US20220175812A1 - Polymer nanoparticle and dna nanostructure compositions and methods for non-viral delivery - Google Patents

Polymer nanoparticle and dna nanostructure compositions and methods for non-viral delivery Download PDF

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US20220175812A1
US20220175812A1 US17/542,055 US202117542055A US2022175812A1 US 20220175812 A1 US20220175812 A1 US 20220175812A1 US 202117542055 A US202117542055 A US 202117542055A US 2022175812 A1 US2022175812 A1 US 2022175812A1
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Prior art keywords
composition
clause
dna
payload
delivery
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Anthony D. Duong
Cherry GUPTA
Kenneth R. SIMS, JR.
Danielle HUK
Jacob Lilly
Stephanie M. Kute
Mike KOERIS
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Battelle Memorial Institute Inc
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Battelle Memorial Institute Inc
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Priority to US17/542,055 priority Critical patent/US20220175812A1/en
Publication of US20220175812A1 publication Critical patent/US20220175812A1/en
Priority to US18/444,146 priority patent/US12109223B2/en
Assigned to BATTELLE MEMORIAL INSTITUTE reassignment BATTELLE MEMORIAL INSTITUTE ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: KOERIS, Mike
Assigned to BATTELLE MEMORIAL INSTITUTE reassignment BATTELLE MEMORIAL INSTITUTE ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: HUK, Danielle, SIMS, KENNETH R., JR., GUPTA, Cherry, LILLY, Jacob, DUONG, Anthony D., KUTE, Stephanie M.
Priority to US18/816,696 priority patent/US12433910B2/en
Priority to US19/331,773 priority patent/US20260014186A1/en
Abandoned legal-status Critical Current

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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
    • A61K47/69—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
    • A61K47/6921—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 particulate, a powder, an adsorbate, a bead or a sphere
    • A61K47/6927—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 particulate, a powder, an adsorbate, a bead or a sphere the form being a solid microparticle having no hollow or gas-filled cores
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    • C08F293/00—Macromolecular compounds obtained by polymerisation on to a macromolecule having groups capable of inducing the formation of new polymer chains bound exclusively at one or both ends of the starting macromolecule
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    • C12N2310/53—Physical structure partially self-complementary or closed
    • C12N2310/531—Stem-loop; Hairpin

Definitions

  • the invention relates to polymer nanoparticle and DNA nanostructure delivery compositions for non-viral delivery, and methods therefor. More particularly, the invention relates to polymer nanoparticle delivery compositions, such as reversible addition-fragmentation chain transfer (RAFT) polymer compositions, and DNA nanostructure delivery compositions, such as DNA origami compositions, for the delivery, for example, of more than one payload, or for the delivery of a nucleic acid construct payload of 3 kB or more, and methods therefor.
  • polymer nanoparticle delivery compositions such as reversible addition-fragmentation chain transfer (RAFT) polymer compositions
  • DNA nanostructure delivery compositions such as DNA origami compositions
  • Genetic medicines including gene therapy, gene silencing, splicing regulators, and nuclease based gene editors
  • Genetic medicines are poised to produce revolutionary treatments, including vaccines, infectious disease treatments, antimicrobial treatments, antiviral treatments, and most notably, genetic disease treatments.
  • the in vivo delivery of these genetic medicine payloads to the specific tissues and cells that need to be treated, while avoiding tissues and cells that can reduce the efficacy or safety of the genetic medicine poses a significant challenge. Additional challenges include the ability to deliver large genetic payloads or multiple payloads.
  • Adeno-associated viruses are the most widely used tool for genetic medicine delivery, but AAVs are not able to deliver large genetic payloads or multiple payloads (such as the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 system), and they sometimes trigger unwanted immune responses, including the generation of anti-AAV antibodies, a cell mediated response. Some of the immune responses caused by AAV in patients are potentially fatal immune responses.
  • CRISPR clustered regularly interspaced short palindromic repeats
  • Therapeutics based on the CRISPR/Cas9 system have an exceptional potential to treat a number of genetic diseases due to the capability of this system for precise and programmable gene editing.
  • Gene editing and repair using the CRISPR/Cas9 system has two main mechanisms, including non-homologous end joining (NHEJ) which repairs the site of cut by inducing random indel mutation, and homology-directed repair (HDR), which repairs the cut site based on a pre-existing template. Because a pre-designed template can be used for HDR-directed repair, therapies based on this mechanism can be tailored to cure a large number of different genetic diseases.
  • NHEJ non-homologous end joining
  • HDR homology-directed repair
  • HDR repair requires the delivery of CRISPR/Cas9, small guide RNA (sgRNA) and a donor DNA strand at the same time to a particular location.
  • sgRNA small guide RNA
  • This requirement becomes particularly limiting for in vivo applications because ensuring co-delivery of multiple large molecules to the same targeted location is currently not feasible.
  • the Cas9 enzyme sequence and guide RNA complex is too large to fit into AAVs.
  • non-viral delivery systems including gene delivery systems.
  • the current state-of-the-art non-viral gene delivery systems such as liposomes, have many drawbacks such as poor biocompatibility and the inability to easily engineer or functionalize them. Additional concerns are that such non-viral gene delivery systems are easily degraded by various enzymes as they pass through intracellular or intercellular compartments, and these systems have not been able to package multiple large payloads.
  • the inventors have designed polymer nanoparticle (e.g., RAFT polymer) and DNA nanostructure delivery compositions (e.g., DNA origami nanostructures). These compositions have the advantage of being biocompatible, non-toxic, and can be programmed in many ways.
  • the polymer nanoparticle and DNA nanostructure delivery compositions can be programmed to have functional groups that enable them to evade early degradation, that enable them to evade immune responses, and that enable intracellular imaging and targeted and controlled delivery of therapeutic genes.
  • these non-viral delivery compositions can enhance the stability, safety, and/or efficacy of genetic medicine payloads by providing immune evasion, tissue-directed intracellular delivery, and the ability to deliver large genetic payloads or multiple payloads.
  • a DNA nanostructure delivery composition comprising: i) a single stranded DNA scaffold and ii) one or more oligonucleotides that bind through complementary base pairing with a segment of the DNA scaffold, wherein the one or more oligonucleotides cause the DNA scaffold to fold, and wherein the composition comprises more than one payload for delivery or a nucleic acid construct payload of 3 kB or more.
  • composition of clause 1 wherein the more than one payload comprises nucleic acids.
  • composition of clause 2 wherein the nucleic acids comprise DNA or RNA.
  • composition of clause 2 wherein the nucleic acids comprise a ribonucleoprotein.
  • composition of clause 2 wherein the payload nucleic acids comprise a short guide RNA (sgRNA) and a donor DNA strand.
  • sgRNA short guide RNA
  • composition of clause 1 wherein the payloads comprise a CRISPR associated enzyme.
  • composition of clause 7 wherein the targeted enzyme is a CRISPR associated enzyme.
  • composition of clause 1 wherein the payloads comprise a CRISPR associated enzyme, an sgRNA, and a donor DNA strand.
  • composition of clause 1 wherein the payloads comprise CRISPR/Cas9, an sgRNA, and a donor DNA strand.
  • composition of clause 1 wherein the payloads comprise a coding sequence for Cas9, an sgRNA, and a donor DNA strand in the form of a plasmid.
  • composition of clause 1 wherein the payloads consist of one molecule each of CRISPR/Cas9, an sgRNA, and a donor DNA strand.
  • composition of clause 1 wherein the nucleic acid construct payload of 3 kB or more comprises a CAR-T DNA construct.
  • composition of clause 1 wherein the payloads comprise an antisense oligonucleotide.
  • nucleic acid construct payload is of a size selected from the group consisting of 3 kB or more, 3.5 kB or more, 4 kB or more, 4.5 kB or more, 5 kB or more, 5.5 kB or more, 6 kB or more, 6.5 kB or more, 7 kB or more, 7.5 kB or more, 8 kB or more, and 8.5 kB or more.
  • composition of clause 1 wherein the payloads comprise a reverse transcriptase.
  • composition of clause 1 wherein the DNA scaffold and the one or more oligonucleotides comprise M13 bacteriophage DNA.
  • composition of clause 2 wherein the one or more oligonucleotides comprise overhangs that bind through complementary base paring with the payload nucleic acids.
  • composition of clause 1 further comprising a pharmaceutically acceptable carrier.
  • composition of clause 26 wherein the pharmaceutically acceptable carrier is for parenteral administration or topical administration.
  • composition of clause 28 wherein the one or more polymers comprise polyethylene glycol.
  • composition of clause 28 wherein the one or more polymers comprise polyethylene glycol poly-L-lysine.
  • composition of clause 28 wherein the one or more polymers comprise polyethylenimine.
  • composition of clause 28 wherein the one or more polymers comprise polyethylene glycol poly-L-lysine and polyethylenimine.
  • composition of clause 1 wherein the DNA nanostructure further comprises a targeting component for targeting to cells.
  • composition of clause 33 wherein the targeting component is a nucleotide that has a three-dimensional structure capable of binding a target cell receptor.
  • composition of clause 34 wherein the nucleotide is an RNA that forms a ‘stem-and-loop’ structure.
  • a method for gene therapy comprising administering to a patient a DNA nanostructure delivery composition comprising: i) a single stranded DNA scaffold and ii) one or more oligonucleotides that bind through complementary base pairing with a segment of the DNA scaffold, wherein the one or more oligonucleotides cause the DNA scaffold to fold, and wherein the composition comprises more than one payload for delivery or a nucleic acid construct payload of 3 kB or more.
  • nucleic acids comprise DNA or RNA.
  • nucleic acids comprise a ribonucleoprotein.
  • the payload nucleic acids comprise a short guide RNA (sgRNA) and a donor DNA strand.
  • sgRNA short guide RNA
  • the payloads comprise a CRISPR associated enzyme, an sgRNA, and a donor DNA strand.
  • the payloads comprise a coding sequence for Cas9, an sgRNA, and a donor DNA strand in the form of a plasmid.
  • nucleic acid construct payload of 3 kB or more comprises a CAR-T DNA construct.
  • nucleic acid construct payload is of a size selected from the group consisting of 3 kB or more, 3.5 kB or more, 4 kB or more, 4.5 kB or more, 5 kB or more, 5.5 kB or more, 6 kB or more, 6.5 kB or more, 7 kB or more, 7.5 kB or more, 8 kB or more, and 8.5 kB or more.
  • the targeting component is a nucleotide that has a three-dimensional structure capable of binding a target cell receptor.
  • nucleotide is an RNA that forms a ‘stem-and-loop’ structure.
  • the cancer is selected from the group consisting of lung cancer, bone cancer, pancreatic cancer, skin cancer, uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, cancer of the esophagus, cancer of the endocrine system, prostate cancer, leukemia, lymphoma, mesothelioma, cancer of the bladder, cancer of the kidney, neoplasms of the central nervous system, brain cancer, and adenocarcinoma.
  • a method for targeting a DNA nanostructure delivery composition to cells of a patient comprising administering to the patient: i) a single stranded DNA scaffold and ii) one or more oligonucleotides that bind through complementary base pairing with a segment of the DNA scaffold, wherein the one or more oligonucleotides cause the DNA scaffold to fold, wherein the composition comprises more than one payload for delivery or a nucleic acid construct payload of 3 kB or more, and wherein the DNA nanostructure comprises a targeting component for targeting to the cells of the patient.
  • nucleic acids comprise DNA or RNA.
  • nucleic acids comprise a ribonucleoprotein.
  • the payload nucleic acids comprise a short guide RNA (sgRNA) and a donor DNA strand.
  • sgRNA short guide RNA
  • the payloads comprise a CRISPR associated enzyme, an sgRNA, and a donor DNA strand.
  • the payloads comprise a coding sequence for Cas9, an sgRNA, and a donor DNA strand in the form of a plasmid.
  • nucleic acid construct payload of 3 kB or more comprises a CAR-T DNA construct.
  • nucleic acid construct payload is of a size selected from the group consisting of 3 kB or more, 3.5 kB or more, 4 kB or more, 4.5 kB or more, 5 kB or more, 5.5 kB or more, 6 kB or more, 6.5 kB or more, 7 kB or more, 7.5 kB or more, 8 kB or more, and 8.5 kB or more.
  • the targeting component is a nucleotide that has a three-dimensional structure capable of binding a target cell receptor.
  • nucleotide is an RNA that forms a ‘stem-and-loop’ structure.
  • a method comprising:
  • each non-viral gene delivery composition differs from each other non-viral gene delivery composition of the diverse set with respect to at least one of a set of composition characteristics
  • composition characteristics comprise one or more of molecular weight, degree of branching, number of ionizable groups, core-to-corona molecular weight ratio, hydrophilicity, hydrophobicity, propensity for aggregation, size, pKa, log P, and surface charge.
  • each of the non-viral gene delivery compositions of the diverse set is a DNA nanostructure delivery composition according to one of clauses 1-36.
  • a RAFT block copolymer comprising
  • a first terminus comprising a first capping unit derived from a first chain transfer agent in a RAFT copolymerization process
  • a first block prepared from one or more monomer units covalently attached to the first reactive functional unit, and having a molecular weight (M n ) in the range of about 20 kDa to about 40 kDa and a degree of polymerization in the range of about 300 to about 400;
  • a second block prepared from one or more monomer units covalently attached to the first block, and having a molecular weight (M n ) in the range of about 5 kDa to about 20 kDa and a degree of polymerization in the range of about 400 to about 500; and
  • a second terminus comprising a second capping unit derived from a second chain transfer agent
  • the RAFT block copolymer has one or more of an overall molecular weight (M n ) in the range of about 25 kDa to about 60 kDa, and overall degree of polymerization in the range of about 700 to about 900, a target size in the range of about of about 10 to about 60 nm, and a maximum corona-to-core ratio (CCR) of about 1.5 to about 3.5.
  • M n overall molecular weight
  • CCR maximum corona-to-core ratio
  • each chain transfer agent is independently selected from the group consisting of bis(carboxymethyl)trithiocarbonate, bis(2-amino-2-oxoethyl) trithiocarbonate, bis[4-(2-hydroxyethoxycarbonyl)benzyl] trithiocarbonate, 4-cyano-4-(ethylsulfanylthiocarbonyl) sulfanylvpentanoic acid, 4-cyano-4-((phenylcarbonothioyl)thio)pentanoic acid, and 4-cyano-4-[(dodecylsulfanylthiocarbonyl)sulfanyl] pentanoic acid.
  • R is —SC 2 —C 12 alkyl or C 6 H 5 ,
  • a method of preparing a RAFT block copolymer comprising:
  • step (i) The method of any one of clauses 128 to 133, wherein the one or more monomer units in step (i) are independently selected from the group consisting of 2-dimethylaminoethyl acrylate, 2-(diethylamino) ethyl methacrylate, 2-(diisopropylamino) ethyl methacrylate, butyl methacrylate, ethyl acrylic acid, propyl acrylic acid, (hydroxyethyl)methacrylate, and methyl methacrylate.
  • step (i) is one of 2-dimethylaminoethyl acrylate, 2-(diethylamino) ethyl methacrylate, 2-(diisopropylamino) ethyl methacrylate, butyl methacrylate, ethyl acrylic acid, propyl acrylic acid, (hydroxyethyl)methacrylate, or methyl methacrylate.
  • step (ii) are independently selected from the group consisting of 2-dimethylaminoethyl acrylate, 2-(diethylamino) ethyl methacrylate, 2-(diisopropylamino) ethyl methacrylate, butyl methacrylate, ethyl acrylic acid, propyl acrylic acid, (hydroxyethyl)methacrylate, and methyl methacrylate.
  • step (ii) are two different monomer units independently selected from the group consisting of 2-dimethylaminoethyl acrylate. 2-(diethylamino) ethyl methacrylate, 2-(diisopropylamino) ethyl methacrylate, butyl methacrylate, ethyl acrylic acid, propyl acrylic acid, (hydroxyethyl)methacrylate, and methyl methacrylate.
  • step (ii) are three different monomer units independently selected from the group consisting of 2-dimethylaminoethyl acrylate, 2-(diethylamino) ethyl methacrylate, 2-(diisopropylamino) ethyl methacrylate, butyl methacrylate, ethyl acrylic acid, propyl acrylic acid, (hydroxyethyl)methacrylate, and methyl methacrylate.
  • step (ii) are 2-dimethylaminoethyl acrylate, butyl methacrylate, and propyl acrylic acid; or 2-dimethylaminoethyl acrylate and butyl methacrylate; or 2-dimethylaminoethyl acrylate, butyl methacrylate, and ethyl acrylic acid.
  • RAFT block copolymer has one or more of an overall molecular weight (M n ) in the range of about 25 kDa to about 60 kDa, and overall degree of polymerization in the range of about 700 to about 900, a target size in the range of about of about 10 to about 60 nm, and a maximum corona-to-core ratio (CCR) of about 1.5 to about 3.5.
  • M n overall molecular weight
  • CCR maximum corona-to-core ratio
  • a method of preparing a library of RAFT block copolymers comprising:
  • each well comprises a mixture of a first chain transfer agent, a first initiator, one or more monomer units, and optionally a solvent or solvent mixture;
  • step (viii) reacting the components of step (vii) under conditions that promote RAFT copolymerization to provide a series of RAFT block copolymers in the wells of the multiwell plate;
  • xi optionally characterizing the RAFT block copolymer in each well of the multiwell plate.
  • step (i) is independently selected from the group consisting of 2-dimethylaminoethyl acrylate, 2-(diethylamino) ethyl methacrylate, 2-(diisopropylamino) ethyl methacrylate, butyl methacrylate, ethyl acrylic acid, propyl acrylic acid, (hydroxyethyl)methacrylate, and methyl methacrylate.
  • step (i) is one of 2-dimethylaminoethyl acrylate, 2-(diethylamino) ethyl methacrylate, 2-(diisopropylamino) ethyl methacrylate, butyl methacrylate, ethyl acrylic acid, propyl acrylic acid, (hydroxyethyl)methacrylate, or methyl methacrylate.
  • step (vii) The method of any one of clauses 141 to 143, wherein the one or more monomer units in step (vii) are independently selected from the group consisting of 2-dimethylaminoethyl acrylate, 2-(diethylamino) ethyl methacrylate, 2-(diisopropylamino) ethyl methacrylate, butyl methacrylate, ethyl acrylic acid, propyl acrylic acid, (hydroxyethyl)methacrylate, and methyl methacrylate.
  • step (vii) The method of any one of clauses 141 to 144, wherein the one or more monomer units in step (vii) are two different monomer units independently selected from the group consisting of 2-dimethylaminoethyl acrylate, 2-(diethylamino) ethyl methacrylate, 2-(diisopropylamino) ethyl methacrylate, butyl methacrylate, ethyl acrylic acid, propyl acrylic acid, (hydroxyethyl)methacrylate, and methyl methacrylate.
  • the one or more monomer units in step (vii) are two different monomer units independently selected from the group consisting of 2-dimethylaminoethyl acrylate, 2-(diethylamino) ethyl methacrylate, 2-(diisopropylamino) ethyl methacrylate, butyl methacrylate, ethyl acrylic acid, propyl acrylic acid, (hydroxyeth
  • step (vii) The method of any one of clauses 141 to 145, wherein the one or more monomer units in step (vii) are three different monomer units independently selected from the group consisting of 2-dimethylaminoethyl acrylate, 2-(diethylamino) ethyl methacrylate, 2-(diisopropylamino) ethyl methacrylate, butyl methacrylate, ethyl acrylic acid, propyl acrylic acid, (hydroxyethyl)methacrylate, and methyl methacrylate.
  • the one or more monomer units in step (vii) are three different monomer units independently selected from the group consisting of 2-dimethylaminoethyl acrylate, 2-(diethylamino) ethyl methacrylate, 2-(diisopropylamino) ethyl methacrylate, butyl methacrylate, ethyl acrylic acid, propyl acrylic acid, (hydroxyeth
  • step (vii) The method of any one of clauses 141 to 146, wherein the one or more monomer units in step (vii) are 2-dimethylaminoethyl acrylate, butyl methacrylate, and propyl acrylic acid; or 2-dimethylaminoethyl acrylate and butyl methacrylate; or 2-dimethylaminoethyl acrylate, butyl methacrylate, and ethyl acrylic acid.
  • first and second chain transfer are each independently selected from the group consisting of bis(carboxymethyl)trithiocarbonate, bis(2-amino-2-oxoethyl) trithiocarbonate, bis[4-(2-hydroxyethoxycarbonyl)benzyl] trithiocarbonate, 4-cyano-4-(ethylsulfanylthiocarbonyl) sulfanylvpentanoic acid, 4-cyano-4-((phenylcarbonothioyl)thio)pentanoic acid, and 4-cyano-4-[(dodecylsulfanylthiocarbonyl)sulfanyl] pentanoic acid.
  • a composition comprising a RAFT block copolymer according to any one of clauses 118 to 127 or a RAFT block copolymer prepared according to the method of any one of clauses 128 to 156.
  • a RAFT block copolymer conjugate comprising a RAFT block copolymer according to any one of clauses 118 to 127 or a RAFT block copolymer prepared according to the method of any one of clauses 128 to 156, and further comprising a biomolecule, drug, or label covalently attached to the RAFT block copolymer through a functional group on one of the first or second chain transfer agents that is incorporated into the RAFT block copolymer.
  • a method of preparing a RAFT block copolymer conjugate comprising a RAFT block copolymer according to any one of clauses 118 to 127 or a RAFT block copolymer prepared according to the method of any one of clauses 128 to 156 and a biomolecule, drug, or label, wherein the RAFT block copolymer and the biomolecule, drug, or label are covalently attached through a functional group on one of the first or second chain transfer agents that is incorporated into the RAFT block copolymer.
  • a RAFT block copolymer complex comprising a RAFT block copolymer according to any one of clauses 118 to 127 or a RAFT block copolymer prepared according to the method of any one of clauses 128 to 156, and further comprising a payload complexed to the RAFT block copolymer through electrostatic interaction.
  • sgRNA short guide RNA
  • the RAFT block copolymer complex of clause 167 further comprising a targeting component for targeting to cells.
  • a method for gene therapy comprising administering to a patient a RAFT block copolymer of any one of clauses 167 to 188.
  • a method for targeting a polymer nanoparticle composition to cells of a patient comprising administering to the patient a RAFT block copolymer of any one of clauses 167 to 188.
  • each of the non-viral gene delivery compositions of the diverse set is a RAFT block copolymer according to one of clauses 118-127.
  • FIG. 1A shows a schematic of a DNA nanostructure showing a central cavity to encapsulate a CRISPR RNP.
  • FIG. 1B shows the designed dimensions.
  • FIG. 1C and FIG. 1D show measured dimensions of the DNA nanostructure as measured with DynaPro and ZetaSizer.
  • FIG. 1E shows a TEM image showing one to one encapsulation of Cas9 RNP (arrows) in the DNA nanostructure and uptake in HEK 293 cells.
  • FIG. 1F shows results of an MTT assay to study cytotoxicity of the empty DNA nanostructrure.
  • FIG. 1G and FIG. 1H show results demonstrating concentration dependent uptake of the DNA nanostructure and that EGFP Cas9 colocalizes with the cell nucleus indicating nuclear delivery.
  • FIG. 2 shows a schematic of the input parameters for polymer nanoparticle synthesis and the highly tunable output characteristics.
  • FIG. 3 shows the results of a cytotoxicity assay for polymer nanoparticle compositions.
  • FIG. 4 shows delivery of polymer nanoparticle compositions to HEK-293 cells.
  • FIG. 5A shows a side view of a DNA nanostructure delivery composition with a capsule with lid, designed to have a height of 23.4 nm and a width of 26 nm.
  • FIG. 5B shows the transverse view of the design, with a length of 60 nm.
  • the cavity has dimensions of 13 nm in height and 15.6 nm in width and is designed to encapsulate CRISPR RNP.
  • the cylindrical structures represent helix “bundles”.
  • FIG. 6 is a chart showing polymer library size (diameter) data for Libraries 0006 (left most bar), 0007 (left-center bar), 0009 (right-center bar), and 0011 (right most bar) prepared as described herein.
  • FIG. 7A-C are charts showing polymer Library Block 1 Molecular Weight (Mw) Data for Block 12 of Libraries 0006 ( FIG. 7A ), 0007 ( FIG. 7B ), and 0008 ( FIG. 7C ) prepared as described herein and measured as weight average molecular weight.
  • Mw Polymer Library Block 1 Molecular Weight
  • FIG. 8A-B are charts showing polymer Library Block 1 Molecular Weight (Mw) Data for Block 12 of Libraries 0009 ( FIG. 8A ) and 0011 ( FIG. 8B ) prepared as described herein and measured as weight average molecular weight.
  • FIG. 9A-C are cartoons showing a 96-well plate having, in each well, the completed Block 1 polymer of varying molecular weights for each of library 0001 ( FIG. 9A ), 0003 ( FIG. 9B ), and 0005 ( FIG. 9C ).
  • FIG. 10A-C are graphs showing MTT assay results for the completed Block 1 polymer of varying molecular weights for each of library 0001 ( FIG. 10A ), 0003 ( FIG. 10B ), and 0005 ( FIG. 10C ).
  • the invention relates to polymer nanoparticle and DNA nanostructure delivery compositions for non-viral delivery, and methods therefor. More particularly, the invention relates to polymer nanoparticle delivery compositions, such as reversible addition-fragmentation chain transfer (RAFT) polymer compositions, and DNA nanostructure delivery compositions, such as DNA origami compositions, for the delivery of more than one payload, or for the delivery of a nucleic acid construct payload of 3 kB or more, and methods therefor.
  • polymer nanoparticle delivery compositions such as reversible addition-fragmentation chain transfer (RAFT) polymer compositions
  • DNA nanostructure delivery compositions such as DNA origami compositions
  • a DNA nanostructure delivery composition comprising: i) a single stranded DNA scaffold and ii) one or more oligonucleotides that bind through complementary base pairing with a segment of the DNA scaffold, wherein the one or more oligonucleotides cause the DNA scaffold to fold, and wherein the composition comprises more than one payload for delivery or a nucleic acid construct payload of 3 kB or more.
  • composition of clause 1 wherein the more than one payload comprises nucleic acids.
  • composition of clause 2 wherein the nucleic acids comprise DNA or RNA.
  • composition of clause 2 wherein the nucleic acids comprise a ribonucleoprotein.
  • composition of clause 2 wherein the payload nucleic acids comprise a short guide RNA (sgRNA) and a donor DNA strand.
  • sgRNA short guide RNA
  • composition of clause 1 wherein the payloads comprise a CRISPR associated enzyme.
  • composition of clause 7 wherein the targeted enzyme is a CRISPR associated enzyme.
  • composition of clause 1 wherein the payloads comprise a CRISPR associated enzyme, an sgRNA, and a donor DNA strand.
  • composition of clause 1 wherein the payloads comprise CRISPR/Cas9, an sgRNA, and a donor DNA strand.
  • composition of clause 1 wherein the payloads comprise a coding sequence for Cas9, an sgRNA, and a donor DNA strand in the form of a plasmid.
  • composition of clause 1 wherein the payloads consist of one molecule each of CRISPR/Cas9, an sgRNA, and a donor DNA strand.
  • composition of clause 1 wherein the nucleic acid construct payload of 3 kB or more comprises a CAR-T DNA construct.
  • composition of clause 1 wherein the payloads comprise an antisense oligonucleotide.
  • nucleic acid construct payload is of a size selected from the group consisting of 3 kB or more, 3.5 kB or more, 4 kB or more, 4.5 kB or more, 5 kB or more, 5.5 kB or more, 6 kB or more, 6.5 kB or more, 7 kB or more, 7.5 kB or more, 8 kB or more, and 8.5 kB or more.
  • composition of clause 1 wherein the payloads comprise a reverse transcriptase.
  • composition of clause 1 wherein the DNA scaffold and the one or more oligonucleotides comprise M13 bacteriophage DNA.
  • composition of clause 2 wherein the one or more oligonucleotides comprise overhangs that bind through complementary base paring with the payload nucleic acids.
  • composition of clause 1 further comprising a pharmaceutically acceptable carrier.
  • composition of clause 26 wherein the pharmaceutically acceptable carrier is for parenteral administration or topical administration.
  • composition of clause 28 wherein the one or more polymers comprise polyethylene glycol.
  • composition of clause 28 wherein the one or more polymers comprise polyethylene glycol poly-L-lysine.
  • composition of clause 28 wherein the one or more polymers comprise polyethylenimine.
  • composition of clause 28 wherein the one or more polymers comprise polyethylene glycol poly-L-lysine and polyethylenimine.
  • composition of clause 1 wherein the DNA nanostructure further comprises a targeting component for targeting to cells.
  • composition of clause 33 wherein the targeting component is a nucleotide that has a three-dimensional structure capable of binding a target cell receptor.
  • composition of clause 34 wherein the nucleotide is an RNA that forms a ‘stem-and-loop’ structure.
  • a method for gene therapy comprising administering to a patient a DNA nanostructure delivery composition comprising: i) a single stranded DNA scaffold and ii) one or more oligonucleotides that bind through complementary base pairing with a segment of the DNA scaffold, wherein the one or more oligonucleotides cause the DNA scaffold to fold, and wherein the composition comprises more than one payload for delivery or a nucleic acid construct payload of 3 kB or more.
  • nucleic acids comprise DNA or RNA.
  • nucleic acids comprise a ribonucleoprotein.
  • the payload nucleic acids comprise a short guide RNA (sgRNA) and a donor DNA strand.
  • sgRNA short guide RNA
  • the payloads comprise a CRISPR associated enzyme, an sgRNA, and a donor DNA strand.
  • the payloads comprise a coding sequence for Cas9, an sgRNA, and a donor DNA strand in the form of a plasmid.
  • nucleic acid construct payload of 3 kB or more comprises a CAR-T DNA construct.
  • nucleic acid construct payload is of a size selected from the group consisting of 3 kB or more, 3.5 kB or more, 4 kB or more, 4.5 kB or more, 5 kB or more, 5.5 kB or more, 6 kB or more, 6.5 kB or more, 7 kB or more, 7.5 kB or more, 8 kB or more, and 8.5 kB or more.
  • the targeting component is a nucleotide that has a three-dimensional structure capable of binding a target cell receptor.
  • nucleotide is an RNA that forms a ‘stem-and-loop’ structure.
  • the cancer is selected from the group consisting of lung cancer, bone cancer, pancreatic cancer, skin cancer, uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, cancer of the esophagus, cancer of the endocrine system, prostate cancer, leukemia, lymphoma, mesothelioma, cancer of the bladder, cancer of the kidney, neoplasms of the central nervous system, brain cancer, and adenocarcinoma.
  • a method for targeting a DNA nanostructure delivery composition to cells of a patient comprising administering to the patient: i) a single stranded DNA scaffold and ii) one or more oligonucleotides that bind through complementary base pairing with a segment of the DNA scaffold, wherein the one or more oligonucleotides cause the DNA scaffold to fold, wherein the composition comprises more than one payload for delivery or a nucleic acid construct payload of 3 kB or more, and wherein the DNA nanostructure comprises a targeting component for targeting to the cells of the patient.
  • nucleic acids comprise DNA or RNA.
  • nucleic acids comprise a ribonucleoprotein.
  • the payload nucleic acids comprise a short guide RNA (sgRNA) and a donor DNA strand.
  • sgRNA short guide RNA
  • the payloads comprise a CRISPR associated enzyme, an sgRNA, and a donor DNA strand.
  • the payloads comprise a coding sequence for Cas9, an sgRNA, and a donor DNA strand in the form of a plasmid.
  • nucleic acid construct payload of 3 kB or more comprises a CAR-T DNA construct.
  • nucleic acid construct payload is of a size selected from the group consisting of 3 kB or more, 3.5 kB or more, 4 kB or more, 4.5 kB or more, 5 kB or more, 5.5 kB or more, 6 kB or more, 6.5 kB or more, 7 kB or more, 7.5 kB or more, 8 kB or more, and 8.5 kB or more.
  • the targeting component is a nucleotide that has a three-dimensional structure capable of binding a target cell receptor.
  • nucleotide is an RNA that forms a ‘stem-and-loop’ structure.
  • a method comprising:
  • each non-viral gene delivery composition differs from each other non-viral gene delivery composition of the diverse set with respect to at least one of a set of composition characteristics
  • composition characteristics comprise one or more of molecular weight, degree of branching, number of ionizable groups, core-to-corona molecular weight ratio, hydrophilicity, hydrophobicity, propensity for aggregation, size, pKa, log P, and surface charge.
  • each of the non-viral gene delivery compositions of the diverse set is a DNA nanostructure delivery composition according to one of clauses 1-36.
  • a RAFT block copolymer comprising
  • a first terminus comprising a first capping unit derived from a first chain transfer agent in a RAFT copolymerization process
  • a first block prepared from one or more monomer units covalently attached to the first reactive functional unit, and having a molecular weight (M n ) in the range of about 20 kDa to about 80 kDa and a degree of polymerization in the range of about 20 to about 400;
  • a second block prepared from one or more monomer units covalently attached to the first block, and having a molecular weight (M n ) in the range of about 5 kDa to about 80 kDa and a degree of polymerization in the range of about 10 to about 500; and
  • a second terminus comprising a second capping unit derived from a second chain transfer agent
  • the RAFT block copolymer has one or more of an overall molecular weight (M n ) in the range of about 25 kDa to about 160 kDa, and overall degree of polymerization in the range of about 30 to about 900, a size in the range of about of about 10 to about 60 nm, and a maximum corona-to-core ratio (CCR) of about 1 to about 4.
  • M n overall molecular weight
  • CCR maximum corona-to-core ratio
  • each chain transfer agent is independently selected from the group consisting of bis(carboxymethyl)trithiocarbonate, bis(2-amino-2-oxoethyl) trithiocarbonate, bis[4-(2-hydroxyethoxycarbonyl)benzyl] trithiocarbonate, 4-cyano-4-(ethylsulfanylthiocarbonyl) sulfanylvpentanoic acid, 4-cyano-4-((phenylcarbonothioyl)thio)pentanoic acid, and 4-cyano-4-[(dodecylsulfanylthiocarbonyl)sulfanyl] pentanoic acid.
  • R is —SC 2 —C 12 alkyl or C 6 H 5 ,
  • a method of preparing a RAFT block copolymer comprising:
  • step (i) The method of any one of clauses 128 to 133, wherein the one or more monomer units in step (i) are independently selected from the group consisting of 2-dimethylaminoethyl acrylate, 2-(diethylamino) ethyl methacrylate, 2-(diisopropylamino) ethyl methacrylate, butyl methacrylate, ethyl acrylic acid, propyl acrylic acid, (hydroxyethyl)methacrylate, and methyl methacrylate.
  • step (i) is one of 2-dimethylaminoethyl acrylate, 2-(diethylamino) ethyl methacrylate, 2-(diisopropylamino) ethyl methacrylate, butyl methacrylate, ethyl acrylic acid, propyl acrylic acid, (hydroxyethyl)methacrylate, or methyl methacrylate.
  • step (ii) are independently selected from the group consisting of 2-dimethylaminoethyl acrylate, 2-(diethylamino) ethyl methacrylate, 2-(diisopropylamino) ethyl methacrylate, butyl methacrylate, ethyl acrylic acid, propyl acrylic acid, (hydroxyethyl)methacrylate, and methyl methacrylate.
  • step (ii) are two different monomer units independently selected from the group consisting of 2-dimethylaminoethyl acrylate. 2-(diethylamino) ethyl methacrylate, 2-(diisopropylamino) ethyl methacrylate, butyl methacrylate, ethyl acrylic acid, propyl acrylic acid, (hydroxyethyl)methacrylate, and methyl methacrylate.
  • step (ii) are three different monomer units independently selected from the group consisting of 2-dimethylaminoethyl acrylate, 2-(diethylamino) ethyl methacrylate, 2-(diisopropylamino) ethyl methacrylate, butyl methacrylate, ethyl acrylic acid, propyl acrylic acid, (hydroxyethyl)methacrylate, and methyl methacrylate.
  • step (ii) are 2-dimethylaminoethyl acrylate, butyl methacrylate, and propyl acrylic acid; or 2-dimethylaminoethyl acrylate and butyl methacrylate; or 2-dimethylaminoethyl acrylate, butyl methacrylate, and ethyl acrylic acid.
  • RAFT block copolymer has one or more of an overall molecular weight (M n ) in the range of about 25 kDa to about 160 kDa, and overall degree of polymerization in the range of about 30 to about 900, a size in the range of about of about 10 to about 60 nm, and a maximum corona-to-core ratio (CCR) of about 1 to about 4.
  • M n overall molecular weight
  • CCR maximum corona-to-core ratio
  • a method of preparing a library of RAFT block copolymers comprising:
  • each well comprises a mixture of a first chain transfer agent, a first initiator, one or more monomer units, and optionally a solvent or solvent mixture;
  • step (viii) reacting the components of step (vii) under conditions that promote RAFT copolymerization to provide a series of RAFT block copolymers in the wells of the multiwell plate;
  • xi optionally characterizing the RAFT block copolymer in each well of the multiwell plate.
  • step (i) is independently selected from the group consisting of 2-dimethylaminoethyl acrylate, 2-(diethylamino) ethyl methacrylate, 2-(diisopropylamino) ethyl methacrylate, butyl methacrylate, ethyl acrylic acid, propyl acrylic acid, (hydroxyethyl)methacrylate, and methyl methacrylate.
  • step (i) is one of 2-dimethylaminoethyl acrylate, 2-(diethylamino) ethyl methacrylate, 2-(diisopropylamino) ethyl methacrylate, butyl methacrylate, ethyl acrylic acid, propyl acrylic acid, (hydroxyethyl)methacrylate, or methyl methacrylate.
  • step (vii) The method of any one of clauses 141 to 143, wherein the one or more monomer units in step (vii) are independently selected from the group consisting of 2-dimethylaminoethyl acrylate, 2-(diethylamino) ethyl methacrylate, 2-(diisopropylamino) ethyl methacrylate, butyl methacrylate, ethyl acrylic acid, propyl acrylic acid, (hydroxyethyl)methacrylate, and methyl methacrylate.
  • step (vii) The method of any one of clauses 141 to 144, wherein the one or more monomer units in step (vii) are two different monomer units independently selected from the group consisting of 2-dimethylaminoethyl acrylate, 2-(diethylamino) ethyl methacrylate, 2-(diisopropylamino) ethyl methacrylate, butyl methacrylate, ethyl acrylic acid, propyl acrylic acid, (hydroxyethyl)methacrylate, and methyl methacrylate.
  • the one or more monomer units in step (vii) are two different monomer units independently selected from the group consisting of 2-dimethylaminoethyl acrylate, 2-(diethylamino) ethyl methacrylate, 2-(diisopropylamino) ethyl methacrylate, butyl methacrylate, ethyl acrylic acid, propyl acrylic acid, (hydroxyeth
  • step (vii) The method of any one of clauses 141 to 145, wherein the one or more monomer units in step (vii) are three different monomer units independently selected from the group consisting of 2-dimethylaminoethyl acrylate, 2-(diethylamino) ethyl methacrylate, 2-(diisopropylamino) ethyl methacrylate, butyl methacrylate, ethyl acrylic acid, propyl acrylic acid, (hydroxyethyl)methacrylate, and methyl methacrylate.
  • the one or more monomer units in step (vii) are three different monomer units independently selected from the group consisting of 2-dimethylaminoethyl acrylate, 2-(diethylamino) ethyl methacrylate, 2-(diisopropylamino) ethyl methacrylate, butyl methacrylate, ethyl acrylic acid, propyl acrylic acid, (hydroxyeth
  • step (vii) The method of any one of clauses 141 to 146, wherein the one or more monomer units in step (vii) are 2-dimethylaminoethyl acrylate, butyl methacrylate, and propyl acrylic acid; or 2-dimethylaminoethyl acrylate and butyl methacrylate; or 2-dimethylaminoethyl acrylate, butyl methacrylate, and ethyl acrylic acid.
  • first and second chain transfer are each independently selected from the group consisting of bis(carboxymethyl)trithiocarbonate, bis(2-amino-2-oxoethyl) trithiocarbonate, bis[4-(2-hydroxyethoxycarbonyl)benzyl] trithiocarbonate, 4-cyano-4-(ethylsulfanylthiocarbonyl) sulfanylvpentanoic acid, 4-cyano-4-((phenylcarbonothioyl)thio)pentanoic acid, and 4-cyano-4-[(dodecylsulfanylthiocarbonyl)sulfanyl] pentanoic acid.
  • a composition comprising a RAFT block copolymer according to any one of clauses 118 to 127 or a RAFT block copolymer prepared according to the method of any one of clauses 128 to 156.
  • a RAFT block copolymer conjugate comprising a RAFT block copolymer according to any one of clauses 118 to 127 or a RAFT block copolymer prepared according to the method of any one of clauses 128 to 156, and further comprising a biomolecule, drug, or label covalently attached to the RAFT block copolymer through a functional group on one of the first or second chain transfer agents that is incorporated into the RAFT block copolymer.
  • a method of preparing a RAFT block copolymer conjugate comprising a RAFT block copolymer according to any one of clauses 118 to 127 or a RAFT block copolymer prepared according to the method of any one of clauses 128 to 156 and a biomolecule, drug, or label, wherein the RAFT block copolymer and the biomolecule, drug, or label are covalently attached through a functional group on one of the first or second chain transfer agents that is incorporated into the RAFT block copolymer.
  • a RAFT block copolymer complex comprising a RAFT block copolymer according to any one of clauses 118 to 127 or a RAFT block copolymer prepared according to the method of any one of clauses 128 to 156, and further comprising a payload complexed to the RAFT block copolymer through electrostatic interaction.
  • sgRNA short guide RNA
  • the RAFT block copolymer complex of clause 167 further comprising a targeting component for targeting to cells.
  • a method for gene therapy comprising administering to a patient a RAFT block copolymer of any one of clauses 167 to 188.
  • a method for targeting a polymer nanoparticle composition to cells of a patient comprising administering to the patient a RAFT block copolymer of any one of clauses 167 to 188.
  • each of the non-viral gene delivery compositions of the diverse set is a RAFT block copolymer according to one of clauses 118-127.
  • the polymer nanoparticle or DNA nanostructure delivery compositions described herein may comprise any non-viral composition for in vivo delivery of the payloads.
  • the polymer nanoparticle or nanostructure DNA delivery compositions described herein may be selected from the group comprising: polymer nanoparticles, reversible addition-fragmentation chain transfer (RAFT) polymers, polyplexes, micelles, polymersomes, dendrimers, emulsion, synthetic virus-like particles, carbon nanotubes, emulsions, and any DNA nanostructure delivery composition, such as DNA origami structures.
  • RAFT reversible addition-fragmentation chain transfer
  • the two platforms have a high degree of tunability in structure and function, opportunities to protect payloads from adverse reactions or degradation by the immune system, and cell targeting via surface charge, particle size, or conjugation with various aptamers.
  • These delivery systems also lend themselves to computer aided design, and they both have suitable pathways to robust, commercial scale manufacturing processes with higher yields and fewer purification steps than viral manufacturing processes.
  • a DNA nanostructure delivery composition is provided.
  • a DNA nanostructure delivery composition e.g., a DNA origami structure
  • a delivery platform is programmable and offers an opportunity for precise scale-up and manufacturing.
  • the biologic and non-viral nature of the DNA nanostructure delivery composition reduces the chance of adverse immune reactions.
  • control of each nucleotide that forms a part of the DNA nanostructure delivery composition allows for the precise design and modification of the structure, including suitable chemical moieties which can make in vivo delivery and endosomal escape possible.
  • the DNA nanostructure delivery composition can undergo self-base pairing (i.e., a DNA origami structure) to fold into structures that can form the single-stranded DNA scaffold that can encapsulate a payload.
  • self-base pairing i.e., a DNA origami structure
  • the DNA nanostructure delivery composition can comprise i) a single stranded DNA scaffold and ii) one or more oligonucleotides that bind through complementary base pairing with a segment of the DNA scaffold, wherein the one or more oligonucleotides cause the DNA scaffold to fold.
  • the one or more oligonucleotides can comprise overhangs that bind through complementary base paring with the payload nucleic acids.
  • the overhangs can be located within a cavity within the DNA scaffold, and the cavity can be covered by a lid and a hinge allowing the payloads to be completely enclosed within the cavity when the lid is shut.
  • the lid can further comprise oligonucleotide strands that bind through complementary base pairing with other oligonucleotide strands attached to the DNA scaffold when the lid is in the closed position.
  • DNA nanostructure delivery compositions e.g., DNA origami structures
  • DNA origami structures are described in U.S. Pat. No. 9,765,341, incorporated herein by reference.
  • complementary base pairing refers to the ability of purine and pyrimidine nucleotide sequences to associate through hydrogen bonding to form double-stranded nucleic acid molecules. Guanine and cytosine, adenine and thymine, and adenine and uracil are complementary and can associate through hydrogen bonding resulting in the formation of double-stranded nucleic acid molecules when two nucleic acid molecules have “complementary” sequences.
  • the complementary sequences can be DNA or RNA sequences.
  • the complementary DNA or RNA sequences are referred to as a “complement.”
  • the polymer nanoparticle composition (e.g., RAFT polymer) or the DNA nanostructure delivery compositions of the invention can comprise more than one payload for delivery to target cells, or a nucleic acid construct payload of 3 kB or more for delivery to target cells.
  • the nucleic acid construct payload of 3 kB or more can be DNA or RNA.
  • the DNA scaffold and the one or more oligonucleotides can comprise M13 bacteriophage DNA.
  • the DNA nanostructure delivery composition further comprises a targeting component for targeting to cells.
  • the targeting component can be a nucleotide that is an RNA that forms a ‘stem-and-loop’ structure.
  • the DNA nanostructure delivery composition can be designed so that the polynucleotide strands fold into three-dimensional structures via a series of highly tuned ‘stem-and-loop’ configurations.
  • the DNA nanostructure delivery composition can have a high affinity for protein receptors expressed on specific cells resulting in targeting of the DNA nanostructure delivery composition and the payload to the specific cells.
  • the polynucleotide that binds to the target cell receptor can bind in conjunction with a peptide aptamer.
  • the DNA nanostructure delivery composition can be folded so that, in the presence of certain biomarkers such as cell receptors, microRNA, DNA, RNA or an antigen, the self-base pairs are disrupted and the DNA nanostructure delivery composition can unfold, resulting in the triggered release of the payload only in the presence of the specific biomarker.
  • a lock-and-key mechanism for triggered opening of a DNA nanostructure delivery composition e.g., a DNA origami construct
  • the use of the DNA nanostructure delivery composition to create three-dimensional structures that target cells and tissues allows for more efficient delivery of payloads with fewer side effects, since the DNA nanostructure delivery composition can have low immunogenicity, and the payload will be released only in the presence of RNA or peptide biomarkers, for example, that exist in the cytosol of target cells and tissues.
  • DNA nanostructure delivery composition In the embodiment where a DNA nanostructure delivery composition is used, computer aided design tools can predict the nucleotide sequence necessary to produce highly engineered DNA nanostructure delivery compositions. For gene delivery, these DNA nanostructure delivery compositions offer the advantages of encapsulation efficiency, as the size and shape of the structure can be tailored to fit the cargo. In another aspect, loading efficiency can be increased by incorporating nucleic acid payloads into the encapsulating DNA nanostructure delivery composition itself.
  • the non-viral delivery vehicles needed for translation of gene editing treatments can be synthesized with repeatable, versatile and scalable methods to meet GMP requirements.
  • lipid nanoparticles have been used for most non-viral nucleic acid delivery vehicles in clinical trials.
  • polymer nanoparticles have been less commonly used for clinical nucleic acid delivery, polymer synthesis methods provide these types of scalable manufacturing benefits in ways that cannot be matched by other biomaterials such as lipids.
  • Recently, methods of producing cationic block copolymer nanoparticles using reversible-addition fragmentation chain transfer (RAFT) polymerization have been standardized to demonstrate rigor and reproducibility necessary for commercial scale nanocarrier production. Given the robustness, versatility and sophistication of the RAFT copolymerization process, it is an attractive route to synthesizing non-viral delivery vehicle alternatives to AAVs.
  • RAFT reversible-addition fragmentation chain transfer
  • polymer nanoparticle delivery vehicles are designed using cationic polymers that form complexes with negatively charged nucleic acids and enhance interaction with the negative resting potential of the cellular membrane.
  • the same positive surface charge may also lead to cytotoxicity in high enough doses.
  • the RAFT copolymers prepared according to the methods described herein have been shown to be well tolerated by cells as provided in the examples described herein.
  • polymer nanoparticles may be used as delivery vehicles according to the present disclosure.
  • the polymer nanoparticles may be made by RAFT copolymerization to synthesize a diverse set of block copolymers, and to screen their ability to form complexes with a payload.
  • polymer nanoparticles e.g., RAFT copolymers
  • payloads may be combined with the polymer nanoparticles or DNA nanostructure delivery compositions using any or all of covalent bonds, electrostatic interactions, and ligand affinity interactions.
  • covalent bonding methods include the use of EDC/NHS to form stable amide bonds between the payload and the polymer nanoparticles for improved stability (both “on the shelf” and in vivo), ease of separation and extraction, and sensitive detection.
  • electrostatic bonding methods include the use of cationic polymer nanoparticles or DNA nanostructure delivery compositions that electrostatically complex with the payload.
  • ligand affinity bonding includes the use of ligands such as avidin and biotin, both covalently bonded to the polymer nanoparticles or DNA nanostructure delivery compositions and the payload via EDC/NHS chemistry to yield the stable combination of the payload and the polymer nanoparticles or DNA nanostructure delivery compositions.
  • ligands such as avidin and biotin
  • RAFT copolymerization may be achieved using chain transfer agents (CTAs) containing one or more terminal carboxyl groups in order to obtain carboxy terminated polymers with ends available for bonding to the payload via the methods described above.
  • CTAs chain transfer agents
  • the resulting mono or di-carboxy terminated polymer is dispersed in a low pH (e.g., a pH of less than 6) buffer, both ends of the polymer are exposed and available for labeling via EDC/NHS chemistry.
  • a physiological pH ⁇ pH 7
  • the core blocks self-assemble, encapsulating the payload in the hydrophobic core, to be released and exposed upon acidification in the endosomal compartment of a cell.
  • RAFT copolymers as prepared herein can be described by the following structure:
  • each CTACap is a capping unit derived from the chain transfer agent(s) used in the process for preparing the RAFT copolymer.
  • the CTA used for preparing each of Block 1 and Block 2 can be the same or different.
  • the CTA used to prepare each of Block 1 and Block 2 is the same (e.g. macroCTA).
  • the CTA used to prepare each of Block 1 and Block 2 is different.
  • the CTA used to prepare one or both of Block 1 and Block 2 comprises a functional group for the covalent attachment of a biomolecule, drug, or label to the RAFT copolymer.
  • the covalent attachment can be via an ester or an amide bond.
  • the covalent attachment can be via EDC-NHS chemistry.
  • the first capping unit is of the formula
  • the second capping unit is of the formula
  • R is —SC 2 —C 12 alkyl or C 6 H 5 ,
  • the RAFT copolymer can be complexed with a biological molecule, such as a DNA molecule, via electrostatic interaction.
  • each of Block 1 and Block 2 can comprise one or more monomer units polymerized using a RAFT polymerization process. It will be appreciated that the identity of the monomer units is not particularly limited so long as the monomer units being used are compatible with a RAFT polymerization process.
  • Suitable monomer units include but are not limited to 2-dimethylaminoethyl acrylate (DMAEMA), 2-(diethylamino) ethyl methacrylate (DEAEMA), 2-(diisopropylamino) ethyl methacrylate, butyl methacrylate (BMA), ethyl acrylic acid (EAA), propyl acrylic acid (PAA), (hydroxyethyl)methacrylate (HEMA), and methyl methacrylate (MMA), Acrylic acid (AA), Aminoethyl methacrylate (AEM), 2-(2-aminoethylamino) ethyl methacrylate (AEAEMA), N-(2-Aminoethyl) methacrylamide (AEMA), 3-amino-2-hydroxypropyl methacrylate (AEAHPMA), 3-aminopropyl methacrylamide (AHPMA), Amidoamine (AMA), N-(3-Aminopropyl)meth
  • the monomer units used to make Block 1 and/or Block 2 of RAFT copolymers as described herein are selected from the group consisting of 2-(dimethylamino) ethyl acrylate (DMAEEA), 2-(diethylamino) ethyl methacrylate (DEAEEA), 2-(diisopropylamino) ethyl methacrylate (DIEAMA), butyl methacrylate (BMA), ethyl acrylic acid (EAA), propyl acrylic acid (PAA), (hydroxyethyl)methacrylate, and methyl methacrylate (MMA).
  • DMAEEA 2-(dimethylamino) ethyl acrylate
  • DEAEEA 2-(diethylamino) ethyl methacrylate
  • DIEAMA 2-(diisopropylamino) ethyl methacrylate
  • BMA butyl methacrylate
  • EAA ethyl acrylic acid
  • the RAFT copolymers provided herein can be described by the formula:
  • RAFT copolymer as described herein having a single monomer in Block 1 of 25 units and 3 different monomers in Block 2 having an average monomer unit ratio of 20:10:5 for a total n of 35, can be described by the general formula
  • the polymers prepared using a RAFT polymerization are random polymers having a distribution of units and hence molecular weights. Therefore, the cartoon representation of Block 2 in the example above is a random copolymer comprising 35 monomer units of B2M1, B2M2, and B2M3 in the ratio described above.
  • the polymer nanoparticle composition or the DNA nanoparticle delivery composition can be coated with one or more polymers to protect the compositions from immune responses or to enhance endosomal escape.
  • the one or more polymers comprise polyethylene glycol.
  • the one or more polymers comprise polyethylene glycol poly-L-lysine.
  • the one or more polymers comprise polyethylenimine.
  • the one or more polymers comprise polyethylene glycol poly-L-lysine and polyethylenimine.
  • RAFT copolymers described herein can be advantageous to their use in the compositions and methods as described herein. Accordingly, the methods for preparing RAFT copolymers either in singleton or in library format as described herein are capable of providing particular parameters and properties of the RAFT copolymers.
  • a RAFT block copolymer as described herein has one or more of an overall molecular weight (M n ) in the range of about 25 kDa to about 160 kDa, and overall degree of polymerization in the range of about 30 to about 900, a size in the range of about of about 10 to about 60 nm, and a maximum corona-to-core ratio (CCR) of about 1 to about 4.
  • M n overall molecular weight
  • CCR maximum corona-to-core ratio
  • the size is in the range of about of about 10 to about 50 nm, about 15 to about 45 nm, about 20 to about 40 nm, or about 25 to about 35 nm.
  • the maximum corona-to-core ratio (CCR) is less than 4, or less than 3, about 1 to about 3.8, about 1.2 to about 3.5, about 1.5 to about 3, about 1.5 to about 2.5, or about 1 to about 2.
  • the first block can be prepared from one or more monomer units and have a molecular weight (M n ) in the range of about 20 kDa to about 80 kDa and a degree of polymerization in the range of about 20 to about 400.
  • the first block molecular weight (M n ) is in the range of about 25 kDa to about 60 kDa, or about 30 kDa to about 55 kDa, about 30 kDa to about 50 kDa, or about 30 kDa to about 40 kDa, and the like.
  • the first block degree of polymerization is in the range of about 30 to about 350, about 50 to about 300, about 70 to about 250, about 80 to about 240, about 100 to about 200, and the like.
  • the second block can be prepared from one or more monomer units, and can have a molecular weight (M n ) in the range of about 1 kDa to about 80 kDa and a degree of polymerization in the range of about 3 to about 500.
  • M n molecular weight
  • the second block molecular weight (M n ) is in the range of about 10 kDa to about 70 kDa, about 15 kDa to about 65 kDa, about 20 kDa to about 60 kDa, about 25 kDa to about 55 kDa, about 30 kDa to about 50 kDa, about 35 kDa to about 45 kDa, about 5 kDa to about 15 kDa, and the like.
  • the second block degree of polymerization is in the range of about 10 to about 500, about 12 to about 450, 20 to about 400, about 25 to about 350, about 50 to about 300, about 100 to about 250, about 150 to about 200, about 5 to about 50, about 5 to about 20, and the like.
  • RAFT polymerization is generally known in the art. Suitable reagents, monomers, and conditions for RAFT polymerization previously investigated can be used in the copolymers, methods, and compositions described herein, such as those described in U.S. Pat. Nos. 9,006,193, 9,464,300, and 9,476,063, the disclosures of each of which are incorporated by reference in their entirety. It will be appreciated that a variety of solvents can be used in the RAFT polymerization method steps and purification steps described herein.
  • Suitable solvents include, but are not limited to, 2-Chloroethanol, Acetic Acid (Glacial), Acetone, Acetonitrile, Acetophenone, Aniline, Benzaldehyde, Benzyl Acetate, Carbon disulfide, Cyclohexane, Cyclohexanol, Di(ethylene glycol), Di(propylene glycol), Diacetone alcohol, Diethyl ether, Dimethylsulfoxide, Ethanol, Ethyl acetate, Ethylene glycol, Formaldehyde (37% solution), Formamide, Formic acid, Formic acid (96%), HexaneIsobutanol, Isopropanol, Isopropyl acetate, Isopropyl ether, m-Cresol, Methanol, Methyl acetate, Methyl ethyl ketone, Mineral Oil, N,N-Dimethylformamide, n-Butanol, n-Octan
  • Illustrative payloads for the polymer nanoparticle or nanostructure DNA delivery compositions described herein can include any one or a combination of compositions selected from the group comprising: nucleic acids (e.g., DNA or RNA), pDNA, oligodeoxyribonucleic acids (ODNs), dsDNA, ssDNA, antisense oligonucleotides, antisense RNA, siRNA, messenger RNA, guide RNA (e.g., small guide RNA), ribonucleoproteins, donor DNA strands used in the CRISPR/Cas9 system, and enzymes, such as CRISPR-associated enzymes, e.g., Cas9, enzymes used in other gene editing systems, such as ZFNs, custom designed homing endonucleases, TALENS systems, other gene editing endonucleases, and reverse transcriptase.
  • nucleic acids e.g., DNA or RNA
  • ODNs oligodeoxyribon
  • CAR-T cells are T cells expressing chimeric antigen receptors (CARs).
  • the CAR is a genetically engineered receptor that is designed to target a specific antigen, for example, a tumor antigen. This targeting can result in cytotoxicity against the tumor, for example, such that CAR-T cells expressing CARs can target and kill tumors via the specific tumor antigens.
  • CARs can comprise a recognition region, e.g., a single chain fragment variable (scFv) region derived from an antibody for recognition and binding to the antigen expressed by the tumor, an activation signaling domain, e.g., the CD3 ⁇ chain of T cells can serve as a T cell activation signal in CARs, and a co-stimulation domain (e.g., CD137, CD28 or CD134) to achieve prolonged activation of T cells in vivo.
  • scFv single chain fragment variable
  • an activation signaling domain e.g., the CD3 ⁇ chain of T cells can serve as a T cell activation signal in CARs
  • a co-stimulation domain e.g., CD137, CD28 or CD134
  • the payload can be a nucleic acid construct (e.g., DNA or RNA) with a size selected from the group consisting of 3 kB or more, 3.1 kB or more, 3.2 kB or more, 3.3 kB or more, 3.4 kB or more, 3.5 kB or more, 3.6 kB or more, 3.7 kB or more, 3.8 kB or more, 3.9 kB or more, 4 kB or more, 4.1 kB or more, 4.2 kB or more, 4.3 kB or more, 4.4 kB or more, 4.5 kB or more, 4.6 kB or more, 4.7 kB or more, 4.8 kB or more, 4.9 kB or more, 5 kB or more, 5.1 kB or more, 5.2 kB or more, 5.3 kB or more, 5.4 kB or more, 5.5 kB or more, 5.6 kB or more, 5.7 k
  • the payload can be any one or more of the components of the CRISPR RNP system including a CRISPR-associated enzyme (e.g., Cas9), a short guide RNA (sgRNA), and a donor DNA strand.
  • a CRISPR-associated enzyme e.g., Cas9
  • sgRNA short guide RNA
  • the payload can comprise an sgRNA used for targeting an enzyme to a specific genomic sequence.
  • the targeted enzyme can be a CRISPR-associated enzyme.
  • the payload can comprise one molecule each of CRISPR/Cas9, an sgRNA, and a donor DNA strand in the polymer nanoparticle or DNA nanostructure delivery compositions described herein.
  • the payloads can be nucleic acids used for homology directed repair or as transposable elements.
  • the payloads can be any of the payloads described herein in the form of a plasmid construct.
  • the DNA nanostructure delivery composition described herein can encapsulate a payload that is used for gene editing.
  • the CRISPR/Cas9 system can be the payload and can be used for gene editing.
  • another gene editing system can be the payload, such as ZFNs, custom designed homing endonucleases, and TALENS systems.
  • the Cas9 endonuclease is capable of introducing a double strand break into a DNA target sequence.
  • the Cas9 endonuclease is guided by the guide polynucleotide (e.g., sgRNA) to recognize and optionally introduce a double strand break at a specific target site into the genome of a cell.
  • the Cas9 endonuclease can unwind the DNA duplex in close proximity to the genomic target site and can cleave both target DNA strands upon recognition of a target sequence by a guide polynucleotide (e.g., sgRNA), but only if the correct protospacer-adjacent motif (PAM) is approximately oriented at the 3′ end of the target.
  • the donor DNA strand can then be incorporated into the genomic target site.
  • the CRISPR/Cas9 system for gene editing is well-known in the art.
  • the payload may include DNA segments that serve as nuclear localization signals, enhancing nuclear delivery of the polymer nanoparticles (e.g., RAFT copolymers) or DNA nanostructure delivery compositions upon endosomal escape.
  • the payload may include a nucleotide sequence designed to bind as an aptamer to endosomal receptors, enhancing intracellular trafficking of the polymer nanoparticles (e.g., RAFT copolymers) or DNA nanostructure delivery compositions.
  • a DNA nanostructure delivery composition (e.g., DNA origami) is provided to package the Cas9 protein, the sgRNA and the single stranded donor DNA strand together in one nanostructure to ensure co-delivery of all the components to a particular location at the same time.
  • the single stranded nature of the sgRNA and the donor DNA strand can be used to convert these components into constitutive parts of the DNA nanostructure delivery composition (e.g., the DNA origami structure) such that they get delivered together and dissociate at the same time from the DNA nanostructure delivery composition upon reaching the target site (e.g., a target cell).
  • the DNA nanostructure delivery composition can deliver either a plasmid or the ribonucleoprotein (RNP) form of CRISPR/Cas 9.
  • a method for gene therapy comprises administering to a patient a DNA nanostructure delivery composition comprising i) a single stranded DNA scaffold and ii) one or more oligonucleotides that bind through complementary base pairing with a segment of the DNA scaffold, wherein the one or more oligonucleotides cause the DNA scaffold to fold, and wherein the composition comprises more than one payload for delivery or a nucleic acid construct payload of 3 kB or more.
  • the method comprises administering to the patient a polymer nanoparticle composition, such as a RAFT copolymer composition.
  • a method for targeting a DNA nanostructure delivery composition to cells of a patient is provided.
  • the method comprises administering to the patient i) a single stranded DNA scaffold and ii) one or more oligonucleotides that bind through complementary base pairing with a segment of the DNA scaffold, wherein the one or more oligonucleotides cause the DNA scaffold to fold, wherein the composition comprises more than one payload for delivery or a nucleic acid construct payload of 3 kB or more, and wherein the DNA nanostructure comprises a targeting component for targeting to the cells of the patient.
  • the targeting method comprises administering to the patient a polymer nanoparticle composition, such as a RAFT copolymer composition.
  • compositions described herein may be formulated as pharmaceutical compositions for parenteral or topical administration.
  • Such pharmaceutical compositions and processes for making the same are known in the art for both humans and non-human mammals. See, e.g., R EMINGTON : T HE S CIENCE AND PRACTICE OF PHARMACY , (1995) A. Gennaro, et al., eds., 19 th ed., Mack Publishing Co. Additional active ingredients may be included in the compositions.
  • the polymer nanoparticle composition or the DNA nanostructure delivery composition may be administered, for example, directly into the blood stream of a patient, into muscle, into an internal organ, or can be administered in a topical formulation.
  • suitable routes for such parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, epidural, intracerebroventricular, intraurethral, intrasternal, intracranial, intratumoral, intramuscular and subcutaneous delivery.
  • means for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • parenteral formulations are typically aqueous solutions which may contain carriers or excipients such as salts, carbohydrates and buffering agents (preferably at a pH of from 3 to 9), but they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water or sterile saline.
  • a suitable vehicle such as sterile, pyrogen-free water or sterile saline.
  • the preparation under sterile conditions, by lyophilization to produce a sterile lyophilized powder for a parenteral formulation may readily be accomplished using standard pharmaceutical techniques well-known to those skilled in the art.
  • the solubility of the composition used in the preparation of a parenteral formulation may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
  • compositions for parenteral administration comprise: a) a pharmaceutically active amount of the polymer nanoparticle composition or the DNA nanostructure delivery composition; b) a pharmaceutically acceptable pH buffering agent to provide a pH in the range of about pH 4.5 to about pH 9; c) an ionic strength modifying agent in the concentration range of about 0 to about 300 millimolar; and d) water soluble viscosity modifying agent in the concentration range of about 0.25% to about 10% total formula weight or any combinations of a), b), c) and d) are provided.
  • the pH buffering agents for use in the compositions and methods herein described are those agents known to the skilled artisan and include, for example, acetate, borate, carbonate, citrate, and phosphate buffers, as well as hydrochloric acid, sodium hydroxide, magnesium oxide, monopotassium phosphate, bicarbonate, ammonia, carbonic acid, hydrochloric acid, sodium citrate, citric acid, acetic acid, disodium hydrogen phosphate, borax, boric acid, sodium hydroxide, diethyl barbituric acid, and proteins, as well as various biological buffers, for example, TAPS, Bicine, Tris, Tricine, HEPES, TES, MOPS, PIPES, cacodylate, or MES.
  • acetate, borate, carbonate, citrate, and phosphate buffers as well as hydrochloric acid, sodium hydroxide, magnesium oxide, monopotassium phosphate, bicarbonate, ammonia, carbonic acid, hydrochloric acid, sodium citrate,
  • the ionic strength modulating agents include those agents known in the art, for example, glycerin, propylene glycol, mannitol, glucose, dextrose, sorbitol, sodium chloride, potassium chloride, and other electrolytes.
  • Useful viscosity modulating agents include but are not limited to, ionic and nonionic water soluble polymers; crosslinked acrylic acid polymers such as the “carbomer” family of polymers, e.g., carboxypolyalkylenes that may be obtained commercially under the Carbopol® trademark; hydrophilic polymers such as polyethylene oxides, polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol; cellulosic polymers and cellulosic polymer derivatives such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, methyl cellulose, carboxymethyl cellulose, and etherified cellulose; gums such as tragacanth and xanthan gum; sodium alginate; gelatin, hyaluronic acid and salts thereof, chitosans, gellans or any combination thereof.
  • non-acidic viscosity enhancing agents such as
  • solubility of the compositions described herein used in the preparation of a parenteral formulation may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
  • compositions described herein may be administered topically.
  • a variety of dose forms and bases can be applied to the topical preparations, such as an ointment, cream, gel, gel ointment, plaster (e.g. cataplasm, poultice), solution, powders, and the like.
  • These preparations may be prepared by any conventional method with conventional pharmaceutically acceptable carriers or diluents as described below.
  • vaseline higher alcohols, beeswax, vegetable oils, polyethylene glycol, etc.
  • fats and oils waxes, higher fatty acids, higher alcohols, fatty acid esters, purified water, emulsifying agents etc.
  • gel formulations conventional gelling materials such as polyacrylates (e.g. sodium polyacrylate), hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, purified water, lower alcohols, polyhydric alcohols, polyethylene glycol, and the like are used.
  • an emulsifying agent preferably nonionic surfactants
  • an oily substance e.g. liquid paraffin, triglycerides, and the like
  • a plaster such as cataplasm or poultice can be prepared by spreading a gel preparation as mentioned above onto a support (e.g. fabrics, non-woven fabrics).
  • paraffins, squalane, lanolin, cholesterol esters, higher fatty acid esters, and the like may optionally be used.
  • antioxidants such as BHA, BHT, propyl gallate, pyrogallol, tocopherol, etc. may also be incorporated.
  • the dosage of the polymer nanoparticle composition or the DNA nanostructure delivery composition can vary significantly depending on the patient condition, or the disease state being treated, the route of administration and tissue distribution, and the possibility of co-usage of other therapeutic treatments.
  • the effective amount to be administered to a patient is based on body surface area, patient weight or mass, and physician assessment of patient condition.
  • the polymer nanoparticle composition or the DNA nanostructure delivery composition can be administered to a patient with a disease or a disorder selected from the group consisting of cancer, a muscular disorder, a pulmonary disorder, a skin disorder, a neurological disease, neurofibromatosis 1 (NF1), and a hemoglobinopathy.
  • a disease or a disorder selected from the group consisting of cancer, a muscular disorder, a pulmonary disorder, a skin disorder, a neurological disease, neurofibromatosis 1 (NF1), and a hemoglobinopathy.
  • the cancer is selected from the group consisting of lung cancer, bone cancer, pancreatic cancer, skin cancer, uterine cancer, ovarian cancer, endometrial cancer, rectal cancer, stomach cancer, colon cancer, breast cancer, cancer of the esophagus, cancer of the endocrine system, prostate cancer, leukemia, lymphoma, mesothelioma, cancer of the bladder, cancer of the kidney, neoplasms of the central nervous system, brain cancer, and adenocarcinoma.
  • the skin disorder is a Staphylococcus aureus infection.
  • the muscular disorder is muscular dystrophy (e.g., Duchenne Muscular Dystrophy).
  • the polymer nanoparticle composition and the DNA nanostructure delivery composition are not cytotoxic to the cells of the patient.
  • the gene therapy may result in the inactivation of a pathogen (i.e., a microorganism) rather than altering the genome of the patient.
  • a method comprising synthesizing a diverse set of non-viral gene delivery compositions, wherein each non-viral gene delivery composition differs from each other non-viral gene delivery composition of the diverse set with respect to at least one of a set of composition characteristics, simultaneously testing one or more quality attributes of each of the non-viral gene delivery composition of the diverse set, and creating, using results of the testing, a predictive model that correlates the composition characteristics with the quality attributes.
  • the composition characteristics can comprise one or more of molecular weight, degree of branching, number of ionizable groups, core-to-corona molecular weight ratio, hydrophilicity, hydrophobicity, propensity for aggregation, size, pKa, log P, and surface charge.
  • the quality attributes can comprise one or more of cytotoxicity, immunogenicity, transfection efficiency, zeta potential, size, pKa, log P, and loading efficiency.
  • the diverse set can comprises hundreds or thousands of non-viral gene delivery compositions.
  • each of the non-viral gene delivery compositions of the diverse set can be a DNA nanostructure delivery composition according to one of clauses 1-36 or 118-154 or a RAFT block copolymer according to one of clauses 118-127 above. above.
  • high-throughput testing, and machine learning data analysis can accelerate the design-build-test-learn (DBTL) cycle for development of CRISPR-based therapeutics.
  • the polymer nanoparticle composition or the DNA nanostructure delivery composition may be labelled to enhance downstream separation.
  • this may include covalently bonding the polymer nanoparticle composition or the DNA nanostructure delivery composition to a magnetic nanoparticle (e.g., superparamagnetic iron oxide), to polyhistidine tags for metal ion chromatography, and/or to fluorescent labels for fluorescent assisted separation (such as with FACS).
  • the labels may be used to track the polymer nanoparticle composition or the DNA nanostructure delivery composition in vivo.
  • Possible “endpoints” include, but are not limited to, quantitative presence in various physiological tissue, post administration, measured via, for example, fluorescence.
  • the labels allow for rapid in vivo screening of many non-viral nanoparticle variants with parallel determination of quantitative bio-distribution, and rapid in vitro screening of many non-viral nanoparticle variants for stability, cytotoxicity, immunogenicity, and efficacy.
  • This embodiment allows for the construction of a large library of non-viral delivery vehicles that can be drawn from for use as delivery vehicles for genetic medicines, including gene therapies, genetic vaccines, gene editing, and gene regulators.
  • a large library of similar, but unique polymer nanoparticle compositions or the DNA nanostructure delivery compositions may be constructed for use in a high-throughput screening process to identify targeting components that bind to specific targets.
  • This rapid screening platform can quickly determine an effective targeting molecule that can be used for targeted delivery to a specific cell or tissue, or for use as a neutralizing molecule for a pathogen.
  • references in the specification to “one embodiment,” “an embodiment,” “an illustrative embodiment,” etc., indicate that the embodiment described may include a particular feature, structure, or characteristic, but every embodiment may or may not necessarily include that particular feature, structure, or characteristic. Moreover, such phrases are not necessarily referring to the same embodiment. Further, when a particular feature, structure, or characteristic is described in connection with an embodiment, it is submitted that it is within the knowledge of one skilled in the art to effect such feature, structure, or characteristic in connection with other embodiments whether or not explicitly described.
  • items included in a list in the form of “at least one A, B, and C” can mean (A); (B); (C); (A and B); (A and C); (B and C); or (A, B, and C).
  • items listed in the form of “at least one of A, B, or C” can mean (A); (B); (C); (A and B); (A and C); (B and C); or (A, B, and C).
  • DNA nanostructure delivery compositions uses nucleic acids themselves (the DNA origami structure) to encapsulate the CRISPR RNP construct.
  • a single-stranded DNA scaffold is used and is grown and isolated in the M13 phage and combined with oligonucleotide staples that pair with the scaffold at pre-programed segments to form highly controlled and tuned three-dimensional structures.
  • computer aided design (CAD) tools can predict the sequences in oligonucleotide staples necessary to produce highly engineered nanostructures, resulting in the possibility of a virtual library of nanoparticles from which to begin a custom delivery vehicle design.
  • CAD computer aided design
  • these DNA nanostructures offer significant advantages, including precise tuning of the size and shape of the structure to match the cargo.
  • nanoparticles can be functionalized with nucleic acid aptamers for targeted binding to specific cell and tissue types.
  • the inventors have designed a novel DNA origami delivery platform customized for the delivery, for example, of CRISPR RNP ( FIG. 5 ). Loading efficiency can be further increased by strategically incorporating overhangs in the origami sequence to bind the guide and repair DNA constructs within the encapsulating nanostructure itself.
  • highly specific targeted delivery can be achieved with the incorporation of “lock and key” mechanisms into the nucleotide sequence as discussed herein.
  • DNA scaffolds can be produced in high yield using cell density fermentation of Escherichia coli libraries.
  • Oligonucleotides used as the “staples” for the origami structure can be produced synthetically and then cloned in large numbers using PCR.
  • two delivery vehicle platforms polymer nanoparticles and DNA origami to encapsulate and deliver CRISPR RNPs have been developed.
  • the processing steps for each platform include several critical processing parameters (CPPs) that can be tuned to produce desirable critical quality attributes (CQAs).
  • CCPs critical processing parameters
  • CQAs critical quality attributes
  • several desired CQA outputs include decreasing the cytotoxicity and immunogenicity of the delivery vehicles while enhancing their uptake by and subsequent transfection efficiency.
  • the size, hydrophilicity and hydrophobicity, propensity for aggregation, and zeta potential of these delivery vehicles with and without their cargo can be characterized. Then, a series of in vitro assays can be run in parallel to identify how changes in the CPPs affect cytotoxicity, immunogenicity, and transfection efficiency of the delivery vehicles.
  • the inventors have established machine learning to analyze large data sets and build models which can be applied to the exploration of nanocarrier design spaces. This framework will be set up to build a suitability surface for optimization of the CQAs via a machine learning algorithm. This system will accelerate the design of nanocarriers capable of efficiently delivering CRISPR/Cas9 gene editing tools, for example, to cells.
  • DNA nanostructures can be used to encapsulate RNP, to demonstrate triggered release in cells in vitro, and to assess efficacy in vivo using an animal model.
  • the design shown in FIG. 5 can be used to encapsulate a Cas9/gRNA RNP that is delivered to a HEK-293 reporter cell in vitro.
  • the cell can be modified with a GFP reporter with a stop codon preceding it.
  • the gRNA is targeted to disrupt the stop codon, leading to a GFP signal indicating successful gene editing.
  • the nanostructure can be tagged with a Cy5 red fluorescent label and tracked using the IVIS to determine biodistribution.
  • DNA nanostructures were fabricated, loaded with CRISPR/Cas9 and coated with polyethylene glycol (PEG)-Poly-L-Lysine to protect the structures from degradation and clearance in vivo and polyethylenimine (PEI) to enhance endosomal escape.
  • PEG polyethylene glycol
  • PEI polyethylenimine
  • the encapsulation of a CRISPR/Cas9 RNP in a DNA nanostructure with one-to-one precision demonstrates the unique capability of DNA nanostructures (e.g., DNA origami structures) to produce nanostructures with a high degree of predictability (i.e., fabricated structures looked exactly as designed) and structural control. Only one molecule of Cas9 RNP was encapsulated per structure. This is not possible with any other delivery vector currently available.
  • FIG. 1E Delivery of the Cas9 RNP via closed DNA nanostructures to HEK 293 cells ( FIG. 1E ) was also demonstrated based on co-localization of fluorescence. Furthermore, the DNA nanostructures were folded and cuboid shaped DNA nanostructures were imaged ( FIG. 1E ). Cytotoxicity experiments (MTT assay) performed with empty DNA nanostructures showed that empty DNA nanostructures even up to 10 nM were not cytotoxic to HEK293 cells after 24 hours of incubation ( FIG. 1F ). Cell viability was relatively high (75%) even at 20 nM considering most transfections exposed cells to the DNA nanostructure treatment for ⁇ 5 hours.
  • HDR-mediated gene editing experiments will use the same DNA nanostructures which in addition to having the CRISPR RNP also have two HDR donor DNA strand oligos per DNA nanostructure for an in vivo study.
  • the DNA nanostructures will be labeled with Cy5.5 dye for biodistribution and toxicity analysis.
  • the non-viral delivery vehicles needed for translation of gene editing treatments can be synthesized with repeatable, versatile and scalable methods to meet GMP requirements.
  • lipid nanoparticles have been used for most non-viral nucleic acid delivery vehicles in clinical trials.
  • polymer nanoparticles have been less commonly used for clinical nucleic acid delivery, polymer synthesis methods provide scalable manufacturing benefits in ways that cannot be matched by other biomaterials such as lipids.
  • RAFT reversible-addition fragmentation chain transfer
  • RAFT copolymerization process is an attractive route for synthesizing non-viral delivery vehicle alternatives to AAVs. It has recently been demonstrated that these RAFT copolymers can be synthesized in multiplex, high-throughput arrays in multi-well plates. These methods are being used for the encapsulation and delivery of pDNA encoding for Cas9 and gRNA editing systems to somatic cell lines. As is the case with lipid nanoparticles, polymer nanoparticle delivery vehicles are designed using cationic polymers that form complexes with negatively charged nucleic acids and enhance interaction with the negative resting potential of the cellular membrane. However, the same positive surface charge may also lead to cytotoxicity in high enough doses. To address this concern, the inventors have conducted cytotoxicity assays ( FIG. 3 —see Example 4).
  • Block 1 reagents were combined in a round bottom flask, purged with argon, and heated to 60° C. for 6 hours using a heating mantle.
  • the reaction product was purified using four 80:20 pentane:ether precipitation washes and centrifugation cycles and dried in vacuo.
  • the Block 1 product was used as the macroRAFT agent for Block 2, and the calculated reagent volumes (as calculated based on theoretical molecular weight information for Block 1) were combined in a round bottom for the Block 2 reaction.
  • the reaction mixture was argon purged before being heated at 60° C. for 24 hours.
  • the reaction product was purified using the same purification process and dried in vacuo.
  • the resulting polymer was dialyzed in deionized water for 4 days with multiple water changes each day. Finally, the dialyzed material was lyophilized for 4 days and stored at room temperature for experimental use. Size was measured using a Malvern Zetasizer Nano. Molecular weights for Blocks 1 and 2 were measured, and molecular weight for Block 1 was measured internally using a DynaPro Plate Reader III. All molecular weights are reported in this example as number average molecular weight (M n ).
  • ECT end groups (R & Z) were still present to perform their function, but they were on the end of the p(DMAEMA) polymer synthesized as block 1.
  • ECT showing the R & Z groups on either side of the trithiocarbonyl group.
  • Azobisisobutyronitrile Initiator 1.7 mg 4.93 mg AIBN Dimethylformamide Solvent 7045.0 mg 20828.8 mg DMF Block 2 Reaction Yield % Yield 73.33% 70.99%
  • GPC Data was obtained using a TDA-305 Tetra Detector System by Malvern. Data acquisition and handling were made with OmniSec software.
  • Block 1 140 (140 DMAEMAs)
  • Block 2 52 (8 DMAEMAs, 6 PAAs, and 38 BMAs)
  • Block 1 100% dimethylaminoethyl methacrylate
  • Block 2 ⁇ 17% dimethylaminoethyl methacrylate, ⁇ 74% butyl methacrylate, and 9% propyl acrylic acid
  • RAFT copolymers made using CTAs that contain at least one carboxyl terminal group were further functionalized with avidin as an example of the functionalization of the PNP with an amine containing molecule.
  • a RAFT copolymer (160 mg) prepared according to example 3A was transferred into a 50 mL conical tube and reconstituted in MES buffer at 8 mg/mL. The sample was sonicated for 30 minutes. EDC reagent (10.5 mg) and Sulfo-NHS (29.7 mg) was added to the polymer. The sample was incubated for 15 minutes at room temperature to allow the reaction to occur. The reaction volume was transferred to Amicon ultra-4 centrifuge tubes (MWCO 30 kDa). (Max 3.5 mL/Tube) and centrifuged at 4,000 ⁇ g for 15 minutes. The filtrated was discarded and sterile PBS was added to the retentate to reconstitute to 8 mg/mL polymer.
  • MWCO 30 kDa Amicon ultra-4 centrifuge tubes
  • An avidin stock solution was created at 205.8 ⁇ M by reconstituting 10 mg of avidin in 720 ⁇ L of PBS to prepare an Avidin calibration curve in triplicate.
  • Dulbeccos PBS (322 ⁇ L) was added to wells A1-A3 of a 96 well plate.
  • Stock Avidin (78 ⁇ L) was added to yield a 40 ⁇ M solution in wells A1-A3.
  • Dulbeccos PBS 200 ⁇ L was added to remaining wells of columns 1-3 and a 2:1 serial dilution was performed from first row of wells.
  • Avidin coated polymer 200 ⁇ L was added to three wells of the same 96 well plate. Native polymer (no avidin) (200 ⁇ L) was added to three other wells of the same 96 well plate. The absorbance at 280 nm and 260 nm was read against the calibration curve. 100% loading efficiency is 27.3 ⁇ M.
  • RAFT copolymers were prepared according to the general procedure provided in Example 3A above, and using a 96 well plate. All reagent amounts were determined according to the same method as described in Example 3A.
  • Block 1 reagents were combined in wells of a polypropylene 96-well u-shaped bottom microplate (Greiner Bio-One) or in polypropylene Eppendorf microcentrifuge tubes (Sigma-Aldrich) and placed in a VWR 1400E Sheldon vacuum oven.
  • a 20 mL glass vial was filled with approximately 10-15 mL of dimethylformamide, and the vial was placed in the oven to provide a source for atmosphere saturation.
  • the oven was purged with argon at ⁇ 3 L/min for approximately 45 minutes, and heated to between 60° C. and 75° C. for 6 hours.
  • reaction product solutions were transferred to 1.5 mL Eppendorf tubes (if necessary) and purified via four precipitation washes using an appropriate purification solvent solution (e.g., 80:20 pentane:ether, isopropyl alcohol, methanol, etc.) and centrifugation cycles and dried in vacuo.
  • an appropriate purification solvent solution e.g. 80:20 pentane:ether, isopropyl alcohol, methanol, etc.
  • the Block 1 product was used as the macroRAFT agent for Block 2, and the calculated reagent volumes (as calculated based on theoretical molecular weight information for Block 1) were combined in either a polypropylene 96-well u-shaped bottom microplate (Greiner Bio-One) or in polypropylene Eppendorf microcentrifuge tubes (Sigma-Aldrich) for the Block 2 reaction.
  • the reaction mixtures were placed in a VWR 1400E Sheldon vacuum oven, which was argon purged at ⁇ 3 L/min for approximately 45 minutes before being heated to between 60° C. and 75° C. for 24 hours.
  • the reaction products were purified using the same purification process as used for Block 1 library materials and dried in vacuo.
  • the resulting polymers were resuspended in either acetone or chloroform and aliquoted as needed for experimental use (these transfer solvents evaporated prior to material use), stored in a dry state at room temperature, or dissolved in deionized water, frozen, and lyophilized prior to experimental use. Size was measured using a Wyatt Technology DynaPro Plate Reader III. Molecular weights for Block 1 materials were measured using a DynaPro Plate Reader III. Nanoparticle sizes above the DynaPro Plate Reader III molar mass capability threshold prevented measurement of Block 2 molecular weights for these polymer libraries. All molecular weights for high-throughput polymer libraries are reported as weight average molecular weight (MW).
  • Diameter data is provided for Libraries 0006, 0007, 0009, and 0011 in FIG. 6 . Diameter data is calculated as follows:
  • Library Block 1 for libraries 0001, 0003, and 0005 were prepared in 96-well plates as shown in FIGS. 9A-9C .
  • MTT assay A standard methylthiazolyldiphenyl-tetrazolium bromide (MTT assay) was used to measure cell viability on day 3 (after ⁇ 30 hours of exposure to test doses). Approximately 2.4 ml of MTT in cell media at 5 mg/ml was used and 20 ul of the solution was added to each well of the cell plate. The plate was wrapped in foil and incubated for 3 hours. After 3 hours, the plate was removed from incubator and all media was aspirated off with a pipet. 200 ul of isopropanol was added to each well to dissolve the crystals. The plate was wrapped in foil and placed on an orbital shaker for ⁇ 5 minutes for full dissolution.
  • the plate was then read in a plate reader at 560 nm and 670 nm.
  • the background at 670 nm was subtracted from the absorbance at 560 nm.
  • Cell viability is reported as a percentage of the absorbance read for cells that were given no treatment (i.e. were dispersed in media only).
  • the cytotoxicity results for DNA nanostructure delivery compositions are described in Example 2 and the results are FIG. 1F .
  • the results for polymer nanoparticle compositions are shown in FIG. 3 .
  • Polymer nanoparticle compositions were not cytotoxic at concentrations below ⁇ 73 nM.
  • Lipofectamine was cytotoxic at concentrations above 0.28 vol % of the stock solution. This is equivalent to 0.625 ⁇ l per well, which is about 2 times the highest dose recommended by the manufacturer.
  • the two negative controls (PBS and optimum) showed positive cell growth (near 110% cell proliferation) above that of medium only.
  • the two negative controls (9% and 33% ethanol) showed almost complete cell death ( ⁇ 2% cell viability).
  • MTT solution at a concentration of 5 mg/mL in media at a volume equivalent to 25 uL per a sample was prepared. Added 20 uL of MTT solution to each well of the cell plate, including 3 blank wells. Gently shook the plate to mix the solution. Placed lid or 96-well plate sticker over the plate. Wrapped plate with aluminum foil. Sprayed plate down with 70% ethanol and placed in cell incubator (37° C., 5% CO 2 ) for 3-4 hours. After incubation, aspirated off the media from the wells using a Pasteur pipet and the vacuum in the laminar flow hood. Resuspended the formazan (MTT metabolic product) in 200 uL isopropanol.
  • HEK-293T cells were seeded in a 96-well plate at 30,000 cells per well in 0.2 ml of media and left in an incubator at 37 degrees C. overnight. The next day, a serial dilution of polymer nanoparticles was prepared in PBS. Lipofectamine 3000 reagent was prepared according to the manufacturer protocol. The pDNA was added to the dilutions of polymer nanoparticles and lipofectamine to yield 11-fold higher concentrations of both components than those indicated in the images. To each well, 0.02 ml of each dilution was added, to yield an 11-fold dilution.
  • the cells were incubated with the treatments overnight, and fluorescence images were captured with a GFP filter cube set (ex 475 nm, em 509 nm).
  • the dose of polymer nanoparticles ( FIG. 4C ) showed the most fluorescence and corresponded to a polymer to DNA ratio of ⁇ 4, which is consistent with the previous convention. This shows that the polymer nanoparticle platform can be further optimized with our high-throughput platform to deliver genes to cells for treatments.
  • Oligonucleotide staples can be designed for a single stranded DNA scaffold that Is produced from M13 bacteriophage DNA cloned in Escherichia coli using fermentation. These oligos can be designed to form, for example, a DNA nanostructure deliver composition (i.e. a DNA origami structure) with a cavity that is ⁇ 13 ⁇ 15 nm (the approximate dimensions of an RNP).
  • the oligo staples can be chosen to include overhangs with sticky ends that will bind to the gRNA of the RNP as well as the ends of the homology directed repair donor DNA strand.
  • the lid on the hinge can be designed with sticky overhangs that will self-anneal after the RNP is loaded, resulting in a compact particle containing all the machinery needed in one particle to effectively deliver multiple payloads, such as the CRISPR RNP to a target cell. Fluorescence microscopy experiments can aid in understanding where the DNA nanostructures traffic within the cells. Using a DAPI (4′,6-diamidino-2-phenylindole) blue fluorescent stain, the cell nuclei can be stained blue to examine the extent to which the RNPs co-localize within the nucleus.
  • DAPI 4′,6-diamidino-2-phenylindole
  • the surface of the DNA nanostructure can be designed with polyethylene glycol (PEG) polylysine moieties to reduce immunogenicity.
  • PEG polyethylene glycol
  • nucleotide “stem-and-loop” features can take on three-dimensional structures able to bind target cell receptors with or without the help of peptide aptamers.
  • the folding of the DNA nanostructures can be confirmed via transmission electron microscopy (TEM).
  • TEM transmission electron microscopy
  • the loading of the RNP into the DNA nanostructure can be confirmed with a fluorescently labeled RNP (EGFP) and a fluorescence microscope.
  • Particle size, surface charge, and aggregation state can be analyzed in a multi-well plate format via dynamic light scattering. Zeta potential can be analyzed with a Malvern zetasizer.
  • the DNA nanostructures loaded with RNP can be assayed in the same array of 96-well plate assays as the polymer nanoparticle compositions.
  • the RNP system can be used to produce green fluorescence in a line of HEK-293 cells that have been modified with a GFP reporter preceded by a stop codon.
  • the gRNA in the RNP can target the stop codon, and when it is disrupted, the cells will report a green fluorescence.
  • a similar test can be done with other cells.
  • the RNP can simply be labeled with EGFP, and the co-localization of the DNA nanostructures in the cells can be evaluated via fluorescence microscopy with DAPI stained cells.
  • THP-1 cells and RAW264 cells can be treated with the DNA nanostructures and the immune response can be quantified using ELISA assays for inflammatory cytokines as well as a Greiss assay for a rapid evaluation of inflammatory response associated with nitrous oxide production.
  • the THP-1 cells do not have a strong nitrous oxide production read-out, but the RAW254 mouse cells are sensitive to the inflammation and produce a strong nitrous oxide signal.
  • the bioactivity read-outs can be connected to the physical characteristics and the design parameters of the DNA nanostructures.

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