US20100104645A1 - Methods for the preparation of targeting agent functionalized diblock copolymers for use in fabrication of therapeutic targeted nanoparticles - Google Patents
Methods for the preparation of targeting agent functionalized diblock copolymers for use in fabrication of therapeutic targeted nanoparticles Download PDFInfo
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- US20100104645A1 US20100104645A1 US12/485,818 US48581809A US2010104645A1 US 20100104645 A1 US20100104645 A1 US 20100104645A1 US 48581809 A US48581809 A US 48581809A US 2010104645 A1 US2010104645 A1 US 2010104645A1
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- 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)
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- A—HUMAN NECESSITIES
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- 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
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
- A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6905—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion
- A61K47/6911—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a colloid or an emulsion the form being a liposome
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P35/00—Antineoplastic agents
Definitions
- controlled release polymer systems can be designed to provide a drug level in the optimum range over a longer period of time than other drug delivery methods, thus increasing the efficacy of the drug and minimizing problems with patient compliance.
- Biodegradable particles have been developed as sustained release vehicles used in the administration of small molecule drugs, proteins and peptide drugs, and nucleic acids.
- the drugs are typically encapsulated in a polymer matrix which is biodegradable and biocompatible. As the polymer is degraded and/or as the drug diffuses out of the polymer, the drug is released into the body.
- Targeting controlled release polymer systems e.g., targeted to a particular tissue or cell type or targeted to a specific diseased tissue but not normal tissue
- Targeting controlled release polymer systems is desirable because it reduces the amount of a drug present in tissues of the body that are not targeted. This is particularly important when treating a condition such as cancer where it is desirable that a cytotoxic dose of the drug is delivered to target cells without killing the surrounding tissue. Accordingly, a need exists to develop delivery systems which can deliver therapeutic levels of drug to treat diseases such as cancer, while also reducing patient side effects.
- This application provides methods of making nanoparticles using pre-functionalized poly(ethylene glycol) (also referred to as PEG) as a macroinitiator for the synthesis of diblock copolymers.
- diblock copolymers comprise a functional PEG polymer block bearing a targeting agent on one of its termini and a second biocompatible and biodegradable hydrophobic polymer block (e.g. a poly(ester)).
- the poly(ethylene glycol) is hetero-bifunctional with a targeting agent (TA) covalently bound to its ⁇ terminus and a polymerization initiating functional group (e.g., a hydroxyl group) present on its ⁇ terminus.
- TA targeting agent
- the poly(ethylene glycol) is functionalized with a TA on its ⁇ terminus and a functional group capable of covalent attachment to a poly(ester) that in turn is functionalized with a reactive end group.
- a functional group capable of covalent attachment to a poly(ester) that in turn is functionalized with a reactive end group.
- examples include an amino-terminated PEG and a carboxylic acid terminated poly(ester) or an azide terminated PEG and an alkyne terminated poly(ester).
- Nanoparticles produced according to the disclosed methods and their use in the treatment of various diseases and disorders is also provided.
- FIGS. 1A-C Proton NMR spectra of HO-PEG-lys-urea-glu (protected), lot numbers 11-189-1 and 11-176-1.
- FIG. 1 A HO-PEG-lys-urea-glu (protected) Lot# 11-176-1.
- FIG. 1 A HO-PEG-lys-urea-glu (protected) Lot# 11-176-1.
- 1H NMR spectrum expansion #1 used for lys-urea-glu (protected) content calculation (% lys-urea-glu (protected) end functionalization [Int. ⁇ 1.95-2.1]*2/[In
- FIG. 1 B HO-PEG-lys-urea-glu (protected) Lot# 11-176-1; 1H NMR spectrum expansion #2.
- FIG. 1 C HO-PEG-lys-urea-glu (protected) Lot# 11-176-1; 1H NMR spectrum expansion #3.
- FIGS. 2A-B Size Exclusion Chromatograms (SEC) of HO-PEG-lys-urea-glu (protected), lot numbers 11-189-1 ( FIG. 2B ) and 11-176-1 ( FIG. 2A ).
- RI Refractive Index detection
- RI Detector temperature 35° C.
- FIGS. 3A-F Proton NMR spectra of PLA-PEG-lys-urea-glu (protected), lot numbers 11-187-1, 11-188-1 and 11-198-1.
- FIG. 3 A—PLA-PEG-lys-urea-glu (protected), Lot # 11-187-1; 1H NMR Spectrum Expansion #1 showing lactide methine and allyl end group peak used in the determination the determination of the absolute number average molar mass (Mn) of PLA-PEG-lys-urea-glu (protected).
- Method for determination of absolute number average molar mass (M n ) of PLA-PEG-lys-urea-glu (protected): M n (PLA-PEG-lys-urea-glu (protected) M n (PEG-lys-urea-glu (protected)+(Molar mass of lactide repeat unit*((Int.
- FIG. 3 B PLA-PEG-lys-urea-glu (protected), Lot# 11-187-1; 1H NMR Spectrum Expansion #2 showing PEG peak and lactide methyl peaks of PLA-PEG-lys-urea-glu (protected).
- FIG. 3 D—PLA-PEG-lys-urea-glu (protected), Lot# 11-188-1; 1H NMR Spectrum Expansion #2 showing PEG peak and lactide methyl peaks of PLA-PEG-lys-urea-glu (protected).
- FIG. 3 F-PLA-PEG-lys-urea-glu (protected), Lot# 11-198-1; 1H NMR Spectrum Expansion #2 showing PEG peak and lactide methyl peaks of PLA-PEG-lys-urea-glu (protected).
- FIG. 4 Size Exclusion Chromatograms (SEC) of HO-PEG-lys-urea-glu (protected), lot numbers 11-189-1 (labeled 44-44-6 for SEC analysis) and 11-176-1.
- RI Refractive Index detection
- RI Detector temperature 35° C.
- FIGS. 5A-E Efficiency of deprotection and estimate of Molar mass of crude PLA-PEG-lys-urea-glu (prior to palladium removal) by 1 H NMR Spectroscopy.
- FIG. 5 A Crude PLA-PEG-lys-urea-glu Lot# 11-190-1; 1H NMR Spectrum Expansion #1 showing: a) lactide methine peak, b) peaks of aromatic protons of tetrakis(triphenyl-phosphine)palladium (0), and c) absence of residual allyl peaks ( ⁇ 5.85-5.95) indicating quantitative removal of protecting groups.
- FIG. 5 B —Crude PLA-PEG-lys-urea-glu Lot# 11-190-1; 1H NMR Spectrum Expansion #2 showing the PEG and lactide methyl peaks.
- FIG. 5 B Crude PLA-PEG-lys-urea-glu Lot# 11-190-1; 1H NMR Spectrum Expansion #2 showing the PEG and lactide methyl peaks.
- FIG. 5 C—Crude PLA-PEG-lys-urea-glu Lot# 11-191-1; 1H NMR Spectrum Expansion #1 showing: a) lactide methine peak, b) peaks of aromatic protons of tetrakis(triphenyl-phosphine)palladium (0), and c) ⁇ 3% (relative to the PLA-PEG-lys-urea-glu (protected) precursor) residual allyl peaks ( ⁇ 5.85-5.95) indicating >96% removal of protecting groups.
- FIG. 5 D—Crude PLA-PEG-lys-urea-glu Lot# 11-191-1; 1H NMR Spectrum Expansion #2 showing PEG and lactide methyl peaks.
- FIG. 5 E—Crude PLA-PEG-lys-urea-glu Lot# 11-199-1; 1H NMR Spectrum Expansion #1 showing: a) lactide methine peak, b) absence of residual allyl peaks ( ⁇ 5.85-5.95) indicating quantitative removal of protecting groups.
- FIGS. 6A-B Molar Mass and PEG fraction of purified PLA-PEG-lys-urea-glu by 1 H NMR Spectroscopy.
- FIG. 6 A PLA-PEG-lys-urea-glu Lot# 44-49-1; 1H NMR Spectrum Expansion #1 showing: a) lactide methine peak, b) absence of residual allyl peaks ( ⁇ 5.85-5.95) indicating quantitative removal of protecting groups.
- FIG. 6 B Purified PLA-PEG-lys-urea-glu Lot# 44-49-1; 1H NMR Spectrum Expansion #2 showing PEG and lactide methyl peaks.
- FIG. 7 Molecular weight of PLA-PEG-lys-urea-glu and the protected precursor PLA-PEG-lys-urea-glu (protected) by Inherent Viscosity measurements.
- FIG. 8 Palladium Content in crude (prior to palladium removal) PLA-PEG-lys-urea-glu lot number 44-48-1 (sample code 11-204-1) and purified (after palladium removal) PLA-PEG-lys-urea-glu lot number 44-49-1 (sample code 11-204-2) determined by ICP Spectrometry.
- This application provides methods of making nanoparticles using pre-functionalized poly(ethylene glycol) (also referred to as PEG) as a macroinitiator for the synthesis of diblock copolymers.
- diblock copolymers comprise a bio-active poly(ethylene glycol) block and a second biocompatible and biodegradable hydrophobic polymer block (e.g. a poly(ester)).
- the poly(ethylene glycol) is hetero-bifunctional with a targeting moiety (agent) covalently bound to its ⁇ terminus and a polymerization initiating functional group (e.g., a hydroxyl group) present on its ⁇ terminus.
- the subject application also provides for the use of derivatives of targeting agents (TA's) (e.g., analogs where functional groups, such as carboxylic acids or other functional groups, are protected) in the synthesis of the poly(ethylene glycol) polymer to which TA's are attached that improve its solubility and avoid potential side reactions.
- TA's derivatives of targeting agents
- PRO-TA protected targeting agent
- the functionalized PEG HO-PEG-TA-PRO
- HO-PEG-TA-PRO is utilized as a macroinitiator to synthesize a poly(ester) block.
- HO-PEG-TA-PRO is added to a mixture of cyclic lactone monomers such as lactide, glycolide or caprolactone and the mixture is heated to melt conditions.
- a polymerization catalyst such as tin (II) 2-ethylhexanoate is then added to the monomer/initiator melt.
- the resulting polymer is purified from un-reacted monomer and polymerization catalyst by precipitation into a non-solvent mixture such as ether/hexane (70/30) and recovered by decantation followed by vacuum drying. Subsequent deprotection of the protected functional groups can be performed to regain the original chemically active functional group (e.g., a carboxylic acid).
- This approach enables the desired polymerization reaction to proceed efficiently and avoids side reactions between the polymerization catalyst and the functional groups on the targeting moiety in its native unprotected form.
- composition and molecular weight of the poly(ester) can be tuned as desired by controlling the composition of the monomer melt and the molar ratio of the HO-PEG-TA(PRO) to the monomers.
- the protected targeting moiety is freely soluble in a wide range of organic solvents relative to the un-protected analogues. This enables the coupling of the targeting moiety to poly(ethylene glycol) with a high degree of polymer end group functionalization.
- this application provides a method for efficient coupling of the un-protected targeting moiety to poly(ethylene glycol) under aqueous conditions.
- the pH of the reaction medium is used to maximize yield of the desired product.
- Advantages to this aspect of the invention relate to the utilization of the high water solubility of the targeting agent (TA).
- the acid end group of a ⁇ -azide- ⁇ -carboxylic acid poly(ethylene glycol) (N 3 -PEG-CO 2 H) is first activated by conversion to the succinimide ester N 3 -PEG-COSu) by reaction with N-hydroxysuccinimide (NHS) and ethyl dimethylaminopropylcarbodiimide hydrochloride (EDC) or dicyclohexylcarbodiimide (DCC) under anhydrous organic solvent conditions such as in dichloromethane.
- NHS N-hydroxysuccinimide
- EDC ethyl dimethylaminopropylcarbodiimide hydrochloride
- DCC dicyclohexylcarbodiimide
- the activated poly(ethylene glycol) (N 3 -PEG-COSu) is subsequently purified from small molecule reagents precipitation into an anhydrous non-solvent such as ether-hexane (70/30).
- the activated acid (N 3 -PEG-COSu) is dissolved in DI water is added dropwise to a large molar excess of the H 2 N-TA solution.
- conversion to the desired PEG-targeting agent conjugate (N 3 -PEG-TA) while minimizing exposure of the N 3 -PEG-COSu to basic conditions, thereby avoiding hydrolysis of the succinimide ester.
- the N 3 -PEG-TA is subsequently coupled to an alkyne terminal poly(ester) using copper catalyst under conventional click chemistry conditions in an organic solvent such as dimethylformamide (DMF) or dimethylsulfoxide (DMSO).
- Alkyne terminal poly(ester) is prepared by ring opening polymerization of lactide and glycolide monomers using for example propargyl alcohol as polymerization initiator and tin (II) 2-ethyl hexanoate as polymerization catalyst.
- a targeting moiety/agent may target or cause the particle to become localized at specific locations within a subject and the bioactive agent/therapeutic agent is thus delivered to a target site.
- a drug or therapeutic agent can be released in a controlled release manner from the particle and allowed to interact locally with the particular targeted site (e.g., a tumor).
- controlled release (and variations of that phrase (e.g., in the context of “controlled-release system”)) is generally meant to encompass release of a therapeutic agent (e.g., a drug) at a selected site in a controllable rate, interval, and/or amount.
- Controlled release encompasses, but is not necessarily limited to, substantially continuous delivery, patterned delivery (e.g., intermittent delivery over a period of time that is interrupted by regular or irregular time intervals) or delivery of a bolus of a selected therapeutic agent (or various combinations thereof) as a predetermined, discrete amount over a relatively short period of time (e.g., a few seconds or minutes).
- Examples of second biocompatible and biodegradable hydrophobic polymer blocks that can be used in the manufacture of the claimed nanoparticles can be polyesters.
- Examplary polyesters suitable for use in the manufacture of the disclosed nanoparticles include copolymers comprising lactic acid and glycolic acid units, such as polylactic acid-co-glycolic acid) and poly(lactide-co-glycolide), collectively referred to herein as “PLGA”; and homopolymers comprising glycolic acid units, referred to herein as “PGA,” and lactic acid units, such as poly-L-lactic acid, poly-D-lactic acid, poly-D,L-lactic acid, poly-L-lactide, poly-D-lactide, and poly-D,L-lactide, collectively referred to herein as “PLA.”
- exemplary polyesters include, for example, polyhydroxyacids; PEGylated polymers and copolymers of lactide and glycolide (e.g., PEGylated PLA, P
- polyesters include, for example, polyanhydrides, poly(ortho ester) PEGylated poly(ortho ester), poly(caprolactone), PEGylated poly(caprolactone), poly(L-lactide-co-L-lysine), poly(serine ester), poly(4-hydroxy-L-proline ester), poly[a-(4-aminobutyl)-L-glycolic acid], and derivatives thereof.
- Second biocompatible and biodegradable hydrophobic polymer block utilized in the manufacture of the disclosed nanoparticles can contain functional groups that react with the ⁇ terminus of the poly(ethylene glycol).
- functional groups include, and are not limited to, amines, hydroxyl groups, carboxylic acid groups, NHS groups, alkyne groups or azide groups.
- Groups with which the second biocompatible and biodegradable hydrophobic polymer block functional groups react at the w terminus of the poly(ethylene glycol) polymer are provided in the following table.
- Polyester functional group poly(ethylene glycol) N-hydroxysuccinimide (NHS) Amine Amine Hydroxyl, Carboxylic acid Hydroxyl Amine Carboxylic acid Amine Alkyne Azide
- Targeting agents disclosed herein can contain, or be modified to contain, a functional group that can be reacted with the ⁇ terminus of a polymer (e.g., PEG) in order to produce a polymer conjugated to a targeting moiety.
- the functional groups include any moiety that can be used to create a covalent bond with a polymer (e.g., PEG), such as amino, hydroxy, azide, alkyne and thio.
- targeting agents can be can be substituted with NH 2 , SH or OH, which are either bound directly to the targeting agent or via an additional group, e.g., alkyl or phenyl.
- aniline, alkyl-NH 2 (e.g., (CH 2 ) 1-6 NH 2 ), or alkyl-SH (e.g., (CH 2 ) 1-6 NH 2 ) can be used to link the targeting agent to a polymer via the free NH 2 and SH groups to form a covalent bond.
- a functionalized PEG polymer (a PEG polymer comprising one or more targeting agents at its ⁇ terminus and reactive functional groups at the ⁇ terminus) and a second biocompatible and biodegradable hydrophobic polymer can be performed according to methods known in the art via functional groups at the ⁇ terminus of a functionalized PEG polymer and reactive groups present in the second biocompatible and biodegradable hydrophobic polymer.
- EDC-NHS chemistry (1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride and N-hydroxysuccinimide) or a reaction involving a maleimide or a carboxylic acid can be used.
- the conjugation of a poly(ester) and a poly(ether) to form a poly(ester-ether), can be performed in an organic solvent, such as, but not limited to, dichloromethane, acetonitrile, chloroform, dimethylformamide, tetrahydrofuran, acetone, or the like.
- organic solvent such as, but not limited to, dichloromethane, acetonitrile, chloroform, dimethylformamide, tetrahydrofuran, acetone, or the like.
- Specific reaction conditions can be determined by those of ordinary skill in the art using no more than routine experimentation.
- a functionalized PEG polymer (a PEG polymer comprising one or more targeting agents (TA) at its ⁇ terminus and reactive functional groups at the ⁇ terminus) and a second biocompatible and biodegradable hydrophobic polymer can also be performed using chemistries that are orthogonal to the amide bond forming EDC-NHS chemistry.
- chemistries that are orthogonal to the amide bond forming EDC-NHS chemistry.
- Such methods include “click” chemistry techniques.
- an alkyne terminated poly(ester) may be reacted with a heterobifunctional polyethylene glycol) bearing a TA at its ⁇ -terminus and an alkyne reactive azide moiety at its ⁇ -terminus.
- the conjugation of a poly(ester) and a poly(ether) to form a poly(ester-ether), can be performed in an organic solvent, such as, but not limited to, dichloromethane, acetonitrile, chloroform, dimethylformamide, tetrahydrofuran, acetone, or the like.
- organic solvent such as, but not limited to, dichloromethane, acetonitrile, chloroform, dimethylformamide, tetrahydrofuran, acetone, or the like.
- Conventional “click” chemistry catalysts such as copper sulfate may be employed.
- a conjugation reaction may be performed by reacting a polymer that comprises a carboxylic acid functional group (e.g., a poly(ester-ether) compound) with a polymer or other moiety (such as a targeting moiety) comprising an amine.
- a targeting moiety such as a low-molecular weight PSMA ligand
- Such a reaction may occur as a single-step reaction, i.e., the conjugation is performed without using intermediates such as N-hydroxysuccinimide or a maleimide.
- the conjugation reaction between the amine-containing moiety and the carboxylic acid-terminated polymer may be achieved, in one set of embodiments, by adding the amine-containing moiety, solubilized in an organic solvent such as (but not limited to) dichloromethane, acetonitrile, chloroform, tetrahydrofuran, acetone, formamide, dimethylformamide, pyridines, dioxane, or dimethysulfoxide, to a solution containing the carboxylic acid-terminated polymer.
- an organic solvent such as (but not limited to) dichloromethane, acetonitrile, chloroform, tetrahydrofuran, acetone, formamide, dimethylformamide, pyridines, dioxane, or dimethysulfoxide
- the carboxylic acid-terminated polymer may be contained within an organic solvent such as, but not limited to, dichloromethane, acetonitrile, chloroform, dimethylformamide, tetrahydrofuran, or acetone. Reaction between the amine-containing moiety and the carboxylic acid-terminated polymer may occur spontaneously, in some cases. Unconjugated reactants may be washed away after such reactions, and the polymer may be precipitated in solvents such as, for instance, ethyl ether, hexane, methanol, or ethanol.
- solvents such as, for instance, ethyl ether, hexane, methanol, or ethanol.
- the particles may have a substantially spherical (i.e., the particles generally appear to be spherical), or non-spherical configuration. For instance, the particles, upon swelling or shrinkage, may adopt a non-spherical configuration.
- the particles may include polymeric blends.
- a polymer blend may be formed that includes a first PEG polymer comprising a targeting moiety (i.e., a low-molecular weight PSMA ligand) and a second polymer comprising a biocompatible polymer (e.g., lacking a targeting moiety).
- the polymer may be PLGA in some embodiments.
- PLGA is a biocompatible and biodegradable co-polymer of lactic acid and glycolic acid, and various forms of PLGA are characterized by the ratio of lactic acid:glycolic acid.
- Lactic acid can be L-lactic acid, D-lactic acid, or D,L-lactic acid.
- the degradation rate of PLGA can be adjusted by altering the lactic acid-glycolic acid ratio.
- PLGA to be used in accordance with the present invention is characterized by a lactic acid:glycolic acid ratio of approximately 85:15, approximately 75:25, approximately 60:40, approximately 50:50, approximately 40:60, approximately 25:75, or approximately 15:85.
- nanoparticle parameters such as water uptake, therapeutic agent release (e.g., “controlled release”) and polymer degradation kinetics can be optimized.
- polymers that may be one or more acrylic polymers.
- acrylic polymers include, for example, copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, methacrylic acid alkylamide copolymer, poly(methyl methacrylate), aminoalkyl methacrylate copolymer, glycidyl methacrylate copolymers, polycyanoacrylates, and combinations comprising one or more of the foregoing polymers.
- polymers can be cationic polymers.
- cationic polymers are able to condense and/or protect negatively charged strands of nucleic acids (e.g. DNA, RNA, or derivatives thereof).
- Amine-containing polymers such as poly(lysine) (Zauner et al., 1998 , Adv. Drug Del. Rev., 30:97; and Kabanov et al., 1995 , Bioconjugate Chem., 6:7), poly(ethylene imine) (PEI; Boussif et al, 1995 , Proc. Natl. Acad.
- polymers can be degradable polyesters bearing cationic side chains (Putnam et al., 1999 , Macromolecules, 32:3658; Barrera et al., 1993, J. Am. Chem. Soc., 115:11010; Urn et al., 1999, J. Am. Chem., Soc., 121:5633; and Zhou et al, 1990 , Macromolecules, 23:3399).
- hydrophobic comonomers e.g., lactide, glycolide, caprolactone, or hydrophobic amino acids such as alanine, valine, leucine, isoleucine or phenylalanine
- hydrophobic comonomers e.g., lactide, glycolide, caprolactone, or hydrophobic amino acids such as alanine, valine, leucine, isoleucine or phenylalanine
- these polyesters include poly(L-lactide-co-L-lysine) (Barrera et al, 1993, J. Am. Chem.
- poly(serine ester) Zhou et al, 1990 , Macromolecules, 23:3399
- poly(4-hydroxy-L-proline ester) Poly(4-hydroxy-L-proline ester) was demonstrated to condense plasmid DNA through electrostatic interactions, and to mediate gene transfer (Putnam et al, 1999 , Macromolecules, 32:3658; and Lim et al, 1999 , J. Am. Chem. Soc., 121:5633).
- Poly(4-hydroxy-L-proline ester) was demonstrated to condense plasmid DNA through electrostatic interactions, and to mediate gene transfer (Putnam et al, 1999 , Macromolecules, 32:3658; and Lim et al, 1999 , J. Am. Chem. Soc., 121:5633).
- These new polymers are less toxic than poly(lysine) and PEI, and they degrade into non-toxic metabolites.
- the molecular weight of the polymers of the nanoparticles of the invention are optimized for effective treatment of cancer, e.g., prostate cancer.
- the molecular weight of the polymer influences nanoparticle degradation rate (particularly when the molecular weight of a biodegradable polymer is adjusted), solubility, water uptake, and drug release kinetics (e.g. “controlled release”).
- the molecular weight of the polymer can be adjusted such that the nanoparticle biodegrades in the subject being treated within a reasonable period of time (ranging from a few hours to 1-2 weeks, 3-4 weeks, 5-6 weeks, 7-8 weeks, etc.).
- the PEG has a molecular weight of 1,000-20,000 Da (e.g., 5,000-20,000, e.g., 10,000-20,000) and, in some embodiments, 5000 Da
- the PLGA has a molecular weight of 5,000-100,000 Da (e.g., 20,000-70,000, e.g., 20,000-50,000), or in some embodiments, 15,000-30,000 Da.
- a subject may be a human or non-human animal.
- subjects include, but are not limited to, a mammal such as a dog, a cat, a horse, a donkey, a rabbit, a cow, a pig, a sheep, a goat, a rat, a mouse, a guinea pig, a hamster, a primate, a human or the like.
- a functionalized targeting agent conjugated diblock copolymer is synthesized by initiating the polymerization of biocompatible and biodegradable hydrophobic polymer (such as poly(ester)) from the ⁇ terminus of the poly(ethylene glycol).
- Scheme 1 illustrates this process as exemplified by a poly(ethylene glycol) bearing a hydroxyl functional group on its ⁇ -terminus and targeting agent (TA) on its co-terminus.
- TA targeting agent
- a diblock copolymer bearing a targeting agent (TA) on its poly(ethylene glycol) terminus may be prepared by conjugation of a suitably protected form of the targeting agent (TA-PRO) to the poly(ethylene glycol) polymer (yielding HO-PEG-TA(PRO)), and subsequently using this macroinitiator in the ring opening polymerization of a cyclic lactone monomer such as lactide, glycolide or a mixture thereof. Removal of the protecting groups of the targeting agent using standard deprotection methodology provides the desired Poly(ester)-block-PEG-TA (see scheme 2).
- a functional diblock copolymer (Poly(ester)-PEG-TA) may be prepared by the covalent coupling of the targeting PEG-TA to a pre-formed poly(ester).
- a carboxylic acid terminated poly(lactide-co-glycolide) (Poly(ester)-CO 2 H) and poly(ethylene glycol) bearing the targeting agent on its ⁇ -terminus and an acid reactive amino functional group on its co-terminus (H 2 N-PEG-TA) may be reacted under organic solvent conditions.
- Targeting agents may be comprised of individual natural or non-natural amino acids, or a combination of two or more amino acid residues covalently bound either by a amide or a urea linkage.
- TA's may also be comprised of nucleic acids.
- TA's may contain side chain moieties bearing functional groups including carboxylic acids, amines, thiols, alcohols, phenols, guanidine, purines (such as adenine, guanine), pyrimidines (such as cytosine, uracil, thymine).
- the method of scheme 2 is preferred over the method of scheme 1 when TA's contain functional groups that may either initiate a ring opening polymerization (such as an alcohol, a phenol, an amine, or a thiol) or react with and structurally alter the polymerization catalyst (such as guanidine, 1,5-pentandioic acid moieties as found when a dipeptide or polypeptide TA has a glutamic acid residue on its C-terminus, or a urea linkage capable of binding to the polymerization catalyst).
- a ring opening polymerization such as an alcohol, a phenol, an amine, or a thiol
- the polymerization catalyst such as guanidine, 1,5-pentandioic acid moieties as found when a dipeptide or polypeptide TA has a glutamic acid residue on its C-terminus, or a urea linkage capable of binding to the polymerization catalyst.
- This invention also describes methods for the synthesis of covalent conjugates of heterobifunctional polyethylene glycol) and targeting agents (TA's).
- Poly(ethyleneglycol) (PEG) bearing a hydroxyl group at its ⁇ -terminus and a reactive functional group on its co-terminus such as a carboxylic acid, an aldehyde, an azide, an alkyne, a maleimido group, are described herein.
- Such heterobinfunctional PEG's may be reacted with a TA bearing an amine, a thiol, an alkyne or an azide moiety to yield a covalent conjugate of PEG and TA (HO-PEG-TA).
- Preferred reactive moieties include amine and carboxylic acid and amine and aldehyde that yield naturally occurring linkages such as amides or secondary amines.
- Scheme 3 provides chemical synthetic methodologies to enable such covalent conjugation.
- This invention also describes methods for the synthesis of HO-PEG-TA(PRO) conjugates under anhydrous organic solvent condition using the preferred amidation reaction of an amine moiety of the TA(PRO) and an acid terminus of PEG.
- Scheme 4 illustrates the method used for covalent conjugation of HO-PEG-CO 2 H to a allyl protected lysine-urea-glutamic acid (lys-urea-glu) targeting agent.
- lys-urea-glu allyl protected lysine-urea-glutamic acid
- Use of the allyl protected analog of the lys-urea-glu targeting agent improves its solubility in organic solvents most suitable (such as dichloromethane) for EDC/NHS acid activation chemistry.
- Amidation reaction under anhydrous organic solvent conditions enables a high degree of conjugation efficiency and yields over 80% end group functionalization in HO-PEG-lys-urea-glu(allyl protected). Furthermore, the allyl protected lys-urea-glu (TA(PRO)) enables the ring opening polymerization of lactone monomers without undesirable side reaction with the preferred polymerization catalyst (tin (II) 2-ethylhexanoate).
- This invention also describes methods for the synthesis of HO-PEG-TA(PRO) conjugates under organic solvent condition using reductive alkylation reaction of an amine moiety of the TA(PRO) and an aldehyde terminus of PEG.
- Scheme 5 illustrates the method used for covalent conjugation of HO-PEG-CHO to allyl protected lysine-urea-glutamic acid (TA(PRO)).
- TA(PRO) allyl protected analog of the lys-urea-glu targeting moiety improves its solubility in organic solvents (such as dichloromethane, dimethylformamide) suitable for reductive alkylation chemistry.
- Reductive alkylation under organic solvent conditions enables a high degree of conjugation efficiency and yields over 80% end group functionalization in HO-PEG-lys-urea-glu(allyl protected).
- This invention also describes the ring opening polymerization of cyclic lactone monomers using the HO-PEG-lys(urea)glu(allyl protected) (HO-PEG-TA(PRO)) conjugate as a macroinitiator and tin(II) 2-ethyl hexanoate as polymerization catalyst under monomer melt conditions at 130° C. (scheme 6), this method is also referred to as the “polymerization from” approach.
- poly(D,L-lactide)-block-poly(ethylene glycol)-lys-urea-glu(allyl protected) obtained by such polymerization is then converted to poly(D,L-lactide)-block-poly(ethylene glycol)-lys-urea-glu by removal of the allyl protecting groups using organic base (morpholine) and tetrakis(triphenylphosphine) palladium (0) as catalyst (scheme 7).
- the deprotection reaction conditions are optimized with regards to molar equivalents of morpholine, palladium catalyst and reaction time to enable quantitative removal of allyl protecting groups (>98%, determined by NMR spectroscopy), without any measurable reduction in the molar mass (as determined by size exclusion chromatography and dilute solution viscometry) of the block copolymer.
- This application also describes the removal of residual palladium from the functionalized diblock copolymer PLA-PEG-lys-urea-glu (PLA-PEG-TA).
- Scheme 8 shows the chemical structures of several commercially available resins used for scavenging palladium contaminants. Trimercaptotriazide (TMT) functional resin is preferred for the removal of palladium from PLA-PEG-lys-urea-glu samples with minimal loss of polymer yield in the palladium removal step. Yield loss is observed when resins functionalized with palladium binding moieties other than TMT are used. This is due to interaction between the resin bound palladium binding moieties and the TA in PLA-PEG-TA.
- TMT Trimercaptotriazide
- This application also describes the covalent conjugation of targeting agents (TA's) in their native unprotected form under aqueous solution conditions to heterobifunctional poly(ethylene glycol).
- This method utilizes the high water solubility of the targeting moiety such as lys-urea-glu or other peptide based targeting ligands.
- the solubility properties of the PEG-lys-urea-glu conjugate are dominated by the poly(ethylene glycol) polymer.
- PEG-lys-urea-glu is soluble in common organic solvents including but not limited to dichloromethane, dimethyl formamide, tetrahydrofuran, chloroform, or dimethylsulfoxide.
- the PEG-lys-urea-glu is covalently coupled to an end functional poly(ester) using chemistries that proceed without side reactions with the carboxylic acid moieties of lys-urea-glu.
- an ⁇ -azido- ⁇ -carboxylic acid may be conjugated to the amino moiety of the lys-urea-glu by its reaction with the carboxy terminus of such PEG.
- the targeting agent functional PEG, ⁇ -azido- ⁇ -(lys-urea-glu)polyethylene glycol may be prepared by synthesis of a heterobifunctional precursor such as ⁇ -azido- ⁇ -carboxy polyethylene glycol (N 3 -PEG-CO 2 H) from commercially available starting materials such as ⁇ -amino- ⁇ -carboxy-poly(ethylene glycol) and for example 4-azidophenyl isothiocyanate, O-(2-azidoethyl)-O-[2-diglycolyl-amino)ethyl]heptaethylene glycol or azide-PEG4-NHS using standard conjugation methodologies (scheme 9).
- the heterobifunctional polymer, N 3 -PEG-CO 2 H is subsequently reacted with the amine functionality of lys-urea-glu under aqueous conditions using methods illustrated in scheme 10.
- N 3 -PEG-NHS may be prepared by activation of the carboxy terminus of N 3 -PEG-CO 2 H under anhydrous organic solvent conditions such as in dichloromethane using organic soluble ethyldimethyl aminopropylcarbodiimide (EDC), N-hydroxysuccinimide (NHS) and diisopropyl ethylamine (DIEA) and subsequently purified by precipitation into anhydrous ether/hexane (70/30).
- EDC organic soluble ethyldimethyl aminopropylcarbodiimide
- NHS N-hydroxysuccinimide
- DIEA diisopropyl ethylamine
- the activated polymer (N 3 -PEG-NHS) is then recovered by filtration and vacuum drying and stored in a dry environment under dry nitrogen (1 ppm water dry glove box for 48 hours) prior to storage at ⁇ 20° C.
- N 3 -PEG-NHS prepared by this method is then
- this application also describes the covalent coupling of N 3 -PEG-lys-urea-glu to an end functional poly(ester) bearing a alkyne moiety at its ⁇ -terminus and a hydroxy terminus at its ⁇ -terminus using well established “click” chemistry techniques such as using a copper sulfate catalyst under organic solvent conditions, for example in dimethylformamide (DMF) (scheme 11).
- This “click” chemistry methodology is particularly useful since the carboxylic acid functionalities of lys-urea-glu are not reactive towards the alkyne functionality of the poly(ester).
- Bioactive agents include, and are not limited to, therapeutic agents (e.g. anti-cancer agents), diagnostic agents (e.g. contrast agents; radionuclides; and fluorescent, luminescent, and magnetic moieties), prophylactic agents (e.g. vaccines), and/or nutraceutical agents (e.g. vitamins, minerals, etc.).
- therapeutic agents e.g. anti-cancer agents
- diagnostic agents e.g. contrast agents; radionuclides; and fluorescent, luminescent, and magnetic moieties
- prophylactic agents e.g. vaccines
- nutraceutical agents e.g. vitamins, minerals, etc.
- bioactive agents may be administered to an individual as disclosed herein.
- Exemplary therapeutic agents to be delivered in accordance with the present invention include, but are not limited to, small molecules (e.g.
- the agent to be delivered is an agent useful in the treatment of cancer (e.g., prostate cancer).
- cancer e.g., prostate cancer
- therapeutic agents that can be delivered within the nanoparticles produced in accordance with the disclosed methods include, but are not limited to agents such as penicillins, aminopenicillins, penicillins in conjunction with penicillinase inhibitor and/or anti-fungal agents), cephalosporins, cephamycins and carbapenems, fluoroquinolones, tetracyclines, macrolides and aminoglycosides.
- erythromycin bacitracin zinc
- polymyxin polymyxin B sulfates
- neomycin gentamycin
- tobramycin gramicidin
- ciprofloxacin trimethoprim
- ofloxacin levofloxacin
- gatifloxacin moxifloxacin
- norfloxacin sodium sulfacetamide
- chloramphenicol tetracycline
- azithromycin clarithyromycin, trimethoprim sulfate and bacitracin.
- NSAIDs non-steroidal
- anti-inflammatory agents including both COX-1 and COX-2 inhibitors
- examples include, but are not limited to, corticosteroids, medrysone, prednisolone, prednisolone acetate, prednisolone sodium phosphate, fluormetholone, dexamethasone, dexamethasone sodium phosphate, betamethasone, fluoromethasone, antazoline, fluorometholone acetate, rimexolone, loteprednol etabonate, diclofenac (diclofenac sodium), ketorolac, ketorolac tromethamine, hydrocortisone, bromfenac, flurbiprofen, antazoline and xylometazoline.
- anti-histamines examples include anti-histamines, mast cell stabilizers and other anti-allergy agents.
- anti-histamines include anti-histamines, mast cell stabilizers and other anti-allergy agents.
- examples include, but are not limited, cromolyn sodium, lodoxamide tromethamine, olopatadine HCl, nedocromil sodium, ketotifen fumurate, levocabastine HCL, azelastine HCL, pemirolast (pemirolast potassium), epinastine HCL, naphazoline HCL, emedastine, antazoline, pheniramine, sodium cromoglycate, N-acetyl-aspartyl glutamic acid and amlexanox.
- anti-cancer agents such as 5-fluorouracil (5-FU), CPT-11, 10-hydroxy-7-ethylcamptothecin (SN38), S-1 capecitabine, ftorafur, 5′deoxyfluorouridine, UFT, eniluracil, deoxycytidine, 5-azacytosine, 5-azadeoxycytosine, allopurinol, 2-chloroadenosine, aminopterin, methylene-10-deazaminopterin (MDAM), oxaplatin, picoplatin, tetraplatin, satraplatin, platinum-DACH, ormaplatin, CI-973, JM-216, and analogs thereof, 9-aminocamptothecin, 10,11-methylenedioxycamptothecin, karenitecin, 9-nitrocamptothecin, TAS 103, L-phenylalanine mustard, ifosphamide
- anti-cancer agents such as 5-fluorouracil (5-FU
- the nanoparticles of this invention can contain siRNA as a therapeutic agent.
- the siRNA molecule has a length from about 10-50 or more nucleotides. More preferably, the siRNA molecule has a length from about 15-45 nucleotides. Even more preferably, the siRNA molecule has a length from about 19-40 nucleotides. Even more preferably, the siRNA molecule has a length of from about 21-23 nucleotides.
- the siRNA of the invention preferably mediates RNAi against a target mRNA.
- the siRNA molecule can be designed such that every residue is complementary to a residue in the target molecule. Alternatively, one or more substitutions can be made within the molecule to increase stability and/or enhance processing activity of said molecule. Substitutions can be made within the strand or can be made to residues at the ends of the strand.
- siRNA molecules used as therapeutic agents in the disclosed nanoparticles can be modified to improve stability either in vivo or in vitro.
- the 3′-residues may be stabilized against degradation, e.g., they may be selected such that they consist of purine nucleotides, particularly adenosine or guanosine nucleotides.
- substitution of pyrimidine nucleotides by modified analogues e.g., substitution of uridine by 2′-deoxythymidine is tolerated and does not affect the efficiency of RNA interference.
- the absence of a 2′hydroxyl may significantly enhance the nuclease resistance of the siRNAs.
- RNA expression cassettes such as those available from Ambion, Inc. (Austin, Tex.), and the Whitehead Institute of Biomedical Research at MIT (Cambridge, Mass.) allow for the design and production of siRNA.
- a desired mRNA sequence can be entered into a sequence program that will generate sense and antisense target strand sequences. These sequences can then be entered into a program that determines the sense and antisense siRNA oligonucleotide templates.
- the programs can also be used to add, e.g., hairpin inserts or T1 promoter primer sequences. Kits also can then be employed to build siRNA expression cassettes.
- siRNAs are synthesized in vivo, in situ, and in vitro.
- Endogenous RNA polymerase of the cell may mediate transcription in vivo or in situ, or cloned RNA polymerase can be used for transcription in vivo or in vitro.
- a regulatory region e.g., promoter, enhancer, silencer, splice donor and acceptor, polyadenylation
- Inhibition may be targeted by specific transcription in an organ, tissue, or cell type; stimulation of an environmental condition (e.g., infection, stress, temperature, chemical inducers); and/or engineering transcription at a developmental stage or age.
- a transgenic organism that expresses siRNAs from a recombinant construct may be produced by introducing the construct into a zygote, an embryonic stem cell, or another multipotent cell derived from the appropriate organism.
- the siRNA molecules target mRNA encoding at least one a cellular protein (e.g., a nuclear, cytoplasmic, transmembrane, or membrane-associated protein). In another embodiment, the siRNA molecules target mRNA encoding one or more extracellular protein (e.g., an extracellular matrix protein or secreted protein).
- a cellular protein e.g., a nuclear, cytoplasmic, transmembrane, or membrane-associated protein.
- the siRNA molecules target mRNA encoding one or more extracellular protein (e.g., an extracellular matrix protein or secreted protein).
- target mRNA can encode developmental proteins (e.g., adhesion molecules, cyclin kinase inhibitors, Wnt family members, Pax family members, Winged helix family members, Hox family members, cytokines/lymphokines and their receptors, growth/differentiation factors and their receptors, neurotransmitters and their receptors); oncogene-encoded proteins (e.g., ABLI, BCLI, BCL2, BCL6, CBFA2.
- developmental proteins e.g., adhesion molecules, cyclin kinase inhibitors, Wnt family members, Pax family members, Winged helix family members, Hox family members, cytokines/lymphokines and their receptors, growth/differentiation factors and their receptors, neurotransmitters and their receptors
- oncogene-encoded proteins e.g., ABLI, BCLI, BCL2, BCL6, CBFA2.
- tumor suppressor proteins e.g., APC, BRCA1, BRCA2, MADH4, MCC, NF 1, NF2, RB 1, TP53, or WTI
- enzymes e.g., ACC synthases and oxidases, ACP desaturases and hydroxylases, ADPglucose pyrophorylases, acetylases and deacetylases, ATPases, alcohol dehydrogenases, amylases, amyloglucosidases, catalases, cellulases
- Target mRNA can also encode proteins involved in tumor growth (including vascularization) or in metastatic activity or potential (e.g., cell surface receptors and their ligands).
- Target mRNA can also encode one or more secreted protein, cell cycle regulatory protein, gene regulatory protein, apoptosis regulatory protein, or proteins involved in the immune response, inflammation, complement cascade, or clotting systems.
- siRNA constructs can designed include c-myc, c-myb, mdm2, PKA-I (protein kinase A type I), Ras, c-Raf kinase, CDC25 phosphatases, cyclins, cyclin dependent kinases (cdks), telomerase, PDGF/sis and mos.
- siRNA can also be used to target the mRNA encoded by a fusion gene that results from chromosomal translocation, for example, the Bcr/Abl fusion oncogene.
- siRNA can also be targeted against mRNA encoding proteins such as cyclin dependent kinases, proliferating cell nuclear antigen (PCNA), transforming growth factor-beta (TGF-beta), nuclear factor kappa B (NF- ⁇ B), E2F, HER-2/neu, PKA, TGF-alpha, EGFR, TGF-beta, IGFIR, P12, MDM2, VEGF, MDR, transferring, ferritin, ferritin receptor, transferrin receptor, IRE, C-fos, HSP27, metallothionein.
- proteins such as cyclin dependent kinases, proliferating cell nuclear antigen (PCNA), transforming growth factor-beta (TGF-beta), nuclear factor kappa B (NF- ⁇ B), E2F, HER-2/neu, PKA, TGF-alpha, EGFR, TGF-beta, IGFIR, P12, MDM2, VEGF, MDR, transferring
- nanoparticles produced by the instant invention can also incorporate one or more targeting agent via the functionalized PEG moieties.
- Suitable targeting agents include, for example, antibodies and polypeptides that bind to polypeptides that are commonly overexpressed by tumor or cancer cells.
- Non-limiting examples of such polypeptides are epidermal growth factor receptor (EGFR), somatostatin receptor (SSTR), insulin-like growth factor receptor, folic acid-receptor, HER 2 receptor, interleukin-13 receptor, gastrin-releasing peptide receptor, CD30, vasoactive intestinal peptide receptor, gastrin receptor, prostate-specific antigen, and the estrogen receptor.
- small molecule ligands can be used to target cancers that express particular target proteins.
- PSMA prostate specific membrane antigen
- the low-molecular weight PSMA ligand is of the Formulae I, II, III or IV:
- n are each, independently, 0, 1, 2 or 3;
- p is 0 or 1;
- R 1 , R 2 , R 4 and R 5 are each, independently, selected from the group consisting of substituted or unsubstituted alkyl (e.g., C 1-10 -alkyl, C 1-6 -alkyl, or C i-4 -alkyl), substituted or unsubstituted aryl (e.g., phenyl or pyrdinyl), and any combination thereof; and
- R 3 is H or C 1-6 -alkyl (e.g., CH 3 ).
- R 1 , R 2 , R 4 and R 5 comprise points of attachment to the nanoparticle within the PEG portion of the nanoparticle.
- the point of attachment may be formed by a covalent bond, ionic bond, hydrogen bond, a bond formed by adsorption including chemical adsorption and physical adsorption, a bond formed from van der Waals bonds, or dispersion forces.
- any hydrogen (e.g., an amino hydrogen) of these functional groups could be removed such that the low-molecular weight PSMA ligand is covalently bound to the polymeric matrix (e.g., the PEG-block of the polymeric matrix) of the nanoparticle.
- covalent bond refers to a bond between two atoms formed by sharing at least one pair of electrons.
- R 1 , R 2 , R 4 and R 5 are each, independently, C 1-6 -alkyl or phenyl, or any combination of C 1-6 -alkyl or phenyl, which are independently substituted one or more times with OH, SH, NH 2 , or CO 2 H, and wherein the alkyl group may be interrupted by N(H), S or O.
- R 1 , R 2 , R 4 and R 5 are each, independently, CH 2 -Ph, (CH 2 ) 2 —SH, CH 2 —SH, (CH 2 ) 2 C(H)(NH 2 )CO 2 H, CH 2 C(H)(NH 2 )CO 2 H, CH(NH 2 )CH 2 CO 2 H, (CH 2 ) 2 C(H)(SH)CO 2 H, CH 2 —N(H)-Ph, O—CH 2 -Ph, or O—(CH 2 ) 2 -Ph, wherein each Ph may be independently substituted one or more times with OH, NH 2 , CO 2 H or SH.
- the NH 2 , OH or SH groups serve as the point of covalent attachment to the nanoparticle (e.g., —N(H)-PEG, —O-PEG, or S-PEG).
- the low-molecular weight PSMA ligand is selected from the group consisting of
- NH 2 , OH or SH groups serve as the point of covalent attachment to the nanoparticle (e.g., —N(H)-PEG, —O-PEG, or S-PEG).
- the low-molecular weight PSMA ligand is selected from the group consisting of
- R is independently selected from the group consisting of NH 2 , SH, OH, CO 2 H, C 1-6 -alkyl that is substituted with NH 2 , SH, OH or CO 2 H, and phenyl that is substituted with NH 2 , SH, OH or CO 2 H, and wherein R serves as the point of covalent attachment to the nanoparticle (e.g., —N(H)-PEG, S-PEG, —O-PEG, or CO 2 -PEG).
- the low-molecular weight PSMA ligand is selected from the group consisting of
- NH 2 or CO 2 H groups serve as the point of covalent attachment to the nanoparticle (e.g., —N(H)-PEG, or CO 2 -PEG).
- these compounds may be further substituted with NH 2 , SH, OH, CO 2 H, C 1-6 -alkyl that is substituted with NH 2 , SH, OH or CO 2 H, or phenyl that is substituted with NH 2 , SH, OH or CO 2 H, wherein these functional groups can also serve as the point of covalent attachment to the nanoparticle.
- the low-molecular weight PSMA ligand is
- the NH 2 group serves as the point of covalent attachment to the nanoparticle (e.g., —N(H)-PEG).
- the low-molecular weight PSMA ligand is
- the butyl-amine compound has the advantage of ease of synthesis, especially because of its lack of a benzene ring. Furthermore, without wishing to be bound by theory, the butyl-amine compound will likely break down into naturally occurring molecules (i.e., lysine and glutamic acid), thereby minimizing toxicity concerns.
- the NH 2 groups serve as the point of covalent attachment to the nanoparticle (e.g., —N(H)-PEG). Accordingly, the present invention provides the low-molecular weight PSMA ligands shown above, wherein the amine substituents of the compounds are covalently bound to polyethylene glycol), e.g., the
- n 20 to 1720.
- Another aspect of the invention provides for a PEG polymer conjugated to a targeting agents and/or bioactive moieties/therapeutic agents as disclosed herein.
- the nanoparticles produced in accordance with the disclosed methods can be administered alone or in a composition.
- the composition can be a pharmaceutical (e.g., physiologically acceptable) composition.
- the composition comprises a carrier (e.g., a pharmaceutically or physiologically acceptable carrier) and the nanoparticles.
- a carrier e.g., a pharmaceutically or physiologically acceptable carrier
- Any suitable carrier e.g., water, saline, and PBS
- the choice of carrier will be determined, in part, by the particular site to which the composition is to be administered and the particular method used to administer the composition.
- compositions of the invention are known in the art (e.g., Remington's Pharmaceutical Sciences, 17th ed., (Mack Publishing Company, Philadelphia, Pa.: 1985)). Additionally, the composition can comprise additional active agents, such as anti-cancer/chemotherapeutic agents.
- the nanoparticles and composition thereof can be administered to a subject to treat or prevent particular disorders and diseases.
- diseases or disorders include cancer, such as lung cancer, breast cancer, prostate cancer, head and neck cancer, ovarian cancer, skin cancer, testicular cancer, pancreatic cancer, esophageal cancer, colorectal cancer, kidney cancer, cervical cancer, gastrointestinal cancer, and combinations thereof.
- the nanoparticles or the composition thereof preferably are administered to the subject in a therapeutically effective amount.
- a therapeutically effective amount refers to an amount of the nanoparticles necessary to treat or prevent the particular disease or disorder.
- nanoparticles disclosed herein can be used to inhibit tumor growth, inhibit or reduce proliferation, invasiveness, or metastasis of tumor or cancer cells, slow the growth of tumors or cancers or reduce the size of tumors.
- Suitable routes of administration can be used to deliver the nanoparticles to the subject.
- Suitable administration routes include intramuscular injection, transdermal administration, inhalation, topical application to tissue (e.g., tumor/cancer tissue), intratumoral administration, and parenteral administration (e.g., intravenous, peritoneal, intraarterial, subcutaneous, rectal, or vaginal, administration).
- tissue e.g., tumor/cancer tissue
- parenteral administration e.g., intravenous, peritoneal, intraarterial, subcutaneous, rectal, or vaginal, administration.
- An appropriate administration route easily can be determined by those skilled in the art.
- compositions comprising nanoparticles can be useful in the treatment or prevention or amelioration of one or more symptoms of cancer, particularly cancers that express prostate specific membrane antigen (PSMA).
- PSMA prostate specific membrane antigen
- cancers include, but are not limited to, prostate cancer, non-small cell lung cancer, colorectal carcinoma, and glioblastoma, and solid tumors expressing PSMA in the tumor neovasculature.
- a method of preparing a nanoparticle comprising:
- the PEG polymer has a molecular weight of between 1,000-20,000 Da (e.g., 5,000-20,000, e.g., 10,000-20,000) and, in some specific embodiments, 5000 Da; and the second polymer has a molecular weight of 5,000-100,000 Da (e.g., 20,000-70,000, e.g., 20,000-50,000), or in some specific embodiments, 15,000-30,000 Da;
- the second polymer comprises a blend of two or more polymers and contains at least one functional group that reacts the functional group present at the free ⁇ terminus of said poly(ethylene glycol) and said at least one functional group of said blend of two or more polymers is a hydroxyl group, a NHS group or an amine group;
- the second polymer or the copolymer is a polyester copolymer that contains at least one functional group selected from a hydroxyl group, a NHS group or an amine group and that reacts the functional group present at the free ⁇ terminus of said poly(ethylene glycol);
- polyester copolymer comprises a heteropolymer or a homopolymer
- heteropolymer comprises lactic acid and glycolic acid units or poly(lactic acid-co-glycolic acid) and poly(lactide-co-glycolide) units (PLGA); and said homopolymer comprises glycolic acid units (PGA), lactic acid units (PLA), poly-L-lactic acid units, poly-D-lactic acid units, poly-D,L-lactic acid units, poly-L-lactide units, poly-D-lactide units or poly-D,L-lactide units;
- polyester copolymer is selected from polyhydroxyacids; PEGylated polymers and copolymers of lactide units and glycolide units, PEGylated PLA, PEGylated PGA, PEGylated PLGA, polyanhydrides, poly(ortho ester) PEGylated poly(ortho ester), poly(caprolactone), PEGylated poly(caprolactone), polylysine, PEGylated polylysine, poly(ethylene inline), PEGylated poly(ethylene imine), poly(L-lactide-co-L-lysine), poly(serine ester), poly(4-hydroxy-L-proline ester), poly[a-(4-aminobutyl)-L-glycolic acid] or derivatives thereof;
- said second polymer is a blend of at least two polymers which can be the same or different polymer, wherein the first of said at least two polymers contains at least one hydroxyl group or an NHS group as a functional group and the second of said at least two polymers contains at least one amine group as said functional group;
- said therapeutic agent is an antibiotic, anti-cancer agent, antiviral agent, anti-inflammatory agent a diagnostic agent, a vaccine antigen or a nutraceutical;
- said therapeutic agent is/are penicillins, aminopenicillins, penicillins in conjunction with penicillinase inhibitor and/or anti-fungal agents, cephalosporins, cephamycins, carbapenems, fluoroquinolones, tetracyclines, macrolides, aminoglycosides, erythromycin, bacitracin zinc, polymyxin, polymyxin B sulfates, neomycin, gentamycin, tobramycin, gramicidin, ciprofloxacin, trimethoprim, ofloxacin, levofloxacin, gatifloxacin, moxifloxacin, norfloxacin, sodium sulfacetamide, chloramphenicol, tetracycline, azithromycin, clarithyromycin, trimethoprim sulfate, bacitracin, corticosteroids, medrysone, prednisolone, prednisol
- said at least one targeting agent is selected from antibodies, PMSA ligands and polypeptides that bind to epidermal growth factor receptor (EGFR), somatostatin receptor (SSTR), insulin-like growth factor receptor, folic acid-receptor, HER2 receptor, interleukin-13 receptor, gastrin-releasing peptide receptor, CD30, vasoactive intestinal peptide receptor, gastrin receptor, prostate-specific antigen, and/or the estrogen receptor;
- EGFR epidermal growth factor receptor
- SSTR somatostatin receptor
- insulin-like growth factor receptor folic acid-receptor
- HER2 receptor interleukin-13 receptor
- gastrin-releasing peptide receptor CD30
- vasoactive intestinal peptide receptor gastrin receptor
- gastrin receptor prostate-specific antigen, and/or the estrogen receptor
- composition comprising the nanoparticle of embodiment 21 and a pharmaceutically acceptable carrier
- a method of treating a disease comprising the administration of a nanoparticle according of embodiment 21 to a subject in an amount sufficient to treat said disease;
- HO-PEG-lys-urea-glu protected
- Solution C was diafiltered against 29 dia-volumes (1.5 L) of binary solvent mixture of ethanol/chloroform (9:1 by volume) at a flow rate of 800 mL/min and a 30-40 psi back pressure applied by appropriately adjusting a 1 ⁇ 4 turn ball valve. Under these UFDF conditions, the permeate flow rate is approximately 5 mL/min.
- Solvent was removed from the retentate solution (solution CR) by rotary evaporation at 35° C. and subsequently vacuum dried at room temperature of 18 hours to obtain crude product (770 mg, 70%). Crude product was dissolved in 7.7 mL of chloroform (100 mg/mL, solution D).
- Solution D was added drop-wise to 150 ml of ether/hexane (70/30) precipitant while stirring.
- the precipitated product was recovered by filtration using 0.2 micron PTFE membrane filter in a Millipore vacuum filtration apparatus.
- Purified product, HO-PEG-lys-urea-glu (protected) (white powder, 700 mg, 91%) was obtained by vacuum drying at room temperature for 24 hours to remove residual solvents.
- Lys-urea-glu incorporation into HO-PEG-lys-urea-glu (protected) product was estimated using the ratio the ligand multiplet between 1.95-2.1 ppm and PEG multiplet between 2.15-2.3 ppm yielding 82% incorporation of lys-urea-glu (protected) into HO-PEG-lys-urea-glu (protected) conjugate.
- PLA-PEG-lys-urea-glu protected
- Materials used in the synthesis of PLA-PEG-lys-urea-glu included HO-PEG-lys-urea-glu (protected), synthesized as described in Example 1; Tin (II) 2-ethylhexanoate (95%) (Sn(Oct) 2 , Sigma-Aldrich); D,L-lactide ( ⁇ 99.5%, Altasorb, Piedmont, S.C.); Hexane, anhydrous (95% DriSolv, EMD) in polymerization reaction and Hexane (Chromasolv., ⁇ 95%, Sigma) for work-up precipitation; Diethyl ether ( ⁇ 99.0%, Sigma);
- Instrumentation used for In-process characterization and reaction/work-up of PLA-PEG-lys-urea-glu included a Bruker 400 MHz Nuclear Magnetic Resonance Spectrometer for Proton NMR Spectroscopic Analysis at Spectral Data Services, Champaign, Ill.; Vacuum atmospheres dry nitrogen glove box ( ⁇ 1 ppm water); 12-place parallel reaction carusel (Brinkmann-Hiedolph) equipped with a multi-position stir plate and solid state temperature controller (IKA multi-stir plate and temperature controller with feed-back loop; Schlenk reaction tubes equipped with a Teflon stop cock side arm.
- Sn(Oct) 2 250 mg was weighed into a 6 mL glass vial and dissolved in anhydrous hexane (2.5 mL) to yield a 100 mg/mL solution (B) and septum sealed under dry nitrogen.
- Mixture A was removed to a vented fume hood and dried under a steady stream of dry argon for 1 hour at room temperature using argon gas manifold equipped with a 8 inch needles as argon gas inlets.
- Schlenk reaction tube side arms were connected to a silicone oil bubbler to serve as argon gas outlet.
- the Schlenk tubes were subsequently sealed by stopping the inlet argon flow from the argon gas manifold and the side arm gas outlet through the schlenk tube side arm using the Teflon stop cork. Sealed Schlenk tubes were placed in a 130° C. silicone oil bath and magnetically stirrer to obtain a clear colorless lactide monomer melt (about 10 minutes).
- Solution B 80 uL was introduced via a 500 uL syringe via the septum seal.
- the reaction mixture (C) was allowed to stir at 130° C. for 16 hours. Reaction mixture C was cooled to room temperature, Schlenk tube opened in air and polymer pellet dissolved in 5 mL dichloromethane by vortexing for 1 hour at room temperature (solution D).
- Solution D was transferred to a 20 mL glass vial and Schlenk tube rinsed with 2 ⁇ 2.5 mL portion of fresh dichloromethane. The washing were combined with solution D. This slightly turbid solution was filtered using 0.45 micron PTFE syringe filters to obtain a clear colorless solution (Solution E).
- Solution E was added drop-wise to diethyl ether/hexane (70/30) (200 mL) while stirring at room temperature. The cloudy precipitate was allowed to stir at room temperature for 2 hours to allow polymer to coagulate and settle to the bottom of the beaker. The clear supernatant was decanted and the tacky polymer product (700 mg, 70%) was transferred to glass vial using spatula and subsequently dried under vacuum at room temperature for 18 hours.
- PLA-PEG-lys-urea-glu Materials used for the synthesis of PLA-PEG-lys-urea-glu included PLA-PEG-lys-urea-glu (protected), synthesized as described in example 3;
- Tetrakis(triphenylphosphene)palladium(0)(99%) (Pd-tetrakis, Sigma); Morpholine (99.5%, Sigma); Dichloromethane (Anhydrous, ⁇ 99.8%, Sigma); Diethyl ether ( ⁇ 99.0%, Sigma); Hexane (Chromasolv., ⁇ 95%, Sigma).
- Instrumentation and equipment used for work-up procedures and in-process characterization included a Bruker 400 MHz Nuclear Magnetic Resonance Spectrometer for Proton NMR Spectroscopic Analysis; Edwards RV5 Vacuum Pump and a VWR Oven for Vacuum Drying; Rotary Evaporator (Buchi).
- PLA-PEG-lys-urea-glu (1050 mg) was dissolved in dichloromethane (30 mL) to yield a 35 mg/mL solution.
- Palladium scavenging resin (TMT, 5 g in 60 mL column) was solvated with dichloromethane (10 mL) and PLA-PEG-lys-urea-glu solution (30 mL) added.
- Eluant was collected under gravity and column rinsed with additional dichloromethane (40 mL). Main and rinse eluant fractions combined and solvent removed by rotary evaporation to recover polymer.
- Polymer was subsequently dissolved in dichloromethane (10.5 mL, 100 mg/mL solution) and added dropwise to 70/30 ether/hexane (210 mL). The resulting polymer suspension was allowed to stir at room temperature for 2 hours allowing it to coagulate and settle to the bottom of the beaker. The clear supernatant was decanted off and the tacky PLA-PEG-lys-urea-glu polymer was transferred using spatula to a glass vial (940 mg, 90%).
- the efficiency of deprotection reaction was also determined by NMR as 95% (allyl removal). This was calculated using the ratio of the intensity of the residual allyl peak in the product PLA-PEG-lys-urea-glu spectrum to that of the corresponding peak in the starting material (PLA-PEG-lys-urea-glu (protected)) spectrum.
- the molar mass of PLA-PEG-lys-urea-glu was estimated by measurement of inherent viscometry (IV) in dimethylsulfoxide and chloroform (0.309 dL/g and 0.198 dL/g, respectively).
- the I.V. of the protected precursor PLA-PEG-lys-urea-glu (protected) was determined in dimethylsulfoxide (0.217 dL/g).
- a minor drop in viscosity from 0.217 dL to 0.198 dL/g was observed and may be attributed to differences in polymer solvent interactions as a result of the more polar nature of lys-urea-glu relative to the allyl protected precursor.
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Cited By (113)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20100044650A1 (en) * | 2008-08-25 | 2010-02-25 | Lavrentovich Oleg D | nanoparticle composition, a device and a method thereof |
US20100069426A1 (en) * | 2008-06-16 | 2010-03-18 | Zale Stephen E | Therapeutic polymeric nanoparticles with mTor inhibitors and methods of making and using same |
US20100068285A1 (en) * | 2008-06-16 | 2010-03-18 | Zale Stephen E | Drug Loaded Polymeric Nanoparticles and Methods of Making and Using Same |
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US8518963B2 (en) | 2009-12-15 | 2013-08-27 | Bind Therapeutics, Inc. | Therapeutic polymeric nanoparticle compositions with high glass transition temperature or high molecular weight copolymers |
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US8895610B1 (en) | 2007-05-18 | 2014-11-25 | Heldi Kay | Platinum (IV) compounds targeting zinc finger domains |
WO2014191502A1 (en) | 2013-05-28 | 2014-12-04 | Sinvent As | Process for preparing stealth nanoparticles |
WO2015006747A2 (en) | 2013-07-11 | 2015-01-15 | Moderna Therapeutics, Inc. | Compositions comprising synthetic polynucleotides encoding crispr related proteins and synthetic sgrnas and methods of use. |
US20150037419A1 (en) * | 2012-02-28 | 2015-02-05 | Sanofi | Functional PLA-PEG Copolymers, the Nanoparticles Thereof, Their Preparation and Use for Targeted Drug Delivery and Imaging |
WO2015034925A1 (en) | 2013-09-03 | 2015-03-12 | Moderna Therapeutics, Inc. | Circular polynucleotides |
WO2015034928A1 (en) | 2013-09-03 | 2015-03-12 | Moderna Therapeutics, Inc. | Chimeric polynucleotides |
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US9198874B2 (en) | 2008-12-15 | 2015-12-01 | Bind Therapeutics, Inc. | Long circulating nanoparticles for sustained release of therapeutic agents |
WO2016014846A1 (en) | 2014-07-23 | 2016-01-28 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of intrabodies |
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US9314532B2 (en) | 2012-08-10 | 2016-04-19 | University Of North Texas Health Science Center | Drug delivery vehicle |
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WO2017112943A1 (en) | 2015-12-23 | 2017-06-29 | Modernatx, Inc. | Methods of using ox40 ligand encoding polynucleotides |
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US9877923B2 (en) | 2012-09-17 | 2018-01-30 | Pfizer Inc. | Process for preparing therapeutic nanoparticles |
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WO2018213789A1 (en) | 2017-05-18 | 2018-11-22 | Modernatx, Inc. | Modified messenger rna comprising functional rna elements |
WO2018213731A1 (en) | 2017-05-18 | 2018-11-22 | Modernatx, Inc. | Polynucleotides encoding tethered interleukin-12 (il12) polypeptides and uses thereof |
CN109010845A (zh) * | 2018-09-28 | 2018-12-18 | 青岛大学 | 一种抗肿瘤药物的改性方法 |
WO2018232006A1 (en) | 2017-06-14 | 2018-12-20 | Modernatx, Inc. | Polynucleotides encoding coagulation factor viii |
US10213448B2 (en) | 2016-03-25 | 2019-02-26 | Novazoi Theranostics | Ethanolamine-based lipid biosynthetic compounds, method of making and use thereof |
US10221127B2 (en) | 2015-06-29 | 2019-03-05 | Acuitas Therapeutics, Inc. | Lipids and lipid nanoparticle formulations for delivery of nucleic acids |
WO2019048645A1 (en) | 2017-09-08 | 2019-03-14 | Mina Therapeutics Limited | STABILIZED COMPOSITIONS OF SMALL ACTIVATOR RNA (PARNA) FROM CEBPA AND METHODS OF USE |
WO2019048631A1 (en) | 2017-09-08 | 2019-03-14 | Mina Therapeutics Limited | SMALL HNF4A ACTIVATOR RNA COMPOSITIONS AND METHODS OF USE |
CN109771658A (zh) * | 2017-11-14 | 2019-05-21 | 博瑞生物医药(苏州)股份有限公司 | 靶向多臂偶联物 |
WO2019104152A1 (en) | 2017-11-22 | 2019-05-31 | Modernatx, Inc. | Polynucleotides encoding ornithine transcarbamylase for the treatment of urea cycle disorders |
WO2019104195A1 (en) | 2017-11-22 | 2019-05-31 | Modernatx, Inc. | Polynucleotides encoding propionyl-coa carboxylase alpha and beta subunits for the treatment of propionic acidemia |
WO2019104160A2 (en) | 2017-11-22 | 2019-05-31 | Modernatx, Inc. | Polynucleotides encoding phenylalanine hydroxylase for the treatment of phenylketonuria |
WO2019136241A1 (en) | 2018-01-05 | 2019-07-11 | Modernatx, Inc. | Polynucleotides encoding anti-chikungunya virus antibodies |
WO2019197845A1 (en) | 2018-04-12 | 2019-10-17 | Mina Therapeutics Limited | Sirt1-sarna compositions and methods of use |
WO2019200171A1 (en) | 2018-04-11 | 2019-10-17 | Modernatx, Inc. | Messenger rna comprising functional rna elements |
WO2019217964A1 (en) | 2018-05-11 | 2019-11-14 | Lupagen, Inc. | Systems and methods for closed loop, real-time modifications of patient cells |
WO2019226650A1 (en) | 2018-05-23 | 2019-11-28 | Modernatx, Inc. | Delivery of dna |
WO2020023390A1 (en) | 2018-07-25 | 2020-01-30 | Modernatx, Inc. | Mrna based enzyme replacement therapy combined with a pharmacological chaperone for the treatment of lysosomal storage disorders |
WO2020033791A1 (en) | 2018-08-09 | 2020-02-13 | Verseau Therapeutics, Inc. | Oligonucleotide compositions for targeting ccr2 and csf1r and uses thereof |
WO2020047201A1 (en) | 2018-09-02 | 2020-03-05 | Modernatx, Inc. | Polynucleotides encoding very long-chain acyl-coa dehydrogenase for the treatment of very long-chain acyl-coa dehydrogenase deficiency |
WO2020056239A1 (en) | 2018-09-14 | 2020-03-19 | Modernatx, Inc. | Polynucleotides encoding uridine diphosphate glycosyltransferase 1 family, polypeptide a1 for the treatment of crigler-najjar syndrome |
WO2020056147A2 (en) | 2018-09-13 | 2020-03-19 | Modernatx, Inc. | Polynucleotides encoding glucose-6-phosphatase for the treatment of glycogen storage disease |
WO2020056155A2 (en) | 2018-09-13 | 2020-03-19 | Modernatx, Inc. | Polynucleotides encoding branched-chain alpha-ketoacid dehydrogenase complex e1-alpha, e1-beta, and e2 subunits for the treatment of maple syrup urine disease |
WO2020069169A1 (en) | 2018-09-27 | 2020-04-02 | Modernatx, Inc. | Polynucleotides encoding arginase 1 for the treatment of arginase deficiency |
WO2020097409A2 (en) | 2018-11-08 | 2020-05-14 | Modernatx, Inc. | Use of mrna encoding ox40l to treat cancer in human patients |
WO2020114390A1 (en) * | 2018-12-03 | 2020-06-11 | Master Dynamic Limited | Nanoparticle Delivery System |
WO2020208361A1 (en) | 2019-04-12 | 2020-10-15 | Mina Therapeutics Limited | Sirt1-sarna compositions and methods of use |
WO2020227642A1 (en) | 2019-05-08 | 2020-11-12 | Modernatx, Inc. | Compositions for skin and wounds and methods of use thereof |
WO2020263985A1 (en) | 2019-06-24 | 2020-12-30 | Modernatx, Inc. | Messenger rna comprising functional rna elements and uses thereof |
WO2020263883A1 (en) | 2019-06-24 | 2020-12-30 | Modernatx, Inc. | Endonuclease-resistant messenger rna and uses thereof |
WO2021061707A1 (en) | 2019-09-23 | 2021-04-01 | Omega Therapeutics, Inc. | Compositions and methods for modulating apolipoprotein b (apob) gene expression |
WO2021061815A1 (en) | 2019-09-23 | 2021-04-01 | Omega Therapeutics, Inc. | COMPOSITIONS AND METHODS FOR MODULATING HEPATOCYTE NUCLEAR FACTOR 4-ALPHA (HNF4α) GENE EXPRESSION |
WO2021183720A1 (en) | 2020-03-11 | 2021-09-16 | Omega Therapeutics, Inc. | Compositions and methods for modulating forkhead box p3 (foxp3) gene expression |
WO2021247507A1 (en) | 2020-06-01 | 2021-12-09 | Modernatx, Inc. | Phenylalanine hydroxylase variants and uses thereof |
WO2022104131A1 (en) | 2020-11-13 | 2022-05-19 | Modernatx, Inc. | Polynucleotides encoding cystic fibrosis transmembrane conductance regulator for the treatment of cystic fibrosis |
WO2022122872A1 (en) | 2020-12-09 | 2022-06-16 | Ucl Business Ltd | Therapeutics for the treatment of neurodegenerative disorders |
US11453639B2 (en) | 2019-01-11 | 2022-09-27 | Acuitas Therapeutics, Inc. | Lipids for lipid nanoparticle delivery of active agents |
WO2022204380A1 (en) | 2021-03-24 | 2022-09-29 | Modernatx, Inc. | Lipid nanoparticles containing polynucleotides encoding propionyl-coa carboxylase alpha and beta subunits and uses thereof |
WO2022204371A1 (en) | 2021-03-24 | 2022-09-29 | Modernatx, Inc. | Lipid nanoparticles containing polynucleotides encoding glucose-6-phosphatase and uses thereof |
WO2022204390A1 (en) | 2021-03-24 | 2022-09-29 | Modernatx, Inc. | Lipid nanoparticles containing polynucleotides encoding phenylalanine hydroxylase and uses thereof |
WO2022200810A1 (en) | 2021-03-26 | 2022-09-29 | Mina Therapeutics Limited | Tmem173 sarna compositions and methods of use |
WO2022204369A1 (en) | 2021-03-24 | 2022-09-29 | Modernatx, Inc. | Polynucleotides encoding methylmalonyl-coa mutase for the treatment of methylmalonic acidemia |
WO2022204370A1 (en) | 2021-03-24 | 2022-09-29 | Modernatx, Inc. | Lipid nanoparticles and polynucleotides encoding ornithine transcarbamylase for the treatment of ornithine transcarbamylase deficiency |
EP4074834A1 (en) | 2012-11-26 | 2022-10-19 | ModernaTX, Inc. | Terminally modified rna |
WO2022240806A1 (en) | 2021-05-11 | 2022-11-17 | Modernatx, Inc. | Non-viral delivery of dna for prolonged polypeptide expression in vivo |
WO2022266083A2 (en) | 2021-06-15 | 2022-12-22 | Modernatx, Inc. | Engineered polynucleotides for cell-type or microenvironment-specific expression |
WO2022271776A1 (en) | 2021-06-22 | 2022-12-29 | Modernatx, Inc. | Polynucleotides encoding uridine diphosphate glycosyltransferase 1 family, polypeptide a1 for the treatment of crigler-najjar syndrome |
WO2023283359A2 (en) | 2021-07-07 | 2023-01-12 | Omega Therapeutics, Inc. | Compositions and methods for modulating secreted frizzled receptor protein 1 (sfrp1) gene expression |
WO2023006999A2 (en) | 2021-07-30 | 2023-02-02 | CureVac SE | Mrnas for treatment or prophylaxis of liver diseases |
EP4144378A1 (en) | 2011-12-16 | 2023-03-08 | ModernaTX, Inc. | Modified nucleoside, nucleotide, and nucleic acid compositions |
EP4159741A1 (en) | 2014-07-16 | 2023-04-05 | ModernaTX, Inc. | Method for producing a chimeric polynucleotide encoding a polypeptide having a triazole-containing internucleotide linkage |
WO2023056044A1 (en) | 2021-10-01 | 2023-04-06 | Modernatx, Inc. | Polynucleotides encoding relaxin for the treatment of fibrosis and/or cardiovascular disease |
WO2023099884A1 (en) | 2021-12-01 | 2023-06-08 | Mina Therapeutics Limited | Pax6 sarna compositions and methods of use |
WO2023104964A1 (en) | 2021-12-09 | 2023-06-15 | Ucl Business Ltd | Therapeutics for the treatment of neurodegenerative disorders |
WO2023144193A1 (en) | 2022-01-25 | 2023-08-03 | CureVac SE | Mrnas for treatment of hereditary tyrosinemia type i |
WO2023161350A1 (en) | 2022-02-24 | 2023-08-31 | Io Biotech Aps | Nucleotide delivery of cancer therapy |
WO2023170435A1 (en) | 2022-03-07 | 2023-09-14 | Mina Therapeutics Limited | Il10 sarna compositions and methods of use |
WO2023183909A2 (en) | 2022-03-25 | 2023-09-28 | Modernatx, Inc. | Polynucleotides encoding fanconi anemia, complementation group proteins for the treatment of fanconi anemia |
WO2023196399A1 (en) | 2022-04-06 | 2023-10-12 | Modernatx, Inc. | Lipid nanoparticles and polynucleotides encoding argininosuccinate lyase for the treatment of argininosuccinic aciduria |
WO2023215498A2 (en) | 2022-05-05 | 2023-11-09 | Modernatx, Inc. | Compositions and methods for cd28 antagonism |
US11820728B2 (en) | 2017-04-28 | 2023-11-21 | Acuitas Therapeutics, Inc. | Carbonyl lipids and lipid nanoparticle formulations for delivery of nucleic acids |
WO2024026254A1 (en) | 2022-07-26 | 2024-02-01 | Modernatx, Inc. | Engineered polynucleotides for temporal control of expression |
US11976019B2 (en) | 2020-07-16 | 2024-05-07 | Acuitas Therapeutics, Inc. | Cationic lipids for use in lipid nanoparticles |
WO2024097639A1 (en) | 2022-10-31 | 2024-05-10 | Modernatx, Inc. | Hsa-binding antibodies and binding proteins and uses thereof |
WO2024118866A1 (en) | 2022-12-01 | 2024-06-06 | Modernatx, Inc. | Gpc3-specific antibodies, binding domains, and related proteins and uses thereof |
WO2024130158A1 (en) | 2022-12-16 | 2024-06-20 | Modernatx, Inc. | Lipid nanoparticles and polynucleotides encoding extended serum half-life interleukin-22 for the treatment of metabolic disease |
WO2024134199A1 (en) | 2022-12-22 | 2024-06-27 | Mina Therapeutics Limited | Chemically modified sarna compositions and methods of use |
Families Citing this family (71)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20100104645A1 (en) * | 2008-06-16 | 2010-04-29 | Bind Biosciences, Inc. | Methods for the preparation of targeting agent functionalized diblock copolymers for use in fabrication of therapeutic targeted nanoparticles |
CN101773675B (zh) * | 2010-03-05 | 2012-05-30 | 中山大学 | 一种负载液态氟碳的聚合物纳米超声显像囊泡及其制备方法 |
WO2011119262A1 (en) | 2010-03-26 | 2011-09-29 | Cerulean Pharma Inc. | Methods and systems for generating nanoparticles |
WO2011119995A2 (en) | 2010-03-26 | 2011-09-29 | Cerulean Pharma Inc. | Formulations and methods of use |
US8822663B2 (en) | 2010-08-06 | 2014-09-02 | Moderna Therapeutics, Inc. | Engineered nucleic acids and methods of use thereof |
HUE058896T2 (hu) | 2010-10-01 | 2022-09-28 | Modernatx Inc | N1-metil-pszeudo-uracilt tartalmazó ribonukleinsavak és azok felhasználásai |
CN103561726A (zh) | 2010-11-18 | 2014-02-05 | 通用医疗公司 | 用于癌症治疗的抗高血压剂的新型组合物和用途 |
WO2012103182A1 (en) | 2011-01-28 | 2012-08-02 | Cerulean Pharma Inc. | Method for fabricating nanoparticles |
US8710200B2 (en) | 2011-03-31 | 2014-04-29 | Moderna Therapeutics, Inc. | Engineered nucleic acids encoding a modified erythropoietin and their expression |
US9464124B2 (en) | 2011-09-12 | 2016-10-11 | Moderna Therapeutics, Inc. | Engineered nucleic acids and methods of use thereof |
RS62993B1 (sr) | 2011-10-03 | 2022-03-31 | Modernatx Inc | Modifikovani nukleozidi, nukleotidi, i nukleinske kiseline, i njihove upotrebe |
PT2782584T (pt) | 2011-11-23 | 2021-09-02 | Therapeuticsmd Inc | Preparações e terapias de substituição para hormonoterapias naturais combinadas |
US9301920B2 (en) | 2012-06-18 | 2016-04-05 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
US9283287B2 (en) | 2012-04-02 | 2016-03-15 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of nuclear proteins |
US9303079B2 (en) | 2012-04-02 | 2016-04-05 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins |
US9572897B2 (en) | 2012-04-02 | 2017-02-21 | Modernatx, Inc. | Modified polynucleotides for the production of cytoplasmic and cytoskeletal proteins |
US20150196640A1 (en) | 2012-06-18 | 2015-07-16 | Therapeuticsmd, Inc. | Progesterone formulations having a desirable pk profile |
US10806697B2 (en) | 2012-12-21 | 2020-10-20 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US10806740B2 (en) | 2012-06-18 | 2020-10-20 | Therapeuticsmd, Inc. | Natural combination hormone replacement formulations and therapies |
US20130338122A1 (en) | 2012-06-18 | 2013-12-19 | Therapeuticsmd, Inc. | Transdermal hormone replacement therapies |
US9180091B2 (en) | 2012-12-21 | 2015-11-10 | Therapeuticsmd, Inc. | Soluble estradiol capsule for vaginal insertion |
US10537581B2 (en) | 2012-12-21 | 2020-01-21 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US11266661B2 (en) | 2012-12-21 | 2022-03-08 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US11246875B2 (en) | 2012-12-21 | 2022-02-15 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US10471072B2 (en) | 2012-12-21 | 2019-11-12 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US10568891B2 (en) | 2012-12-21 | 2020-02-25 | Therapeuticsmd, Inc. | Vaginal inserted estradiol pharmaceutical compositions and methods |
US9784730B2 (en) | 2013-03-21 | 2017-10-10 | University Of Washington Through Its Center For Commercialization | Nanoparticle for targeting brain tumors and delivery of O6-benzylguanine |
WO2015036792A1 (en) | 2013-09-16 | 2015-03-19 | Astrazeneca Ab | Therapeutic polymeric nanoparticles and methods of making and using same |
EP3052106A4 (en) | 2013-09-30 | 2017-07-19 | ModernaTX, Inc. | Polynucleotides encoding immune modulating polypeptides |
MX2016004249A (es) | 2013-10-03 | 2016-11-08 | Moderna Therapeutics Inc | Polinulcleotidos que codifican el receptor de lipoproteina de baja densidad. |
CA2931547A1 (en) | 2013-12-09 | 2015-06-18 | Durect Corporation | Pharmaceutically active agent complexes, polymer complexes, and compositions and methods involving the same |
JP6443907B2 (ja) * | 2014-02-17 | 2018-12-26 | 浩文 山本 | 造影剤の腫瘍への集積を促進するための集積促進剤 |
KR102472590B1 (ko) | 2014-05-14 | 2022-11-30 | 타르그이뮨 테라퓨틱스 아게 | 개선된 폴리에틸렌이민 폴리에틸렌글리콜 벡터 |
RU2016143081A (ru) | 2014-05-22 | 2018-06-26 | Терапьютиксмд, Инк. | Натуральные комбинированные гормонозаместительные составы и терапии |
CN104551003B (zh) * | 2014-12-30 | 2016-08-24 | 燕山大学 | 一种以醋酸兰瑞肽为模板制备纳米铂螺旋杆的方法 |
CN104546729A (zh) * | 2015-01-22 | 2015-04-29 | 浙江大学 | 一种pgj2纳米粒的制备及应用 |
US10722527B2 (en) | 2015-04-10 | 2020-07-28 | Capsugel Belgium Nv | Abiraterone acetate lipid formulations |
US10328087B2 (en) | 2015-07-23 | 2019-06-25 | Therapeuticsmd, Inc. | Formulations for solubilizing hormones |
SI3350157T1 (sl) | 2015-09-17 | 2022-04-29 | Modernatx, Inc. | Sestave za doziranje terapevtskih sredstev v celice |
AU2016343803B2 (en) | 2015-10-28 | 2021-04-29 | Acuitas Therapeutics, Inc. | Novel lipids and lipid nanoparticle formulations for delivery of nucleic acids |
EP3964200A1 (en) | 2015-12-10 | 2022-03-09 | ModernaTX, Inc. | Compositions and methods for delivery of therapeutic agents |
WO2017106630A1 (en) | 2015-12-18 | 2017-06-22 | The General Hospital Corporation | Polyacetal polymers, conjugates, particles and uses thereof |
JP7114465B2 (ja) | 2015-12-22 | 2022-08-08 | モデルナティエックス インコーポレイテッド | 薬剤の細胞内送達のための化合物および組成物 |
KR101804953B1 (ko) | 2015-12-29 | 2017-12-06 | 영남대학교 산학협력단 | 바이오 패치 및 그 제조방법 |
CA3020153A1 (en) | 2016-04-01 | 2017-10-05 | Therapeuticsmd, Inc. | Steroid hormone pharmaceutical composition |
MA45328A (fr) * | 2016-04-01 | 2019-02-06 | Avidity Biosciences Llc | Compositions acide nucléique-polypeptide et utilisations de celles-ci |
US10286077B2 (en) | 2016-04-01 | 2019-05-14 | Therapeuticsmd, Inc. | Steroid hormone compositions in medium chain oils |
WO2018089540A1 (en) | 2016-11-08 | 2018-05-17 | Modernatx, Inc. | Stabilized formulations of lipid nanoparticles |
US11969506B2 (en) | 2017-03-15 | 2024-04-30 | Modernatx, Inc. | Lipid nanoparticle formulation |
ES2911186T3 (es) | 2017-03-15 | 2022-05-18 | Modernatx Inc | Formas cristalinas de aminolípidos |
DK3596041T3 (da) | 2017-03-15 | 2023-01-23 | Modernatx Inc | Forbindelse og sammensætninger til intracellulær afgivelse af terapeutiske midler |
US9996527B1 (en) | 2017-03-30 | 2018-06-12 | International Business Machines Corporation | Supporting interactive text mining process with natural language and dialog |
WO2019151320A1 (ja) * | 2018-01-30 | 2019-08-08 | 国立大学法人大阪大学 | 抗がん剤 |
AU2019247655A1 (en) | 2018-04-03 | 2020-10-01 | Vaxess Technologies, Inc. | Microneedle comprising silk fibroin applied to a dissolvable base |
EP3794130A4 (en) | 2018-05-16 | 2022-07-27 | Synthego Corporation | METHODS AND SYSTEMS FOR DESIGN AND USE OF GUIDE RNA |
EP3914714A4 (en) | 2019-01-25 | 2024-04-10 | Synthego Corporation | SYSTEMS AND METHODS FOR MODULATING CRISPR ACTIVITY |
FI129022B (en) | 2019-09-10 | 2021-05-14 | Aabo Akademi Univ | Polymer and composition made from a renewable source |
MX2022003269A (es) | 2019-09-19 | 2022-07-04 | Modernatx Inc | Compuestos lipidicos de cola ramificada y composiciones para la administracion intracelular de agentes terapeuticos. |
US11633405B2 (en) | 2020-02-07 | 2023-04-25 | Therapeuticsmd, Inc. | Steroid hormone pharmaceutical formulations |
US20230310647A1 (en) * | 2020-08-19 | 2023-10-05 | The Trustees Of The University Of Pennsylvania | Targeting cartilage egfr pathway for osteoarthritis treatment |
IL301906A (en) | 2020-10-08 | 2023-06-01 | Targimmune Therapeutics Ag | Immunotherapy for cancer treatment |
CN112535678A (zh) * | 2020-12-28 | 2021-03-23 | 烟台大学 | 连接曲妥珠单抗的美登素纳米粒组合物 |
CN112675313A (zh) * | 2020-12-28 | 2021-04-20 | 烟台大学 | 连接曲妥珠单抗片段的美登素纳米粒组合物 |
US11524023B2 (en) | 2021-02-19 | 2022-12-13 | Modernatx, Inc. | Lipid nanoparticle compositions and methods of formulating the same |
WO2023079142A2 (en) | 2021-11-05 | 2023-05-11 | Targimmune Therapeutics Ag | Targeted linear conjugates comprising polyethyleneimine and polyethylene glycol and polyplexes comprising the same |
WO2023250117A2 (en) | 2022-06-24 | 2023-12-28 | Vaxess Technologies, Inc. | Applicator for medicament patch |
WO2024100046A1 (en) | 2022-11-07 | 2024-05-16 | Targimmune Therapeutics Ag | Targeted linear conjugates comprising polyethyleneimine and polyethylene glycol and polyplexes comprising the same |
WO2024100044A1 (en) | 2022-11-07 | 2024-05-16 | Targimmune Therapeutics Ag | Polyplexes of nucleic acids and targeted conjugates comprising polyethyleneimine and polyethylene glycol |
WO2024100040A1 (en) | 2022-11-07 | 2024-05-16 | Targimmune Therapeutics Ag | Psma-targeting linear conjugates comprising polyethyleneimine and polyethylene glycol and polyplexes comprising the same |
CN115804762B (zh) * | 2022-12-20 | 2024-05-31 | 浙江大学 | 一种巨噬细胞膜包覆的异位子宫内膜靶向纳米粒、制备方法及应用 |
CN117838672B (zh) * | 2024-03-07 | 2024-05-10 | 山东第二医科大学 | 一种替米考星/g型褐藻寡糖雾化吸入纳米混悬液及其制备方法 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7550441B2 (en) * | 2003-06-06 | 2009-06-23 | Massachusetts Institute Of Technology | Controlled release polymer nanoparticle containing bound nucleic acid ligand for targeting |
Family Cites Families (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP4215820B2 (ja) * | 1995-06-07 | 2009-01-28 | イマアーレクス・フアーマシユーチカル・コーポレーシヨン | 診断的および治療的使用のための新規な標的化組成物 |
US6548644B1 (en) * | 1997-03-10 | 2003-04-15 | Immunex Corporation | Site protected protein modification |
BR9911062A (pt) * | 1998-05-20 | 2001-02-06 | Expression Genetics Inc | Veìculo de gene polimérico de poli-l-lisina enxertado por polietileno glicol de direcionamento de hepatócito |
US20020197261A1 (en) * | 2001-04-26 | 2002-12-26 | Chun Li | Therapeutic agent/ligand conjugate compositions, their methods of synthesis and use |
WO2004089345A1 (en) * | 2003-04-03 | 2004-10-21 | Semafore Pharmaceuticals Inc. | Bone targeting of biodegradable drug-containing nanoparticles |
WO2004096998A2 (en) * | 2003-04-29 | 2004-11-11 | Vanderbilt University | Nanoparticular tumor targeting and therapy |
US20050042298A1 (en) * | 2003-08-20 | 2005-02-24 | Pardridge William M. | Immunonanoparticles |
EP1722762A2 (en) * | 2004-03-02 | 2006-11-22 | Massachusetts Institute of Technology | Nanocell drug delivery system |
AU2007212700A1 (en) * | 2006-01-26 | 2007-08-16 | University Of Massachusetts | RNA interference agents for therapeutic use |
CA2652280C (en) * | 2006-05-15 | 2014-01-28 | Massachusetts Institute Of Technology | Polymers for functional particles |
PL2097111T3 (pl) * | 2006-11-08 | 2016-01-29 | Molecular Insight Pharm Inc | Heterodimery kwasu glutaminowego |
US20100104645A1 (en) * | 2008-06-16 | 2010-04-29 | Bind Biosciences, Inc. | Methods for the preparation of targeting agent functionalized diblock copolymers for use in fabrication of therapeutic targeted nanoparticles |
-
2009
- 2009-06-16 US US12/485,818 patent/US20100104645A1/en not_active Abandoned
- 2009-06-16 WO PCT/US2009/047554 patent/WO2010005740A2/en active Application Filing
- 2009-06-16 PT PT97949325T patent/PT2285350T/pt unknown
- 2009-06-16 JP JP2011514761A patent/JP2011525180A/ja active Pending
- 2009-06-16 EP EP09794932.5A patent/EP2285350B1/en active Active
- 2009-06-16 PL PL09794932T patent/PL2285350T3/pl unknown
- 2009-06-16 DK DK09794932.5T patent/DK2285350T3/en active
- 2009-06-16 HU HUE09794932A patent/HUE035770T2/en unknown
- 2009-06-16 SI SI200931767T patent/SI2285350T1/en unknown
- 2009-06-16 ES ES09794932.5T patent/ES2654533T3/es active Active
-
2012
- 2012-11-02 US US13/667,299 patent/US8734846B2/en active Active
-
2015
- 2015-07-02 JP JP2015133649A patent/JP2015187160A/ja active Pending
-
2017
- 2017-09-12 JP JP2017175162A patent/JP6659640B2/ja active Active
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7550441B2 (en) * | 2003-06-06 | 2009-06-23 | Massachusetts Institute Of Technology | Controlled release polymer nanoparticle containing bound nucleic acid ligand for targeting |
Non-Patent Citations (1)
Title |
---|
Lupold et al, Identification and Characterization of Nuclease-stabilized RNA Molecules That Bind Human Prostate Cancer Cells via the Prostate-specific Membrane Antigen, Cancer Research, 62, 4029-4033. * |
Cited By (171)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8895610B1 (en) | 2007-05-18 | 2014-11-25 | Heldi Kay | Platinum (IV) compounds targeting zinc finger domains |
US9393310B2 (en) | 2008-06-16 | 2016-07-19 | Bind Therapeutics, Inc. | Drug loaded polymeric nanoparticles and methods of making and using same |
US20100068285A1 (en) * | 2008-06-16 | 2010-03-18 | Zale Stephen E | Drug Loaded Polymeric Nanoparticles and Methods of Making and Using Same |
US20100068286A1 (en) * | 2008-06-16 | 2010-03-18 | Greg Troiano | Drug Loaded Polymeric Nanoparticles and Methods of Making and Using Same |
US8609142B2 (en) | 2008-06-16 | 2013-12-17 | Bind Therapeutics, Inc. | Drug loaded polymeric nanoparticles and methods of making and using same |
US8603534B2 (en) | 2008-06-16 | 2013-12-10 | Bind Therapeutics, Inc. | Drug loaded polymeric nanoparticles and methods of making and using same |
US20100069426A1 (en) * | 2008-06-16 | 2010-03-18 | Zale Stephen E | Therapeutic polymeric nanoparticles with mTor inhibitors and methods of making and using same |
US8613951B2 (en) | 2008-06-16 | 2013-12-24 | Bind Therapeutics, Inc. | Therapeutic polymeric nanoparticles with mTor inhibitors and methods of making and using same |
US9351933B2 (en) | 2008-06-16 | 2016-05-31 | Bind Therapeutics, Inc. | Therapeutic polymeric nanoparticles comprising vinca alkaloids and methods of making and using same |
US8663700B2 (en) | 2008-06-16 | 2014-03-04 | Bind Therapeutics, Inc. | Drug loaded polymeric nanoparticles and methods of making and using same |
US8206747B2 (en) | 2008-06-16 | 2012-06-26 | Bind Biosciences, Inc. | Drug loaded polymeric nanoparticles and methods of making and using same |
US8652528B2 (en) | 2008-06-16 | 2014-02-18 | Bind Therapeutics, Inc. | Drug loaded polymeric nanoparticles and methods of making and using same |
US9579284B2 (en) | 2008-06-16 | 2017-02-28 | Pfizer Inc. | Therapeutic polymeric nanoparticles with mTOR inhibitors and methods of making and using same |
US8293276B2 (en) | 2008-06-16 | 2012-10-23 | Bind Biosciences, Inc. | Drug loaded polymeric nanoparticles and methods of making and using same |
US8318211B2 (en) | 2008-06-16 | 2012-11-27 | Bind Biosciences, Inc. | Therapeutic polymeric nanoparticles comprising vinca alkaloids and methods of making and using same |
US8318208B1 (en) | 2008-06-16 | 2012-11-27 | Bind Biosciences, Inc. | Drug loaded polymeric nanoparticles and methods of making and using same |
US8623417B1 (en) | 2008-06-16 | 2014-01-07 | Bind Therapeutics, Inc. | Therapeutic polymeric nanoparticles with mTOR inhibitors and methods of making and using same |
US8420123B2 (en) | 2008-06-16 | 2013-04-16 | Bind Biosciences, Inc. | Drug loaded polymeric nanoparticles and methods of making and using same |
US9375481B2 (en) | 2008-06-16 | 2016-06-28 | Bind Therapeutics, Inc. | Drug loaded polymeric nanoparticles and methods of making and using same |
US8617608B2 (en) | 2008-06-16 | 2013-12-31 | Bind Therapeutics, Inc. | Drug loaded polymeric nanoparticles and methods of making and using same |
US8613954B2 (en) | 2008-06-16 | 2013-12-24 | Bind Therapeutics, Inc. | Drug loaded polymeric nanoparticles and methods of making and using same |
US9579386B2 (en) | 2008-06-16 | 2017-02-28 | Pfizer Inc. | Drug loaded polymeric nanoparticles and methods of making and using same |
US9324473B2 (en) * | 2008-08-25 | 2016-04-26 | Kent State University | Nanoparticle composition, a device and a method thereof |
US20100044650A1 (en) * | 2008-08-25 | 2010-02-25 | Lavrentovich Oleg D | nanoparticle composition, a device and a method thereof |
US8563041B2 (en) | 2008-12-12 | 2013-10-22 | Bind Therapeutics, Inc. | Therapeutic particles suitable for parenteral administration and methods of making and using same |
US8905997B2 (en) | 2008-12-12 | 2014-12-09 | Bind Therapeutics, Inc. | Therapeutic particles suitable for parenteral administration and methods of making and using same |
US20100226986A1 (en) * | 2008-12-12 | 2010-09-09 | Amy Grayson | Therapeutic Particles Suitable for Parenteral Administration and Methods of Making and Using Same |
US9308179B2 (en) | 2008-12-15 | 2016-04-12 | Bind Therapeutics, Inc. | Long circulating nanoparticles for sustained release of therapeutic agents |
US9198874B2 (en) | 2008-12-15 | 2015-12-01 | Bind Therapeutics, Inc. | Long circulating nanoparticles for sustained release of therapeutic agents |
US20100266642A1 (en) * | 2009-02-20 | 2010-10-21 | Bind Biosciences, Inc. | Modified cells for targeted cell trafficking and uses thereof |
US20100247669A1 (en) * | 2009-03-30 | 2010-09-30 | Cerulean Pharma Inc. | Polymer-agent conjugates, particles, compositions, and related methods of use |
US20110189092A1 (en) * | 2009-03-30 | 2011-08-04 | Scott Eliasof | Polymer-agent conjugates, particles, compositions, and related methods of use |
US20100247668A1 (en) * | 2009-03-30 | 2010-09-30 | Scott Eliasof | Polymer-agent conjugates, particles, compositions, and related methods of use |
US8637083B2 (en) | 2009-12-11 | 2014-01-28 | Bind Therapeutics, Inc. | Stable formulations for lyophilizing therapeutic particles |
US8211473B2 (en) | 2009-12-11 | 2012-07-03 | Bind Biosciences, Inc. | Stable formulations for lyophilizing therapeutic particles |
US9872848B2 (en) | 2009-12-11 | 2018-01-23 | Pfizer Inc. | Stable formulations for lyophilizing therapeutic particles |
US8916203B2 (en) | 2009-12-11 | 2014-12-23 | Bind Therapeutics, Inc. | Stable formulations for lyophilizing therapeutic particles |
US9498443B2 (en) | 2009-12-11 | 2016-11-22 | Pfizer Inc. | Stable formulations for lyophilizing therapeutic particles |
US8603535B2 (en) | 2009-12-11 | 2013-12-10 | Bind Therapeutics, Inc. | Stable formulations for lyophilizing therapeutic particles |
US8357401B2 (en) | 2009-12-11 | 2013-01-22 | Bind Biosciences, Inc. | Stable formulations for lyophilizing therapeutic particles |
US8956657B2 (en) | 2009-12-11 | 2015-02-17 | Bind Therapeutics, Inc. | Stable formulations for lyophilizing therapeutic particles |
US9295649B2 (en) | 2009-12-15 | 2016-03-29 | Bind Therapeutics, Inc. | Therapeutic polymeric nanoparticle compositions with high glass transition temperature or high molecular weight copolymers |
US8912212B2 (en) | 2009-12-15 | 2014-12-16 | Bind Therapeutics, Inc. | Therapeutic polymeric nanoparticle compositions with high glass transition temperature or high molecular weight copolymers |
US8518963B2 (en) | 2009-12-15 | 2013-08-27 | Bind Therapeutics, Inc. | Therapeutic polymeric nanoparticle compositions with high glass transition temperature or high molecular weight copolymers |
US9835572B2 (en) | 2009-12-15 | 2017-12-05 | Pfizer Inc. | Therapeutic polymeric nanoparticle compositions with high glass transition temperature or high molecular weight copolymers |
US9123947B2 (en) * | 2010-05-20 | 2015-09-01 | Samsung Sdi Co., Ltd. | Secondary battery |
US20110287309A1 (en) * | 2010-05-20 | 2011-11-24 | Chiyoung Lee | Secondary battery |
US20130164381A1 (en) * | 2010-09-20 | 2013-06-27 | Southwest Research Institute | Nanoparticle-Based Targeted Drug Delivery For In Vivo Bone Loss Mitigation |
EP4144378A1 (en) | 2011-12-16 | 2023-03-08 | ModernaTX, Inc. | Modified nucleoside, nucleotide, and nucleic acid compositions |
CN102525937A (zh) * | 2012-01-21 | 2012-07-04 | 中国农业科学院兰州畜牧与兽药研究所 | 一种金丝桃素白蛋白纳米粒的制备方法 |
US20130195752A1 (en) * | 2012-02-01 | 2013-08-01 | Regents Of The University Of Minnesota | Functionalized nanoparticles and methods of use thereof |
US10967062B2 (en) | 2012-02-01 | 2021-04-06 | Regents Of The University Of Minnesota | Functionalized nanoparticles and methods of use thereof |
US20150037419A1 (en) * | 2012-02-28 | 2015-02-05 | Sanofi | Functional PLA-PEG Copolymers, the Nanoparticles Thereof, Their Preparation and Use for Targeted Drug Delivery and Imaging |
EP2820002B1 (en) * | 2012-02-28 | 2016-04-20 | Sanofi | Functional pla-peg copolymers, the nanoparticles thereof, their preparation and use for targeted drug delivery and imaging |
US9364444B2 (en) * | 2012-02-28 | 2016-06-14 | Sanofi | Functional PLA-PEG copolymers, the nanoparticles thereof, their preparation and use for targeted drug delivery and imaging |
WO2013151736A2 (en) | 2012-04-02 | 2013-10-10 | modeRNA Therapeutics | In vivo production of proteins |
WO2013151666A2 (en) | 2012-04-02 | 2013-10-10 | modeRNA Therapeutics | Modified polynucleotides for the production of biologics and proteins associated with human disease |
US9314532B2 (en) | 2012-08-10 | 2016-04-19 | University Of North Texas Health Science Center | Drug delivery vehicle |
US9877923B2 (en) | 2012-09-17 | 2018-01-30 | Pfizer Inc. | Process for preparing therapeutic nanoparticles |
WO2014058974A1 (en) * | 2012-10-10 | 2014-04-17 | Emory University | Methods of managing inflammation using glycolysis pathway inhibitors |
EP4074834A1 (en) | 2012-11-26 | 2022-10-19 | ModernaTX, Inc. | Terminally modified rna |
WO2014152211A1 (en) | 2013-03-14 | 2014-09-25 | Moderna Therapeutics, Inc. | Formulation and delivery of modified nucleoside, nucleotide, and nucleic acid compositions |
WO2014152540A1 (en) | 2013-03-15 | 2014-09-25 | Moderna Therapeutics, Inc. | Compositions and methods of altering cholesterol levels |
US10967039B2 (en) | 2013-05-28 | 2021-04-06 | Sintef Tto As | Process for preparing stealth nanoparticles |
WO2014191502A1 (en) | 2013-05-28 | 2014-12-04 | Sinvent As | Process for preparing stealth nanoparticles |
WO2015006747A2 (en) | 2013-07-11 | 2015-01-15 | Moderna Therapeutics, Inc. | Compositions comprising synthetic polynucleotides encoding crispr related proteins and synthetic sgrnas and methods of use. |
EP3971287A1 (en) | 2013-07-11 | 2022-03-23 | ModernaTX, Inc. | Compositions comprising synthetic polynucleotides encoding crispr related proteins and synthetic sgrnas and methods of use |
WO2015034925A1 (en) | 2013-09-03 | 2015-03-12 | Moderna Therapeutics, Inc. | Circular polynucleotides |
WO2015034928A1 (en) | 2013-09-03 | 2015-03-12 | Moderna Therapeutics, Inc. | Chimeric polynucleotides |
US10232058B2 (en) | 2013-10-14 | 2019-03-19 | The Johns Hopkins University | Prostate-specific membrane antigen-targeted photosensitizers for photodynamic therapy |
WO2015057692A1 (en) * | 2013-10-14 | 2015-04-23 | The Johns Hopkins University | Prostate-specific membrane antigen-targeted photosensitizers for photodynamic therapy |
EP3985118A1 (en) | 2013-11-22 | 2022-04-20 | MiNA Therapeutics Limited | C/ebp alpha short activating rna compositions and methods of use |
WO2015075557A2 (en) | 2013-11-22 | 2015-05-28 | Mina Alpha Limited | C/ebp alpha compositions and methods of use |
EP3594348A1 (en) | 2013-11-22 | 2020-01-15 | Mina Therapeutics Limited | C/ebp alpha short activating rna compositions and methods of use |
US9895378B2 (en) | 2014-03-14 | 2018-02-20 | Pfizer Inc. | Therapeutic nanoparticles comprising a therapeutic agent and methods of making and using the same |
US10071100B2 (en) | 2014-03-14 | 2018-09-11 | Pfizer Inc. | Therapeutic nanoparticles comprising a therapeutic agent and methods of making and using the same |
US10723692B2 (en) | 2014-06-25 | 2020-07-28 | Acuitas Therapeutics, Inc. | Lipids and lipid nanoparticle formulations for delivery of nucleic acids |
US11634379B2 (en) | 2014-06-25 | 2023-04-25 | Acuitas Therapeutics, Inc. | Lipids and lipid nanoparticle formulations for delivery of nucleic acids |
US10106490B2 (en) | 2014-06-25 | 2018-10-23 | Acuitas Therapeutics, Inc. | Lipids and lipid nanoparticle formulations for delivery of nucleic acids |
EP4159741A1 (en) | 2014-07-16 | 2023-04-05 | ModernaTX, Inc. | Method for producing a chimeric polynucleotide encoding a polypeptide having a triazole-containing internucleotide linkage |
WO2016014846A1 (en) | 2014-07-23 | 2016-01-28 | Moderna Therapeutics, Inc. | Modified polynucleotides for the production of intrabodies |
US11168051B2 (en) | 2015-06-29 | 2021-11-09 | Acuitas Therapeutics, Inc. | Lipids and lipid nanoparticle formulations for delivery of nucleic acids |
US10221127B2 (en) | 2015-06-29 | 2019-03-05 | Acuitas Therapeutics, Inc. | Lipids and lipid nanoparticle formulations for delivery of nucleic acids |
EP4349404A2 (en) | 2015-10-22 | 2024-04-10 | ModernaTX, Inc. | Respiratory virus vaccines |
WO2017070620A2 (en) | 2015-10-22 | 2017-04-27 | Modernatx, Inc. | Broad spectrum influenza virus vaccine |
EP4011451A1 (en) | 2015-10-22 | 2022-06-15 | ModernaTX, Inc. | Metapneumovirus mrna vaccines |
WO2017070626A2 (en) | 2015-10-22 | 2017-04-27 | Modernatx, Inc. | Respiratory virus vaccines |
WO2017070622A1 (en) | 2015-10-22 | 2017-04-27 | Modernatx, Inc. | Respiratory syncytial virus vaccine |
EP4349405A2 (en) | 2015-10-22 | 2024-04-10 | ModernaTX, Inc. | Respiratory virus vaccines |
WO2017070613A1 (en) | 2015-10-22 | 2017-04-27 | Modernatx, Inc. | Human cytomegalovirus vaccine |
WO2017070601A1 (en) | 2015-10-22 | 2017-04-27 | Modernatx, Inc. | Nucleic acid vaccines for varicella zoster virus (vzv) |
WO2017070623A1 (en) | 2015-10-22 | 2017-04-27 | Modernatx, Inc. | Herpes simplex virus vaccine |
CN105458287A (zh) * | 2015-11-30 | 2016-04-06 | 燕山大学 | 利用醋酸兰瑞肽模板制备笼状金纳米粒子的方法 |
EP4039699A1 (en) | 2015-12-23 | 2022-08-10 | ModernaTX, Inc. | Methods of using ox40 ligand encoding polynucleotides |
WO2017112943A1 (en) | 2015-12-23 | 2017-06-29 | Modernatx, Inc. | Methods of using ox40 ligand encoding polynucleotides |
WO2017120612A1 (en) | 2016-01-10 | 2017-07-13 | Modernatx, Inc. | Therapeutic mrnas encoding anti ctla-4 antibodies |
US11607421B2 (en) | 2016-03-25 | 2023-03-21 | Metanoi Therapeutics, Inc. | Ethanolamine-based lipid biosynthetic compounds, method of making and use thereof |
US10213448B2 (en) | 2016-03-25 | 2019-02-26 | Novazoi Theranostics | Ethanolamine-based lipid biosynthetic compounds, method of making and use thereof |
KR101806740B1 (ko) | 2016-10-06 | 2017-12-07 | 현대자동차주식회사 | 자기조립구조를 제어 가능한 카르바졸 기반의 그래프트 공중합체 및 이의 합성방법 |
EP3808380A1 (en) | 2016-12-08 | 2021-04-21 | CureVac AG | Rna for treatment or prophylaxis of a liver disease |
WO2018104538A1 (en) | 2016-12-08 | 2018-06-14 | Curevac Ag | Rna for treatment or prophylaxis of a liver disease |
WO2018104540A1 (en) | 2016-12-08 | 2018-06-14 | Curevac Ag | Rnas for wound healing |
CN108653746A (zh) * | 2017-03-29 | 2018-10-16 | 北京键凯科技股份有限公司 | 一种多载药点、高载药配基药物偶联物 |
US11820728B2 (en) | 2017-04-28 | 2023-11-21 | Acuitas Therapeutics, Inc. | Carbonyl lipids and lipid nanoparticle formulations for delivery of nucleic acids |
EP4253544A2 (en) | 2017-05-18 | 2023-10-04 | ModernaTX, Inc. | Modified messenger rna comprising functional rna elements |
WO2018213731A1 (en) | 2017-05-18 | 2018-11-22 | Modernatx, Inc. | Polynucleotides encoding tethered interleukin-12 (il12) polypeptides and uses thereof |
WO2018213789A1 (en) | 2017-05-18 | 2018-11-22 | Modernatx, Inc. | Modified messenger rna comprising functional rna elements |
WO2018232006A1 (en) | 2017-06-14 | 2018-12-20 | Modernatx, Inc. | Polynucleotides encoding coagulation factor viii |
WO2019048632A1 (en) | 2017-09-08 | 2019-03-14 | Mina Therapeutics Limited | STABILIZED COMPOSITIONS OF SMALL ACTIVATORY RNA (PARNA) OF HNF4A AND METHODS OF USE |
EP4233880A2 (en) | 2017-09-08 | 2023-08-30 | MiNA Therapeutics Limited | Hnf4a sarna compositions and methods of use |
EP4219715A2 (en) | 2017-09-08 | 2023-08-02 | MiNA Therapeutics Limited | Stabilized cebpa sarna compositions and methods of use |
EP4183882A1 (en) | 2017-09-08 | 2023-05-24 | MiNA Therapeutics Limited | Stabilized hnf4a sarna compositions and methods of use |
WO2019048645A1 (en) | 2017-09-08 | 2019-03-14 | Mina Therapeutics Limited | STABILIZED COMPOSITIONS OF SMALL ACTIVATOR RNA (PARNA) FROM CEBPA AND METHODS OF USE |
WO2019048631A1 (en) | 2017-09-08 | 2019-03-14 | Mina Therapeutics Limited | SMALL HNF4A ACTIVATOR RNA COMPOSITIONS AND METHODS OF USE |
CN109771658A (zh) * | 2017-11-14 | 2019-05-21 | 博瑞生物医药(苏州)股份有限公司 | 靶向多臂偶联物 |
WO2019104160A2 (en) | 2017-11-22 | 2019-05-31 | Modernatx, Inc. | Polynucleotides encoding phenylalanine hydroxylase for the treatment of phenylketonuria |
WO2019104195A1 (en) | 2017-11-22 | 2019-05-31 | Modernatx, Inc. | Polynucleotides encoding propionyl-coa carboxylase alpha and beta subunits for the treatment of propionic acidemia |
WO2019104152A1 (en) | 2017-11-22 | 2019-05-31 | Modernatx, Inc. | Polynucleotides encoding ornithine transcarbamylase for the treatment of urea cycle disorders |
WO2019136241A1 (en) | 2018-01-05 | 2019-07-11 | Modernatx, Inc. | Polynucleotides encoding anti-chikungunya virus antibodies |
WO2019200171A1 (en) | 2018-04-11 | 2019-10-17 | Modernatx, Inc. | Messenger rna comprising functional rna elements |
EP4242307A2 (en) | 2018-04-12 | 2023-09-13 | MiNA Therapeutics Limited | Sirt1-sarna compositions and methods of use |
WO2019197845A1 (en) | 2018-04-12 | 2019-10-17 | Mina Therapeutics Limited | Sirt1-sarna compositions and methods of use |
WO2019217964A1 (en) | 2018-05-11 | 2019-11-14 | Lupagen, Inc. | Systems and methods for closed loop, real-time modifications of patient cells |
WO2019226650A1 (en) | 2018-05-23 | 2019-11-28 | Modernatx, Inc. | Delivery of dna |
WO2020023390A1 (en) | 2018-07-25 | 2020-01-30 | Modernatx, Inc. | Mrna based enzyme replacement therapy combined with a pharmacological chaperone for the treatment of lysosomal storage disorders |
WO2020033791A1 (en) | 2018-08-09 | 2020-02-13 | Verseau Therapeutics, Inc. | Oligonucleotide compositions for targeting ccr2 and csf1r and uses thereof |
WO2020047201A1 (en) | 2018-09-02 | 2020-03-05 | Modernatx, Inc. | Polynucleotides encoding very long-chain acyl-coa dehydrogenase for the treatment of very long-chain acyl-coa dehydrogenase deficiency |
WO2020056155A2 (en) | 2018-09-13 | 2020-03-19 | Modernatx, Inc. | Polynucleotides encoding branched-chain alpha-ketoacid dehydrogenase complex e1-alpha, e1-beta, and e2 subunits for the treatment of maple syrup urine disease |
WO2020056147A2 (en) | 2018-09-13 | 2020-03-19 | Modernatx, Inc. | Polynucleotides encoding glucose-6-phosphatase for the treatment of glycogen storage disease |
WO2020056239A1 (en) | 2018-09-14 | 2020-03-19 | Modernatx, Inc. | Polynucleotides encoding uridine diphosphate glycosyltransferase 1 family, polypeptide a1 for the treatment of crigler-najjar syndrome |
WO2020069169A1 (en) | 2018-09-27 | 2020-04-02 | Modernatx, Inc. | Polynucleotides encoding arginase 1 for the treatment of arginase deficiency |
CN109010845A (zh) * | 2018-09-28 | 2018-12-18 | 青岛大学 | 一种抗肿瘤药物的改性方法 |
WO2020097409A2 (en) | 2018-11-08 | 2020-05-14 | Modernatx, Inc. | Use of mrna encoding ox40l to treat cancer in human patients |
WO2020114390A1 (en) * | 2018-12-03 | 2020-06-11 | Master Dynamic Limited | Nanoparticle Delivery System |
US11453639B2 (en) | 2019-01-11 | 2022-09-27 | Acuitas Therapeutics, Inc. | Lipids for lipid nanoparticle delivery of active agents |
WO2020208361A1 (en) | 2019-04-12 | 2020-10-15 | Mina Therapeutics Limited | Sirt1-sarna compositions and methods of use |
WO2020227642A1 (en) | 2019-05-08 | 2020-11-12 | Modernatx, Inc. | Compositions for skin and wounds and methods of use thereof |
WO2020263985A1 (en) | 2019-06-24 | 2020-12-30 | Modernatx, Inc. | Messenger rna comprising functional rna elements and uses thereof |
WO2020263883A1 (en) | 2019-06-24 | 2020-12-30 | Modernatx, Inc. | Endonuclease-resistant messenger rna and uses thereof |
WO2021061815A1 (en) | 2019-09-23 | 2021-04-01 | Omega Therapeutics, Inc. | COMPOSITIONS AND METHODS FOR MODULATING HEPATOCYTE NUCLEAR FACTOR 4-ALPHA (HNF4α) GENE EXPRESSION |
WO2021061707A1 (en) | 2019-09-23 | 2021-04-01 | Omega Therapeutics, Inc. | Compositions and methods for modulating apolipoprotein b (apob) gene expression |
WO2021183720A1 (en) | 2020-03-11 | 2021-09-16 | Omega Therapeutics, Inc. | Compositions and methods for modulating forkhead box p3 (foxp3) gene expression |
WO2021247507A1 (en) | 2020-06-01 | 2021-12-09 | Modernatx, Inc. | Phenylalanine hydroxylase variants and uses thereof |
US11976019B2 (en) | 2020-07-16 | 2024-05-07 | Acuitas Therapeutics, Inc. | Cationic lipids for use in lipid nanoparticles |
WO2022104131A1 (en) | 2020-11-13 | 2022-05-19 | Modernatx, Inc. | Polynucleotides encoding cystic fibrosis transmembrane conductance regulator for the treatment of cystic fibrosis |
WO2022122872A1 (en) | 2020-12-09 | 2022-06-16 | Ucl Business Ltd | Therapeutics for the treatment of neurodegenerative disorders |
WO2022204371A1 (en) | 2021-03-24 | 2022-09-29 | Modernatx, Inc. | Lipid nanoparticles containing polynucleotides encoding glucose-6-phosphatase and uses thereof |
WO2022204390A1 (en) | 2021-03-24 | 2022-09-29 | Modernatx, Inc. | Lipid nanoparticles containing polynucleotides encoding phenylalanine hydroxylase and uses thereof |
WO2022204380A1 (en) | 2021-03-24 | 2022-09-29 | Modernatx, Inc. | Lipid nanoparticles containing polynucleotides encoding propionyl-coa carboxylase alpha and beta subunits and uses thereof |
WO2022204369A1 (en) | 2021-03-24 | 2022-09-29 | Modernatx, Inc. | Polynucleotides encoding methylmalonyl-coa mutase for the treatment of methylmalonic acidemia |
WO2022204370A1 (en) | 2021-03-24 | 2022-09-29 | Modernatx, Inc. | Lipid nanoparticles and polynucleotides encoding ornithine transcarbamylase for the treatment of ornithine transcarbamylase deficiency |
WO2022200810A1 (en) | 2021-03-26 | 2022-09-29 | Mina Therapeutics Limited | Tmem173 sarna compositions and methods of use |
WO2022240806A1 (en) | 2021-05-11 | 2022-11-17 | Modernatx, Inc. | Non-viral delivery of dna for prolonged polypeptide expression in vivo |
WO2022266083A2 (en) | 2021-06-15 | 2022-12-22 | Modernatx, Inc. | Engineered polynucleotides for cell-type or microenvironment-specific expression |
WO2022271776A1 (en) | 2021-06-22 | 2022-12-29 | Modernatx, Inc. | Polynucleotides encoding uridine diphosphate glycosyltransferase 1 family, polypeptide a1 for the treatment of crigler-najjar syndrome |
WO2023283359A2 (en) | 2021-07-07 | 2023-01-12 | Omega Therapeutics, Inc. | Compositions and methods for modulating secreted frizzled receptor protein 1 (sfrp1) gene expression |
WO2023006999A2 (en) | 2021-07-30 | 2023-02-02 | CureVac SE | Mrnas for treatment or prophylaxis of liver diseases |
WO2023056044A1 (en) | 2021-10-01 | 2023-04-06 | Modernatx, Inc. | Polynucleotides encoding relaxin for the treatment of fibrosis and/or cardiovascular disease |
WO2023099884A1 (en) | 2021-12-01 | 2023-06-08 | Mina Therapeutics Limited | Pax6 sarna compositions and methods of use |
WO2023104964A1 (en) | 2021-12-09 | 2023-06-15 | Ucl Business Ltd | Therapeutics for the treatment of neurodegenerative disorders |
WO2023144193A1 (en) | 2022-01-25 | 2023-08-03 | CureVac SE | Mrnas for treatment of hereditary tyrosinemia type i |
WO2023161350A1 (en) | 2022-02-24 | 2023-08-31 | Io Biotech Aps | Nucleotide delivery of cancer therapy |
WO2023170435A1 (en) | 2022-03-07 | 2023-09-14 | Mina Therapeutics Limited | Il10 sarna compositions and methods of use |
WO2023183909A2 (en) | 2022-03-25 | 2023-09-28 | Modernatx, Inc. | Polynucleotides encoding fanconi anemia, complementation group proteins for the treatment of fanconi anemia |
WO2023196399A1 (en) | 2022-04-06 | 2023-10-12 | Modernatx, Inc. | Lipid nanoparticles and polynucleotides encoding argininosuccinate lyase for the treatment of argininosuccinic aciduria |
WO2023215498A2 (en) | 2022-05-05 | 2023-11-09 | Modernatx, Inc. | Compositions and methods for cd28 antagonism |
WO2024026254A1 (en) | 2022-07-26 | 2024-02-01 | Modernatx, Inc. | Engineered polynucleotides for temporal control of expression |
WO2024097639A1 (en) | 2022-10-31 | 2024-05-10 | Modernatx, Inc. | Hsa-binding antibodies and binding proteins and uses thereof |
WO2024118866A1 (en) | 2022-12-01 | 2024-06-06 | Modernatx, Inc. | Gpc3-specific antibodies, binding domains, and related proteins and uses thereof |
WO2024130158A1 (en) | 2022-12-16 | 2024-06-20 | Modernatx, Inc. | Lipid nanoparticles and polynucleotides encoding extended serum half-life interleukin-22 for the treatment of metabolic disease |
WO2024134199A1 (en) | 2022-12-22 | 2024-06-27 | Mina Therapeutics Limited | Chemically modified sarna compositions and methods of use |
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Publication number | Publication date |
---|---|
EP2285350B1 (en) | 2017-11-15 |
JP6659640B2 (ja) | 2020-03-04 |
WO2010005740A2 (en) | 2010-01-14 |
EP2285350A4 (en) | 2014-08-20 |
ES2654533T3 (es) | 2018-02-14 |
SI2285350T1 (en) | 2018-03-30 |
HUE035770T2 (en) | 2018-05-28 |
US20130115192A1 (en) | 2013-05-09 |
JP2011525180A (ja) | 2011-09-15 |
EP2285350A2 (en) | 2011-02-23 |
WO2010005740A3 (en) | 2010-03-25 |
PL2285350T3 (pl) | 2018-03-30 |
PT2285350T (pt) | 2018-01-04 |
JP2017226696A (ja) | 2017-12-28 |
US8734846B2 (en) | 2014-05-27 |
DK2285350T3 (en) | 2017-12-11 |
JP2015187160A (ja) | 2015-10-29 |
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