WO2013016058A1 - Nouveaux lipides cationiques contenant du bis-azote pour administration d'oligonucléotide - Google Patents

Nouveaux lipides cationiques contenant du bis-azote pour administration d'oligonucléotide Download PDF

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WO2013016058A1
WO2013016058A1 PCT/US2012/046990 US2012046990W WO2013016058A1 WO 2013016058 A1 WO2013016058 A1 WO 2013016058A1 US 2012046990 W US2012046990 W US 2012046990W WO 2013016058 A1 WO2013016058 A1 WO 2013016058A1
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alkyl
optionally substituted
substituents selected
alkenyl
ethyl
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Mark Cameron
Jennifer R. Davis
Matthew G. Stanton
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Merck Sharp & Dohme Corp.
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Definitions

  • the present invention relates to novel cationic lipids that can be used in combination with other lipid components such as cholesterol and PEG-lipids to form lipid nanoparticles with oligonucleotides, to facilitate the cellular uptake and endosomal escape, and to knockdown target mRNA both in vitro and in vivo.
  • Cationic lipids and the use of cationic lipids in lipid nanoparticles for the delivery of oligonucleotides, in particular siRNA and miRNA, have been previously disclosed.
  • Lipid nanoparticles and use of lipid nanoparticles for the delivery of oligonucleotides, in particular siRNA and miRNA has been previously disclosed.
  • Oligonucleotides (including siRNA and miRNA) and the synthesis of oligonucleotides has been previously disclosed. (See US patent applications: US 2006/0083780, US 2006/0240554, US 2008/0020058, US
  • cationic lipids such as CLinDMA and DLinDMA have been employed for siRNA delivery to liver but suffer from non-optimal delivery efficiency along with liver toxicity at higher doses. It is an object of the instant invention to provide a cationic lipid scaffold that demonstrates enhanced efficacy and tolerability.
  • the present invention employs bis-nitrogen containing cationic lipids to enhance the efficiency and tolerability of in vivo delivery of siRNA.
  • the instant invention provides for novel cationic lipids that can be used in combination with other lipid components such as cholesterol and PEG-lipids to form lipid nanoparticles with oligonucleotides. It is an object of the instant invention to provide a cationic lipid scaffold that demonstrates enhanced efficacy and tolerability.
  • the present invention employs bis-nitrogen containing cationic lipids to enhance the efficiency and tolerability of in vivo delivery of siRNA.
  • FIGURE 1 LNP (Compound 1) efficacy in mice.
  • FIGURE 2 LNP (Compound 1) efficacy and tolerability in rat.
  • FIGURE 3 Absolute liver levels of cationic lipid (Compound 1) in rat at 48 hours.
  • the various aspects and embodiments of the invention are directed to the utility of novel cationic lipids useful in lipid nanoparticles to deliver oligonucleotides, in particular, siRNA and miRNA, to any target gene.
  • novel cationic lipids useful in lipid nanoparticles to deliver oligonucleotides, in particular, siRNA and miRNA, to any target gene.
  • Rational design of cationic lipids for siRNA delivery Nature Biotechnology, published online 17 January 2010; doi:10.1038/nbt.l602.
  • the cationic lipids of the instant invention are useful components in a lipid nanoparticle for the delivery of oligonucleotides, specifically siRNA and miRNA.
  • n 1 or 2;
  • Rl and R2 are independently selected from H, (Ci-C4)alkyl, heterocyclyl, and a polyamine, wherein said alkyl, heterocyclyl and polyamine are optionally substituted with one or more substituents selected from R', or Rl and R2 can be taken together with the nitrogen to which they are attached to form a monocyclic heterocyclyl with 4-7 members optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic heterocyclyl is optionally substituted with one or more substituents selected from R';
  • R3 is absent or can be taken together with Rl to form a monocyclic heterocyclyl with 4-7 members optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic heterocyclyl is optionally substituted with one or more substituents selected from R';
  • R' is independently selected from halogen, R", OR", SR", CN, C0 2 R" and
  • R" is selected from H and (Ci-C4)alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from halogen and OH;
  • Li is a C4-C22 alkyl or C4-C22 alkenyl, said alkyl and alkenyl are optionally substituted with one or more substituents selected from R';
  • L2 is a C4-C22 alkyl or C4-C22 alkenyl, said alkyl and alkenyl are optionally substituted with one or more substituents selected from R';
  • the invention features a compound having Formula A, wherein:
  • n 1;
  • Rl and R2 are independently selected from H, (Ci-C4)alkyl, heterocyclyl, and a polyamine, wherein said alkyl, heterocyclyl and polyamine are optionally substituted with one or more substituents selected from R', or Rl and R2 can be taken together with the nitrogen to which they are attached to form a monocyclic heterocyclyl with 4-7 members optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic heterocyclyl is optionally substituted with one or more substituents selected from R';
  • R3 is absent or can be taken together with Rl to form a monocyclic heterocyclyl with 4-7 members optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic heterocyclyl is optionally substituted with one or more substituents selected from R';
  • R' is independently selected from halogen, R", OR", SR", CN, C0 2 R" and
  • R" is selected from H and (Ci-C4)alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from halogen and OH;
  • Li is a C4-C22 alkyl or C4-C22 alkenyl, said alkyl and alkenyl are optionally substituted with one or more substituents selected from R';
  • L2 is a C4-C22 alkyl or C4-C22 alkenyl, said alkyl and alkenyl are optionally substituted with one or more substituents selected from R';
  • the invention features a compound having Formula A, wherein:
  • n 1;
  • Rl and R2 are independently selected from H, (Ci -Chalky 1, heterocyclyl, and a polyamine, wherein said alkyl, heterocyclyl and polyamine are optionally substituted with one or more substituents selected from R 1 , or Rl and R2 can be taken together with the nitrogen to which they are attached to form a monocyclic heterocyclyl with 4-7 members optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic heterocyclyl is optionally substituted with one or more substituents selected from R';
  • R3 is absent or can be taken together with Rl to form a monocyclic heterocyclyl with 4-7 members optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic heterocyclyl is optionally substituted with one or more substituents selected from R';
  • R' is independently selected from halogen, R", OR", SR", CN, C0 2 R" and
  • R" is selected from H and (Ci-C4)alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from halogen and OH;
  • Li is a C4-C22 alkyl or C4-C22 alkenyl, said alkyl and alkenyl are optionally substituted with one or more substituents selected from R';
  • L2 is a C4-C22 alkyl or C4-C22 alkenyl, said alkyl and alkenyl are optionally substituted with one or more substituents selected from R';
  • the cationic lipids are illustrated by the following abbreviations:
  • Rl and R2 are independently selected from H, (Ci-C4)alkyl, heterocyclyl, and a polyamine, wherein said alkyl, heterocyclyl and polyamine are optionally substituted with one or more substituents selected from R', or Rl and R can be taken together with the nitrogen to which they are attached to form a monocyclic heterocyclyl with 4-7 members optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic heterocyclyl is optionally substituted with one or more substituents selected from R';
  • R' is independently selected from halogen, R", OR", SR", CN, C0 2 R" and
  • R" is selected from H and (Ci-C4)alkyl, wherein said alkyl is optionally substituted with one or more substituents selected from halogen and OH;
  • Li is a C4-C22 alkyl or C4-C22 alkenyl, said alkyl and alkenyl are optionally substituted with one or more substituents selected from R';
  • L2 is a C4-C22 alkyl or C4-C22 alkenyl, said alkyl and alkenyl are optionally substituted with one or more substituents selected from R';
  • Specific cationic lipids are:
  • the cationic lipids disclosed are useful in the preparation of lipid nanoparticles.
  • the cationic lipids disclosed are useful components in a lipid nanoparticle for the delivery of oligonucleotides.
  • the cationic lipids disclosed are useful components in a lipid nanoparticle for the delivery of siRNA and miRNA.
  • the cationic lipids disclosed are useful components in a lipid nanoparticle for the delivery of siRNA.
  • the cationic lipids of the present invention may have asymmetric centers, chiral axes, and chiral planes (as described in: E.L. Eliel and S.H. Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119-1190), and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers and mixtures thereof, including optical isomers, being included in the present invention.
  • the cationic lipids disclosed herein may exist as tautomers and both tautomeric forms are intended to be encompassed by the scope of the invention, even though only one tautomeric structure is depicted.
  • substituents and substitution patterns on the cationic lipids of the instant invention can be selected by one of ordinary skill in the art to provide cationic lipids that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below, from readily available starting materials. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, so long as a stable structure results.
  • Si atoms can be incorporated into the cationic lipids of the instant invention by one of ordinary skill in the art to provide cationic lipids that are chemically stable and that can be readily synthesized by techniques known in the art from readily available starting materials.
  • the atoms may exhibit their natural isotopic abundances, or one or more of the atoms may be artificially enriched in a particular isotope having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number predominantly found in nature.
  • the present invention is meant to include all suitable isotopic variations of the compounds of Formula A.
  • different isotopic forms of hydrogen (H) include protium (lH) and deuterium (3 ⁇ 4).
  • Protium is the predominant hydrogen isotope found in nature. Enriching for deuterium may afford certain therapeutic advantages, such as increasing in vivo half-life or reducing dosage requirements, or may provide a compound useful as a standard for characterization of biological samples.
  • Isotopically-enriched compounds within Formula A can be prepared without undue
  • alkyl means a straight chain, cyclic or branched saturated aliphatic hydrocarbon having the specified number of carbon atoms.
  • alkenyl means a straight chain, cyclic or branched unsaturated aliphatic hydrocarbon having the specified number of carbon atoms including but not limited to diene, triene and tetraene unsaturated aliphatic hydrocarbons.
  • heterocyclyl or “heterocycle” means a 4- to 10-membered aromatic or nonaromatic heterocycle containing from 1 to 4 heteroatoms selected from the group consisting of O, N and S, and includes bicyclic groups.
  • Heterocyclyl therefore includes, the following: benzoimidazolyl, benzofuranyl, benzofurazanyl, benzopyrazolyl, benzotriazolyl, benzothiophenyl, benzoxazolyl, carbazolyl, carbolinyl, cinnolinyl, furanyl, imidazolyl, indolinyl, indolyl, indolazinyl, indazolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl, oxazolyl, oxazoline, isoxazoline, oxetanyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl, pyridyl, pyri
  • dihydrothiadiazolyl dihydrothiazolyl, dihydrothienyl, dihydrotriazolyl, dihydroazetidinyl, methylenedioxybenzoyl, tetrahydrofuranyl, and tetrahydrothienyl, and N-oxides thereof all of which are optionally substituted with one to three substituents selected from R".
  • polyamine means compounds having two or more amino groups. Examples include putrescine, cadaverine, spermidine, and spermine.
  • halogen means Br, CI, F and I.
  • n 1 or 2.
  • n 2
  • n 1
  • n 0.
  • Rl and R2 are independently selected from H and (Ci-C4)alkyl, wherein said alkyl is optionally substituted with one to three substituents selected from R', or Rl and R2 can be taken together with the nitrogen to which they are attached to form a monocyclic heterocyclyl with 4-7 members optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic heterocyclyl is optionally substituted with one to three substituents selected from R'.
  • Rl and R2 are independently selected from H, methyl, ethyl and propyl, wherein said methyl, ethyl and propyl are optionally substituted with one to three substituents selected from R 1 , or Rl and R2 can be taken together with the nitrogen to which they are attached to form a monocyclic heterocyclyl with 4-7 members optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O and S, said monocyclic heterocyclyl is optionally substituted with one to three substituents selected from R'.
  • Rl and R2 are independently selected from H, methyl, ethyl and propyl.
  • Rl and R2 are each methyl.
  • R3 is absent.
  • R3 is taken together with Rl to form a monocyclic heterocyclyl.
  • R' is R".
  • R" is independently selected from H, methyl, ethyl and propyl, wherein said methyl, ethyl and propyl are optionally substituted with one or more halogen and OH.
  • R" is independently selected from H, methyl, ethyl and propyl.
  • R" is H.
  • Li is selected from C4-C22 alkyl and C4-C22 alkenyl, which are optionally substituted with halogen and OH.
  • I is selected from C4-C22 alkyl and C4-C22 alkenyl.
  • Li is selected from C12-C22 alkyl and C12-C22 alkenyl.
  • L ⁇ is selected from C16-C20 alkyl and Cl6-C20 lkenyl.
  • Li is selected from Ci 8 alkyl and C ⁇ 8 alkenyl.
  • L2 is selected from C4-C22 alkyl and C4-C22 alkenyl, which are optionally substituted with halogen and OH.
  • L2 is selected from C4-C22 alkyl and C4-C22 alkenyl.
  • L2 is selected from C6-C 18 alkyl and C6-C18 alkenyl.
  • L2 is selected from C6-C18 alkyl. In an embodiment of Formula A or B, L2 is selected from Cs-Cio alkyl. In an embodiment of Formula A or B, Li is
  • L ⁇ is
  • Li is
  • L2 is
  • L2 is
  • L2 is
  • L2 is In an embodiment of Formula A or B, L2 is
  • Li and L2 are
  • L] and L2 are
  • heterocyclyl is pyrolidine, piperidine, morpholine, imidazole or piperazine.
  • "monocyclic heterocyclyl” is pyrolidine, piperidine, morpholine, imidazole or piperazine.
  • polyamine is putrescine, cadaverine, spermidine or spermine.
  • alkyl is a straight chain saturated aliphatic hydrocarbon having the specified number of carbon atoms.
  • alkenyl is a straight chain unsaturated aliphatic
  • hydrocarbon having the specified number of carbon atoms having the specified number of carbon atoms.
  • cationic lipids of Formula A include the free form of cationic lipids of Formula A, as well as the pharmaceutically acceptable salts and stereoisomers thereof.
  • Some of the isolated specific cationic lipids exemplified herein are the protonated salts of amine cationic lipids.
  • the term "free form" refers to the amine cationic lipids in non-salt form.
  • the encompassed pharmaceutically acceptable salts not only include the isolated salts exemplified for the specific cationic lipids described herein, but also all the typical pharmaceutically acceptable salts of the free form of cationic lipids of Formula A.
  • the free form of the specific salt cationic lipids described may be isolated using techniques known in the art.
  • the free form may be regenerated by treating the salt with a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate.
  • a suitable dilute aqueous base solution such as dilute aqueous NaOH, potassium carbonate, ammonia and sodium bicarbonate.
  • the free forms may differ from their respective salt forms somewhat in certain physical properties, such as solubility in polar solvents, but the acid and base salts are otherwise pharmaceutically equivalent to their respective free forms for purposes of the invention.
  • the pharmaceutically acceptable salts of the instant cationic lipids can be synthesized from the cationic lipids of this invention which contain a basic or acidic moiety by conventional chemical methods.
  • the salts of the basic cationic lipids are prepared either by ion exchange chromatography or by reacting the free base with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid in a suitable solvent or various combinations of solvents.
  • the salts of the acidic compounds are formed by reactions with the appropriate inorganic or organic base.
  • pharmaceutically acceptable salts of the cationic lipids of this invention include the conventional non-toxic salts of the cationic lipids of this invention as formed by reacting a basic instant cationic lipids with an inorganic or organic acid.
  • conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like, as well as salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, trifluoroacetic (
  • salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine caffeine, choline, ⁇ , ⁇ 1 - dibenzylethylenediamine, diethylamin, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine tripropylamine, tromethamine and the like.
  • basic ion exchange resins such as arginine,
  • the cationic lipids of the present invention are potentially internal salts or zwitterions, since under physiological conditions a deprotonated acidic moiety in the compound, such as a carboxyl group, may be anionic, and this electronic charge might then be balanced off internally against the cationic charge of a protonated or alkylated basic moiety, such as a quaternary nitrogen atom.
  • Compound 24 is DLinDMA as described in J. Controlled Release, 2005, 107, 276-287, US 2006/0083780 Al, and US 2006/0008910 Al.
  • Compound 25 is DLinKC2DMA as described in Nature Biotechnology, 2010, 28, 172-176, WO 2010/042877 Al, WO 2010/048536 A2, WO 2010/088537 A2, and WO 2009/127060 Al.
  • lipid nanoparticle compositions of the instant invention are useful for the delivery of oligonucleotides, specifically siRNA and miRNA:
  • the Lipid Nano-Particles are prepared by an impinging jet process.
  • the particles are formed by mixing lipids dissolved in alcohol with siRNA dissolved in a citrate buffer.
  • the mixing ratio of lipids to siRNA are targeted at 45-55% lipid and 65-45% siRNA.
  • the lipid solution contains a novel cationic lipid of the instant invention, a helper lipid
  • the ratio of the lipids has a mole percent range of 25-98 for the cationic lipid with a target of 35-65, the helper lipid has a mole percent range from 0-75 with a target of 30-50, the PEG lipid has a mole percent range from 1-15 with a target of 1-6, and the DSPC has a mole precent range of 0-15 with a target of 0-12.
  • the siRNA solution contains one or more siRNA sequences at a concentration range from 0.3 to 1 .0 mg/mL with a target of 0.3 -0.9 mg/mL in a sodium citrate buffered salt solution with pH in the range of 3.5-5.
  • the two liquids are heated to a temperature in the range of 15-40°C, targeting 30-40°C, and then mixed in an impinging jet mixer instantly forming the LNP.
  • the teelD has a range from 0.25 to 1.0 mm and a total flow rate from 10 - 600 mL/min.
  • the combination of flow rate and tubing ID has effect of controlling the particle size of the LNPs between 30 and 200 nm.
  • the solution is then mixed with a buffered solution at a higher pH with a mixing ratio in the range of 1 : 1 to 1 :3 vol:vol but targeting 1 :2 vol:vol.
  • This buffered solution is at a temperature in the range of 15-40°C, targeting 30-40°C.
  • the mixed LNPs are held from 30 minutes to 2 hrs prior to an anion exchange filtration step.
  • the temperature during incubating is in the range of 15-40°C, targeting 30-40°C.
  • After incubating the solution is filtered through a 0.8 um filter containing an anion exchange separation step. This process uses tubing IDs ranging from 1 mm ID to 5 mm ID and a flow rate from 10 to 2000 mL/min.
  • the LNPs are concentrated and diafiltered via an ultrafiltration process where the alcohol is removed and the citrate buffer is exchanged for the final buffer solution such as phosphate buffered saline.
  • the ultrafiltration process uses a tangential flow filtration format (TFF). This process uses a membrane nominal molecular weight cutoff range from 30 -500 KD.
  • the membrane format can be hollow fiber or flat sheet cassette.
  • the TFF processes with the proper molecular weight cutoff retains the LNP in the retentate and the filtrate or permeate contains the alcohol; citrate buffer; final buffer wastes.
  • the TFF process is a multiple step process with an initial concentration to a siRNA concentration of 1 -3 mg/mL.
  • the LNPs solution is diafiltered against the final buffer for 10 -20 volumes to remove the alcohol and perform buffer exchange. The material is then concentrated an additional 1-3 fold. The final steps of the LNP process are to sterile filter the concentrated LNP solution and vial the product.
  • siRNA duplex concentrations are determined by Strong Anion-Exchange High-Performance Liquid Chromatography (SAX-HPLC) using Waters 2695 Alliance system (Water Corporation, Milford MA) with a 2996 PDA detector.
  • the LNPs otherwise referred to as RNAi Delivery Vehicles (RDVs)
  • RDVs RNAi Delivery Vehicles
  • SAX separation using a Dionex BioLC DNAPac PA 200 (4 ⁇ 250 mm) column with UV detection at 254 nm.
  • Mobile phase is composed of A: 25 mM NaC10 4 , 10 mM Tris, 20% EtOH, pH 7.0 and B: 250 mM NaC10 4 , 10 mM Tris, 20% EtOH, pH 7.0 with liner gradient from 0-15 min and flow rate of 1 ml/min.
  • the siRNA amount is determined by comparing to the siRNA standard curve.
  • Fluorescence reagent SYBR Gold is employed for RNA quantitation to monitor the encapsulation rate of RDVs.
  • RDVs with or without Triton X-100 are used to determine the free siRNA and total siRNA amount.
  • the assay is performed using a SpectraMax M5e microplate spectrophotometer from Molecular Devices (Sunnyvale, CA). Samples are excited at 485 nm and fluorescence emission was measured at 530 nm. The siRNA amount is determined by comparing to the siRNA standard curve.
  • Encapsulation rate (1- free siRNA/total siRNA) l00%
  • RDVs containing 1 ⁇ g siRNA are diluted to a final volume of 3 ml with 1 ⁇
  • the particle size and polydispersity of the samples is measured by a dynamic light scattering method using ZetaPALS instrument (Brookhaven Instruments Corporation, Holtsville, NY). The scattered intensity is measured with He-Ne laser at 25°C with a scattering angle of 90°.
  • RDVs containing 1 ⁇ g siRNA are diluted to a final volume of 2 ml with 1 mM Tris buffer (pH 7.4). Electrophoretic mobility of samples is determined using ZetaPALS instrument (Brookhaven Instruments Corporation, Holtsville, NY) with electrode and He-Ne laser as a light source. The Smoluchowski limit is assumed in the calculation of zeta potentials. 5 Lipid analysis
  • lipid concentrations are determined by Reverse Phase High- Performance Liquid Chromatography (RP-HPLC) using Waters 2695 Alliance system (Water Corporation, Milford MA) with a Corona charged aerosol detector (CAD) (ESA Biosciences, Inc, Chelmsford, MA). Individual lipids in RDVs are analyzed using an Agilent Zorbax SB- C18 (50 x 4.6 mm, 1.8 ⁇ particle size) column with CAD at 60 °C. The mobile phase is composed of A: 0.1% TFA in H 2 0 and B: 0.1% TFA in IP A.
  • the gradient changes from 60% mobile phase A and 40% mobile phase B from time 0 to 40% mobile phase A and 60% mobile phase B at 1.00 min; 40% mobile phase A and 60% mobile phase B from 1.00 to 5.00 min; 40% mobile phase A and 60% mobile phase B from 5.00 min to 25% mobile phase A and 75% mobile phase B at 10.00 min; 25%» mobile phase A and 75% mobile phase B from 10.00 min to 5% mobile phase A and 95% mobile phase B at 15.00 min; and 5% mobile phase A and 95% mobile phase B from 15.00 to 60% mobile phase A and 40% mobile phase B at 20.00 min with flow rate of 1 ml/min.
  • the individual lipid concentration is determined by comparing to the standard curve with all the lipid components in the RDVs with a quadratic curve fit. The molar percentage of each lipid is calculated based on its molecular weight.
  • Oligonucleotide synthesis is well known in the art. (See US patent applications: US 2006/0083780, US 2006/0240554, US 2008/0020058, US 2009/0263407 and US
  • siRNAs disclosed and utilized in the Examples were synthesized via standard solid phase procedures.
  • the siRNA targets the mRNA transcript for the firefly (Photinus pyralis) luciferase gene (Accession # Ml 5077).
  • the primary sequence and chemical modification pattern of the luciferase siRNA is displayed above.
  • the in vivo luciferase model employs a transgenic mouse in which the firefly luciferase coding sequence is present in all cells.
  • ROSA26- LoxP-Stop-LoxP-Luc (LSL-Luc) transgenic mice licensed from the Dana Farber Cancer Institute are induced to express the Luciferase gene by first removing the LSL sequence with a recombinant Ad-Cre virus (Vector Biolabs). Due to the organo-tropic nature of the virus, expression is limited to the liver when delivered via tail vein injection. Luciferase expression levels in liver are quantitated by measuring light output, using an IVIS imager (Xenogen) following administration of the luciferin substrate (Caliper Life Sciences). Pre-dose luminescence levels are measured prior to administration of the RDVs.
  • Luciferin in PBS 15mg/mL is intraperitoneally (IP) injected in a volume of 150 ⁇ . After a four minute incubation period mice are anesthetized with isoflurane and placed in the IVIS imager. The RDVs (containing siRNA) in PBS vehicle were tail vein injected n a volume of 0.2 mL. Final dose levels ranged from 0.1 to 0.5 mg/kg siRNA. PBS vehicle alone was dosed as a control. Mice were imaged 48 hours post dose using the method described above.
  • LNPs utilizing compounds in the nominal compositions described above were evaluated for in vivo efficacy and increases in alanine amino transferase and aspartate amino transferase in Sprague-Dawley (Crl:CD(SD) female rats (Charles River Labs).
  • the siRNA targets the mRNA transcript for the ApoB gene (Accession # NM 019287).
  • the primary sequence and chemical modification pattern of the ApoB siRNA is displayed above.
  • the RDVs (containing siRNA) in PBS vehicle were tail vein injected in a volume of 1 to 1.5 mL. Infusion rate is approximately 3 ml/min. Five rats were used in each dosing group. After LNP administration, rats are placed in cages with normal diet and water present.
  • liver tissue was homogenized and total RNA isolated using a Qiagen bead mill and the Qiagen miRNA-Easy RNA isolation kit following the manufacturer's instructions. Liver ApoB mRNA levels were determined by quantitative RT-PCR. Message was amplified from purified RNA utilizing a rat ApoB commercial probe set (Applied Biosystems Cat #
  • RNA samples were analyzed for RNA expression in Eukaryotic cells.
  • the PCR reaction was performed on an ABI 7500 instrument with a 96- well Fast Block.
  • the ApoB mRNA level is normalized to the housekeeping PPIB (NM 011149) mRNA.
  • PPIB mRNA levels were determined by RT-PCR using a commercial probe set (Applied Biosytems Cat. No. Mm00478295_ml). Results are expressed as a ratio of ApoB mRNA/ PPIB mRNA. All mRNA data is expressed relative to the PBS control dose.
  • Serum ALT and AST analysis were performed on the Siemens Advia 1800 Clinical Chemistry Analyzer utilizing the Siemens alanine aminotransferase (Cat# 03039631) and aspartate aminotransferase (Cat# 03039631) reagents. Similar efficacy and improved tolerability were observed in rats dosed with Compound 1 containing RDV than with the RDV containing the cationic lipid DLinKC2DMA (Compound 25, Figure 2).
  • Liver tissue was weighed into 20-ml vials and homogenized in 9 v/w of water using a GenoGrinder 2000 (OPS Diagnostics, 1600 strokes/min, 5min). A 50 aliquot of each tissue homogenate was mixed with 300 of extraction/protein precipitating solvent (50/50 acetonitrile/methanol containing 500 nM internal standard) and the plate was centrifuged to sediment precipitated protein. A volume of 200 ⁇ , of each supernatant was then transferred to separate wells of a 96-well plate and 10 ⁇ samples were directly analyzed by LC/MS-MS.
  • OPS Diagnostics 1600 strokes/min, 5min.
  • a 50 aliquot of each tissue homogenate was mixed with 300 of extraction/protein precipitating solvent (50/50 acetonitrile/methanol containing 500 nM internal standard) and the plate was centrifuged to sediment precipitated protein. A volume of 200 ⁇ , of each supernatant was then transferred to separate wells of a 96-well
  • Absolute quantification versus standards prepared and extracted from rat liver homogenate was performed using an Aria LX-2 HPLC system (Thermo Scientific) coupled to an API 4000 triple quadrupole mass spectrometer (Applied Biosystems). For each run, a total of 10 ⁇ , sample was injected onto a BDS Hypersil C8 HPLC column (Thermo, 50 x 2mm, 3 ⁇ ) at ambient temperature ( Figure 3).
  • Mobile Phase B 40% methanol/60% n-propanol/10 mM ammonium formate/0. l%formic acid
  • the flow rate was 0.5 mL/min and gradient elution profile was as follows: hold at 80% A for 0.25 min, linear ramp to 100% B over 1.6 min, hold at 100% B for 2.5 min, then return and hold at 80% A for 1.75 min. Total run time was 5.8 min.
  • API 4000 source parameters were CAD: 4, CUR: 15, GS1 : 65, GS2: 35, IS: 4000, TEM: 550, CXP: 15, DP: 60, EP: 10.

Abstract

La présente invention concerne de nouveaux lipides cationiques qui peuvent être utilisés en combinaison avec d'autres composants lipidiques tels que le cholestérol et des PEG-lipides pour former des nanoparticules de lipide avec des oligonucléotides. Il est un objet de la présente invention de décrire un échafaudage de lipide cationique qui présente une efficacité et une tolérance améliorées. La présente invention utilise des lipides cationiques contenant du bis-azote pour améliorer l'efficacité et la tolérance de l'administration in vivo d'ARNsi.
PCT/US2012/046990 2011-07-22 2012-07-17 Nouveaux lipides cationiques contenant du bis-azote pour administration d'oligonucléotide WO2013016058A1 (fr)

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