPO determined by UT-7 cell proliferation assay. Circles in each graph indicate the mean values of two measurements.
  • Figure 7 TEM images of dried polymersomes of asymmetric bilayer membrane with cross-linked core prepared by by PEG-PCL and DEX-PCL in water (scale bar 200 nm).
  • Figure 8 Particle size distribution of polymersomes of asymmetric bilayer membrane formed from diblock copolymers of PEG-PCL and DEX-PCL by phase-guided assembly.
  • the present invention demonstrated a method (phase-guided self assembly) to form a unique composition of polymer vesicles (polymersomes of asymmetric bilayer membrane) with diameters ranging form sub-micrometers to micrometers. These and composition offer a convenient encapsulation of soluble proteins and other bio-molecules into submicron-sized particulate systems for drug therapy, immuno-therapy, gene therapy and other applications.
  • amphiphilic molecules to form these polymersomes through the phase-guided assembly can be two different amphiphilic di-block copolymer (A-B type) or a tri-block copolymer with two different hydrophilic blocks at the two distal ends (A-B-C type).
  • Some examples are hydrophilic polyethyleneoxide (PEG) conjugated to hydrophobic poly(caprolactone), hydrophilic dextran (DEX) linked to hydrophobic poly(caprolactone), or a poly(caprolactone) block conjugated with PEG and DEX at its two ends. These blocks were chosen for several favorable criteria such as their non-toxicity, biodegradability and known metabolism pathways in vivo.
  • A-B-C type copolymer may be DEX-PCL-EPG. DEX may be replaced by other polysaccharide or oligo-sugars.
  • the polymersomes of the present invention are prepared by a unique phase-guided assembly method.
  • phase-guided assembly also called self assembly
  • a hydrophilic two-phase system consisting of a dispersed phase and a continuous phase is needed as the "template".
  • the continuous phase must be in liquid form while the dispersed phase can be in either liquid or solid form.
  • Materials selected for forming the dispersed and continuous phases of the hydrophilic two-phase system should possess selective/biased affinity to the different hydrophilic blocks of the block copolymers (defined as above), respectively.
  • Polymeric vesicles of asymmetric membrane are formed by addition of the amphilphilic diblock copolymers (with different hydrophilic blocks) into the aqueous (or hydrophilic) two-phase system.
  • hydrophilic two-phase system may be that consisting of an aqueous dextran solution as the dispersed phase and a PEG aqueous solution as the continuous phase.
  • the DEX dispersed phase may be solidified by cross-linking treatment or be replaced by other aqueous solution or solid particles such as polyplex formed by cationic polymers and nucleotides.
  • the intra-core cross-linking treatment may be achieved by covalent interaction or ionic (electrostaic) interaction between the polymer chains of the core (dispersed phase) material.
  • the selective/biased affinity between the dispersed and continuous phases of the template two-phase system and the hydrophilic blocks of copolymer is based on various intermolecular interactions comprising electrostatic interaction, hydrogen bonding, or hydrodynamic repulsing (such as PEG to other macromolecules).
  • electrostatic interaction the sugar block of the polysaccharide (or oligo sugar)-PCL-EPG copolymer may be modified by charge-generating molecule, such as succinic anhydride.
  • the selected dextran-PEG two-phase system works efficiently for protein purification due to the preferential partition favoring the dextran phase, as well as the protein stabilization effect of the dextran hydroxyls.' 151
  • the copolymer with the dextran block aligned along the surfaces of the dextran droplets, under the guidance of phase separation, to form the inner leaflet of the bilayer; while the copolymer with the PEG block formed the outer layer, with the PEG chain facing the PEG continuous phase.
  • the interior of the new polymersome Being enclosed by the asymmetric bilayer, the interior of the new polymersome possesses a different chemical environment from the continuous phase, and can therefore encapsulate biomolecules efficiently by thermodynamic partition.
  • FIG. 1 schematically describes an example of this phase-guided assembly, as well as the structure of an asymmetric-bilayer polymersome.
  • phase guidance strategy demonstrated in the present invention works well for preparing polymersomes of asymmetric bilayer membrane formed from two different diblock copolymers as well as polymersomes of asymmetric monolayer membrane formed from A-B-C triblock copolymers.
  • hydrophilic-hydrophobic-hydrophilic triblock (A-B-C) copolymers align in an "A to A” and "C to C” style to form an asymmetric monolayer by designed phase selection.
  • the portion and accuracy of phase-selection can be pre-determined by phase diagrams of selected systems or by partition test. There hundreds of reported phase diagrams for the so-called aqueous two-phase systems in the literature including several textbooks [15] .
  • phase-guided assembly demonstrated in this invention may offer a more effective and better defined assembly for block polymer orientation based on the well summarized phase diagrams of aqueous two-phase separation found in textbooks. For example, a dextran/PEG two-phase system in highly concentrated form, the amount of dextran dissolved in the PEG phase and vice versa is below 1.0 wt%.
  • phase-guided assembly enables two well-selected amphiphilic diblock copolymers to form the inner and outer leaflets of a bilayer membrane, respectively, and with defined distribution.
  • aqueous two-phase system was prepared by mixing a dextran (70 KDa) solution (10% in concentration) and a PEG (8 KDa) solution (10% in concentration), with 0.1 wt% FITC labeled dextran, added to the dextran solution for convenient observation.
  • polylactic acid (PLA), polyglycolic acid (PGA), polylactic-co-polygycolic acid (PLGA) may be used as the hydrophobic block.
  • the prepared dextran/PEG two-phase system was then divided into four glass tubes: to each was added nothing, PEG 45 -PCL 30 alone, DEX 22 -PCL 66 alone, and both PEG 45 -PCL 30 and DEX 22 -PCL 66 .
  • the aqueous two-phase system with nothing added readily separated into two clear bulky phases after the stirring was ceased, with the fluorescently labeled dextran phase at the bottom and the PEG phase at the top (Fig. 2a-i).
  • the system separated into two bulky phases (Fig. 2a-ii and 2a-iii).
  • 2D- 1 H-NOESY-NMR spectroscopy was reported as a reference method to indicate/suggest whether has a PEG block and a sugar group of polymersomes formed from A-B-C tri-block molecules.
  • 116 ⁇ 181 2D- 1 H-NOESY-NMR spectrometry is capable of identifying the interaction between individual molecules packed in a physical distance comparable to that of adjacent groups within a molecule by cross peaks.
  • Figure 3 shows chemical shift peaks of the proton signals of methane in PEG units at 3.57 ppm and that of dextran units at 3.60-3.65 ppm, 3.53-3.35 ppm, respectively. 1191 No cross-interaction peak between dextran and PEG was observed.
  • lateral mobility of the asymmetric copolymer bilayer was examined using time-based laser confocal imaging.
  • the hydrophobic and hydrophilic fluorescent dyes (Nile red and FITC-dextran) were used to label the hydrophobic shell of vesicular membrane and the hydrophilic core, respectively.
  • Figure 4a-i and 4a-ii show the laser confocal image of Nile red-labeled surface and the combined image of the surface and core labeled by each of the dye, respectively.
  • Nile red and FITC-dextran are distributed in the surface and the core of the dispersed dextran phase, respectively.
  • Figure 4d shows the time course of fluorescence recovery in the bleached area.
  • the diffusion rate of the dye molecule is not necessarily the same as that of the block copolymers, the rapid diffusion of hydrophobic Nile red can only occur in a mobile and continuous polymer bilayer.
  • the lateral diffusion rate of Nile red may be estimated using a one-dimensional model (along the confocal plane) of Fick's law.
  • the diffusion coefficient of Nile red along the surface, D may be calculated by incorporating the measured values of fluorescent intensity of the bleached region and time into the earlier-state solution of Fick's second equation where L is the length of the opening of the fluorescent circle in cm, t is time after bleaching treatment in seconds, It and I 0 are the measured fluorescent intensities above the background at time t and before bleaching, respectively.
  • the core of the polymersome may be endowed with a capability to respond to intracellular pathways. If the core is solidified by a pH sensitive cross-linking mechanisms, it could retain the shape in neutral environments but dissociate and burst at low pH endosomes by acid-driving cleavage of the intra-core linkages.
  • the microscopic and fluorescent images shown in Figure 5 demonstrate the core property, based on which desired functions can be incorporated.
  • the polymersomes whose core matrices were not cross-linked were enlarged and ruptured when the PEG continuous phase was removed or diluted (Fig. 5a-i, 5a-ii and 5a-iii).
  • the core matrix was formed of methacrylate-grafted dextran and therefore cross-linked by radical polymerization using ammonium peroxydisulfate (APS) and N, N 1 N 1 , N'- tetramethylethylenediamine (TEMED) (0.2 wt% and 0.4 wt% in concentration, respectively) as an initiation system, then it can endure the abrupt change of the osmotic pressure, and dilution of the PEG continuous phase no longer caused enlargement and rupturing of the polymersomes (Fig. 5b, 5c-i, 5c-ii, and 5c-iii).
  • Cross-linked core matrices can effectively hold the bilayer membrane. Breaking the matrix cross-linking will lead to immediate rupture of the particulate. This key characteristic is especially useful for delivering biomolecules into the cytoplasm of target cells through phagocytosis (endosomal escaping).
  • Example 5 Encapsulation of biomolecules in polymersome of asymmetric bilayer and release of biomolecules from the polymersomes Further provided are encapsulation and controlling the release of fragile biomolecules from the polymersomes of asymmetric bilayer membrane.
  • EPO erythropoietin
  • Fig. 6a assays of protein content, release profile and bioactivity
  • Figure 6 shows that the release kinetic profile of EPO from the polymersomes (with a cross-linked core) is identical to the cumulative bioactivity profile by UT-7 cell proliferation assay (Fig. 6b), suggesting that protein activity was well preserved in this particulate system.
  • proteins loaded in the interior of polymersome are stabilized by dextran, they can endure 40 ° C for 6 h and no protein aggregation increase observed by HPLC method.
  • Example 6 Preparation of nano-sized polymersome with asymmetric bilayer polymersome
  • the procedure for preparing nanometer-sized polymersomes of asymmetric bilayer memebrane was extended from the method in Example 1 by increasing the copolymer/dextran ratio.
  • 1 mL diblock copolymer solutions 5 mg • ml. "1 in concentration, was prepared by incubating for 12-24 h at 60 0 C with or without magnetic stirring.
  • PEG/ GMA-dextran (400 mg / 100 mg) and protein were dissolved in 4 mL KCI (0.22 M ) solution flushed for 10 min with nitrogen and subsequently transferred into the above diblock copolymer solution followed by vortexing for 1 min.
  • the system was then incubated for 1 h at 40-50 ° C to cross-link the interior dextran of the polymersome by the addition of ammonium peroxydisulfate (180 ul, 50 mg/mL) and N 1 N 1 N 1 N tetramethylethylenediamine (100 ul, 20% V ⁇ /, adjusted to pH 7 with 4 M HCI ).
  • ammonium peroxydisulfate 180 ul, 50 mg/mL
  • N 1 N 1 N 1 N 1 N tetramethylethylenediamine 100 ul, 20% V ⁇ /, adjusted to pH 7 with 4 M HCI .
  • the polymersomes with cross-linked lumen were characterized by TEM and DLS (See Figure 7 and Figure 8)

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Abstract

Cette invention porte sur un nouveau système de vésicules polymères structuré par une membrane asymétrique qui est formée par deux copolymères à deux blocs amphiphiles (type A et B) ayant différents blocs hydrophiles ou par un copolymère à trois blocs (type A-B-C) avec deux blocs hydrophiles différents à chaque extrémité. Avec ce système, des biomolécules ou macromolécules peuvent être encapsulées sous forme de nanocapsules ou de capsules de dimension inférieure au micron, par partage thermodynamique et peuvent être stabilisées thermodynamiquement. Ce système est applicable en particulier à l'administration de biothérapeutiques. Ce qui est également important dans cette invention est le procédé de formation de vésicules polymères de membrane asymétrique : un auto-assemblage à phases guidées. Ce procédé met en jeu un système à deux phases hydrophiles pour guider les copolymères à blocs ci-dessus pour qu'ils s'alignent sur l'interface hydrophile dans une orientation désignée. Ce procédé aura une application étendue dans le fonctionnement ou le biofonctionnement de surfaces particulaires.
PCT/CN2010/000968 2009-06-26 2010-06-28 Vésicules polymères de membrane asymétrique Ceased WO2010148653A1 (fr)

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US10874611B2 (en) 2016-02-25 2020-12-29 Ucl Business Ltd Chemotactic, drug-containing polymersomes
US10881613B2 (en) 2016-03-17 2021-01-05 Ucl Business Ltd Fumarate polymersomes
US11026891B2 (en) 2016-08-16 2021-06-08 Eth Zurich Transmembrane pH-gradient polymersomes and their use in the scavenging of ammonia and its methylated analogs
WO2021186078A1 (fr) * 2020-03-20 2021-09-23 Heidelberg University Procédé de production de polymersomes
US20230126007A1 (en) * 2014-06-24 2023-04-27 The Trustees Of Princeton University Nanoparticles encapsulating soluble biologics, therapeutics, and imaging agents
US11713376B2 (en) 2017-09-12 2023-08-01 Eth Zurich Transmembrane pH-gradient polymersomes for the quantification of ammonia in body fluids
US12186436B2 (en) 2018-07-19 2025-01-07 The Trustees Of Princeton University Triblock copolymer stabilizers for the formation of nanoparticles encapsulating soluble biologics, therapeutics, and imaging agents
US12257344B2 (en) 2019-01-07 2025-03-25 Ucl Business Ltd Polymersomes functionalised with multiple ligands
US12357582B2 (en) 2017-11-03 2025-07-15 The Trustees Of Princeton University Hydrophobic ion pairing and flash nanoprecipitation for formation of controlled-release nanocarrier formulations

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CN104013967B (zh) * 2014-04-25 2016-06-15 同济大学 一种载钆聚合物囊泡及其制备方法和应用
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EP3538252A1 (fr) * 2016-11-11 2019-09-18 Aquaporin A/S Structures vésiculaires polymériques auto-assemblées avec des molécules fonctionnelles

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