WO2024145965A1 - 长效低毒的新型阳离子脂质化合物及其组合物 - Google Patents
长效低毒的新型阳离子脂质化合物及其组合物 Download PDFInfo
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- 229960001278 teniposide Drugs 0.000 description 1
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- 229960002372 tetracaine Drugs 0.000 description 1
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- TUNFSRHWOTWDNC-HKGQFRNVSA-N tetradecanoic acid Chemical compound CCCCCCCCCCCCC[14C](O)=O TUNFSRHWOTWDNC-HKGQFRNVSA-N 0.000 description 1
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- 239000002562 thickening agent Substances 0.000 description 1
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- 229960004402 tiopronin Drugs 0.000 description 1
- OMDMTHRBGUBUCO-UHFFFAOYSA-N trans-sobrerol Natural products CC1=CCC(C(C)(C)O)CC1O OMDMTHRBGUBUCO-UHFFFAOYSA-N 0.000 description 1
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
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Classifications
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
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- A61K31/7105—Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links
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- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
- C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
- C07C229/16—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of hydrocarbon radicals substituted by amino or carboxyl groups, e.g. ethylenediamine-tetra-acetic acid, iminodiacetic acids
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- C—CHEMISTRY; METALLURGY
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- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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- C07B2200/07—Optical isomers
Definitions
- the present invention belongs to the field of medicine and specifically relates to a cationic lipid compound, a composition containing the same and its use.
- nucleic acid therapeutics face great challenges due to their low cell permeability and high sensitivity to degradation of certain nucleic acid molecules (including RNA).
- G1 is a C1-8 alkylene group
- G2 is a C2-8 alkylene group
- R2 is a C12-25 straight or branched alkyl group
- G3 is: HO( CH2 ) 2N ( R3 ) CH2CH (OH) CH2- , wherein R3 is -CH3 or -CH2CH3 or -CH2CH2OH .
- compositions comprising a carrier, wherein the carrier comprises a cationic lipid, and the cationic lipid comprises the above-mentioned compound of formula (I) or its N-oxide, solvate, pharmaceutically acceptable salt or stereoisomer.
- Another aspect of the present invention provides the use of the above-mentioned compound of formula (I) or its N-oxide, solvate, pharmaceutically acceptable salt or stereoisomer or the above-mentioned composition in the preparation of nucleic acid drugs, gene vaccines, small molecule drugs, polypeptides or protein drugs.
- Another aspect of the present invention provides the use of the above-mentioned compound of formula (I) or its N-oxide, solvate, pharmaceutically acceptable salt or stereoisomer or the above-mentioned composition in the preparation of a medicament for treating a disease or condition in a mammal in need thereof.
- FIG3 shows the results of cell transfection experiments at different molar ratios of polymer-conjugated lipid to carrier when preparing LNP preparations, a being 1.5%, b being 10%, and c being a blank control.
- Figure 4 shows the results of cell transfection experiments with different ratios of the components of the carrier, cationic lipids, neutral lipids DSPC, structural lipids cholesterol and polymer conjugated lipids DMG-PEG2000, when preparing LNP preparations, a is 35:10:53.5:1.5, b is 45:10:43.5:1.5, c is 49:10:39.5:1.5, and d is a blank control.
- FIG5 shows the fluorescence absorption intensity of LNP preparations of Fluc-mRNA prepared from different cationic lipids (a: YK-305; b: YK-310; c: YK-319; d: SM-102).
- FIG6 shows the fluorescence absorption intensity of LNP preparations of Fluc-mRNA prepared from different cationic lipids (a: YK-301; b: YK-302; c: YK-304; d: Compound 21).
- FIG. 7 shows the fluorescence absorption intensity of LNP preparations of Fluc-mRNA prepared from different cationic lipids (a: YK-305; b: YK-310; c: YK-320; d: YK-321).
- Figure 8 shows the cell survival rate after 24 hours of culture in cell culture medium when LNP preparations of Fluc-mRNA prepared with different cationic lipids (YK-305, YK-310, YK-312, YK-319, YK-318, YK-009, SM-102, ALC-0315, compound 21, compound 23 and HHMA) and Lipofectamine 3000 preparations containing Fluc-mRNA were added to the cell culture medium.
- LNP preparations of Fluc-mRNA prepared with different cationic lipids YK-305, YK-310, YK-312, YK-319, YK-318, YK-009, SM-102, ALC-0315, compound 21, compound 23 and HHMA
- Lipofectamine 3000 preparations containing Fluc-mRNA were added to the cell culture medium.
- Figure 9 shows the cell survival rate after 24 hours of culture in cell culture medium when LNP preparations of Fluc-mRNA prepared with different cationic lipids (YK-305, YK-310, YK-312, YK-319, YK-318, YK-301, YK-302, YK-303, YK-304, YK-306, YK-307, SM-102, ALC-0315, compound 21, compound 23 and HHMA) and Lipofectamine 3000 preparations containing Fluc-mRNA were added to the cell culture medium.
- LNP preparations of Fluc-mRNA prepared with different cationic lipids YK-305, YK-310, YK-312, YK-319, YK-318, YK-301, YK-302, YK-303, YK-304, YK-306, YK-307, SM-102, ALC-0315, compound 21, compound 23 and HHMA
- Figure 11 shows the composition of different cationic lipids (YK-305, YK-310, YK-312, YK-319, YK-318, YK-316, YK-317, YK-320, YK-321, SM-102, ALC-0315, compound
- the LNP preparations of Fluc-mRNA prepared by using compounds 21, 23 and HHMA) and the Lipofectamine 3000 preparation containing Fluc-mRNA were added to the cell culture medium, and the cell survival rate was measured after culturing for 24 hours.
- FIG. 12 shows the results of in vivo imaging experiments in mice of LNP formulations of Fluc-mRNA prepared from different cationic lipids (YK-305, YK-312, YK-302, YK-313, SM-102, ALC-0315, Compound 21, Compound 23, and HHMA).
- FIG. 15 shows the protein expression of LNP preparations of Fluc-mRNA prepared from different cationic lipids (ALC-0315, SM-102, YK-305, YK-319, YK-310 and YK-313) in mice.
- solvate refers to a complex formed by combining a compound of formula (I) or a pharmaceutically acceptable salt thereof and a solvent (e.g., ethanol or water) in the present application. It should be understood that any solvate of a compound of formula (I) used in the treatment of a disease or condition, although it may provide different properties (including pharmacokinetic properties), will yield a compound of formula (I) once absorbed into a subject, such that the use of a compound of formula (I) encompasses the use of any solvate of a compound of formula (I).
- a solvent e.g., ethanol or water
- the compound of formula (I) or its pharmaceutically acceptable salt can be separated in the form of a solvate, and therefore any such solvate is included within the scope of the present invention.
- the compound of formula (I) or its pharmaceutically acceptable salt can exist in an unsolvated form and in a solvated form formed with a pharmaceutically acceptable solvent (such as water, ethanol, etc.).
- HCl or hydrochloric acid
- HBr or hydrobromic acid solution
- methanesulfonic acid sulfuric acid, tartaric acid or fumaric acid
- sulfuric acid tartaric acid or fumaric acid
- HBr or hydrobromic acid solution
- methanesulfonic acid sulfuric acid, tartaric acid or fumaric acid
- sulfuric acid tartaric acid or fumaric acid
- fumaric acid can be used to form a pharmaceutically acceptable salt with the compound shown in formula (I).
- the raw material 1-amino-3-chloropropane-2-ol for synthesizing the cationic lipid is (R)-1-amino-3-chloropropane-2-ol or (S)-1-amino-3-chloropropane-2-ol
- a single stereoisomer of the cationic lipid can be obtained
- the raw material 1-amino-3-chloropropane-2-ol for synthesizing the cationic lipid is a racemic mixture
- a racemic cationic lipid can be obtained.
- the present invention also includes all suitable isotopic variants of the compounds of the present invention.
- An isotopic variant is defined as a compound in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass commonly or predominantly found in nature.
- alkyl in the present invention refers to a branched and straight chain saturated aliphatic monovalent hydrocarbon group having a specified number of carbon atoms.
- alkylene in the present invention refers to a branched and straight chain saturated aliphatic divalent hydrocarbon group having a specified number of carbon atoms.
- Cn ⁇ m refers to a group having n to m carbon atoms.
- C2 ⁇ 5 alkylene includes C2 alkylene, C3 alkylene, C4 alkylene, and C5 alkylene.
- the alkyl (or alkylene) group may be unsubstituted, or the alkyl (or alkylene) group may be substituted wherein at least one hydrogen is replaced with another chemical group.
- a “therapeutically effective amount” is an amount of a therapeutic agent that ameliorates a disease or symptom when administered to a patient.
- a “prophylactically effective amount” is an amount of a prophylactic agent that prevents a disease or symptom when administered to a subject.
- the amount of a therapeutic agent that constitutes a “therapeutically effective amount” or the amount of a prophylactic agent that constitutes a “prophylactically effective amount” varies with the therapeutic agent/prophylactic agent, the disease state and its severity, the age, weight, etc. of the patient/subject to be treated/prevented.
- a person of ordinary skill in the art can routinely determine a therapeutically effective amount and a prophylactically effective amount based on his or her knowledge and the present invention.
- compounds of the present invention may include, depending on the context, compounds of formula (I), N-oxides thereof, solvates thereof, pharmaceutically acceptable salts thereof, stereoisomers thereof, and mixtures thereof.
- LNPs lipid nanoparticles
- the present invention is based on at least the following findings:
- a series of designed compounds including YK-305, YK-310, YK-312, YK-319 and YK-318, are compared with representative cationic lipids in the prior art, such as SM-102 (disclosed in WO2017049245A2 Compound 25), ALC-0315 (compound 3 disclosed in CN108368028B), compound 21 and compound 23 disclosed in WO2021055833A1, HHMA (compound 1 disclosed in CN112979483B) and compound YK-009 disclosed in CN114044741B have huge differences in chemical structures.
- the G3 groups are completely different, and the other parts are also very different, so there will be great differences in polarity, acidity, alkalinity and hydrophilicity.
- the LNP preparations prepared from YK-305, YK-310, YK-312, YK-319 and YK-318 have significantly improved cell transfection efficiency, significantly reduced cytotoxicity, significantly increased mRNA expression level and duration in mice, and reduced or no liver toxicity compared with representative cationic lipids in the prior art.
- the cell transfection efficiency of YK-305 can reach 17 times that of SM-102, 19 times that of compound 21, and 20 times that of compound 23; the cell survival rate of YK-305 and YK-310 can be 30% higher than that of ALC-0315, 12% higher than that of SM-102, and 15% higher than that of HHMA; the mRNA expression level in mice of YK-305 and YK-310 can reach 30 times that of SM-102, compound 21, and compound 23.
- the LNP preparations prepared from YK-305, YK-310, YK-312, YK-319 and YK-318 showed significantly improved cell transfection activity, significantly reduced cytotoxicity, and significantly increased mRNA expression level and duration in mice compared with other compounds.
- the structures of this series of compounds are slightly different from those of YK-305, YK-310, YK-312, YK-319 and YK-318 in individual groups.
- the cell transfection activity of YK-305 can reach 1,300 times that of YK-304 and 900 times that of YK-302; the cytotoxicity of YK-305 and YK-310 can be reduced by 65% compared with YK-302; and the mRNA expression level of YK-305 in mice can reach more than 1,000 times that of YK-302.
- cationic lipids of the prior art such as SM-102, ALC-0315, Compound 21, Compound 23, YK-009 and HHMA, are compared with this series of designed compounds:
- the HHMA structure is the most different. From the chemical structure diagram, it can be seen that in the group connected to the central N atom of HHMA, only one side chain is similar to one side chain of this series of structures, and the other parts are completely different.
- the G 1 , G 2 , R 1 and R 2 groups of SM-102, ALC-0315, Compound 21, Compound 23 and YK-009 are also very different.
- YK-305, YK-310, YK-312, YK-319 and YK- 318 have the highest cell transfection efficiency.
- YK-305 and YK-310 are 200 times higher than YK-309.
- YK-305 is 20 times that of YK-321.
- the LNP preparations prepared from YK-305, YK-310, YK-312, YK-319 and YK-318 have the lowest cytotoxicity and significantly improve cell survival rates compared to representative cationic lipids in the prior art.
- the cell survival rates of YK-305 and YK-310 are 30% higher than ALC-0315, 12% higher than SM-102, and 15% higher than HHMA;
- YK-305, YK-310, YK-312, YK-319 and YK- 318 have the lowest cytotoxicity and significantly improve cell survival rate.
- YK-305 and YK-310 can improve cell survival rate by 50% compared with YK-302.
- YK-305, YK-310, YK-312, YK-319 and YK- 318 have the lowest cytotoxicity and significantly improve cell survival rate.
- YK-305 and YK-310 can improve cell survival rate by 20% compared with YK-317.
- the expression level and duration of mRNA in animals are significantly improved compared to representative cationic lipids and structurally similar compounds in the prior art, and the liver toxicity is reduced or non-toxic.
- LNP preparations prepared from YK-305, YK-310, YK-312, YK-319 and YK-318 had the highest mRNA expression intensity and the longest duration in mice.
- YK-305 could reach more than 1000 times that of YK-302 at 48h and still more than 300 times at 7d.
- LNP preparations prepared from YK-305, YK-310, YK-312, YK-319 and YK-318 showed the highest mRNA expression intensity and the longest duration in mice. For example, YK-305 could reach 160 times that of YK-309 at 48h and still reach 100 times at 7d.
- LNP preparations prepared from YK-305, YK-310, YK-312, YK-319 and YK-318 showed the highest mRNA expression intensity and the longest duration in mice.
- YK-310 could reach 29 times that of YK-321 at 24h and 17 times at 7d.
- the liposomes prepared by the compounds designed by us reduce the amount of target protein expressed in the liver, or do not stay in the liver and express the target protein. Therefore, compared with cationic lipids in the prior art, the LNP preparations prepared by the compounds designed by us have reduced or no toxicity to the liver.
- the present invention provides a novel cationic lipid compound for delivering a therapeutic agent or a preventive agent.
- the cationic lipid compound of the present invention can be used to deliver nucleic acid molecules, small molecules, polypeptides or proteins. Compared with known cationic lipid compounds, the cationic lipid compound of the present invention exhibits higher transfection efficiency and less cytotoxicity, thereby improving delivery efficiency and safety.
- the present invention provides a cationic lipid, which is a compound of formula (I)
- G1 is C1-8 alkylene, preferably unsubstituted C3-7 alkylene, more preferably unsubstituted C3 alkylene or unsubstituted C5 alkylene or unsubstituted C6 alkylene;
- G2 is C2-8 alkylene, preferably unsubstituted C3-7 alkylene, more preferably unsubstituted C3 alkylene, C5 alkylene or C6 alkylene;
- G 1 is unsubstituted C 3 alkylene, for example, -(CH 2 ) 3 -.
- G 2 is unsubstituted C 3 alkylene, for example, -(CH 2 ) 3 -.
- G 2 is unsubstituted C 5 alkylene, for example, -(CH 2 ) 5 -.
- G 2 is unsubstituted C 6 alkylene, for example, -(CH 2 ) 6 -.
- G3 is HO( CH2 ) 2N ( CH2CH3 ) CH2CH (OH) CH2- .
- the compound is selected from the following compounds or N-oxides, solvates, pharmaceutically acceptable salts or stereoisomers thereof:
- compositions comprising a carrier, wherein the carrier comprises a cationic lipid, and the cationic lipid comprises the above-mentioned compound of formula (I) or its N-oxide, solvate, pharmaceutically acceptable salt or stereoisomer.
- the neutral lipid part can be selected from the non-limiting group of the following composition: phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidylserine, phosphatidic acid, 2-lysophosphatidylcholine and sphingomyelin.
- the therapeutic and/or preventive agent is shRNA or its encoding vector or plasmid.
- shRNA can be produced inside the target cell after the appropriate construct is delivered to the nucleus.
- the construct and mechanism associated with shRNA are well-known in the relevant field.
- the composition/vector of the present invention can deliver a therapeutic agent or a preventive agent to a subject or patient.
- the therapeutic agent or preventive agent includes, but is not limited to, one or more of a nucleic acid molecule, a small molecule compound, a polypeptide or a protein. Therefore, the composition of the present invention can be used to prepare nucleic acid drugs, gene vaccines, small molecule drugs, polypeptides or protein drugs. Due to the wide variety of the above-mentioned therapeutic agents or preventive agents, the composition of the present invention can be used to treat or prevent a variety of diseases or conditions.
- the disease or disorder is characterized by a malfunction or aberrant protein or polypeptide activity.
- the disease or disorder is selected from the group consisting of infectious diseases, cancer and proliferative diseases, genetic diseases, autoimmune diseases, diabetes, neurodegenerative diseases, cardiovascular and renal vascular diseases, and metabolic diseases.
- Surface-altering agents may include, but are not limited to, anionic proteins (e.g., bovine serum albumin), surfactants (e.g., cationic surfactants such as dimethyldioctadecyl ammonium bromide), sugars or sugar derivatives (e.g., cyclodextrins), nucleic acids, polymers (e.g., heparin, polyethylene glycol, and poloxamer), mucolytic agents (e.g., acetylcysteine, artemisia, bromelain, papain, clerodendrum, bromhexine, carbocisteine, eprazinone, , mesna, ambroxol, sobrerol, domiodol, letosteine, stepronin, tiopronin, gelsolin, thymosin ⁇ 4, dornase alfa, neltenexine and erdosteine) and DNA enzymes
- compositions of the present invention are administered in a therapeutically effective amount, which may vary not only with the specific agent selected, but also with the route of administration, the nature of the disease being treated, and the age and condition of the patient, and may ultimately be determined by the attending physician or clinician.
- a therapeutic or preventive agent may be administered to a mammal (e.g., a human) at a dose of about 0.001 mg/kg to about 10 mg/kg.
- R1 is a C6-25 straight chain or branched chain alkyl group
- a composition comprising a carrier, wherein the carrier comprises a cationic lipid, and the cationic lipid comprises a compound of formula (I) according to any one of the preceding embodiments, or an N-oxide, solvate, pharmaceutically acceptable salt or stereoisomer thereof.
- composition according to embodiment 18, wherein the molar ratio of the cationic lipid to the carrier is 25% to 75%.
- composition according to embodiment 20 wherein the molar ratio of the cationic lipid to the neutral lipid is 1:1 to 15:1, preferably 4.5:1.
- composition according to embodiment 25, wherein the molar ratio of the cationic lipid to the structural lipid is 0.6:1 to 3:1.
- composition according to any one of embodiments 18-32, wherein the carrier comprises neutral lipids, structural lipids and polymer-conjugated lipids, and the molar ratio of the cationic lipids, the neutral lipids, the structural lipids, and the polymer-conjugated lipids is (25-75):(5-25):(15-65):(0.5-10).
- composition of embodiment 39, wherein the mass ratio of the carrier to the therapeutic agent or preventive agent is 10:1 to 30:1.
- compositions 51-56 wherein the composition is administered intravenously, intramuscularly, intradermally, subcutaneously, intranasally or by inhalation.
- YK-301-PM1 300 mg, 1.43 mmol
- 2-(methylamino)ethanol 108 mg, 1.44 mmol
- acetonitrile 3 mL
- potassium carbonate 594 mg, 4.30 mmol
- potassium iodide 48 mg, 0.29 mmol
- the reaction mixture was filtered, the filtrate was concentrated under vacuum, and the residue was purified by silica gel chromatography (methanol/dichloromethane) to obtain YK-301-PM2 (350 mg, 1.41 mmol, 98.6%).
- Step 4 Synthesis of (S)-6-(2-hydroxy-3-((2-hydroxyethyl)(methyl)amino)propyl)hexanoic acid-2-octyldecyl ester (YK-301-PM4) and (R)-bis(2-octyldecyl)-6,6'-((2-hydroxy-3-((2-hydroxyethyl)(methyl)amino)propyl)azadialkyl)dihexanoate (YK-305)
- Step 5 Synthesis of (R)-2-octyldecyl-6-((4-(decyloxy)-4-oxobutyl)(((2-hydroxy-3-(2-hydroxyethyl)(methyl)amino)propyl)amino)hexanoate (YK-301)
- Step 1 Synthesis of (S)-6-(2-hydroxy-3-((2-hydroxyethyl)(methyl)amino)propyl)hexanoic acid-3-hexylnonyl ester (YK-302-PM1) and (R)-bis(3-hexylnonyl)-6,6'-((2-hydroxy-3-((2-hydroxyethyl)(methyl)amino)propyl)azadialkyl)dihexanoate (YK-306)
- YK-301-PM3 160 mg, 1.08 mmol
- 6-bromohexanoic acid-undecyl ester (251 mg, 0.72 mmol) were used as raw materials, and the method for synthesizing YK-301-PM4 was followed to obtain YK-303-PM1 (114 mg, 0.27 mmol, 38.0%), C 23 H 48 N 2 O 4 , MS (ES): m/z (M+H + ) 417.4; and YK-304 (50 mg, 0.07 mmol, 10.1%), C 40 H 80 N 2 O 6 , MS (ES): m/z (M+H + ) 685.6.
- Step 2 Synthesis of (R)-undecyl-6-(4-(4-decyltetradecyloxy)-4-oxobutyl)((2-hydroxy-3-((2-hydroxyethyl)(methyl)amino)propyl)amino)hexanoate (YK-303)
- YK-301-PM3 160 mg, 1.08 mmol
- 4-bromobutyric acid-4-decyltetradecyl ester 362 mg, 0.72 mmol
- YK-307 75 mg, 0.08 mmol, 20.9%
- the synthetic route is as follows:
- Step 1 Synthesis of tert-butyl (S)-2-hydroxy-3-(((2-hydroxyethyl)(ethyl)amino)propyl)carbamate (YK-308-PM1)
- the synthetic route is as follows:
- Step 1 Synthesis of (S)-tert-butyl ((3-(bis(2-hydroxyethyl)amino)-2-hydroxypropyl)carbamate (YK-316-PM1)
- Step 2 Synthesis of (S)-1-amino-3-(bis(2-hydroxyethyl)amino)-2-propanol (YK-316-PM2)
- YK-316-PM1 200 mg, 0.72 mmol was used as raw material, and YK-316-PM2 (128 mg, 0.72 mmol, 100%) was obtained according to the method for synthesizing YK-301-PM3.
- YK-316-PM2 64 mg, 0.36 mmol
- 6-bromohexanoic acid-2-octyldecyl ester 160 mg, 0.36mmol
- the synthetic route is as follows:
- YK-316-PM2 105 mg, 0.59 mmol
- 6-bromohexanoic acid-3-hexylnonyl ester 500 mg, 1.23 mmol
- YK-317 270 mg, 0.33 mmol, 55.3%
- the synthetic route is as follows:
- the synthetic route is as follows:
- the synthetic route is as follows:
- the synthetic route is as follows:
- YK-316-PM2 41 mg, 0.23 mmol
- 4-bromobutyric acid-4-decyltetradecyl ester (266 mg, 0.53 mmol) were used as raw materials, and YK-321 (85 mg, 0.08 mmol, 36.1%) was obtained according to the method for synthesizing YK-301.
- Step 2 Synthesis of 9-heptadecanyl-8-((2-hydroxyethyl)amino)octanoate (Compound 21-PM2)
- Step 3 Synthesis of 8-bromooctanoic acid-3-hexylnonyl ester (Compound 21-PM3)
- Step 4 Synthesis of 9-heptadecyl-8-(8-((3-hexylnonyl)oxy)-8-oxooctyl)-((2-hydroxyethyl)amino)octanoate (Compound 21)
- the synthetic route is as follows:
- the cationic lipid compound YK-305 synthesized in Example 1 was dissolved in ethanol with DSPC (Aiweituo (Shanghai) Pharmaceutical Technology Co., Ltd.), cholesterol (Aiweituo (Shanghai) Pharmaceutical Technology Co., Ltd.) and DMG-PEG2000 at a molar ratio of 49:10:39.5:1.5 to prepare an ethanol lipid solution.
- the LNP preparation encapsulating eGFP-mRNA was prepared according to the method in 1, wherein the cationic lipid YK-305 was The molar ratios of neutral lipid DSPC were 1:1, 3:1, 3.5:1, 4:1, 4.5:1, 4.9:1, 10:1, 15:1 and 20:1, respectively.
- Ultrasonication at 25°C for 15 minutes (ultrasonic frequency 40kHz, ultrasonic power 800W).
- the obtained liposomes were diluted to 10 times the volume with PBS, and then ultrafiltered to remove ethanol with a 300KDa ultrafiltration tube.
- Example 5 Determination of particle size and polydispersity index (PDI) of nanolipid particles
- Seed board The method is the same as Example 3.
- the HHMA structure is the most different. From the chemical structure diagram, it can be seen that in the group connected to the central N atom of HHMA, only one side chain is similar to one side chain of this series of structures, and the other parts are completely different.
- cationic lipids in the prior art such as SM-102, ALC-0315, compound 21, compound 23 and YK-009, have completely different G3 groups.
- This series of compounds has one more tertiary amine group and 1-2 more hydroxyl groups in the G3 group, so there are also great differences in polarity, acidity and alkalinity, and hydrophilicity.
- the G1 group of YK-305 has one less C; the R1 group has one more C in a single chain, and one more C in a double chain; the G2 group has one less C; the R2 group has one more C in a single chain, and one more C in a double chain; the G3 group is completely different, HO( CH2 ) 2N ( CH3 ) CH2CH (OH) CH2- , while ALC-0315 is HO( CH2 ) 4- .
- the directions of the ester bonds between the G1 group and the R1 group, and between the G2 group and the R2 group are also different for YK-305 and ALC-0315.
- the G1 group of YK-305 has 2 fewer Cs; the R1 group has 1 fewer C in a single chain, and each single chain in the double chain has 2 more Cs; the G2 group has 2 fewer Cs; the R2 group has 1 fewer C in a single chain, and each single chain in the double chain has 2 more Cs; the G3 group is completely different, being HO( CH2 ) 2N ( CH3 ) CH2CH (OH) CH2- , while compound 23 is HO( CH2 ) 2- .
- the G1 group of YK-305 has 2 more Cs; the R1 group is a branched structure, while YK-009 is a straight chain structure; the G3 group is completely different, being HO( CH2 ) 2N ( CH3 ) CH2CH (OH) CH2- , while YK-009 is HO( CH2 ) 2- .
- HHMA Compared with HHMA, the structure of YK-305 is completely different. Only one side chain connected to the N atom of HHMA is similar to the side chain structure of YK-305, and the other parts are very different.
- the G 2 group of YK-310 has 4 fewer Cs; the R 2 group has 3 more Cs in the single chain and 2 more Cs in each single chain of the double chain; the G 3 group is completely different, being HO(CH 2 ) 2 N(CH 2 CH 3 )CH 2 CH(OH)CH 2 -, while SM-102 is HO(CH 2 ) 2 -.
- the G1 group of YK-310 has one less C; the R1 group is a straight chain structure, while ALC-0315 is a branched structure; the G2 group has 3 less C; the R2 group has 3 more C in a single chain, 2 more C in one of the double chains, and 4 more C in the other; the G3 group is completely different, HO( CH2 ) 2N ( CH2CH3 )CH2CH ( OH) CH2- , while ALC-0315 is HO( CH2 ) 4- .
- the directions of the ester bonds between the G1 group and the R1 group, and between the G2 group and the R2 group are also different for YK-310 and ALC-0315.
- the G1 group of YK-310 has 2 fewer Cs; the R1 group is a straight chain structure, while compound 21 has a branched structure; the G2 group has 4 fewer Cs; the R2 group has 3 more Cs in a single chain and 2 more Cs in each single chain of the double chain; the G3 group is completely different, being HO( CH2 ) 2N ( CH2CH3 ) CH2CH (OH) CH2- , while compound 21 is HO( CH2 ) 2- .
- the G1 group of YK-310 has 2 fewer Cs; the R1 group is a straight chain structure, while compound 23 is a branched structure; the G2 group has 4 fewer Cs; the R2 group has 1 more C in a single chain, and 4 more Cs in each single chain of the double chain; the G3 group is completely different, being HO( CH2 ) 2N ( CH2CH3 ) CH2CH (OH) CH2- , while compound 23 is HO( CH2 ) 2- .
- the G 1 group of YK-310 has 2 more Cs; the R 1 group has 1 more C; the G 2 group has 2 fewer Cs; the R 2 group has 2 more Cs in the single chain and 2 more Cs in each single chain of the double chain; the G 3 group is completely different, being HO(CH 2 ) 2 N(CH 2 CH 3 )CH 2 CH(OH)CH 2 -, while YK-009 is HO(CH 2 ) 2 -.
- HHMA Compared with HHMA, the structure of YK-310 is completely different. Only one side chain connected to the N atom of HHMA is similar to the side chain structure of YK-310, and the other parts are very different.
- YK-312 has a significant structural difference compared to prior art cationic lipids, such as SM-102, compound 21, compound 23, YK-009 and HHMA.
- the G 1 group of YK-312 has 1 less C; the R 1 group has 1 more C in the single chain, and 2 more Cs in one single chain in the double chain; the G 2 group has 1 less C; the R 2 group has 1 more C in the single chain, and 2 more Cs in one single chain in the double chain;
- the G3 group is completely different, being HO( CH2 ) 2N ( CH2CH3 ) CH2CH (OH) CH2- , while ALC-0315 is HO( CH2 ) 4- .
- the directions of the ester bonds between the G1 group and the R1 group, and between the G2 group and the R2 group are also different between YK-312 and ALC-0315.
- the G1 group of YK-312 has 2 fewer Cs; the R1 group has 1 fewer C in a single chain, and each single chain in a double chain has 2 more Cs; the G2 group has 2 fewer Cs; the R2 group has 1 fewer C in a single chain, and each single chain in a double chain has 2 more Cs; the G3 group is completely different, being HO( CH2 ) 2N ( CH2CH3 ) CH2CH (OH) CH2- , while compound 23 is HO( CH2 ) 2- .
- HHMA Compared with HHMA, the structure of YK-312 is completely different. Only one side chain connected to the N atom of HHMA is similar to the side chain structure of YK-312, and the other parts are very different.
- YK-319 has a significant structural difference compared to prior art cationic lipids, such as SM-102, compound 21, compound 23, YK-009 and HHMA.
- the G1 group of YK-319 has one more C; the R1 group is a branched structure, while SM-102 is a straight chain structure; the G2 group has one less C; the R2 group has 2 more Cs in a single chain, and 2 less Cs in each single chain of the double chain; the G3 group is completely different, being (HO( CH2 ) 2 ) 2NCH2CH (OH) CH2- , while SM-102 is HO( CH2 ) 2- .
- the R1 group of YK-319 has 2 more C in the single chain and 2 less C in one of the double chains; the R2 group has 2 more C in the single chain and 2 less C in one of the double chains; the G3 group is completely different, (HO( CH2 ) 2 ) 2NCH2CH (OH) CH2- , while ALC- 0315 is HO( CH2 ) 4- .
- the directions of the ester bonds between the G1 group and the R1 group, and between the G2 group and the R2 group are also different in YK-319 and ALC-0315.
- the G1 group of YK-319 has 3 more Cs; the R1 group is a branched structure, while YK-009 is a straight chain structure; the G2 group has 1 more C; the R2 group has 1 more C in the single chain, and 2 fewer Cs in each single chain of the double chain; the G3 group is completely different, being (HO( CH2 ) 2 ) 2NCH2CH (OH) CH2- , while YK-009 is HO( CH2 ) 2- .
- HHMA Compared with HHMA, the structure of YK-319 is completely different. Only one side chain connected to the N atom of HHMA is similar to the side chain structure of YK-319, and the other parts are very different.
- YK-318 has a significant structural difference compared to prior art cationic lipids, such as SM-102, compound 21, compound 23, YK-009 and HHMA.
- the G1 group of YK-318 has 2 fewer Cs; the R1 group has 2 fewer Cs in a single chain, and 2 more Cs in each single chain in the double chain; the G2 group has 1 less C; the R2 group has 2 fewer Cs in a single chain, and 2 more Cs in each single chain in the double chain; the G3 group is completely different, being (HO( CH2 ) 2 ) 2NCH2CH (OH) CH2- , while compound 23 is HO( CH2 ) 2- .
- Table 4 shows the difference in chemical structure between the designed compounds and representative cationic lipids in the prior art.
- Table 5 lists the fluorescence detection results of LNP preparations containing Fluc-mRNA prepared by different cationic lipids.
- YK-009 is disclosed in CN114044741B (claim 1)
- compound 21 and compound 23 are disclosed in WO2021055833A1 (page 22 of the specification)
- SM-102 is compound 25 disclosed in WO2017049245A2 (page 29 of the specification)
- ALC-0315 is compound 3 disclosed in CN108368028B (page 24 of the specification)
- HHMA is compound 1 disclosed in CN112979483B (page 12 of the specification);
- Lipofectamine 3000 is a widely used cell transfection reagent.
- These cationic lipids are representative cationic lipids in the prior art and have good transfection performance.
- the activity of YK-310 can reach 16.08 times that of SM-102, 12.69 times that of ALC-0315, 18.01 times that of compound 21, 19.02 times that of compound 23, 12.86 times that of HHMA, 21.76 times that of Lipofectamine 3000 and 5.04 times that of YK-009.
- the activity of YK-319 can reach 15.25 times that of SM-102, 12.03 times that of ALC-0315, 17.08 times that of compound 21, 18.04 times that of compound 23, 12.20 times that of HHMA, 20.63 times that of Lipofectamine 3000 and 4.78 times that of YK-009.
- the activity of YK-318 can reach 6.98 times that of SM-102, 5.50 times that of ALC-0315, 7.81 times that of compound 21, 8.25 times that of compound 23, 5.58 times that of HHMA, 9.44 times that of Lipofectamine 3000 and 2.19 times that of YK-009.
- YK-305, YK-310, YK-312, YK-319 and YK-318 showed significant differences compared with SM-102, ALC-0315, compound 21, compound 23, HHMA, Lipofectamine 3000 and YK-009, and the transfection efficiency was significantly improved.
- the designed series of compounds including YK-305, YK-310, YK-312, YK-319 and YK-318, are very different from the representative cationic lipids in the prior art.
- the structure is completely different from that of HHMA; compared with SM-102, ALC-0315, compound 21, compound 23 and YK-009, the G3 group is completely different, and the G1 , G2 , R1 and R2 groups are also very different.
- the LNP preparations prepared from YK-305, YK-310, YK-312, YK-319 and YK-318 have the highest cell transfection efficiency and are significantly more active than representative cationic lipids in the prior art.
- YK-305 can reach 17 times that of SM-102, 19 times that of compound 21 and 20 times that of compound 23.
- the present application designs for the first time a compound with a chemical structure greatly different from that of cationic lipids in the prior art, and the LNP preparation prepared therefrom has significantly improved transfection efficiency and significantly enhanced cell transfection activity.
- YK-305, YK-310, YK-312, YK-319 and YK-318 have the highest cell transfection efficiency compared to a series of compounds with similar structures and G 3 groups of HO(CH 2 ) 2 N(CH 3 )CH 2 CH(OH)CH 2 -.
- YK-305 is 1300 times that of YK-304 and 900 times that of YK-302.
- the fluorescence absorption values of the LNP preparations prepared from these compounds are very different from those of YK-305, YK-310, YK-312, YK-319 and YK-318.
- the strength of YK-305 can reach 32.53 times that of YK-301, 986.71 times that of YK-302, 43.76 times that of YK-303, 1324.99 times that of YK-304, 12.47 times that of YK-306 and 6.01 times that of YK-307.
- the strength of YK-310 can reach 30.62 times that of YK-301, 928.69 times that of YK-302, 41.19 times that of YK-303, 1247.08 times that of YK-304, 11.74 times that of YK-306 and 5.66 times that of YK-307.
- the strength of YK-312 can reach 23.92 times that of YK-301, 725.34 times that of YK-302, 32.17 times that of YK-303, 974.01 times that of YK-304, 9.17 times that of YK-306 and 4.42 times that of YK-307.
- YK-318 can reach 13.28 times of YK-301, 402.84 times of YK-302, 17.87 times of YK-303, 540.95 times that of YK-304, 5.09 times that of YK-306 and 2.46 times that of YK-307.
- the activity differences among YK-301, YK-302, YK-303, YK-304, YK-306 and YK-307 are also large.
- the cell transfection efficiency of YK-306 and YK-307 is stronger than that of SM-102, which can reach 1.37 times and 2.84 times of SM-102 respectively;
- YK-301 and YK-303 are not much different from SM-102, but slightly lower, which are 0.53 times and 0.39 times respectively;
- YK-302 and YK-304 have the lowest cell transfection efficiency, which is only 0.017 times and 0.013 times of SM-102.
- YK-305, YK-310, YK-312, YK-319 and YK-318 showed significant differences compared with YK-301, YK-302, YK-303, YK-304, YK-306 and YK-307, and the transfection efficiency was significantly improved.
- This series of compounds is very similar to YK-305, YK-310, YK-312, YK-319 and YK-318 in structure, with only slight differences in G1 , G2 , G3 , R1 or R2 groups. This series of compounds is also very similar to each other (see Table 6).
- the G1 group has 2 fewer carbon atoms; the R1 group is a straight chain structure, while YK-305 is a branched structure; the R2 group has 1 more carbon atom in the single chain, and each single chain in the double chain has 2 fewer carbon atoms; the other structures are exactly the same, but the cell transfection efficiency of YK-305 is 986.71 times that of YK-302.
- the R1 group is a straight chain structure, while YK-305 is a branched structure; the G2 group has 2 fewer carbon atoms; the R2 group has 2 more carbon atoms in the single chain, and each single chain in the double chain has 2 more carbon atoms; the other structures are exactly the same, but the cell transfection efficiency of YK-305 is 43.76 times that of YK-303.
- YK-304 Compared with YK-310, YK-304 only has 2 more carbon atoms in the G2 group; the R2 group is a straight chain structure, while YK-310 is a branched structure; the group connected to N in the G3 group has 1 less carbon atom; the other structures are exactly the same, but the cell transfection efficiency of YK-310 is 1247.08 times that of YK-304.
- YK-302 Compared with YK-310, YK-302 only has 2 fewer Cs in the G1 group, 1 less C in the R1 group, 2 more Cs in the G2 group, 1 less C in the single chain of the R2 group, and 4 less Cs in each single chain of the double chain; and 1 less C in the group connected to N in the G3 group.
- the other structures are exactly the same, but the cell transfection efficiency of YK-310 is 928.69 times that of YK-302.
- the G1 group and G2 group each have one less C; the R1 group and R2 group are straight-chain structures, while YK-319 has a branched structure; the group connected to N in the G3 group has one less hydroxymethyl group; the other structures are exactly the same, but the cell transfection efficiency of YK-319 is 1182.82 times that of YK-304.
- YK-305, YK-310, YK-312, YK-319 and YK-318 have the highest cell transfection efficiency compared to a series of compounds with similar structures and G 3 groups of HO(CH 2 ) 2 N(CH 2 CH 3 )CH 2 CH(OH)CH 2 -.
- YK-305 is more than 200 times that of YK-309.
- G1 , R1 , G2 , R2 or G3 groups compared with YK-305, YK-310, YK-312, YK-319 and YK-318 (see Table 8), their effects on cell transfection efficiency are very large, with a difference of more than 200 times.
- the content of YK-305, YK-310, YK-312, YK-319 and YK-318 can reach 218.62 times, 205.77 times, 160.71 times, 195.16 times and 89.26 times of YK-309 respectively.
- the fluorescence absorption values of LNP preparations prepared by YK-311, YK-313, YK-314, and YK-315 were significantly different from those of YK-305, YK-310, YK-312, YK-319, and YK-318 in terms of transfection efficiency.
- YK-305 is 13.96 times that of YK-311, 31.63 times that of YK-313, 50.07 times that of YK-314, and 50.1 times that of YK-315. 17.27 times of 315.
- YK-312 is 10.26 times that of YK-311, 23.25 times that of YK-313, 36.81 times that of YK-314, and 12.69 times that of YK-315.
- YK-319 is 12.46 times that of YK-311, 28.24 times that of YK-313, 44.70 times that of YK-314, and 15.42 times that of YK-315.
- YK-318 is 5.70 times that of YK-311, 12.91 times that of YK-313, 20.44 times that of YK-314, and 7.05 times that of YK-315.
- the weights of YK-305, YK-310, YK-312, YK-318 and YK-319 are 5.44 times, 5.12 times, 4.00 times, 4.86 times and 2.22 times that of YK-308 respectively.
- This series of compounds is very similar to YK-305, YK-310, YK-312, YK-319 and YK-318 in structure, with only slight differences in G1 , G2 , G3 , R1 or R2 groups. This series of compounds is also very similar to each other (see Table 8).
- YK-314 Compared with YK-305, YK-314 only has 2 more Cs in G1 and G2 groups, 1 less C in R1 and R2 single chains, and 1 more C in the group connected to N in G3 group.
- the other structures are exactly the same, but the cell transfection efficiency of YK-305 is 50.07 times that of YK-314.
- YK-313 Compared with YK-312, the only difference between YK-313 and YK-312 is that the single chains of R1 and R2 groups each have one less C; the other structures are exactly the same, but the cell transfection efficiency of YK-312 is 23.25 times that of YK-313.
- YK-321 is very different from YK-305, YK-310, YK-312, YK-318 and YK-319.
- the cell survival rate can represent the toxicity of cationic lipids to cells. The higher the cell survival rate, the lower the toxicity to cells.
- YK-310 was 12.65% higher than SM-102, 31.07% higher than ALC-0315, 11.89% higher than compound 21, 10.60% higher than compound 23, 15.63% higher than HHMA, and 57.09% higher than Lipofectamine 3000.
- YK-318 was 6.11% higher than SM-102, 24.53% higher than ALC-0315, 5.35% higher than compound 21, 4.06% higher than compound 23, 9.09% higher than HHMA, and 50.55% higher than Lipofectamine 3000.
- YK-305, YK-310, YK-312, YK-319 and YK-318 showed the lowest cytotoxicity and significantly improved cell survival rate compared with a series of compounds with similar structures and G 3 groups of HO(CH 2 ) 2 N(CH 3 )CH 2 CH(OH)CH 2 -.
- the cell survival rate of YK-305 and YK-310 was significantly improved. 65% higher.
- YK-305, YK-310, YK-312, YK-319 and YK-318 had the highest cell survival rate.
- YK-305 and YK-310 could both be 65% higher than YK-302.
- the survival rates of YK-305 cells were 29.22% higher than those of YK-301, 18.86% higher than those of YK-303, 48.02% higher than those of YK-304, 39.99% higher than those of YK-306, and 21.04% higher than those of YK-307.
- the survival rates of YK-310 cells were 29.14% higher than those of YK-301, 18.78% higher than those of YK-303, 47.94% higher than those of YK-304, 39.91% higher than those of YK-306, and 20.96% higher than those of YK-307.
- the survival rates of YK-312 cells were 24.00% higher than those of YK-301, 13.64% higher than those of YK-303, 42.80% higher than those of YK-304, 34.77% higher than those of YK-306, and 15.82% higher than those of YK-307.
- the survival rates of YK-319 cells were 22.25% higher than those of YK-301, 11.89% higher than those of YK-303, 41.05% higher than those of YK-304, 33.02% higher than those of YK-306, and 14.07% higher than those of YK-307.
- the survival rates of YK-318 cells were 22.60% higher than those of YK-301, 12.24% higher than those of YK-303, 41.40% higher than those of YK-304, 33.37% higher than those of YK-306, and 14.42% higher than those of YK-307.
- YK-305, YK-310, YK-312, YK-319 and YK-318 had significant differences in cytotoxicity compared with other compounds, with significantly reduced cytotoxicity and significantly increased cell survival rate.
- YK-305, YK-310, YK-312, YK-319 and YK-318 are very close to the structures of other compounds; the other compounds are also very similar to each other.
- YK-305, YK-310, YK-312, YK-319 and YK-318 had significant differences in cytotoxicity compared with YK-308, YK-309, YK-311, YK-313, YK-314 and YK-315, with significantly reduced cytotoxicity and significantly increased cell survival rate.
- the cell survival rates of YK-305, YK-310, YK-312, YK-319 and YK-318 were 23.00%, 22.92%, 17.78%, 16.03% and 16.38% higher than those of YK-317, respectively.
- the LNP preparations prepared from YK-305, YK-310, YK-312, YK-319 and YK-318 have the lowest cytotoxicity and significantly improve the cell survival rate compared to the representative cationic lipids in the prior art.
- the cell survival rates of YK-305 and YK-310 are 30% higher than ALC-0315, 12% higher than SM-102, and 15% higher than HHMA.
- Example 7 In vivo validation of the performance of cationic lipid delivery vehicles
- the LNP preparations prepared by YK-305, YK-310, YK-312, YK-319 and YK-318 expressed mRNA in mice at a very high level and continuously, which was significantly improved compared with the representative cationic lipids in the prior art.
- YK-305 and YK-310 can reach 30 times that of SM-102, compound 21 and compound 23.
- the expression of mRNA in mice is consistent with the cell transfection activity.
- Table 16 lists the LNP preparations containing Fluc-mRNA prepared by different cationic lipids, and the expression intensity of mRNA at different times in mice.
- YK-009 is disclosed in CN114044741B (claim 1)
- SM-102 is compound 25 disclosed in WO2017049245A2 (page 29 of the specification)
- ALC-0315 is compound 3 disclosed in CN108368028B (page 24 of the specification)
- compound 21 and compound 23 are disclosed in WO2021055833A1 (page 22 of the specification)
- HHMA is compound 1 disclosed in CN112979483B (page 12 of the specification).
- These cationic lipids can be used to prepare vectors for delivering mRNA.
- the average radiation intensity of YK-305 was 9239340 at 6 h, which was 13.18 times that of SM-102, 10.70 times that of ALC-0315, 15.14 times that of compound 21, 15.68 times that of compound 23, and 14.19 times that of HHMA; and 2823400 at 24 h, which was 23.44 times that of SM-102, 14.82 times that of ALC-0315, 25.70 times that of compound 21, and 14.19 times that of HHMA.
- the molecular weight of the compound 23 was 27.01 times that of compound 23 and 23.54 times that of HHMA; at 48h, it was 1047720, which was 32.19 times that of SM-102, 26.32 times that of ALC-0315, 33.82 times that of compound 21, 31.63 times that of compound 23 and 32.18 times that of HHMA; at 7d, it was 127015, which was 19.18 times that of SM-102, 18.02 times that of ALC-0315, 19.71 times that of compound 21, 20.35 times that of compound 23 and 21.63 times that of HHMA.
- the average radiation intensity of YK-310 was 9125240 at 6 h, which was 13.01 times that of SM-102, 10.56 times that of ALC-0315, 14.95 times that of compound 21, 15.48 times that of compound 23, and 14.02 times that of HHMA; and 2952310 at 24 h, which was 24.51 times that of SM-102, 15.50 times that of ALC-0315, 26.88 times that of compound 21, 28.24 times that of compound 23, and 29.81 times that of HHMA.
- the average radiation intensity of YK-319 was 8230500 at 6 h, which was 11.74 times that of SM-102, 9.53 times that of ALC-0315, 13.49 times that of compound 21, 13.96 times that of compound 23, and 12.64 times that of HHMA; and 2433960 at 24 h, which was 20.20 times that of SM-102, 12.78 times that of ALC-0315, 22.16 times that of compound 21, 23.28 times that of compound 23, and 24.8 times that of HHMA.
- the present application unexpectedly discovered that the compound designed for the first time in the present application, which has a very different structure from the cationic lipids in the prior art, can express mRNA to a very high degree and continuously in the LNP preparation prepared therefrom.
- mice had very different mRNA expression in mice, among which YK-305, YK-310, YK-312, YK-319 and YK-318 had the highest expression levels and the longest duration.
- the expression level of YK-305 could reach more than 1,000 times that of YK-302.
- YK-305 can reach 633.70 times of YK-302 in 6 hours, 713.70 times in 24 hours, 1022.17 times in 48 hours and 330.77 times in 7 days.
- YK-310 can reach 625.87 times of YK-302 in 6 hours, 746.29 times in 24 hours, 957.07 times in 48 hours and 305.89 times in 7 days.
- YK-318 can reach 228.10 times of YK-302 in 6 hours, 244.83 times in 24 hours, 348.11 times in 48 hours and 131.92 times in 7 days.
- YK-305, YK-310, YK-312, YK-319, and YK-318 showed the highest mRNA expression in mice and the longest duration compared with a series of compounds with similar structures and G 3 groups of HO(CH 2 ) 2 N(CH 2 CH 3 )CH 2 CH(OH)CH 2 -.
- the expression of YK-305 was 160 times that of YK-309.
- the expression of mRNA in mice was consistent with the cell transfection activity.
- the results showed that YK-305, YK-310, YK-312, YK-319 and YK-318 had the highest expression levels and the longest duration, which were significantly higher than other compounds. For example, YK-305 could reach 160 times that of YK-309.
- the LNP preparations prepared from YK-305, YK-310, YK-312, YK-319 and YK-318 have the highest mRNA expression level and duration in mice.
- the expression level of YK-305 was 140.67 times that of YK-309 and 20.89 times that of YK-313 at 6 hours, 167.86 times that of YK-309 and 27.04 times that of YK-313 at 24 hours, 159.93 times that of YK-309 and 40.99 times that of YK-313 at 48 hours, and 101.13 times that of YK-309 and 39.26 times that of YK-313 at 7 days.
- This series of compounds is very similar in structure to YK-305, YK-310, YK-312, YK-319 and YK-318, except for slight differences in the G 1 , G 2 , G 3 , R 1 or R 2 groups.
- the LNP preparations prepared by YK-305, YK-310, YK-312, YK-319 and YK-318 have the highest mRNA expression intensity and the longest duration in mice.
- YK-305 can reach 160 times that of YK-309 at 48h and can still reach 100 times at 7d.
- the mRNA expression in mice is consistent with the results of the cell transfection experiment in Example 6.
- YK-305, YK-310, YK-312, YK-319, and YK-318 showed the highest and longest-lasting mRNA expression in mice compared to a series of compounds with similar structures and G 3 groups of (HO(CH 2 ) 2 ) 2 NCH 2 CH(OH)CH 2 -.
- YK-310 showed a 29-fold increase over YK-321.
- the mRNA expression in mice was consistent with the cell transfection activity.
- the expression level of YK-305 was 17.92 times that of YK-321 at 6h, 27.89 times at 24h, 28.65 times at 48h, and 19.29 times at 7d.
- the expression level of YK-310 was 17.70 times that of YK-321 at 6 h, 29.16 times at 24 h, 26.83 times at 48 h, and 17.84 times at 7 d.
- the expression level of YK-312 was 15.54 times that of YK-321 at 6h, 22.51 times at 24h, 22.24 times at 48h, and 16.02 times at 7d.
- the expression level of YK-319 was 15.96 times that of YK-321 at 6 h, 24.04 times at 24 h, 24.28 times at 48 h, and 15.92 times at 7 d.
- the expression level of YK-318 was 6.45 times that of YK-321 at 6 h, 9.57 times at 24 h, 9.76 times at 48 h, and 7.69 times at 7 d.
- This series of compounds is very similar in structure to YK-305, YK-310, YK-312, YK-319 and YK-318, except for slight differences in the G 1 , G 2 , G 3 , R 1 or R 2 groups.
- LNP preparations prepared from YK-305, YK-310, YK-312, YK-319 and YK-318 have the highest mRNA expression intensity and the longest duration in mice.
- YK-310 can reach 29 times that of YK-321 in 24 hours and still reach 17 times in 7 days.
- the mRNA expression in mice is consistent with the results of the cell transfection experiment in Example 6.
- mice We also found that there was no correspondence between mRNA expression in mice and the structure of the cationic lipids, and that even LNP formulations made from a group of compounds with very similar structures, differing only slightly in the G1 , G2 , G3 , R1 , or R2 groups, were likely to have very different levels and durations of mRNA expression in mice.
- the LNP preparations prepared by YK-305, YK-310, YK-312, YK-319 and YK-318 have significantly improved cell transfection efficiency, significantly reduced cytotoxicity, significantly improved mRNA expression and duration in mice, reduced target protein expression in the liver, or will not stay in the liver and express the target protein, and reduced or no liver toxicity.
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Abstract
本发明提供一种长效低毒的新型阳离子脂质化合物,其为式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体。还提供了包含前述化合物的组合物以及它们用于递送治疗剂或预防剂的用途。
Description
本申请要求于2023年1月5日递交的中国专利申请第202310010912.6号的优先权,在此全文引用上述中国专利申请公开的内容以作为本申请的一部分。
本发明属于医药领域。本发明具体涉及一种阳离子脂质化合物、包含其的组合物及用途。
生物活性物质如小分子药物、多肽、蛋白质和核酸尤其是核酸的有效靶向递送是一个持久的医学难题。核酸治疗剂因低细胞渗透性和对某些核酸分子(包括RNA)降解的高敏感性而面临很大挑战。
证实,含阳离子脂质的组合物、脂质体和脂质体复合物(lipoplex)作为运输媒介物,有效地将生物活性物质如小分子药物、多肽、蛋白质和核酸运送至细胞和/或细胞内隔室中。这些组合物一般包含一种或多种“阳离子性”和/或氨基(可离子化)脂质、包括中性脂质、结构脂质以及聚合物共轭脂质。阳离子性和/或可离子化脂质包括例如可容易地质子化的含胺脂质。尽管已经展示多种此类含脂质的纳米粒子组合物,但安全性、功效和特异性仍有待改良。值得注意的是,脂质纳米颗粒(Lipid Nanoparticle,LNP)复杂性的增加使其生产复杂化,并可能增加其毒性,这是一个可能限制其临床应用的主要担忧。例如,LNP siRNA颗粒(如patisiran)需要预先使用类固醇和抗组胺药来消除不必要的免疫反应(T.Coelho,D.Adams,A.Silva,et al.,Safety and efficacy of RNAi therapy for transthyretin amyloidosis,N Engl J Med,369(2013)819-829.)。因此,需要开发有助于将治疗剂和/或预防剂如核酸递送至细胞的改进的阳离子脂质化合物,及包含其的组合物的需求。
发明内容
本发明一方面提供一种新的阳离子脂质化合物,其为式(I)化合物
或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体,其中:
G1为C1~8亚烷基;
G2为C2~8亚烷基;
R1为C6~25直链或支链烷基;
R2为C12~25直链或支链烷基;
G3为:HO(CH2)2N(R3)CH2CH(OH)CH2-,其中R3为-CH3或-CH2CH3或-CH2CH2OH。
例如,式(I)化合物具有以下结构中的一种:
本发明的又一方面提供一种组合物,其包含载体,所述载体包括阳离子脂质,所述阳离子脂质包括上述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体。
本发明的又一方面提供上述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体或者上述的组合物在制备核酸药物、基因疫苗、小分子药物、多肽或蛋白质药物中的用途。
本发明的又一方面提供上述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体或者上述的组合物在制备用于治疗有需要哺乳动物的疾病或病症的药物中的用途。
图1显示制备LNP制剂时所用载体与mRNA的不同重量比的细胞转染实验结果,a为载体:mRNA=5:1,b为载体:mRNA=15:1,c为载体:mRNA=35:1;d为
空白对照。
图2显示制备LNP制剂时所用阳离子脂质与中性脂质DSPC不同摩尔比的细胞转染实验结果,a为3.5:1,b为4.5:1,c为4.9:1,d为空白对照。
图3显示制备LNP制剂时聚合物共轭脂质占载体不同摩尔比的细胞转染实验结果,a为1.5%,b为10%,c为空白对照。
图4显示制备LNP制剂时载体中各成分阳离子脂质、中性脂质DSPC、结构脂质胆固醇和聚合物共轭脂质DMG-PEG2000不同比例的细胞转染实验结果,a为35:10:53.5:1.5,b为45:10:43.5:1.5,c为49:10:39.5:1.5,d为空白对照。
图5显示由不同的阳离子脂质制备的Fluc-mRNA的LNP制剂荧光吸收强度(a:YK-305;b:YK-310;c:YK-319;d:SM-102)。
图6显示由不同的阳离子脂质制备的Fluc-mRNA的LNP制剂荧光吸收强度(a:YK-301;b:YK-302;c:YK-304;d:化合物21)。
图7显示由不同的阳离子脂质制备的Fluc-mRNA的LNP制剂荧光吸收强度(a:YK-305;b:YK-310;c:YK-320;d:YK-321)。
图8显示由不同的阳离子脂质(YK-305、YK-310、YK-312、YK-319、YK-318、YK-009、SM-102、ALC-0315、化合物21、化合物23和HHMA)制备的Fluc-mRNA的LNP制剂以及含有Fluc-mRNA的Lipofectamine 3000制剂加入细胞培养液中,培养24小时后的细胞存活率。
图9显示由不同的阳离子脂质(YK-305、YK-310、YK-312、YK-319、YK-318、YK-301、YK-302、YK-303、YK-304、YK-306、YK-307、SM-102、ALC-0315、化合物21、化合物23和HHMA)制备的Fluc-mRNA的LNP制剂以及含有Fluc-mRNA的Lipofectamine 3000制剂加入细胞培养液中,培养24小时后的细胞存活率。
图10显示由不同的阳离子脂质(YK-305、YK-310、YK-312、YK-319、YK-318、YK-308、YK-309、YK-311、YK-313、YK-314、YK-315、SM-102、ALC-0315、化合物21、化合物23和HHMA)制备的Fluc-mRNA的LNP制剂以及含有Fluc-mRNA的Lipofectamine 3000制剂加入细胞培养液中,培养24小时后的细胞存活率。
图11显示由不同的阳离子脂质(YK-305、YK-310、YK-312、YK-319、YK-318、YK-316、YK-317、YK-320、YK-321、SM-102、ALC-0315、化合物
21、化合物23和HHMA)制备的Fluc-mRNA的LNP制剂以及含有Fluc-mRNA的Lipofectamine 3000制剂加入细胞培养液中,培养24小时后的细胞存活率。
图12显示由不同的阳离子脂质(YK-305、YK-312、YK-302、YK-313、SM-102、ALC-0315、化合物21、化合物23和HHMA)制备的Fluc-mRNA的LNP制剂的小鼠活体成像实验结果。
图13显示由不同的阳离子脂质(YK-310、YK-318、YK-309、SM-102、ALC-0315、化合物21、化合物23和HHMA)制备的Fluc-mRNA的LNP制剂的小鼠活体成像实验结果。
图14显示由不同的阳离子脂质(YK-319、YK-321、YK-009、SM-102、ALC-0315、化合物21、化合物23和HHMA)制备的Fluc-mRNA的LNP制剂的小鼠活体成像实验结果。
图15显示由不同的阳离子脂质(ALC-0315、SM-102、YK-305、YK-319、YK-310和YK-313)制备的Fluc-mRNA的LNP制剂,在小鼠体内蛋白表达情况。
为使本发明实施例的目的、技术方案和优点更加清楚,下面将结合本发明实施例的附图,对本发明实施例的技术方案进行清楚、完整地描述。显然,所描述的实施例是本发明的一部分实施例,而不是全部的实施例。基于所描述的本发明的实施例,本领域普通技术人员在无需创造性劳动的前提下所获得的所有其它实施例,都属于本发明保护的范围。
本发明可在不偏离本发明基本属性的情况下以其它具体形式来实施。应该理解的是,在不冲突的前提下,本发明的任一和所有实施方案都可与任一其它实施方案或多个其它实施方案中的技术特征进行组合以得到另外的实施方案。本发明包括这样的组合得到的另外的实施方案。
本发明中提及的所有出版物和专利在此通过引用以它们的全部内容纳入本发明。如果通过引用纳入的任何出版物和专利中使用的用途或术语与本发明中使用的用途或术语冲突,那么以本发明的用途和术语为准。
本文所用的章节标题仅用于组织文章的目的,而不应被解释为对所述主题的限制。
除非另有规定,本文使用的所有技术术语和科学术语具有要求保护主题所
属领域的通常含义。倘若对于某术语存在多个定义,则以本文定义为准。
除了在工作实施例中或另外指出之外,在说明书和权利要求中陈述的定量性质例如剂量的所有数字应理解为在所有情况中被术语“约”修饰。还应理解的是,本申请列举的任何数字范围意在包括该范围内的所有的子范围和该范围或子范围的各个端点的任何组合。
本发明中使用的“包括”、“含有”或者“包含”等类似的词语意指出现该词前面的要素涵盖出现在该词后面列举的要素及其等同,而不排除未记载的要素。本文所用的术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之,所述术语也包括“基本上由…组成”、或“由…组成”。
术语“药学上可接受的”在本申请中是指:化合物或组合物在化学上和/或在毒理学上与构成制剂的其它成分和/或与用其预防或治疗疾病或病症的人类或哺乳动物相容。
术语“受试者”或“患者”在本申请中包括人类和哺乳动物。
本文所用的术语“治疗”是指给患有疾病或者具有所述疾病的症状的患者或受试者施用一种或多种药物物质,用以治愈、缓解、减轻、改善或影响所述疾病或者所述疾病的症状。在本申请的上下文中,除非作出相反的具体说明,术语“治疗”也可包括预防。
术语“溶剂合物”在本申请中指的是通过组合式(I)化合物或其药学上可接受的盐和溶剂(例如乙醇或水)而形成的复合物。应理解的是,在治疗疾病或病症中使用的式(I)化合物的任何溶剂合物尽管可能提供不同的性质(包括药代动力学性质),但是一旦吸收至受试者中,会得到式(I)化合物,使得式(I)化合物的使用分别涵盖式(I)化合物的任何溶剂合物的使用。
术语“水合物”指的是上述术语“溶剂合物”中溶剂为水的情形。
应进一步理解,式(I)化合物或其药学上可接受的盐可以溶剂合物形式分离,并且因此任何所述溶剂合物皆包括于本发明的范围内。例如,式(I)化合物或其药学上可接受的盐可以未溶剂化形式以及与药学上可接受的溶剂(诸如,水、乙醇等)形成的溶剂化形式存在。
术语“药学上可接受的盐”是指本发明化合物的相对无毒、无机酸或有机酸加成盐。例如,参见S.M.Berge等人“Pharmaceutical Salts”,J.Pharm.Sci.1977,66,1-19。其中,无机酸例如盐酸、氢溴酸、氢碘酸、硫酸、磷酸或硝酸等;有
机酸例如甲酸、乙酸、乙酰乙酸、丙酮酸、三氟乙酸、丙酸、丁酸、己酸、庚酸、十一酸、月桂酸、苯甲酸、水杨酸、2-(4-羟基苯甲酰基)-苯甲酸、樟脑酸、肉桂酸、环戊烷丙酸、二葡萄糖酸、3-羟基-2-萘甲酸、烟酸、巴莫酸、果胶酯酸、3-苯基丙酸、苦味酸、特戊酸、2-羟基乙磺酸、衣康酸、胺基磺酸、三氟甲磺酸、十二烷基硫酸、乙磺酸、苯磺酸、对-甲苯磺酸、甲磺酸、2-萘磺酸、萘二磺酸、樟脑磺酸、柠檬酸、酒石酸、硬脂酸、乳酸、草酸、丙二酸、琥珀酸、苹果酸、己二酸、海藻酸、马来酸、富马酸、D-葡萄糖酸、扁桃酸、抗坏血酸、葡庚糖酸、甘油磷酸、天冬胺酸、磺基水杨酸等。例如,可使用HCl(或盐酸)、HBr(或氢溴酸溶液)、甲磺酸、硫酸、酒石酸或富马酸与式(I)所示的化合物形成药学上可接受的盐。
本发明的式(I)的含氮化合物可通过用氧化剂(例如间氯过氧苯甲酸、过氧化氢、臭氧)处理而转化成N-氧化物。因此,在价态和结构允许的条件下,本申请要求保护的化合物不但包括结构式所示的含氮化合物,而且还包括其N-氧化物衍生物。
本发明的某些化合物可以以一种或多种立体异构体的形式存在。立体异构体包括几何异构体、非对映异构体和对映异构体。因此,本发明要求保护的化合物还包括外消旋混合物、单一的立体异构体和具有光学活性的混合物。本领域技术人员应该理解的是,一种立体异构体可能比其它立体异构体具有更好的功效和/或更低的副作用。单一的立体异构体和具有光学活性的混合物可手性源合成法、手性催化、手性拆分等方法得到。消旋体可通过色谱拆分法或者化学拆分法进行手性拆分。例如,可通过加入手性酒石酸、手性苹果酸等手性酸类拆分试剂与本发明的化合物成盐,利用产物的物理化学性质例如溶解度不同进行分离。例如,在合成阳离子脂质的原料1-氨基-3-氯丙烷-2-醇是(R)-1-氨基-3-氯丙烷-2-醇或者(S)-1-氨基-3-氯丙烷-2-醇时可以获得单一立体异构体的阳离子脂质;而在合成阳离子脂质的原料1-氨基-3-氯丙烷-2-醇是消旋混合物时可以获得外消旋的阳离子脂质。
本发明还包括本发明化合物所有适合的同位素变体。同位素变体定义为这样的化合物,其中至少一个原子被具有相同原子序数但其原子质量不同于自然界中常见的或主要存在的原子质量的原子替代。可以引入到本发明化合物中的同位素的实例包括氢、碳、氮和氧的同位素,分别例如2H(氘)、3H(氚)、11C、
13C、14C、15N、17O和18O。
术语“烷基”在本发明中是指包括具有规定碳原子数的支链和直链饱和脂族一价烃基。术语“亚烷基”在本发明中是指包括具有规定碳原子数的支链和直链饱和脂族二价烃基。Cn~m是指包括具有n至m个碳原子数的基团。例如C2~5亚烷基包括C2亚烷基、C3亚烷基、C4亚烷基、C5亚烷基。
烷基(或亚烷基)可未经取代,或烷基(或亚烷基)可经取代,其中至少一个氢被另一种化学基团代替。
“治疗有效量”为当给予患者时能改善疾病或症状的治疗剂的量。“预防有效量”为当给予受试者时能预防疾病或症状的预防剂的量。构成“治疗有效量”的治疗剂的量或“预防有效量”的预防剂的量随着治疗剂/预防剂、疾病状态及其严重性、待治疗/预防的患者/受试者的年龄、体重等而变化。本领域普通技术人员可根据其知识以及本发明常规地确定治疗有效量和预防有效量。
在本申请中,当化合物的名称与结构式不一致时,以结构式为准。
应理解,本申请所用的术语“本发明化合物”根据语境可包括:式(I)化合物、其N-氧化物、其溶剂合物、其药学上可接受的盐、其立体异构体、以及它们的混合物。
本文所用术语阳离子脂质是指在选定的pH值带正电荷的脂质。
阳离子脂质体易于与带负电荷的核酸结合,即通过静电力与核酸中存在的带负电的磷酸基团相互作用,形成脂质纳米颗粒(LNP)。LNP是目前主流的递送载体之一。
发明人在筛选大量化合物时发现,筛选出满足以下条件的合适的阳离子脂质化合物是非常困难的:与现有技术代表性阳离子脂质结构差异巨大,同时具有极高的转染效率和极低的细胞毒性,并且在小鼠体内具有高表达及持续表达。发明人发现了一些化合物,例如YK-305、YK-310、YK-312、YK-319和YK-318等,与现有技术中化学结构区别很大的阳离子脂质相比,能够以显著提高的细胞内转染效率,显著降低的细胞毒性,以及在动物体内显著提高的表达量和持续时间来递送核酸。
简单来说,本发明至少基于以下发现:
1.设计的一系列化合物,包括YK-305、YK-310、YK-312、YK-319和YK-318,与现有技术代表性阳离子脂质,例如SM-102(WO2017049245A2中公开的
化合物25)、ALC-0315(CN108368028B中公开的化合物3)、WO2021055833A1中公开的化合物21和化合物23、HHMA(CN112979483B中公开的化合物1)和CN114044741B中公开的化合物YK-009化学结构差异巨大,G3基团完全不同,其它部位也均差别非常大,所以在极性、酸碱性和亲水性等方面也会有很大差别。
因此,无法根据上述现有技术公开的阳离子脂质化合物,推测出由此系列化合物制备的LNP制剂的细胞转染效率、细胞毒性,以及在动物体内表达情况。
SM-102、ALC-0315、化合物21、化合物23和HHMA化学结构如下:
2.在设计的此系列化合物中,由YK-305、YK-310、YK-312、YK-319和YK-318制备的LNP制剂,与现有技术中代表性的阳离子脂质相比,细胞转染效率显著提高,细胞毒性显著降低,mRNA在小鼠体内的表达量及持续时间均显著提高,对肝脏毒性降低或无毒性。
例如,细胞转染效率YK-305可达SM-102的17倍、化合物21的19倍和化合物23的20倍;细胞存活率YK-305和YK-310均可比ALC-0315高30%,比SM-102高12%,比HHMA高15%;mRNA在小鼠体内表达量,YK-305和YK-310均可达到SM-102、化合物21和化合物23的30倍。
在我们设计的化学结构差异很小的一系列化合物中,由YK-305、YK-310、YK-312、YK-319和YK-318制备的LNP制剂,同其它化合物相比,细胞转染活性显著提高,细胞毒性显著降低,mRNA在小鼠体内的表达量与持续时间均显著提高。
此系列化合物结构上与YK-305、YK-310、YK-312、YK-319和YK-318相比,仅是个别基团稍有差别,但是YK-305细胞转染活性可达YK-304的1300倍和YK-302的900倍;细胞毒性YK-305和YK-310可比YK-302降低65%;mRNA在小鼠体内的表达量YK-305可达YK-302的1000倍以上。
3.阳离子脂质化合物的结构与细胞内转染效率、对细胞产生的毒性以及由其制备的LNP制剂中的mRNA在动物体内的高表达和持续表达之间无明显的对应关系。结构差异很小的化合物,在转染效率和/或对细胞的毒性、细胞内的表达方面极有可能差异非常大。
例如,与YK-305相比,YK-302仅是G1基团少2个C;R1基团为直链结构,而YK-305为支链结构;R2基团单链多1个C,双链中每条单链少2个C;其它结构完全相同,但细胞转染效率YK-305是YK-302的900倍,对转染细胞的毒性YK-305比YK-302降低65%,mRNA在小鼠体内的表达YK-305可达YK-302的1000倍;与YK-310相比,YK-303仅是G3基团与N相连的基团少1个C;其它结构完全相同,但细胞转染效率YK-310是YK-303的40倍,对转染细胞的毒性YK-310比YK-303降低了18%。
因此,筛选合适的阳离子脂质化合物,能同时具有高的转染效率和对细胞
的低毒性、mRNA在小鼠体内的高表达及持续表达是非常困难的事情,需要付出大量创造性劳动。
4.本发明通过独特的设计和大量的筛选,发现了一些化合物,例如YK-305、YK-310、YK-312、YK-319和YK-318,相对于现有技术的其它化合物,能够以显著提高的细胞转染效率、显著降低的细胞毒性以及在动物体内显著提高的表达量和持续时间来递送核酸,并且对肝脏毒性降低或无毒性。取得了预料不到的技术效果。
总之,本发明通过独特的设计和大量的筛选,发现了一些化合物,例如YK-305、YK-310、YK-312、YK-319和YK-318。这些化合物与现有技术代表性阳离子脂质化学结构差异巨大,相对于现有技术的其它化合物,能够以显著提高的细胞转染效率、显著降低的细胞毒性以及在动物体内显著提高的表达量和持续时间来递送核酸,并且对肝脏毒性降低或无毒性。取得了预料不到的技术效果。
具体如下:
1.与现有技术代表性阳离子脂质,例如SM-102、ALC-0315、化合物21、化合物23、YK-009和HHMA相比,化学结构差别巨大
现有技术代表性阳离子脂质,例如SM-102、ALC-0315、化合物21、化合物23、YK-009和HHMA,与设计的此系列化合物相比:
a.HHMA结构差别最大,从化学结构图中可以看出,HHMA与中心N原子相连的基团,仅1个侧链与此系列结构的1个侧链相近,其它部分完全不同。
b.现有技术中其它阳离子脂质,例如SM-102、ALC-0315、化合物21、化合物23和YK-009,G3基团完全不同。此系列化合物G3基团中多1个叔胺基团,并且多1-2个羟基,因此在极性、酸碱性和亲水性等方面也会有很大差别。
c.SM-102、ALC-0315、化合物21、化合物23和YK-009的G1、G2、R1和R2基团也有巨大差别。
2.体外细胞转染效率相比于现有技术中代表性阳离子脂质和结构类似的化合物显著提高
1)由YK-305、YK-310、YK-312、YK-319和YK-318制备的LNP制剂细胞转染效率最高,相比于现有技术中代表性阳离子脂质活性显著提高,例如,YK-305可达SM-102的17.09倍、化合物21的19.14倍和化合物23的20.21倍。
2)与结构类似、G3基团为HO(CH2)2N(CH3)CH2CH(OH)CH2-的化合物相比,YK-305、YK-310、YK-312、YK-319和YK-318细胞转染效率最高。YK-305
可比YK-304高1300倍,比YK-302高900倍。
3)与结构类似、G3基团为HO(CH2)2N(CH2CH3)CH2CH(OH)CH2-的化合物相比,YK-305、YK-310、YK-312、YK-319和YK-318细胞转染效率最高。YK-305和YK-310可比YK-309高200倍。
4)与结构类似、G3基团为(HO(CH2)2)2NCH2CH(OH)CH2-的化合物相比,YK-305、YK-310、YK-312、YK-319和YK-318细胞转染效率最高。例如,YK-305可达YK-321的20倍。
5)化合物的结构和细胞内转染效率之间无对应关系,结构差异很小的化合物,在转染效率方面也极有可能差异非常大。因此,筛选出具有高转染效率的阳离子脂质化合物,是非常困难的,需要付出大量创造性劳动。
3.细胞毒性相比于现有技术中代表性阳离子脂质和结构类似的化合物显著降低
1)由YK-305、YK-310、YK-312、YK-319和YK-318制备的LNP制剂细胞毒性最低,与现有技术中代表性阳离子脂质相比,细胞存活率显著提高。例如,YK-305和YK-310细胞存活率均可比ALC-0315高30%,比SM-102提高12%,比HHMA提高15%;。
2)与结构类似、G3基团为HO(CH2)2N(CH3)CH2CH(OH)CH2-的化合物相比,YK-305、YK-310、YK-312、YK-319和YK-318细胞毒性最低,细胞存活率显著提高。例如,YK-305和YK-310与YK-302相比,均可提高65%。
3)与结构类似、G3基团为HO(CH2)2N(CH2CH3)CH2CH(OH)CH2-的化合物相比,YK-305、YK-310、YK-312、YK-319和YK-318细胞毒性最低,细胞存活率显著提高。例如,YK-305和YK-310可比YK-302提高50%。
4)与结构类似、G3基团为(HO(CH2)2)2NCH2CH(OH)CH2-的化合物相比,YK-305、YK-310、YK-312、YK-319和YK-318细胞毒性最低,细胞存活率显著提高。例如,YK-305和YK-310可比YK-317提高20%。
5)化合物的结构和细胞毒性之间无对应关系,即使结构差异很小的化合物,在细胞毒性方面也极有可能差异非常大。因此无法根据化学结构预测其细胞毒性,筛选出具有低细胞毒性的阳离子脂质化合物非常困难,需要付出大量创造性劳动。
4.mRNA在动物体内表达量和持续时间相比于现有技术中代表性阳离子脂质和结构类似的化合物显著提高,并且对肝脏毒性降低或无毒性。
1)由YK-305、YK-310、YK-312、YK-319和YK-318制备的LNP制剂,mRNA在小鼠体内表达量最高,且持续表达,在6h、24h、48h和7d表达量相比
于现有技术中代表性阳离子脂质均显著提高。例如,YK-305和YK-310可达SM-102、化合物21和化合物23的30倍。
2)与结构类似、G3基团为HO(CH2)2N(CH3)CH2CH(OH)CH2-的化合物相比,由YK-305、YK-310、YK-312、YK-319和YK-318制备的LNP制剂,mRNA在小鼠体内表达强度最高,持续时间最长。例如,YK-305在48h可达YK-302的1000倍以上,在7d仍可达300倍以上。
3)与结构类似、G3基团为HO(CH2)2N(CH2CH3)CH2CH(OH)CH2-的化合物相比,由YK-305、YK-310、YK-312、YK-319和YK-318制备的LNP制剂,mRNA在小鼠体内表达强度最高,持续时间最长。例如,YK-305在48h可达YK-309的160倍,在7d仍可达100倍。
4)与结构类似、G3基团为(HO(CH2)2)2NCH2CH(OH)CH2-的化合物相比,由YK-305、YK-310、YK-312、YK-319和YK-318制备的LNP制剂,mRNA在小鼠体内表达强度最高,持续时间最长。例如,YK-310在24h可达YK-321的29倍,在7d仍可达17倍。
5)与现有技术代表性阳离子脂质,例如SM-102、ALC-0315、化合物21、化合物23和HHMA相比,由我们设计的化合物制备的脂质体,在肝脏表达目的蛋白量减少,或不会在肝内停留并表达目的蛋白。因此相比于现有技术阳离子脂质,由我们设计的化合物制备的LNP制剂,对肝脏毒性降低或无毒性。
6)阳离子脂质的结构和递送的mRNA在小鼠体内的高表达及持续表达之间无对应关系,即使结构差异很小的阳离子脂质化合物,由其制备得到的LNP制剂中的mRNA在动物体内表达方面极有可能差异非常大。无法根据阳离子脂质化学结构预测mRNA在动物体内是否高表达和持续表达,筛选出具有mRNA高表达且持续表达的阳离子脂质化合物非常困难,需要付出大量创造性劳动。
本发明一方面提供一种新的用于递送治疗剂或预防剂的阳离子脂质化合物。本发明的阳离子脂质化合物可用于递送核酸分子、小分子化合物、多肽或蛋白质。相对于已知的阳离子脂质化合物,本发明的阳离子脂质化合物表现出较高的转染效率和较小的细胞毒性,提高了递送效率和安全性。
本发明提供一种阳离子脂质,其为式(I)化合物
或其N-氧化物、溶剂合物、药学上可接受的盐或立
体异构体,其中
G1为C1~8亚烷基,优选为未取代的C3~7亚烷基,更优选为未取代的C3亚烷基或者未取代的C5亚烷基或者未取代的C6亚烷基;
G2为C2~8亚烷基,优选为未取代的C3~7亚烷基,更优选为未取代的C3亚烷基或C5亚烷基或C6亚烷基;
R1为C6~25直链或支链烷基,优选为未取代的C11直链烷基或未取代的C12~24支链烷基,其中未取代的C12~24支链烷基优选为未取代的C18支链烷基或C15支链烷基或C24支链烷基或C17支链烷基;
R2为C12~25直链或支链烷基,优选为为未取代的C11直链烷基或未取代的C14~24支链烷基,其中未取代的C14~24支链烷基优选为未取代的C18支链烷基或C24支链烷基或C15支链烷基或C17支链烷基;
G3为:HO(CH2)2N(R3)CH2CH(OH)CH2-,其中R3为-CH3或-CH2CH3或-CH2CH2OH。
在一种实施方案中,G1为未取代的C3亚烷基,例如,-(CH2)3-。
在一种实施方案中,G1为未取代的C5亚烷基,例如,-(CH2)5-。
在一种实施方案中,G1为未取代的C6亚烷基,例如,-(CH2)6-。
在一种实施方案中,G2为未取代的C3亚烷基,例如,-(CH2)3-。
在一种实施方案中,G2为未取代的C5亚烷基,例如,-(CH2)5-。
在一种实施方案中,G2为未取代的C6亚烷基,例如,-(CH2)6-。
在一种实施方案中,G3为HO(CH2)2N(CH3)CH2CH(OH)CH2-。
在一种实施方案中,G3为HO(CH2)2N(CH2CH3)CH2CH(OH)CH2-。
在一种实施方案中,G3为(HO(CH2)2)2NCH2CH(OH)CH2-。
在一种实施方案中,R1为未取代的C11直链烷基,即-(CH2)10CH3。
在一种实施方案中,R1为未取代的C18支链烷基、C15支链烷基、C24支链烷基或C17支链烷基。例如,R1为:
在一种实施方案中,R2为未取代的C11直链烷基,即-(CH2)10CH3。
在一种实施方案中,R2为未取代的C18支链烷基、C24支链烷基、C15支链烷基或C17支链烷基。例如,R2为:
在一种实施方式中,G1为-(CH2)5-,G2为-(CH2)5-,G3为HO(CH2)2N(CH3)CH2CH(OH)CH2-,R1为:R2为:
在一种实施方式中,G1为-(CH2)5-,G2为-(CH2)3-,G3为HO(CH2)2N(CH2CH3)CH2CH(OH)CH2-,R1为-(CH2)10CH3,R2为:
在一种实施方式中,G1为-(CH2)5-,G2为-(CH2)5-,G3为HO(CH2)2N(CH2CH3)CH2CH(OH)CH2-,R1为:R2为:
在一种实施方式中,G1为-(CH2)6-,G2为-(CH2)6-,G3为(HO(CH2)2)2NCH2CH(OH)CH2-,R1为:R2为:
在一种实施方式中,G1为-(CH2)5-,G2为-(CH2)5-,G3为(HO(CH2)2)2NCH2CH(OH)CH2-,R1为:R2为:
在示例性的实施方案中,所述的化合物选自下面的化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体:
本发明的又一方面提供一种组合物,其包含载体,所述载体包括阳离子脂质,所述阳离子脂质包括上述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体。
在一种实施方案中,所述组合物为纳米颗粒制剂,所述纳米颗粒制剂的平均尺寸为10nm~300nm,优选为90nm~280nm;所述纳米颗粒制剂的多分散系数≤50%,优选≤45%,更优选优选≤40%。
阳离子脂质
在本发明的组合物/载体的一种实施方式中,所述阳离子脂质为选自上述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体中的一种或多种。在一种实施方案中,所述阳离子脂质为选自上述的式(I)化合物。例如,阳离子脂质为化合物YK-301、YK-302、YK-303、YK-304、YK-305、YK-306、YK-307、YK-308、YK-309、YK-310、YK-311、YK-312、YK-313、YK-314、YK-315、YK-316、YK-317、YK-318、YK-319、YK-320和YK-321。在一种优选实施方案中,所述阳离子脂质为化合物YK-305,在另一种优选实施方案中,所述阳离子脂质为化合物YK-310,在另一种优选实施方案中,所述阳离子脂质为化合物YK-312,在另一种优选实施方案中,所述阳离子脂质为化合物YK-319,在另一种优选实施方案中,所述阳离子脂质为化合物YK-318。
在本发明的组合物/载体的另一种实施方式中,所述阳离子脂质包括:(a)选自上述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体中的一种或多种;(b)一种或多种与(a)不同的其它可电离的脂质化合物。(b)阳离子脂质化合物可以是可商购的阳离子脂质,或者文献中报道的阳离子脂质化合物。例如,(b)阳离子脂质化合物可以是SM-102(WO2017049245A2中化合物25),还可以是WO2021055833中的化合物21和化合物23,还可以是HHMA(CN112979483B中化合物1)。
在一种实施方案中,所述阳离子脂质占载体的摩尔比为25%~75%,例如30%、40%、49%、55%、60%、65%、70%。
该载体可用于递送活性成分例如治疗剂或预防剂。活性成分可包封在载体内或者与载体结合。
例如,所述治疗剂或预防剂包括核酸分子、小分子化合物、多肽或蛋白质
中的一种或多种。所述核酸包括但不限于单链DNA、双链DNA和RNA。适宜的RNA包括但不限于小干扰RNA(siRNA)、不对称干扰RNA(aiRNA)、微RNA(miRNA)、Dicer-底物RNA(dsRNA)、小发夹RNA(shRNA)、信使RNA(mRNA)以及其混合物。
中性脂质
载体可包含中性脂质。中性脂质在本发明中是指在选定的pH值不带电荷或者以两性离子形式存在的起辅助作用的脂质。该中性脂质可能通过促进脂质相变来调节纳米颗粒流动性成脂质双层结构并提高效率,同时还可能影响靶器官的特异性。
在一种实施方案中,所述阳离子脂质与所述中性脂质的摩尔比为约1:1~15:1,例如约14:1、13:1、12:1、11:1、10:1、9:1、8:1、7:1、6:1、5:1、4:1、3:1和2:1。在一种优选的实施方案中,所述阳离子脂质与所述中性脂质的摩尔比为约4.5:1。在另一种优选的实施方案中,所述阳离子脂质与所述中性脂质的摩尔比为约4.9:1
例如,中性脂质可包括磷脂酰胆碱、磷脂酰乙醇胺、鞘磷脂、神经酰胺、甾醇及其衍生物中的一种或多种。
包含阳离子脂质的组合物的载体组分可以包括一种或多种中性脂质-磷脂,如一种或多种(多)不饱和脂质。磷脂可以组装成一个或多个脂质双层。一般来说,磷脂可以包括磷脂部分和一个或多个脂肪酸部分。
中性脂质部分可以选自由以下组成的非限制性组:磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰甘油、磷脂酰丝氨酸、磷脂酸、2-溶血磷脂酰胆碱和鞘磷脂。脂肪酸部分可以选自由以下组成的非限制性组:月桂酸、肉豆蔻酸、肉豆蔻烯酸、棕榈酸、棕榈油酸、硬脂酸、油酸、亚油酸、α-亚麻酸、芥酸、植烷酸、花生酸、花生四烯酸、二十碳五烯酸、山萮酸、二十二碳五烯酸和二十二碳六烯酸。还涵盖包括带有修饰和取代的天然物种的非天然物种,所述修饰和取代包括分支、氧化、环化和炔烃。例如,磷脂可以用一种或多种炔烃(例如一个或多个双键被三键置换的烯基)官能化或与该一种或多种炔烃交联。在适当反应条件下,炔基在暴露于叠氮化物时可能经历铜催化的环加成反应。这些反应可用于使组合物的脂质双层官能化以促进膜渗透或细胞识别,或将组合物与有用组
分如靶向或成像部分(例如染料)偶联。
可用于这些组合物中的中性脂质可以选自由以下组成的非限制性组:1,2-二亚油酰基-sn-甘油-3-磷酸胆碱(DLPC)、1,2-二肉豆蔻酰基-sn-甘油-磷酸胆碱(DMPC)、1,2-二油酰基-sn-甘油-3-磷酸胆碱(DOPC)、1,2-二棕榈酰基-sn-甘油-3-磷酸胆碱(DPPC)、1,2-二硬脂酰基-sn-甘油-3-磷酸胆碱(DSPC)、1,2-双十一烷酰基-sn-甘油-磷酸胆碱(DUPC)、1-棕榈酰基-2-油酰基-sn-甘油-3-磷酸胆碱(POPC)、1,2-二-O-十八碳烯基-sn-甘油-3-磷酸胆碱(18:0Diether PC)、1-油酰基-2-胆固醇基半琥珀酰基-sn-甘油-3-磷酸胆碱(OChemsPC)、1-十六烷基-sn-甘油-3-磷酸胆碱(C16Lyso PC)、1,2-二亚麻酰基-sn-甘油-3-磷酸胆碱、1,2-二花生四烯酰基-sn-甘油-3-磷酸胆碱、1,2-双二十二碳六烯酰基-sn-甘油-3-磷酸胆碱、1,2-二油酰基-sn-甘油-3-磷酸乙醇胺(DOPE)、1,2-二植烷酰基-sn-甘油-3-磷酸乙醇胺(ME 16.0PE)、1,2-二硬脂酰基-sn-甘油-3-磷酸乙醇胺、1,2-二亚油酰基-sn-甘油-3-磷酸乙醇胺、1,2-二亚麻酰基-sn-甘油-3-磷酸乙醇胺、1,2-二花生四烯酰基-sn-甘油-3-磷酸乙醇胺、1,2-双二十二碳六烯酰基-sn-甘油-3-磷酸乙醇胺、1,2-二油酰基-sn-甘油-3-磷酸-rac-(1-甘油)钠盐(DOPG)、二棕榈酰基磷脂酰甘油(DPPG)、棕榈酰基油酰基磷脂酰乙醇胺(POPE)、二硬脂酰基-磷脂酰-乙醇胺(DSPE)、二棕榈酰基磷脂酰乙醇胺(DPPE)、二肉豆蔻酰基磷酸乙醇胺(DMPE)、1-硬脂酰基-2-油酰基-硬脂酰乙醇胺(SOPE)、1-硬脂酰基-2-油酰基-磷脂酰胆碱(SOPC)、鞘磷脂、磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰丝氨酸、磷脂酰肌醇、磷脂酸、棕榈酰基油酰基磷脂酰胆碱、溶血磷脂酰胆碱、溶血磷脂酰乙醇胺(LPE)以及其混合物。
在一些实施方案中,中性脂质包括DSPC。在某些实施方案中,中性脂质包括DOPE。在一些实施方案中,中性脂质包括DSPC和DOPE两种。
结构性脂质
包含阳离子脂质的组合物的载体还可以包括一种或多种结构性脂质。结构性脂质在本发明中是指通过填充脂质之间的间隙来增强纳米颗粒的稳定性的脂质。
在一种实施方案中,所述阳离子脂质与所述结构性脂质的摩尔比为约0.6:1~3:1,例如,约1.0:1、1.1:1、1.2:1、1.3:1、1.4:1、1.5:1、1.6:1、1.7:1、
1.8:1、1.9:1、2.0:1。
结构性脂质可以选自但不限于由以下组成的组:胆固醇、非甾醇、谷固醇、麦角固醇、菜油甾醇、豆甾醇、芸苔甾醇、番茄碱、番茄碱、熊果酸、α-生育酚、皮质类固醇以及其混合物。在一些实施方案中,结构性脂质是胆固醇。在一些实施方案中,结构性脂质包括胆固醇和皮质类固醇(如泼尼松龙(prednisolone)、地塞米松、泼尼松(prednisone)和氢化可的松(hydrocortisone))或其组合。
聚合物共轭脂质
包含阳离子脂质的组合物的载体还可以包括一种或多种聚合物共轭脂质。聚合物共轭脂质主要是指聚乙二醇(PEG)修饰的脂质。亲水性PEG稳定LNP,通过限制脂质融合来调节纳米颗粒大小,并通过减少与巨噬细胞的非特异性相互作用来增加纳米颗粒的半衰期。
在一种实施方案中,所述聚合物共轭脂质选自以下中的一种或多种:PEG修饰的磷脂酰乙醇胺、PEG修饰的磷脂酸、PEG修饰的神经酰胺、PEG修饰的二烷基胺、PEG修饰的二酰基甘油、PEG修饰的二烷基甘油。PEG修饰的PEG分子量通常为350-5000Da。
例如,所述聚合物共轭脂质选自以下中的一种或多种:二硬脂酰基磷脂酰乙醇胺聚乙二醇2000(DSPE-PEG2000),二肉豆蔻酰甘油-3-甲氧基聚乙二醇2000(DMG-PEG2000)和甲氧基聚乙二醇双十四烷基乙酰胺(ALC-0159)。
在本发明的组合物/载体的一种实施方案中,所述聚合物共轭脂质是DMG-PEG2000。
在本发明的组合物/载体的一种实施方案中,载体包括中性脂质、结构脂质以及聚合物共轭脂质,所述阳离子脂质、所述中性脂质、所述结构脂质、以及所述聚合物共轭脂质的摩尔比为(25~75):(5~25):(15~65):(0.5~10),例如(35~49):(7.5~15):(35~55):(1~5)。
在本发明的组合物/载体的一种实施方案中,载体包括中性脂质、结构脂质以及聚合物共轭脂质,所述阳离子脂质、所述中性脂质、所述结构脂质、以及所述聚合物共轭脂质的摩尔比为49:10:39.5:1.5或45:10:43.5:1.5或35:10:53.5:1.5。
治疗剂和/或预防剂
组合物可以包括一种或多种治疗剂和/或预防剂。在一种实施方案中,载体与所述治疗剂或预防剂的质量比为10:1~30:1,例如12:1、13:1、14:1、15:1、16:1、17:1、18:1、19:1、20:1、21:1、22:1、23:1、24:1、25:1。
在一种实施方案中,载体与所述治疗剂或预防剂的质量比为12.5:1~20:1,优选为15:1。
所述治疗剂或预防剂包括但不限于核酸分子、小分子化合物、多肽或蛋白质中的一种或多种。
例如,所述治疗剂或预防剂是能够引起免疫响应的疫苗或化合物。
本发明的载体可将治疗剂和/或预防剂递送至哺乳动物细胞或器官,因此本发明还提供治疗有需要哺乳动物的疾病或病症的方法,这些方法包括向哺乳动物施用包括治疗剂和/或预防剂的组合物和/或使哺乳动物细胞与该组合物接触。
治疗剂和/或预防剂包括生物活性物质并且替代地称为“活性剂”。治疗剂和/或预防剂可以是在递送至细胞或器官后在该细胞或器官中或者其它身体组织或系统中引起所希望的变化的物质。此类物种可用于治疗一种或多种疾病、病症或病况。在一些实施方案中,治疗剂和/或预防剂是可用于治疗特定疾病、病症或病况的小分子药物。可用于组合物的药物的实例包括但不限于抗赘生剂(例如长春新碱(vincristine)、多柔比星(doxorubicin)、米托蒽醌(mitoxantrone)、喜树碱(camptothecin)、顺铂(cisplatin)、博莱霉素(bleomycin)、环磷酰胺(cyclophosphamide)、甲氨蝶呤和链脲佐菌素(streptozotocin))、抗肿瘤剂(例如放线菌素D(actinomycin D)、长春新碱、长春碱(vinblastine)、胞嘧啶阿拉伯糖苷(cytosine arabinoside)、蒽环霉素(anthracycline)、烷化剂、铂类化合物、抗代谢物以及核苷类似物,如甲氨蝶呤以及嘌呤和嘧啶类似物)、抗感染剂、局部麻醉剂(例如地布卡因(dibucaine)和氯丙嗪(chlorpromazine))、β-肾上腺素能阻断剂(例如普萘洛尔(propranolol)、第莫洛(timolol)和拉贝洛尔(labetalol))、抗高血压剂(例如可乐定(clonidine)和肼酞嗪(hydralazine))、抗抑郁剂(例如丙咪嗪(imipramine)、阿米替林(amitriptyline)和多虑平(doxepin))、抗痉挛剂(例如苯妥英(phenytoin))、抗组胺(例如苯海拉明(diphenhydramine)、氯苯那敏(chlorpheniramine)和异丙嗪(promethazine))、抗生素/抗细菌剂(例如庆大霉素(gentamycin)、环丙沙星(ciprofloxacin)和头孢西丁(cefoxitin))、抗真菌剂(例如咪康唑(miconazole)、特康
唑(terconazole)、益康唑(econazole)、异康唑(isoconazole)、布康唑(butaconazole)、克霉唑(clotrimazole)、伊曲康唑(itraconazole)、制霉菌素(nystatin)、奈替芬(naftifine)和两性霉素B(amphotericin B))、抗寄生虫剂、激素、激素拮抗剂、免疫调节剂、神经递质拮抗剂、抗青光眼药、维生素、镇静剂以及成像剂。
在一些实施方案中,治疗剂和/或预防剂是细胞毒素、放射性离子、化学治疗剂、疫苗、引起免疫响应的化合物和/或另一治疗剂和/或预防剂。细胞毒素或细胞毒性剂包括对细胞有害的任何试剂。实例包括但不限于紫杉酚(taxol)、细胞松弛素B(cytochalasin B)、短杆菌肽D(gramicidin D)、溴化乙锭(ethidium bromide)、依米丁(emetine)、丝裂霉素(mitomycin)、依托泊苷(etoposide)、替尼泊苷(teniposide)、长春新碱、长春碱、秋水仙碱(colchicine)、多柔比星、柔红霉素(daunorubicin)、二羟基蒽二酮(dihydroxy anthracin dione)、米托蒽醌、光辉霉素(mithramycin)、放线菌素D、1-去氢睾酮、糖皮质激素、普鲁卡因(procaine)、丁卡因(tetracaine)、利多卡因(lidocaine)、普萘洛尔、嘌呤霉素、类美登素(maytansinoid)如美登醇(maytansinol)、拉奇霉素(rachelmycin)(CC-1065),以及其类似物或同系物。放射性离子包括但不限于碘(例如碘125或碘131)、锶89、磷、钯、铯、铱、磷酸根、钴、钇90、钐153和镨。疫苗包括能够提供针对与感染性疾病如流感、麻疹、人乳头瘤病毒(HPV)、狂犬病、脑膜炎、百日咳、破伤风、瘟疫、肝炎和肺结核相关的一种或多种病况的免疫性的化合物和制剂并且可以包括编码感染性疾病源性抗原和/或表位的mRNA。疫苗还可以包括引导针对癌细胞的免疫响应的化合物和制剂并且可以包括编码肿瘤细胞源性抗原、表位和/或新表位的mRNA。引起免疫响应的化合物可以包括疫苗、皮质类固醇(例如地塞米松)和其它物种。在一些实施方案中,通过包括根据式(I)、(IA)、(IB)、(II)、(IIa)、(IIb)、(IIc)、(IId)、(IIe)、(IIf)、(IIg)或(III)的化合物(例如化合物3、18、20、25、26、29、30、60、108-112或122)的组合物肌肉内施用能够引起免疫响应的疫苗和/或化合物。其它治疗剂和/或预防剂包括但不限于抗代谢物(例如甲氨蝶呤、6-巯基嘌呤、6-硫鸟嘌呤、阿糖胞苷和5-氟尿嘧啶达卡巴嗪(dacarbazine))、烷化剂(例如氮芥(mechlorethamine)、噻替哌(thiotepa)、苯丁酸氮芥(chlorambucil)、拉奇霉素(CC-1065)、美法兰(melphalan)、卡莫司汀(carmustine,BSNU)、罗莫司丁(lomustine,CCNU)、环磷酰胺、白消安
(busulfan)、二溴甘露醇、链脲佐菌素、丝裂霉素C和顺二氯二胺络铂(II)(DDP)、顺铂)、蒽环霉素(例如柔红霉素(以前称为道诺霉素(daunomycin))和多柔比星)、抗生素(例如更生霉素(dactinomycin)(以前称为放线菌素)、博莱霉素、光辉霉素(mithramycin)和安曲霉素(anthramycin,AMC))以及抗有丝分裂剂(例如长春新碱、长春碱、紫杉酚和类美登素)。
在其它实施方案中,治疗剂和/或预防剂是蛋白质。可用于本发明中的纳米粒子中的治疗性蛋白质包括但不限于庆大霉素、阿米卡星(amikacin)、胰岛素、促红细胞生成素(EPO)、粒细胞集落刺激因子(G-CSF)、粒细胞-巨噬细胞集落刺激因子(GM-CSF)、因子VIR、黄体激素释放激素(LHRH)类似物、干扰素、肝素、乙型肝炎表面抗原、伤寒疫苗和霍乱疫苗。
在一些实施方案中,治疗剂是多核苷酸或核酸(例如核糖核酸或脱氧核糖核酸)。术语“多核苷酸”的最广泛含义包括呈寡核苷酸链或可以并入寡核苷酸链中的任何化合物和/或物质。根据本发明使用的示例性多核苷酸包括但不限于以下一种或多种:脱氧核糖核酸(DNA);核糖核酸(RNA),包括信使mRNA(mRNA)、其杂交体;RNAi诱导因子;RNAi因子;siRNA;shRNA;miRNA;反义RNA;核糖酶;催化性DNA;诱导三股螺旋形成的RNA;适体等。在一些实施方案中,治疗剂和/或预防剂是RNA。可用于本文所描述的组合物和方法中的RNA可以选自由但不限于以下组成的组:shortmer、antagomir、反义RNA、核糖酶、小干扰RNA(siRNA)、不对称干扰RNA(aiRNA)、微RNA(miRNA)、Dicer-底物RNA(dsRNA)、小发夹RNA(shRNA)、转运RNA(tRNA)、信使RNA(mRNA)及其混合物。在某些实施方案中,RNA是mRNA。
在某些实施方案中,治疗剂和/或预防剂是mRNA。mRNA可以编码任何所关注多肽,包括任何天然或非天然存在或以其它方式修饰的多肽。由mRNA编码的多肽可以具有任何大小并且可以具有任何二级结构或活性。在一些实施方案中,由mRNA编码的多肽当在细胞中表达时可以具有治疗作用。
在其它实施方案中,治疗剂和/或预防剂是siRNA。siRNA能够选择性降低所关注基因的表达或下调该基因的表达。例如,siRNA的选择可以使得在将包括该siRNA的组合物施用给有需要受试者后使与特定疾病、病症或病况有关的基因沉默。siRNA可以包含与编码所关注基因或蛋白质的mRNA序列互补的序列。在
一些实施方案中,siRNA可以是免疫调节性siRNA。
在某些实施方案中,治疗剂和/或预防剂是sgRNA和/或cas9mRNA。sgRNA和/或cas9mRNA可以用作基因编辑工具。例如,sgRNA-cas9复合物可以影响细胞基因的mRNA翻译。
在一些实施方案中,治疗剂和/或预防剂是shRNA或者其编码载体或质粒。shRNA可以在将适当构建体递送至核中后在目标细胞内部产生。与shRNA相关的构建体和机制是相关领域中众所周知的。
疾病或病症
本发明的组合物/载体可以向受试者或患者递送治疗剂或预防剂。所述治疗剂或预防剂包括但不限于核酸分子、小分子化合物、多肽或蛋白质中的一种或多种。因此,本发明的组合物可用于制备核酸药物、基因疫苗、小分子药物、多肽或蛋白质药物。由于上述治疗剂或预防剂的种类广泛,本发明的组合物可用于治疗或预防多种疾病或病症。
在一种实施方案中,所述疾病或病症以功能失常或异常的蛋白质或多肽活性为特征。
例如,所述疾病或病症选自由以下组成的组:感染性疾病、癌症和增生性疾病、遗传性疾病、自体免疫性疾病、糖尿病、神经退化性疾病、心血管和肾血管疾病以及代谢性疾病。
在一种实施方案中,所述感染性疾病选自由冠状病毒,流感病毒,或HIV病毒引起的疾病、小儿肺炎,裂谷热,黄热病,狂犬病,多种疱疹。
其它组分
组合物可以包括一种或多种除前述部分中所描述的那些外的组分。例如,组合物可以包括一个或多个疏水性小分子,如维生素(例如维生素A或维生素E)或固醇。
组合物还可以包括一个或多个渗透性增强分子、碳水化合物、聚合物、表面改变剂或其它组分。渗透性增强分子可以是例如美国专利申请公布第2005/0222064号所描述的分子。碳水化合物可以包括简单糖(例如葡萄糖)和多糖(例如糖原以及其衍生物和类似物)。
表面改变剂可以包括但不限于阴离子性蛋白质(例如牛血清白蛋白)、表面活性剂(例如阳离子性表面活性剂,如二甲基双十八烷基溴化铵)、糖或糖衍生物(例如环糊精)、核酸、聚合物(例如肝素、聚乙二醇和泊洛沙姆)、粘液溶解剂(例如乙酰半胱氨酸、艾蒿、菠萝蛋白酶(bromelain)、木瓜蛋白酶、大青(clerodendrum)、溴己新(bromhexine)、羧甲司坦(carbocisteine)、依普拉酮(eprazinone)、美司钠(mesna)、氨溴索(ambroxol)、索布瑞醇(sobrerol)、多米奥醇(domiodol)、来托司坦(letosteine)、司替罗宁(stepronin)、硫普罗宁(tiopronin)、凝溶胶蛋白(gelsolin)、胸腺肽(thymosin)β4、链球菌DNA酶α(dornase alfa)、奈替克新(neltenexine)和厄多司坦(erdosteine))和DNA酶(例如rhDNA酶)。表面改变剂可以被安置在组合物的纳米粒子内和/或表面上(例如通过涂布、吸附、共价连接或其它方法)。
组合物还可以包含一种或多种官能化脂质。例如,脂质可以用炔基官能化,该炔基当在适当反应条件下暴露于叠氮化物时可能经历环加成反应。确切地说,脂质双层可以通过这一方式,用一个或多个可有效地促进膜渗透、细胞识别或成像的基团官能化。组合物的表面还可以与一种或多种有用抗体偶联。可用于靶向细胞递送、成像和膜渗透的官能团和偶联物是本领域中众所周知的。
除这些组分外,组合物可以包括可用于药物组合物中的任何物质。例如,组合物可以包括一种或多种药学上可接受的赋形剂或辅助成分,如但不限于一种或多种溶剂、分散介质、稀释剂、分散助剂、悬浮助剂、造粒助剂、崩解剂、填充剂、助流剂、液体媒剂、粘合剂、表面活性剂、等渗剂、增稠剂或乳化剂、缓冲剂、润滑剂、油、防腐剂、调味剂、着色剂等。赋形剂例如淀粉、乳糖或糊精。药学上可接受的赋形剂是本领域中众所周知的(参见例如Remington’s The Science and Practice of Pharmacy,第21版,A.R.Gennaro;Lippincott,Williams&Wilkins,Baltimore,MD,2006)。
稀释剂的实例可以包括但不限于碳酸钙、碳酸钠、磷酸钙、磷酸二钙、硫酸钙、磷酸氢钙、磷酸钠、乳糖、蔗糖、纤维素、微晶纤维素、高岭土、甘露糖醇、山梨糖醇、肌醇、氯化钠、干淀粉、玉米淀粉、粉末状糖和/或其组合。
在一些实施方案中,包括一种或多种本文所述的脂质的组合物还可以包括一种或多种佐剂,例如吡喃葡萄糖基脂质佐剂(GLA)、CpG寡聚脱氧核糖核苷酸
(例如A类或B类)、多聚(I:C)、氢氧化铝和Pam3CSK4。
本发明的组合物可以制成固体、半固体、液体或气体的形式的制剂,例如片剂、胶囊剂、软膏剂、酏剂、糖浆、溶液、乳液、悬浮液、注射剂、气溶胶。本发明的组合物可以通过制药领域熟知的方法来制备。例如,无菌注射溶液可通过将所需量的治疗剂或预防剂与所需的上述各种其它成分掺入适当的溶剂例如无菌蒸馏水中,然后过滤灭菌来制备。还可以加入表面活性剂以促进形成均匀的溶液或悬浮液。
例如,本发明的组合物可以经静脉内、肌肉内、皮内、皮下、鼻内或通过吸入施用。在一种实施方案中,所述组合物是皮下施用的。
本发明的组合物以治疗有效量给药,所述量不仅可以随所选择的特定试剂而变化,还可以随给药途径,所治疗疾病的性质以及患者的年龄和状况而变化,并且最终可以由主治医师或临床医生自行决定。例如,可将约0.001mg/kg至约10mg/kg剂量的所述治疗剂或预防剂施用给哺乳动物(例如人)。
本发明包括但不限于以下实施方案:
1.一种式(I)化合物
或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体,其中
G1为C1~8亚烷基;
G2为C2~8亚烷基;
R1为C6~25直链或支链烷基;
R2为C12~25直链或支链烷基;
G3为:HO(CH2)2N(R3)CH2CH(OH)CH2-,其中R3为-CH3或-CH2CH3或-CH2CH2OH。
2.根据实施方案1所述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体,其中G1为未取代的C3~7亚烷基。
3.根据实施方案1或2所述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体,其中G1为未取代的C3亚烷基或C5亚烷基或C6亚
烷基。
4.根据前述实施方案中任一项所述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体,其中G2为未取代的C3~7亚烷基。
5.根据前述实施方案中任一项所述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体,其中G2为未取代的C3亚烷基或C5亚烷基或C6亚烷基。
6.根据前述实施方案中任一项所述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体,其中R1为未取代的C11直链烷基或未取代的C12~24支链烷基。
7.根据实施方案6所述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体,其中R1为未取代的C18支链烷基或C15支链烷基或C24支链烷基或C17支链烷基。
8.根据实施方案7所述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体,其中R1为:
9.根据前述实施方案中任一项所述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体,其中R2为未取代的C11直链烷基或未取代的C14~24支链烷基。
10.根据实施方案9所述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体,其中R2为未取代的C18支链烷基或C24支链烷基或C15支链烷基或C17支链烷基。
11.根据实施方案10所述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体,其中R2为:
12.根据前述实施方案中任一项所述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体,其中所述式(I)化合物具有以下结构中的一种:
13.根据前述实施方案中任一项所述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体,其中所述式(I)化合物是具有以下结构的化合物YK-305:
14.根据实施方案1-12中任一项所述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体,其中所述式(I)化合物是具有以下结构的化合物YK-310:
15.根据实施方案1-12中任一项所述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体,其中所述式(I)化合物是具有以下结构的
化合物YK-312:
16.根据实施方案1-12中任一项所述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体,其中所述式(I)化合物是具有以下结构的化合物YK-319:
17.根据实施方案1-12中任一项所述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体,其中所述式(I)化合物是具有以下结构的化合物YK-318:
18.一种组合物,其包含载体,所述载体包括阳离子脂质,所述阳离子脂质包括根据前述实施方案中任一项所述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体。
19.根据实施方案18所述的组合物,其中所述阳离子脂质占载体的摩尔比为25%~75%。
20.根据实施方案18-19中任一项所述的组合物,其中所述载体还包含中性
脂质。
21.根据实施方案20所述的组合物,其中所述阳离子脂质与所述中性脂质的摩尔比为1:1~15:1,优选为4.5:1。
22.根据实施方案20-21中任一项所述的组合物,其中所述中性脂质包括磷脂酰胆碱、磷脂酰乙醇胺、鞘磷脂、神经酰胺、甾醇及其衍生物中的一种或多种。
23.根据实施方案20-22中任一项所述的组合物,其中所述中性脂质选自以下中的一种或多种:1,2-二亚油酰基-sn-甘油-3-磷酸胆碱(DLPC)、1,2-二肉豆蔻酰基-sn-甘油-磷酸胆碱(DMPC)、1,2-二油酰基-sn-甘油-3-磷酸胆碱(DOPC)、1,2-二棕榈酰基-sn-甘油-3-磷酸胆碱(DPPC)、1,2-二硬脂酰基-sn-甘油-3-磷酸胆碱(DSPC)、1,2-双十一烷酰基-sn-甘油-磷酸胆碱(DUPC)、1-棕榈酰基-2-油酰基-sn-甘油-3-磷酸胆碱(POPC)、1,2-二-O-十八碳烯基-sn-甘油-3-磷酸胆碱(18:0Diether PC)、1-油酰基-2-胆固醇基半琥珀酰基-sn-甘油-3-磷酸胆碱(OChemsPC)、1-十六烷基-sn-甘油-3-磷酸胆碱(C16Lyso PC)、1,2-二亚麻酰基-sn-甘油-3-磷酸胆碱、1,2-二花生四烯酰基-sn-甘油-3-磷酸胆碱、1,2-双二十二碳六烯酰基-sn-甘油-3-磷酸胆碱、1,2-二油酰基-sn-甘油-3-磷酸乙醇胺(DOPE)、1,2-二植烷酰基-sn-甘油-3-磷酸乙醇胺(ME 16.0PE)、1,2-二硬脂酰基-sn-甘油-3-磷酸乙醇胺、1,2-二亚油酰基-sn-甘油-3-磷酸乙醇胺、1,2-二亚麻酰基-sn-甘油-3-磷酸乙醇胺、1,2-二花生四烯酰基-sn-甘油-3-磷酸乙醇胺、1,2-双二十二碳六烯酰基-sn-甘油-3-磷酸乙醇胺、1,2-二油酰基-sn-甘油-3-磷酸-rac-(1-甘油)钠盐(DOPG)、二棕榈酰基磷脂酰甘油(DPPG)、棕榈酰基油酰基磷脂酰乙醇胺(POPE)、二硬脂酰基-磷脂酰-乙醇胺(DSPE)、二棕榈酰基磷脂酰乙醇胺(DPPE)、二肉豆蔻酰基磷酸乙醇胺(DMPE)、1-硬脂酰基-2-油酰基-硬脂酰乙醇胺(SOPE)、1-硬脂酰基-2-油酰基-磷脂酰胆碱(SOPC)、鞘磷脂、磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰丝氨酸、磷脂酰肌醇、磷脂酸、棕榈酰基油酰基磷脂酰胆碱、溶血磷脂酰胆碱、溶血磷脂酰乙醇胺(LPE)以及其混合物。
24.根据实施方案23所述的组合物,其中所述中性脂质是DOPE和/或DSPC。
25.根据实施方案18-24中任一项所述的组合物,其中所述载体还包含结构性脂质。
26.根据实施方案25所述的组合物,其中所述阳离子脂质与所述结构性脂质的摩尔比为0.6:1~3:1。
27.根据实施方案25-26中任一项所述的组合物,其中所述结构性脂质选自以下中的一种或多种:胆固醇、非甾醇、谷固醇、麦角固醇、菜油甾醇、豆甾醇、芸苔甾醇、番茄碱、番茄碱、熊果酸、α-生育酚、皮质类固醇。
28.根据实施方案27所述的组合物,其中所述结构性脂质是胆固醇。
29.根据实施方案18-28中任一项所述的组合物,其中所述载体还包含括聚合物共轭脂质。
30.根据实施方案29所述的组合物,其中所述聚合物共轭脂质占载体的摩尔比为0.5%~10%,优选为1.5%。
31.根据实施方案29-30中任一项所述的组合物,其中所述聚合物共轭脂质选自以下中的一种或多种:PEG修饰的磷脂酰乙醇胺、PEG修饰的磷脂酸、PEG修饰的神经酰胺、PEG修饰的二烷基胺、PEG修饰的二酰基甘油、PEG修饰的二烷基甘油。
32.根据实施方案31所述的组合物,其中所述聚合物共轭脂质选自以下中的一种或多种:二硬脂酰基磷脂酰乙醇胺聚乙二醇2000(DSPE-PEG2000),二肉豆蔻酰甘油-3-甲氧基聚乙二醇2000(DMG-PEG2000)和甲氧基聚乙二醇双十四烷基乙酰胺(ALC-0159)。
33.根据实施方案18-32中任一项所述的组合物,其中所述载体包括中性脂质、结构脂质以及聚合物共轭脂质,所述阳离子脂质、所述中性脂质、所述结构脂质、以及所述聚合物共轭脂质的摩尔比为(25~75):(5~25):(15~65):(0.5~10)。
34.根据实施方案33所述的组合物,其中所述阳离子脂质、所述中性脂质、所述结构脂质、以及所述聚合物共轭脂质的摩尔比为(35~49):(7.5~15):(35~55):(1~5)。
35.根据实施方案34所述的组合物,其中所述阳离子脂质、所述中性脂质、所述结构脂质、以及所述聚合物共轭脂质的摩尔比为45:10:43.5:1.5。
36.根据实施方案18-35中任一项所述的组合物,其中所述组合物为纳米颗粒制剂,所述纳米颗粒制剂的平均粒径为10nm~300nm;所述纳米颗粒制剂的多分散系数≤50%。
37.根据实施方案36所述的组合物,其中所述组合物为纳米颗粒制剂,所
述纳米颗粒制剂的平均粒径为90nm~280nm;所述纳米颗粒制剂的多分散系数≤45%。
38.根据实施方案18-37中任一项所述的组合物,其中所述阳离子脂质还包括一种或多种其它可电离的脂质化合物。
39.根据实施方案18-38中任一项所述的组合物,其还包含治疗剂或预防剂。
40.根据实施方案39所述的组合物,其中所述载体与所述治疗剂或预防剂的质量比为10:1~30:1。
41.根据实施方案40所述的组合物,其中所述载体与所述治疗剂或预防剂的质量比为12.5:1~20:1。
42.根据实施方案41所述的组合物,其中所述载体与所述治疗剂或预防剂的质量比为15:1。
43.根据实施方案39-42中任一项所述的组合物,其中所述治疗剂或预防剂包括核酸分子、小分子化合物、多肽或蛋白质中的一种或多种。
44.根据实施方案39-42中任一项所述的组合物,其中所述治疗剂或预防剂是能够引起免疫响应的疫苗或化合物。
45.根据前述实施方案39-44中任一项所述的组合物,其中所述治疗剂或预防剂是核酸。
46.根据实施方案45所述的组合物,其中所述治疗剂或预防剂是核糖核酸(RNA)。
47.根据实施方案45所述的组合物,其中所述治疗剂或预防剂是脱氧核糖核酸(DNA)。
48.根据实施方案46所述的组合物,其中所述RNA选自由以下组成的组:小干扰RNA(siRNA)、不对称干扰RNA(aiRNA)、微RNA(miRNA)、Dicer-底物RNA(dsRNA)、小发夹RNA(shRNA)、信使RNA(mRNA)以及其混合物。
49.根据实施方案48所述的组合物,其中所述RNA是mRNA。
50.根据实施方案18-49中任一项所述的组合物,其中所述组合物还包括药物可用的赋形剂或稀释剂中的一种或多种。
51.根据前述实施方案1-17中任一项所述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体或者如前述实施方案18-50中任一项所
述的组合物在制备核酸药物、基因疫苗、小分子药物、多肽或蛋白质药物中的用途。
52.一种如前述实施方案1-17中任一项所述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体或者前述实施方案18-50中任一项所述的组合物在制备用于治疗有需要哺乳动物的疾病或病症的药物中的用途。
53.根据实施方案52所述的用途,其中所述疾病或病症以功能失常或异常的蛋白质或多肽活性为特征。
54.根据实施方案52-53中任一项所述的用途,其中所述疾病或病症选自由以下组成的组:感染性疾病、癌症和增生性疾病、遗传性疾病、自体免疫性疾病、糖尿病、神经退化性疾病、心血管和肾血管疾病以及代谢性疾病。
55.根据实施方案54所述的用途,其中所述感染性疾病选自:由冠状病毒、流感病毒或HIV病毒引起的疾病,小儿肺炎,裂谷热,黄热病,狂犬病,或多种疱疹。
56.根据实施方案52-55中任一项所述的用途,其中所述哺乳动物是人。
57.根据实施方案51-56中任一项所述的用途,其中所述组合物经静脉内、肌肉内、皮内、皮下、鼻内或通过吸入施用。
58.根据实施方案57所述的用途,其中所述组合物是皮下施用的。
59.根据实施方案51-58中任一项所述的用途,其中将约0.001mg/kg至约10mg/kg剂量的所述治疗剂或预防剂施用给所述哺乳动物。
实施例
下面结合实施例对本发明作进一步描述。但本发明并不限于以下实施例。实施例中采用的实施条件可以根据具体使用的不同要求做进一步调整,未注明的实施条件为本行业中的常规条件。本发明中具体实施例中,所使用的原料均可通过市售获得。除非另有说明,上下文中百分比为重量百分比,所有的温度以摄氏度给出。本发明各个实施方式中所涉及到的技术特征只要彼此之间未构成冲突就可以相互组合。
实施例1:阳离子脂质化合物的合成
1.YK-301和YK-305的合成
合成路线如下:
步骤一:(S)-(3-氯-2-羟丙基)氨基甲酸叔丁酯(YK-301-PM1)的合成
将(S)-1-氨基-3-氯丙烷-2-醇(5.0g,45.6mmol)与三乙胺(5.1g,50.4mmol)溶于二氯甲烷(50mL)中,将碳酸酐二叔丁酯(10.9g,49.9mmol)溶于二氯甲烷
(20mL),缓慢滴入上述溶液中,室温下搅拌反应5小时。反应完毕后向反应液中加入100mL水,再加入二氯甲烷(200mL×2)萃取,合并有机相后再用盐水(50mL×3)洗涤,无水硫酸钠干燥,过滤,滤液经真空减压浓缩。将残余物通过硅胶色谱法(乙酸乙酯/正己烷)纯化,得YK-301-PM1(7.0g,33.4mmol,73.2%)。C8H16ClNO3,MS(ES):m/z(M+H+)210.1。
步骤二:(S)-2-羟基-3-(((2-羟乙基)(甲基)氨基)丙基)氨基甲酸叔丁酯(YK-301-PM2)的合成
将YK-301-PM1(300mg,1.43mmol)与2-(甲氨基)乙醇(108mg,1.44mmol)溶于乙腈(3mL)中,向上述体系加入碳酸钾(594mg,4.30mmol)和碘化钾(48mg,0.29mmol),加热至70℃搅拌反应5小时。反应完毕后将反应混合物过滤,滤液经真空减压浓缩,将残余物通过硅胶色谱法(甲醇/二氯甲烷)纯化,得YK-301-PM2(350mg,1.41mmol,98.6%)。C11H24N2O4,MS(ES):m/z(M+H+)249.2。
步骤三:(S)-1-氨基-3-((2-羟乙基)(甲基)氨基)丙烷-2-醇(YK-301-PM3)的合成
将上述制备所得YK-301-PM2(350mg,1.41mmol)加入4M盐酸/1,4-二氧六环(2mL)中,室温搅拌反应10小时。反应完毕浓缩,加入100mL二氯甲烷和100mL饱和碳酸氢钠水溶液,搅拌后分液,再加入二氯甲烷(100mL×2)萃取,合并有机相后再用盐水(50mL×2)洗涤,无水硫酸钠干燥,过滤。将滤液经真空减压浓缩得YK-301-PM3(200mg,1.35mmol,95.7%)。C6H16N2O2,MS(ES):m/z(M+H+)149.1。
步骤四:(S)-6-(2-羟基-3-((2-羟乙基)(甲基)氨基)丙基)己酸-2-辛基癸酯(YK-301-PM4)和(R)-双(2-辛基癸基)-6,6'-((2-羟基-3-((2-羟乙基)(甲基)氨基)丙基)氮杂二烷基)二己酸酯(YK-305)的合成
将上述制备所得YK-301-PM3(200mg,1.35mmol)、6-溴己酸-2-辛基癸酯(604mg,1.35mmol)溶于乙腈(2mL)中,向上述体系加入碳酸钾(583mg,4.22mmol)加热至70℃搅拌反应7小时。反应完毕后反应液加入20mL水,再加入乙酸乙酯(20mL×2)萃取,合并有机相后再用盐水(20mL×2)洗涤,无水硫酸钠干燥,过滤,滤液经真空减压浓缩除去溶剂。将残余物通过硅胶色谱法(二氯甲烷/甲醇)纯化,得YK-301-PM4(210mg,0.41mmol,30.2%)。C30H62N2O4,MS(ES):m/z(M+H+)515.4;得YK-305(160mg,0.18mmol,13.4%)。C54H108N2O6,MS(ES):
m/z(M+H+)881.8。
步骤五:(R)-2-辛基癸基-6-((4-(癸氧基)-4-氧代丁基)(((2-羟基-3-(2-羟乙基)(甲基)氨基)丙基)氨基)己酸酯(YK-301)的合成
将上述制备所得YK-301-PM4(210mg,0.41mmol)、4-溴丁酸-正癸酯(150mg,0.49mmol)溶于乙腈(2mL)中,向上述体系加入碳酸钾(169mg,1.22mmol)和碘化钾(14mg,0.084mmol),加热至70℃搅拌反应10小时。反应完毕后反应液加入20mL水,再加入乙酸乙酯(20mL×2)萃取,合并有机相后再用盐水(20mL×2)洗涤,无水硫酸钠干燥,过滤,滤液经真空减压浓缩除去溶剂。将残余物通过硅胶色谱法(二氯甲烷/甲醇)纯化,得所述目标化合物(93mg,0.12mmol,30.2%)。C44H88N2O6,MS(ES):m/z(M+H+)741.6。
YK-301:1H NMR(400MHz,Chloroform-d)δ4.06(t,J=6.8Hz,2H),3.96(d,J=5.8Hz,2H),3.90(s,1H),3.81–3.76(m,1H),3.70(t,J=4.7Hz,4H),2.76(s,2H),2.63–2.41(m,10H),2.31(q,J=7.3,6.3Hz,4H),1.79(dp,J=13.5,6.9Hz,2H),1.63(q,J=7.2Hz,5H),1.54–1.43(m,2H),1.28(d,J=14.3Hz,44H),0.88(t,J=6.6Hz,9H).
YK-305:1H NMR(400MHz,Chloroform-d)δ4.07(s,2H),3.96(d,J=5.8Hz,4H),3.76–3.69(m,1H),2.87–2.55(m,10H),2.51(s,3H),2.31(t,J=7.4Hz,4H),1.62(dq,J=15.5,7.7Hz,10H),1.27(s,62H),0.88(t,J=6.7Hz,12H).
2.YK-302和YK-306的合成
合成路线如下:
步骤一:(S)-6-(2-羟基-3-((2-羟乙基)(甲基)氨基)丙基)己酸-3-己基壬酯(YK-302-PM1)和(R)-双(3-己基壬基)-6,6'-((2-羟基-3-((2-羟乙基)(甲基)氨基)丙基)氮杂二烷基)二己酸酯(YK-306)的合成
以YK-301-PM3(221mg,0.99mmol)和6-溴己酸-3-己基壬酯(400mg,1.49mmol)为原料,按照合成YK-301-PM4的方法,得YK-302-PM1(160mg,0.34mmol,35.2%),C27H56N2O4,MS(ES):m/z(M+H+)473.4;得YK-306(35mg,0.04mmol,4.4%)。C48H96N2O6,MS(ES):m/z(M+H+)797.7。
步骤二:(R)-3-己基壬基-6-(4-(癸氧基)-4-氧代丁基)(((2-羟基-3-(2-羟乙基)(甲基)氨基)丙基)氨基)己酸酯(YK-302)的合成
以YK-302-PM1(160mg,0.34mmol)和4-溴丁酸-正癸酯(114mg,0.37mmol)为原料,按照合成YK-301的方法,得YK-302(120mg,0.17mmol,50.5%),C41H82N2O6,MS(ES):m/z(M+H+)699.6。
YK-302:1H NMR(400MHz,Chloroform-d)δ4.12–3.85(m,8H),3.75(t,J=4.9Hz,2H),2.86(t,J=4.8Hz,2H),2.73–2.50(m,9H),2.31(dt,J=15.1,7.2Hz,4H),1.90–1.75(m,2H),1.65–1.54(m,6H),1.28(d,J=18.9Hz,40H),0.88(t,J=6.5Hz,9H).
YK-306:1H NMR(400MHz,Chloroform-d)δ4.37(s,1H),4.08(t,J=7.1Hz,4H),3.82(t,J=4.5Hz,2H),3.48(s,4H),3.04–2.80(m,8H),2.64(s,3H),2.31(t,J=7.2Hz,4H),1.67(dq,J=15.1,7.5Hz,7H),1.60–1.53(m,4H),1.25(s,48H),0.88(t,J=6.4Hz,12H).
3.YK-303和YK-304的合成
合成路线如下:
步骤一:(S)-6-(2-羟基-3-((2-羟乙基)(甲基)氨基)丙基)己酸-正十一酯(YK-303-PM1)和(R)-双(十一烷基)-6,6'-((2-羟基-3-((2-羟乙基)(甲基)氨基)丙基)氮杂二烷基)二己酸酯(YK-304)的合成
以YK-301-PM3(160mg,1.08mmol)和6-溴己酸-正十一烷酯(251mg,0.72mmol)为原料,按照合成YK-301-PM4的方法,得YK-303-PM1(114mg,0.27mmol,38.0%),C23H48N2O4,MS(ES):m/z(M+H+)417.4;得YK-304(50mg,0.07mmol,10.1%)。C40H80N2O6,MS(ES):m/z(M+H+)685.6。
步骤二:(R)-十一烷基-6-(4-(4-癸基十四烷氧基)-4-氧代丁基)((2-羟基-3-((2-羟乙基)(甲基)氨基)丙基)氨基)己酸酯(YK-303)的合成
以YK-303-PM1(114mg,0.27mmol)和4-溴丁酸-4-癸基十四烷酯(156mg,
0.31mmol)为原料,按照合成YK-301的方法,得YK-303(75mg,0.09mmol,33.1%),C51H102N2O6,MS(ES):m/z(M+H+)839.8。
YK-303:1H NMR(400MHz,Chloroform-d)δ4.42(s,1H),4.08–4.00(m,4H),3.91(s,2H),3.49(s,1H),3.14(s,3H),2.82(d,J=10.5Hz,10H),2.39(t,J=6.6Hz,2H),2.31(t,J=7.2Hz,2H),1.95(s,3H),1.63(dt,J=15.4,7.3Hz,8H),1.25(d,J=11.9Hz,62H),0.88(t,J=6.6Hz,9H).
YK-304:1H NMR(400MHz,Chloroform-d)δ5.30(s,1H),4.80(s,2H),4.16–4.02(m,4H),3.75(q,J=7.6,6.4Hz,2H),3.02–2.61(m,9H),2.56(s,3H),2.31(t,J=7.4Hz,4H),1.71–1.54(m,12H),1.40–1.22(m,36H),0.88(t,J=6.6Hz,6H).
4.YK-307的合成
合成路线如下:
(R)-双(4-癸基十四烷基)-4,4'-(2-羟基-3-((2-羟乙基)(甲基)氨基)丙基)氮杂二烷基)二丁酸酯(YK-307)的合成
以YK-301-PM3(160mg,1.08mmol)和4-溴丁酸-4-癸基十四烷基酯(362mg,0.72mmol)为原料,按照合成YK-301-PM4的方法,得YK-307(75mg,0.08mmol,20.9%)。C62H124N2O6,MS(ES):m/z(M+H+)993.9。
1H NMR(400MHz,Chloroform-d)δ5.30(s,1H),4.04(t,J=6.8Hz,4H),3.89–3.74(m,2H),3.03(d,J=4.1Hz,4H),2.60(dd,J=16.6,9.7Hz,7H),2.32(t,J=6.8Hz,4H),1.87–1.74(m,4H),1.63–1.55(m,4H),1.25(d,J=12.2Hz,80H),0.88(t,J=6.7Hz,12H).
5.YK-308和YK-312的合成
合成路线如下:
步骤一:(S)-2-羟基-3-(((2-羟乙基)(乙基)氨基)丙基)氨基甲酸叔丁酯(YK-308-PM1)的合成
以YK-301-PM1(600mg,2.87mmol)和2-(乙氨基)乙醇(256mg,2.87mmol)为原料,按照合成YK-301-PM2的方法,得YK-308-PM1(300mg,1.14mmol,39.8%),C12H26N2O4,MS(ES):m/z(M+H+)263.2。
步骤二:(S)-1-氨基-3-((2-羟乙基)(乙基)氨基)丙烷-2-醇(YK-308-PM2)的合成
以YK-308-PM1(200mg,0.76mmol)为原料,按照合成YK-301-PM3的方法,得YK-308-PM2(120mg,0.74mmol,97.3%),C7H18N2O2,MS(ES):m/z(M+H+)163.1。
步骤三:(S)-6-(2-羟基-3-(((2-羟乙基)(乙基)氨基)丙基)己酸-2-辛基癸酯(YK-308-PM3)和(S)-双(2-辛基癸基)-6,6'-((2-羟基-3-((2-羟乙基)(乙基)氨基)丙基)氮杂二烷基)二己酸酯(YK-312)的合成
以YK-308-PM2(185mg,1.14mmol)和6-溴己酸-2-辛基癸酯(349mg,1.14mmol)为原料,按照合成YK-301-PM4的方法,得YK-308-PM3(150mg,0.28mmol,24.9%),C31H64N2O4,MS(ES):m/z(M+H+)529.5;得YK-312(71mg,0.08mmol,7.0%)。C55H110N2O6,MS(ES):m/z(M+H+)895.8。
步骤四:(S)-2-辛基癸基-6-(4-(癸氧基)-4-氧代丁基)(((2-羟基-3-(2-羟乙基)(乙基)氨基)丙基)氨基)己酸酯(YK-308)的合成
以YK-308-PM3(150mg,0.28mmol)和4-溴丁酸-正癸酯(104mg,0.34mmol)为原料,按照合成YK-301的方法,得YK-308(90mg,0.12mmol,42.6%),C45H90N2O6,MS(ES):m/z(M+H+)755.7。
YK-308:1H NMR(400MHz,Chloroform-d)δ4.06(t,J=6.7Hz,2H),3.96(d,J=5.8Hz,2H),3.74(s,1H),2.90(s,3H),2.84–2.38(m,10H),2.31(q,J=7.1,6.6Hz,4H),1.80(s,2H),1.69–1.58(m,5H),1.49(s,2H),1.26(s,48H),0.88(t,J=6.6Hz,9H).
YK-312:1H NMR(400MHz,Chloroform-d)δ3.96(d,J=5.8Hz,4H),3.84(s,2H),2.91(d,J=94.1Hz,12H),2.32(t,J=7.3Hz,4H),1.72–1.54(m,10H),1.27(s,66H),0.88(t,J=6.7Hz,12H).
6.YK-309和YK-311的合成
合成路线如下:
步骤一:(S)-4-(2-羟基-3-((2-羟乙基)(乙基)氨基)丙基)己酸-3-己基壬酯(YK-309-PM1)和(S)-双(3-己基壬基)-6,6'-((((2-羟乙基)(乙基)氨基)丙基)氮杂二烷基)二己酸酯(YK-311)的合成
以YK-308-PM2(247mg,1.52mmol)和6-溴己酸-3-己基壬酯(680mg,1.67mmol)为原料,按照合成YK-301-PM4的方法,得YK-309-PM1(260mg,0.53mmol,35.1%),C28H58N2O4,MS(ES):m/z(M+H+)487.4;得YK-311(160mg,0.20mmol,13.0%)。C49H98N2O6,MS(ES):m/z(M+H+)811.7。
步骤二:(S)-3-己基壬酯-6-(4-(癸氧基)-4-氧代丁基)(2-羟基-3-(((2-羟乙基)(乙基)氨基)丙基)氨基)己酸酯(YK-309)的合成
以YK-309-PM1(160mg,0.33mmol)和4-溴丁酸-3-正癸酯(101mg,0.33mmol)为原料,按照合成YK-301的方法,得YK-309(160mg,0.22mmol,68.0%),C42H84N2O6,MS(ES):m/z(M+H+)713.6。
YK-309:1H NMR(400MHz,Chloroform-d)δ4.07(q,J=7.2Hz,4H),3.86(dt,J=8.3,4.3Hz,1H),3.68(t,J=5.0Hz,2H),2.80(q,J=7.0Hz,4H),2.70–2.37(m,8H),2.34–2.27(m,3H),1.78(tt,J=13.8,7.1Hz,2H),1.60(dp,J=20.9,7.2Hz,6H),1.51–1.23(m,40H),1.13(t,J=7.1Hz,3H),0.88(t,J=6.7Hz,9H).
YK-311:1H NMR(400MHz,Chloroform-d)δ4.08(t,J=7.1Hz,4H),3.87(s,1H),3.66(t,J=5.1Hz,2H),2.82–2.71(m,4H),2.69–2.37(m,8H),2.29(t,J=7.4Hz,4H),1.69–1.44(m,12H),1.39(s,2H),1.26(s,44H),1.11(t,J=7.1Hz,3H),0.88(t,J=6.7Hz,12H).
7.YK-310和YK-315的合成
合成路线如下:
步骤一:(S)-4-(2-羟基-3-((2-羟乙基)(乙基)氨基)丙基)丁酸-4-癸基十四烷酯(YK-310-PM1)和(S)-双(4-癸基十四烷基)-4,4'-(((2-羟乙基)(乙基)氨基)丙基)氮杂二烷基)二丁酸酯(YK-315)的合成
以YK-308-PM2(124mg,0.76mmol)和4-溴丁酸-4-癸基十四烷基酯(385mg,0.76mmol)为原料,按照合成YK-301-PM4的方法,得YK-310-PM1(142mg,0.24mmol,31.9%),C35H72N2O4,MS(ES):m/z(M+H+)585.6;得YK-315(30mg,0.03mmol,3.9%)。C63H126N2O6,MS(ES):m/z(M+H+)1008.0。
步骤二:(S)-4-癸基十四烷基-4-(6-(十一烷氧基)-6-氧代己基)(2-羟基-3-(2-羟乙基)(乙基)氨基)丙基)氨基)丁酸酯(YK-310)的合成
以YK-310-PM1(142mg,0.24mmol)和6-溴己酸-十一烷基酯(153mg,
0.44mmol)为原料,按照合成YK-301的方法,得YK-310(90mg,0.11mmol,43.9%),C52H104N2O6,MS(ES):m/z(M+H+)853.8。
YK-310:1H NMR(400MHz,Chloroform-d)δ4.10–3.94(m,5H),3.75(q,J=6.2,5.6Hz,2H),2.95–2.80(m,4H),2.74–2.46(m,6H),2.36–2.23(m,4H),1.81(q,J=7.7Hz,2H),1.68–1.56(m,6H),1.49(d,J=7.3Hz,2H),1.25(d,J=12.2Hz,62H),0.88(t,J=6.7Hz,9H).
YK-315:1H NMR(400MHz,Chloroform-d)δ4.39(s,1H),4.08–3.96(m,6H),3.27(d,J=7.1Hz,4H),2.72(s,5H),2.35(t,J=6.8Hz,4H),1.85(d,J=6.9Hz,4H),1.59(s,4H),1.42(t,J=7.1Hz,4H),1.25(d,J=12.1Hz,80H),0.88(t,J=6.6Hz,12H).
8.YK-313的合成
合成路线如下:
(S)-双(十七烷-9-基)-6,6'-(((2-羟乙基)(乙基)氨基)丙基)氮杂二烷基)二己酸酯(YK-313)的合成
以YK-308-PM2(62mg,0.38mmol)和十七烷-9-基-6-溴己酸酯(330mg,0.76mmol)为原料,按照合成YK-301-PM4的方法,得YK-313(170mg,0.20mmol,51.6%)。C53H106N2O6,MS(ES):m/z(M+H+)867.8。
1H NMR(400MHz,Chloroform-d)δ4.86(p,J=6.2Hz,2H),3.84(s,1H),3.65(t,J=5.1Hz,2H),2.80–2.69(m,4H),2.64–2.35(m,8H),2.28(t,J=7.5Hz,4H),1.63(p,J=7.6Hz,4H),1.56–1.44(m,12H),1.28(d,J=15.2Hz,54H),1.09(t,J=7.1Hz,3H),0.88(t,J=6.8Hz,12H).
9.YK-314的合成
合成路线如下:
(S)-双(十七烷-9-基)-8,8'-(((2-羟乙基)(乙基)氨基)丙基)氮杂二烷基)二辛酸酯(YK-314)的合成
以YK-308-PM2(60mg,0.37mmol)和十七烷-9-基-8-溴辛酸酯(512mg,1.11mmol)为原料,按照合成YK-301-PM4的方法,得YK-314(120mg,0.13mmol,35.1%)。C57H114N2O6,MS(ES):m/z(M+H+)923.9。
1H NMR(400MHz,Chloroform-d)δ4.86(p,J=6.1Hz,2H),3.87(s,1H),3.64(t,J=5.1Hz,2H),2.78–2.68(m,4H),2.66–2.35(m,8H),2.27(t,J=7.5Hz,4H),1.65–1.57(m,4H),1.50(s,12H),1.29(d,J=22.9Hz,62H),1.09(t,J=7.0Hz,3H),0.88(t,J=6.6Hz,12H).
10.YK-316的合成
合成路线如下:
步骤一:(S)-((3-(双(2-羟乙基)氨基)-2-羟丙基)氨基甲酸叔丁酯(YK-316-PM1)的合成
以YK-301-PM1(1.0g,4.78mmol)和双羟乙基胺(452mg,4.30mmol)为原料,按照合成YK-301-PM2的方法,得YK-316-PM1(550mg,1.98mmol,46.0%),C12H26N2O5,MS(ES):m/z(M+H+)279.2。
步骤二:(S)-1-氨基-3-(双(2-羟乙基)氨基)-2-丙醇(YK-316-PM2)的合成
以YK-316-PM1(200mg,0.72mmol)为原料,按照合成YK-301-PM3的方法,得YK-316-PM2(128mg,0.72mmol,100%),C7H18N2O3,MS(ES):m/z(M+H+)179.1。
步骤三:(S)-双(2-辛基癸基)-6,6'-(((3-(双(2-羟乙基)氨基)-2-羟丙基)氮杂二烷基)二己酸酯(YK-316)的合成
以YK-316-PM2(64mg,0.36mmol)和6-溴己酸-2-辛基癸基酯(160mg,
0.36mmol)为原料,按照合成YK-301的方法,得YK-316(90mg,0.10mmol,27.4%)。C55H110N2O7,MS(ES):m/z(M+H+)911.8。
1H NMR(400MHz,Chloroform-d)δ3.96(d,J=5.8Hz,4H),3.71(s,4H),3.09–2.77(m,10H),2.33(t,J=7.2Hz,4H),1.66(dd,J=15.3,7.5Hz,6H),1.27(s,69H),0.88(t,J=6.8Hz,12H).
11.YK-317的合成
合成路线如下:
(S)-双(3-己基壬基)-6,6'-((3-(双(2-羟乙基)氨基)-2-羟丙基)氮杂二烷基)二己酸酯(YK-317)的合成
以YK-316-PM2(105mg,0.59mmol)和6-溴己酸-3-己基壬酯(500mg,1.23mmol)为原料,按照合成YK-301的方法,得YK-317(270mg,0.33mmol,55.3%)。C49H98N2O7,MS(ES):m/z(M+H+)827.7。
1H NMR(400MHz,Chloroform-d)δ4.08(t,J=6.9Hz,4H),3.67(s,4H),3.48(s,2H),2.64(dd,J=34.4,20.4Hz,12H),2.30(t,J=7.2Hz,4H),1.60(dt,J=31.5,6.9Hz,12H),1.28(d,J=19.3Hz,48H),0.88(t,J=6.2Hz,12H).
12.YK-318的合成
合成路线如下:
(S)-双(十七烷-9-基)-6,6'-((3-(双(2-羟乙基)氨基)-2-羟丙基)氮杂二烷基)二己酸酯(YK-318)的合成
以YK-316-PM2(125mg,0.70mmol)和十七烷-9-基-6-溴己酸酯(666mg,
1.54mmol)为原料,按照合成YK-301的方法,得YK-318(300mg,0.34mmol,48.5%)。C53H106N2O7,MS(ES):m/z(M+H+)883.8。
1H NMR(400MHz,Chloroform-d)δ4.92–4.80(m,2H),3.90(s,4H),3.71–3.62(m,2H),3.62–3.53(m,2H),2.81–2.72(m,2H),2.72–2.48(m,9H),2.29(t,J=7.3Hz,4H),1.68–1.60(m,4H),1.59–1.44(m,12H),1.26(s,53H),0.88(t,J=5.5Hz,12H).
13.YK-319的合成
合成路线如下:
(S)-双(3-己基壬基)-7,7'-(((3-(双(2-羟乙基)氨基)-2-羟丙基)氮杂二烷基)二庚酸酯(YK-319)的合成
以YK-316-PM2(34mg,0.19mmol)和3-己基壬基-7-溴庚酸酯(160mg,0.38mmol)为原料,按照合成YK-301的方法,得YK-319(40mg,0.05mmol,24.6%)。C51H102N2O7,MS(ES):m/z(M+H+)855.8。
1H NMR(400MHz,Chloroform-d)δ4.08(t,J=7.1Hz,4H),3.65(s,4H),2.76(t,J=45.6Hz,12H),2.29(t,J=7.3Hz,4H),1.74–1.51(m,12H),1.25(s,54H),0.88(t,J=6.4Hz,12H).
14.YK-320的合成
合成路线如下:
(S)-双(十七烷-9-基)-8,8'-(((3-(双(2-羟乙基)氨基)-2-羟丙基)氮杂二烷基)二辛酸酯(YK-320)的合成
以YK-316-PM2(41mg,0.23mmol)和十七烷-9-基-8-溴辛酸酯(244mg,0.53mmol)为原料,按照合成YK-301的方法,得YK-320(150mg,0.16mmol,
69.4%)。C57H114N2O7,MS(ES):m/z(M+H+)939.9。
1H NMR(400MHz,Chloroform-d)δ5.30(s,1H),4.85(p,J=6.0Hz,2H),4.19(s,2H),3.76–3.55(m,5H),2.98–2.60(m,10H),2.28(t,J=7.4Hz,4H),1.64(dd,J=15.8,7.4Hz,8H),1.55–1.46(m,8H),1.30(d,J=31.6Hz,60H),0.88(t,J=6.7Hz,12H).
15.YK-321的合成
合成路线如下:
(S)-双(4-癸基十四烷基)-4,4'-((3-(双(2-羟乙基)氨基)-2-羟丙基)氮杂二烷基)二丁酸酯(YK-321)的合成
以YK-316-PM2(41mg,0.23mmol)和4-溴丁酸-4-癸基十四烷基酯(266mg,0.53mmol)为原料,按照合成YK-301的方法,得YK-321(85mg,0.08mmol,36.1%)。C63H126N2O7,MS(ES):m/z(M+H+)1024.0。
1H NMR(400MHz,Chloroform-d)δ5.30(s,1H),4.04(t,J=6.8Hz,4H),3.71(s,4H),2.72(s,10H),2.35(t,J=6.8Hz,4H),1.89(s,4H),1.63–1.55(m,4H),1.25(d,J=12.2Hz,80H),0.88(t,J=6.6Hz,12H).
16.YK-009的合成
按照CN114044741B中方法,得到YK-009 105mg。
17. 9-十七烷基-8-(8-((3-己基壬基)氧基)-8-氧代辛基)-((2-羟乙基)氨基)辛酸酯(化合物21)的合成
合成路线如下:
步骤一:8-溴辛酸-9-十七烷酯制备(化合物21-PM1)的合成
将9-十七醇(1.00g,3.90mmol)与8-溴辛酸(1.04g,4.66mmol)溶于二氯甲烷(10mL)中,加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.90g,4.68mmol)和4-二甲基氨基吡啶(24mg,0.20mmol),于30-35℃下搅拌反应8小时。反应完毕后将反应液用饱和碳酸钠洗涤、饱和食盐水洗涤,并经Na2SO4干燥。将混合物过滤,滤液经真空减压浓缩,经硅胶色谱法(乙酸乙酯/正己烷)纯化,得到8-溴辛酸-9-十七烷酯(1.20g,2.60mmol,66.7%)。
步骤二:9-十七烷基-8-((2-羟乙基)氨基)辛酸酯(化合物21-PM2)的合成
将8-溴辛酸-9-十七烷酯(500mg,1.08mmol)与乙醇胺(119mg,3.25mmol)溶于乙腈(5mL)中,加入碳酸钾(149mg,1.08mmol),加热至70℃搅拌反应2小时。反应完毕待反应液冷却至室温后过滤,滤液经真空减压浓缩除去溶剂。将残余物通过硅胶色谱法(甲醇/二氯甲烷)纯化,得9-十七烷基-8-((2-羟乙基)氨基)辛酸
酯(372mg,0.84mmol,78.0%),C27H55NO3,MS(ES):m/z(M+H+)442.3。
步骤三:8-溴辛酸-3-己基壬酯制备(化合物21-PM3)的合成
以3-己基壬醇(1.00g,4.38mmol)与8-溴辛酸(1.17g,5.25mmol)为原料,按照制备化合物21-PM1的方法,经硅胶色谱法(乙酸乙酯/正己烷)纯化,得到8-溴辛酸-3-己基壬酯(1.62g,3.74mmol,85.3%)。
步骤四:9-十七烷基-8-(8-((3-己基壬基)氧基)-8-氧代辛基)-((2-羟乙基)氨基)辛酸酯(化合物21)的合成
将9-十七烷基-8-((2-羟乙基)氨基)辛酸酯(200mg,0.46mmol)和8-溴辛酸-3-己基壬酯(336mg,0.82mmol)溶于乙腈(6mL)中,加入碳酸钾(254mg,1.84mmol)和碘化钾(8.3mg,0.05mmol),加热至70℃搅拌反应20小时。反应液冷却至室温后过滤,滤液经真空减压浓缩除去溶剂。将残余物通过硅胶色谱法(乙酸乙酯/正己烷)纯化,得所述目标化合物(213mg,0.27mmol,58.4%)。C50H99NO5,MS(ES):m/z(M+H+)794.8。
1H NMR(400MHz,CDCl3)δ4.90(p,J=6.3Hz,1H),4.21–4.02(m,2H),3.66(s,2H),2.73(s,2H),2.60(s,4H),2.43–2.20(m,4H),2.12–1.99(m,1H),1.75–1.49(m,13H),1.48–1.39(m,2H),1.42–1.15(m,56H),0.92(td,J=6.8,2.2Hz,12H).
18.双(3-己基壬基)-8,8'-((2-羟乙基)氮杂二烷基)二辛酸酯(化合物23)的合成
合成路线如下:
将8-溴辛酸-3-己基壬酯(710mg,1.64mmol)和乙醇胺(40mg,0.66mmol)溶于乙腈(10mL)中,向上述体系加入碳酸钾(1.09g,7.92mmol)和碘化钾(66mg,0.39mmol),加热至70℃搅拌反应20小时。反应完毕后待反应液冷却至室温后过滤,滤液经真空减压浓缩除去溶剂。将残余物通过硅胶色谱法(甲醇/二氯甲烷)纯化,得到双(3-己基壬基)-8,8'-((2-羟乙基)氮杂二烷基)二辛酸酯(150mg,0.20mmol,29.7%),C48H95NO5,MS(ES):m/z(M+H+)766.5。
1H NMR(400MHz,CDCl3)δ4.12(t,J=7.1Hz,4H),3.62(s,2H),2.68(s,2H),
2.51(d,J=25.8Hz,4H),2.32(t,J=7.5Hz,4H),1.72–1.57(m,8H),1.55–1.40(m,6H),1.40–1.17(m,55H),0.92(t,J=6.8Hz,12H).
实施例2:纳米脂质颗粒(LNP制剂)制备条件优化
1.载体(脂质体)与mRNA比例优化
将实施例1中合成的阳离子脂质化合物YK-305分别与DSPC(艾伟拓(上海)医药科技有限公司)、胆固醇(艾伟拓(上海)医药科技有限公司)和DMG-PEG2000按照49:10:39.5:1.5的摩尔比溶于乙醇,制备乙醇脂质溶液。通过乙醇注入法将乙醇脂质溶液快速加入柠檬酸盐缓冲液(pH=4~5),涡旋30s备用。将eGFP-mRNA在柠檬酸盐缓冲液(pH=4~5)中稀释得到mRNA水溶液。将一定体积的脂质体溶液与mRNA水溶液,分别以总脂质与mRNA的重量比为5:1、10:1、15:1、20:1、30:1和35:1制备脂质体。25℃超声15min(超声频率40kHz,超声功率800W)。所得脂质体用PBS稀释至10倍体积后,300KDa超滤管进行超滤除乙醇。再经PBS定容至一定体积,得到使用阳离子脂质YK-305/DSPC/胆固醇/DMG-PEG2000(摩尔百分比为49:10:39.5:1.5)包封eGFP-mRNA的LNP制剂。
细胞转染实验结果显示,载体与mRNA重量比在10:1~30:1范围内,均有较好转染效果,其中转染效果最好为15:1,比例为5:1和35:1转染效果差,不能用此比例来运载mRNA。(图1)
用YK-310、YK-312、YK-319和YK-318制备得到的LNP制剂,得到同样的结果,图未显示。
2.阳离子脂质与中性脂质比例优化
按照1中方法制备包封eGFP-mRNA的LNP制剂,其中阳离子脂质YK-305与
中性脂质DSPC摩尔比分别为1:1、3:1、3.5:1、4:1、4.5:1、4.9:1、10:1、15:1和20:1。
通过细胞转染实验可以看出,阳离子脂质与中性脂质摩尔比为1:1~15:1均有转染效果,其中转染效率最高的是4.5:1,比例为3.5:1和4.9:1也有较好的转染效果。(图2)
用YK-310、YK-312、YK-319和YK-318制备得到的LNP制剂,得到同样的结果,图未显示。
3.聚合物共轭脂质占载体(脂质体)比例优化
按照1中方法制备包封eGFP-mRNA的LNP制剂,载体中阳离子脂质为YK-305,其中聚合物共轭脂质DMG-PEG2000占载体摩尔比分别为0.5%、1.5%、3.5%、5%、10%和15%。
细胞转染实验结果显示,聚合物共轭脂质占载体摩尔比在0.5%~10%范围内,均有转染效果,1.5%时转染效率最高,10%时最低。(图3)
用YK-310、YK-312、YK-319和YK-318制备得到的LNP制剂,得到同样的结果,图未显示。
4.载体(脂质体)中各成分比例优化
按照1中方法制备包封eGFP-mRNA的LNP制剂,其中阳离子脂质YK-305、中性脂质DSPC、结构脂质胆固醇和聚合物共轭脂质DMG-PEG2000摩尔比分别为75:5:15:5、49:10:39.5:1.5、45:10:43.5:1.5、45:25:20:10、40:10:48.5:1.5、35:10:53.5:1.5和25:5:65:5。
通过细胞转染实验可知,阳离子脂质、中性脂质、结构脂质和聚合物共轭脂质摩尔比在75:5:15:5、49:10:39.5:1.5、45:10:43.5:1.5、45:25:20:10、40:10:48.5:1.5、35:10:53.5:1.5和25:5:65:5比例下均能转染。在比例为(35~49):(7.5~15):(35~55):(1~5)的范围内具有良好的转染效果,其中比例为45:10:43.5:1.5转染效果最好。(图4)说明阳离子脂质、中性脂质、结构脂质和聚合物共轭脂质摩尔比在(25~75):(5~25):(15~65):(0.5~10)范围内均可用来制备LNP制剂,优选比例为(35~49):(7.5~15):(35~55):(1~5),其中最佳比例为45:10:43.5:1.5。
用YK-310、YK-312、YK-319和YK-318制备得到的LNP制剂,得到同样的
结果,图未显示。
实施例3:eGFP-mRNA的LNP制剂细胞转染实验
细胞复苏与传代:将293T细胞复苏,于培养皿中培养传代至所需的细胞数量。
种板:将培养皿中的细胞消化并计数,以每孔1万个细胞铺在96孔板中,以每孔15万个细胞铺在12孔板中,过夜培养至细胞贴壁。
细胞转染实验:分别将含有1.5μg实施例2中制备的eGFP-mRNA的LNP制剂(载体中阳离子脂质为YK-305)以及eGFP-mRNA的Lipofectamin 3000制剂加入12孔板的细胞培养液中,继续培养24h后,经荧光显微镜观察,根据荧光强度考察不同样品的转染效率。
根据实验结果,最后确定了纳米脂质颗粒(LNP制剂)的制备条件:载体与mRNA重量比为15:1;阳离子脂质与中性脂质摩尔比为4.9:1;聚合物共轭脂质占脂质体摩尔比1.5%;阳离子脂质、中性脂质、结构脂质和聚合物共轭脂质摩尔比为49:10:39.5:1.5,此比例中本申请设计的各种阳离子脂质以及现有技术中所使用的阳离子脂质均有较优的转染效果(由实施例2确定,部分实验结果未显示),后面的实验用此条件制备纳米脂质颗粒(LNP制剂)。
实施例4:纳米脂质颗粒(LNP制剂)的制备(最优配比)
表1 阳离子脂质结构
将表1中所列阳离子脂质分别与DSPC(艾伟拓(上海)医药科技有限公司)、胆固醇(艾伟拓(上海)医药科技有限公司)和DMG-PEG2000按照49:10:39.5:1.5的摩尔比溶于乙醇,制备乙醇脂质溶液,通过乙醇注入法将乙醇脂质溶液快速加入柠檬酸盐缓冲液(pH=4~5),涡旋30s备用。将eGFP-mRNA(上海起发实验试剂有限公司)或Fluc-mRNA(上海起发实验试剂有限公司)在柠檬酸盐缓冲液(pH=4~5)中稀释得到mRNA水溶液。将一定体积的脂质体溶液与mRNA水溶液,以总脂质与mRNA的重量比为15:1制备脂质体。25℃超声15min(超声频率40kHz,超声功率800W)。所得脂质体经用PBS稀释至10倍体积后,300KDa超滤管进行超滤除乙醇。再经PBS定容至一定体积,得到使用阳离子脂质/DSPC/胆固醇/DMG-PEG2000(摩尔百分比为49:10:39.5:1.5)包封eGFP-mRNA或Fluc-mRNA的LNP制剂。
Lipofectamine 3000转染试剂目前广泛用来进行细胞转染,具有非常好的转染性能和优异的转染效率,并可提高细胞活性,而且适用于难转染的细胞种类。我们选用Lipofectamine 3000转染试剂进行对照,按照Lipofectamine 3000(英潍捷基(上海)贸易有限公司)说明书中方法,制备得到eGFP-mRNA或Fluc-mRNA的Lipofectamin 3000制剂。
实施例5:纳米脂质颗粒粒径及多分散系数(PDI)的测定
利用动态光散射,采用马尔文激光粒度仪测定粒径及多分散系数(PDI)。
取脂质体溶液10μL,用无RNA酶去离子水稀释至1mL,加入样品池,每个样品重复测定3次。测定条件为:90°散射角,25℃。检测结果如下表:
表2 粒径及多分散系数(PDI)
实施例4中制备的纳米脂质颗粒粒径在140~280nm之间,均可用于递送mRNA,其中由化合物23和YK-304制备的颗粒粒径最小,分别为147nm和149nm,由YK-317制备的颗粒粒径最大,为255nm。所有纳米脂质颗粒的多分散系数在5%~45%之间,其中最小的是YK-301,为7.0%,最大的是YK-321,为
39.1%。
实施例6:体外验证LNP递送载体的性能
细胞复苏与传代:方法同实施例3。
种板:方法同实施例3。
1.Fluc-mRNA的荧光检测
将含有0.3μg Fluc-mRNA的LNP制剂(LNP制剂载体组分为阳离子脂质、中性脂质、结构脂质和聚合物共轭脂质,摩尔比为49:10:39.5:1.5,其中阳离子脂质为表1中所列阳离子脂质)加入96孔板的细胞培养液中,继续培养24小时后,按照Gaussia Luciferase Assay Kit说明书加入相应试剂,经IVIS荧光检测系统检测每孔荧光表达强度。本实验验证了LNP制剂在细胞内的转染效率,具体检测结果见表4-7。
实验结果:
(1)本申请的化合物,其中包括YK-305、YK-310、YK-312、YK-319和YK-
318,与现有技术阳离子脂质化学结构差别非常大。
本申请设计的一系列化合物,包括YK-305、YK-310、YK-312、YK-319和YK-318,与现有技术阳离子脂质化学结构差别非常大。例如,这些化合物与HHMA结构完全不同;与SM-102、化合物21、化合物23和YK-009相比,G3基团完全不同,G1、G2、R1和R2基团也都区别巨大。具体结构对比见表3。
表3 设计的化合物与现有技术代表性阳离子脂质
从表3可以看出,设计的这一系列化合物,包括YK-305、YK-310、YK-312、YK-319和YK-318,与现有技术代表性阳离子脂质化学结构差别巨大。YK-009在CN114044741B中公开(权利要求1),化合物21和化合物23在WO2021055833A1中公开(说明书第22页),SM-102是WO2017049245A2中公开的化合物25(说明书第29页),ALC-0315是CN108368028B中公开的化合物3(说明书第24页),HHMA
为CN112979483B中公开的化合物1(说明书第12页)。
与此系列化合物相比:
a.HHMA结构差别最大,从化学结构图中可以看出,HHMA与中心N原子相连的基团,仅1个侧链与此系列结构的1个侧链相近,其它部分完全不同。
b.现有技术中其它阳离子脂质,例如SM-102、ALC-0315、化合物21、化合物23和YK-009,G3基团完全不同。此系列化合物G3基团中多1个叔胺基团,并且多1-2个羟基,因此在极性、酸碱性和亲水性等方面也会有很大差别。
c.SM-102、ALC-0315、化合物21、化合物23和YK-009的G1、G2、R1和R2基团也有巨大差别。
具体如下:
I.YK-305
YK-305与现有技术阳离子脂质,例如SM-102、化合物21、化合物23、YK-009和HHMA相比,结构差异巨大。
与SM-102相比,YK-305的R1基团为支链结构,而SM-102为直链结构;G2基团少2个C;R2基团单链多1个C;G3基团完全不同,为HO(CH2)2N(CH3)CH2CH(OH)CH2-,而SM-102为HO(CH2)2-。
与ALC-0315相比,YK-305的G1基团少1个C;R1基团单链多1个C,双链中1条单链多2个C;G2基团少1个C;R2基团单链多1个C,双链中1条单链多2个C;G3基团完全不同,为HO(CH2)2N(CH3)CH2CH(OH)CH2-,而ALC-0315为HO(CH2)4-。并且,G1基团和R1基团之间、G2基团和R2基团之间的酯键方向,YK-305与ALC-0315也均不相同。
与化合物21相比,YK-305的G1基团少2个C;R1基团单链少1个C,双链中每条单链多2个C;G2基团少2个C;R2基团单链多1个C;G3基团完全不同,为HO(CH2)2N(CH3)CH2CH(OH)CH2-,而化合物21为HO(CH2)2-。
与化合物23相比,YK-305的G1基团少2个C;R1基团单链少1个C,双链中每条单链多2个C;G2基团少2个C;R2基团单链少1个C,双链中每条单链多2个C;G3基团完全不同,为HO(CH2)2N(CH3)CH2CH(OH)CH2-,而化合物23为HO(CH2)2-。
与YK-009相比,YK-305的G1基团多2个C;R1基团为支链结构,而YK-009为直链结构;G3基团完全不同,为HO(CH2)2N(CH3)CH2CH(OH)CH2-,而YK-009为HO(CH2)2-。
与HHMA相比,YK-305的结构完全不同,HHMA仅1个与N原子相连的侧链与YK-305的1个侧链结构相近,其它部分差异巨大。
II.YK-310
YK-310与现有技术阳离子脂质,例如SM-102、化合物21、化合物23、YK-009和HHMA相比,结构差异巨大。
与SM-102相比,YK-310的G2基团少4个C;R2基团单链多3个C,双链中每条单链多2个C;G3基团完全不同,为HO(CH2)2N(CH2CH3)CH2CH(OH)CH2-,而SM-102为HO(CH2)2-。
与ALC-0315相比,YK-310的G1基团少1个C;R1基团为直链结构,而ALC-0315为支链结构;G2基团少3个C;R2基团单链多3个C,双链中1条单链多2个C,另1条单链多4个C;G3基团完全不同,为HO(CH2)2N(CH2CH3)CH2CH(OH)CH2-,而ALC-0315为HO(CH2)4-。并且,G1基团和R1基团之间、G2基团和R2基团之间的酯键方向,YK-310与ALC-0315也均不相同。
与化合物21相比,YK-310的G1基团少2个C;R1基团为直链结构,而化合物21为支链结构;G2基团少4个C;R2基团单链多3个C,双链中每条单链多2个C;G3基团完全不同,为HO(CH2)2N(CH2CH3)CH2CH(OH)CH2-,而化合物21为HO(CH2)2-。
与化合物23相比,YK-310的G1基团少2个C;R1基团为直链结构,而化合物23为支链结构;G2基团少4个C;R2基团单链多1个C,双链中每条单链多4个C;G3基团完全不同,为HO(CH2)2N(CH2CH3)CH2CH(OH)CH2-,而化合物23为HO(CH2)2-。
与YK-009相比,YK-310的G1基团多2个C;R1基团多1个C;G2基团少2个C;R2基团单链多2个C,双链中每条单链多2个C;G3基团完全不同,为HO(CH2)2N(CH2CH3)CH2CH(OH)CH2-,而YK-009为HO(CH2)2-。
与HHMA相比,YK-310的结构完全不同,HHMA仅1个与N原子相连的侧链与YK-310的1个侧链结构相近,其它部分差异巨大。
III.YK-312
YK-312与现有技术阳离子脂质,例如SM-102、化合物21、化合物23、YK-009和HHMA相比,结构差异巨大。
与SM-102相比,YK-312的R1基团为支链结构,而SM-102为直链结构;G2基团少2个C;R2基团单链多1个C;G3基团完全不同,为HO(CH2)2N(CH2CH3)CH2CH(OH)CH2-,而SM-102为HO(CH2)2-。
与ALC-0315相比,YK-312的G1基团少1个C;R1基团单链多1个C,双链中1条单链多2个C;G2基团少1个C;R2基团单链多1个C,双链中1条单链多2个C;
G3基团完全不同,为HO(CH2)2N(CH2CH3)CH2CH(OH)CH2-,而ALC-0315为HO(CH2)4-。并且,G1基团和R1基团之间、G2基团和R2基团之间的酯键方向,YK-312与ALC-0315也均不相同。
与化合物21相比,YK-312的G1基团少2个C;R1基团单链少1个C,双链中每条单链多2个C;G2基团少2个C;R2基团单链多1个C;G3基团完全不同,为HO(CH2)2N(CH2CH3)CH2CH(OH)CH2-,而化合物21为HO(CH2)2-。
与化合物23相比,YK-312的G1基团少2个C;R1基团单链少1个C,双链中每条单链多2个C;G2基团少2个C;R2基团单链少1个C,双链中每条单链多2个C;G3基团完全不同,为HO(CH2)2N(CH2CH3)CH2CH(OH)CH2-,而化合物23为HO(CH2)2-。
与YK-009相比,YK-312的G1基团多2个C;R1基团为支链结构,而YK-009为直链结构;G3基团完全不同,为HO(CH2)2N(CH2CH3)CH2CH(OH)CH2-,而YK-009为HO(CH2)2-。
与HHMA相比,YK-312的结构完全不同,HHMA仅1个与N原子相连的侧链与YK-312的1个侧链结构相近,其它部分差异巨大。
IV.YK-319
YK-319与现有技术阳离子脂质,例如SM-102、化合物21、化合物23、YK-009和HHMA相比,结构差异巨大。
与SM-102相比,YK-319的G1基团多1个C;R1基团为支链结构,而SM-102为直链结构;G2基团少1个C;R2基团单链多2个C,双链中每条单链少2个C;G3基团完全不同,为(HO(CH2)2)2NCH2CH(OH)CH2-,而SM-102为HO(CH2)2-。
与ALC-0315相比,YK-319的R1基团单链多2个C,双链中1条单链少2个C;R2基团单链多2个C,双链中1条单链少2个C;G3基团完全不同,为(HO(CH2)2)2NCH2CH(OH)CH2-,而ALC-0315为HO(CH2)4-。并且,G1基团和R1基团之间、G2基团和R2基团之间的酯键方向,YK-319与ALC-0315也均不相同。
与化合物21相比,YK-319的G1基团少1个C;G2基团少1个C;R2基团单链多2个C,双链中每条单链少2个C;G3基团完全不同,为(HO(CH2)2)2NCH2CH(OH)CH2-,而化合物21为HO(CH2)2-。
与化合物23相比,YK-319的G1基团少1个C;G2基团少1个C;G3基团完全不同,为(HO(CH2)2)2NCH2CH(OH)CH2-,而化合物23为HO(CH2)2-。
与YK-009相比,YK-319的G1基团多3个C;R1基团为支链结构,而YK-009为直链结构;G2基团多1个C;R2基团单链多1个C,双链中每条单链少2个C;G3基团完全不同,为(HO(CH2)2)2NCH2CH(OH)CH2-,而YK-009为HO(CH2)2-。
与HHMA相比,YK-319的结构完全不同,HHMA仅1个与N原子相连的侧链与YK-319的1个侧链结构相近,其它部分差异巨大。
V.YK-318
YK-318与现有技术阳离子脂质,例如SM-102、化合物21、化合物23、YK-009和HHMA相比,结构差异巨大。
与SM-102相比,YK-318的R1基团为支链结构,而SM-102为直链结构;G2基团少2个C;G3基团完全不同,为(HO(CH2)2)2NCH2CH(OH)CH2-,而SM-102为HO(CH2)2-。
与ALC-0315相比,YK-318的G1基团少1个C;R1基团双链中1条单链多2个C;G2基团少1个C;R2基团双链中1条单链多2个C;G3基团完全不同,为(HO(CH2)2)2NCH2CH(OH)CH2-,而ALC-0315为HO(CH2)4-。并且,G1基团和R1基团之间、G2基团和R2基团之间的酯键方向,YK-318与ALC-0315也均不相同。
与化合物21相比,YK-318的G1基团少2个C;R1基团单链少2个C,双链中每条单链多2个C;G2基团少2个C;G3基团完全不同,为(HO(CH2)2)2NCH2CH(OH)CH2-,而化合物21为HO(CH2)2-。
与化合物23相比,YK-318的G1基团少2个C;R1基团单链少2个C,双链中每条单链多2个C;G2基团少1个C;R2基团单链少2个C,双链中每条单链多2个C;G3基团完全不同,为(HO(CH2)2)2NCH2CH(OH)CH2-,而化合物23为HO(CH2)2-。
与YK-009相比,YK-318的G1基团多2个C;R1基团为支链结构,而YK-009为直链结构;R2基团单链少1个C;G3基团完全不同,为(HO(CH2)2)2NCH2CH(OH)CH2-,而YK-009为HO(CH2)2-。
与HHMA相比,YK-318的结构完全不同,HHMA仅1个与N原子相连的侧链与YK-318的1个侧链结构相近,其它部分差异巨大。
由以上比较可知,设计的此系列化合物,包括YK-305、YK-310、YK-312、YK-319和YK-318,在化学结构上与现有技术阳离子脂质化合物,例如SM-102、ALC-0315、化合物21、化合物23、HHMA和YK-009差别非常大。此系列化合物与HHMA结构完全不同;与SM-102、ALC-0315、化合物21、化合物23和YK-009的G3基团完全不同,此系列化合物的G3基团中多1个叔胺基团,并且多1-2个羟基,并且G1、G2、R1和R2基团也都差别巨大。
由于化学结构的巨大差异,此系列化合物的理化性质,如极性、酸碱性和亲水性等,同SM-102、ALC-0315、化合物21、化合物23、HHMA和YK-009相比,也会有巨大差异。因此,无法根据现有技术公开的上述阳离子脂质化合物,推测出由此系列化合物制备的LNP制剂的细胞转染效率、细胞毒性,以及
在动物体内表达情况。
(2)设计的一系列化合物中,由YK-305、YK-310、YK-312、YK-319和YK-318制备的LNP制剂细胞转染效率最高,相比于现有技术中代表性阳离子脂质显著提高。例如,YK-305可达SM-102的17倍、化合物21的19倍和化合物23的20倍。
表4 设计的化合物与现有技术代表性阳离子脂质化学结构
表5 Fluc-mRNA的荧光检测结果-1
细胞转染效率差别
表4显示了设计的化合物与现有技术代表性阳离子脂质化学结构区别。表5列出了由不同阳离子脂质制备的含有Fluc-mRNA的LNP制剂荧光检测结果。其中YK-009在CN114044741B中公开(权利要求1),化合物21和化合物23在WO2021055833A1中公开(说明书第22页),SM-102是WO2017049245A2中公开的化合物25(说明书第29页),ALC-0315是CN108368028B中公开的化合物3(说明书第24页),HHMA为CN112979483B中公开的化合物1(说明书第12页);Lipofectamine 3000是目前广泛应用的细胞转染试剂。这些阳离子脂质是现有技术中代表性的阳离子脂质,具有较好的转染性能。
由表5和图5可知,由YK-305、YK-310、YK-312、YK-319和YK-318制备的含有Fluc-mRNA的LNP制剂,荧光吸收最强,RLU值分别为27408734、25797040、20148450、24467760和11190068。
YK-305可达SM-102的17.09倍、ALC-0315的13.48倍、化合物21的19.14倍、化合物23的20.21倍、HHMA的13.66倍、Lipofectamine 3000的23.12倍和YK-009的5.35倍。
YK-310可达SM-102的16.08倍、ALC-0315的12.69倍、化合物21的18.01倍、化合物23的19.02倍、HHMA的12.86倍、Lipofectamine 3000的21.76倍和YK-009的5.04倍。
YK-312可达SM-102的12.56倍、ALC-0315的9.91倍、化合物21的14.07倍、化合物23的14.86倍、HHMA的10.04倍、Lipofectamine 3000的16.99倍和YK-009的3.94倍。
YK-319可达SM-102的15.25倍、ALC-0315的12.03倍、化合物21的17.08倍、化合物23的18.04倍、HHMA的12.20倍、Lipofectamine 3000的20.63倍和YK-009的4.78倍。
YK-318可达SM-102的6.98倍、ALC-0315的5.50倍、化合物21的7.81倍、化合物23的8.25倍、HHMA的5.58倍、Lipofectamine 3000的9.44倍和YK-009的2.19倍。
用GraphPad Prism软件对数据进行分析,YK-305、YK-310、YK-312、YK-319和YK-318中的任一个,与SM-102、ALC-0315、化合物21、化合物23、HHMA、Lipofectamine 3000和YK-009均有显著差异,转染效率显著提高。
小结:
化学结构方面,设计的一系列化合物,包括YK-305、YK-310、YK-312、YK-319和YK-318,与现有技术代表性阳离子脂质相比差异非常大,例如,与HHMA结构完全不同;与SM-102、ALC-0315、化合物21、化合物23和YK-009相比,G3基团完全不同,G1、G2、R1和R2基团也都区别非常大。
由YK-305、YK-310、YK-312、YK-319和YK-318制备的LNP制剂细胞转染效率最高,相比于现有技术中代表性阳离子脂质活性显著提高,例如,YK-305可达SM-102的17倍、化合物21的19倍和化合物23的20倍。
同时,本申请首次设计了与现有技术阳离子脂质化学结构差异巨大的化合物,由其制备的LNP制剂具有显著提高的转染效率、显著增强的细胞转染活性。
(3)YK-305、YK-310、YK-312、YK-319和YK-318,与结构类似、G3基团为HO(CH2)2N(CH3)CH2CH(OH)CH2-的一系列化合物相比,细胞转染效率最高。例如,YK-305可达YK-304的1300倍和YK-302的900倍。
我们把结构类似、G3基团为HO(CH2)2N(CH3)CH2CH(OH)CH2-的一系列化合物与YK-305、YK-310、YK-312、YK-319和YK-318进行了比较。这些化合物结构上的区别仅在于:G1、G2、G3、R1或R2基团稍有不同(表6)。结果表明,此系列化合物活性差别非常大,其中YK-305、YK-310、YK-312、YK-319和YK-318的细胞转染效率最高,分别可达活性最低的YK-304的1300倍、1200倍、900倍、1100倍和400倍,转染效率显著提高。
表6 设计的化合物化学结构
表7 Fluc-mRNA的荧光检测结果-2
a.细胞转染效率差别
从表7和图6可以看出,这些化合物制备的LNP制剂,荧光吸收值与YK-305、YK-310、YK-312、YK-319和YK-318相差很大。
YK-305可达YK-301的32.53倍、YK-302的986.71倍、YK-303的43.76倍、YK-304的1324.99倍、YK-306的12.47倍和YK-307的6.01倍。
YK-310可达YK-301的30.62倍、YK-302的928.69倍、YK-303的41.19倍、YK-304的1247.08倍、YK-306的11.74倍和YK-307的5.66倍。
YK-312可达YK-301的23.92倍、YK-302的725.34倍、YK-303的32.17倍、YK-304的974.01倍、YK-306的9.17倍和YK-307的4.42倍。
YK-319可达YK-301的29.04倍、YK-302的880.83倍、YK-303的39.07倍、YK-304的1182.82倍、YK-306的11.14倍和YK-307的5.37倍。
YK-318可达YK-301的13.28倍、YK-302的402.84倍、YK-303的17.87倍、
YK-304的540.95倍、YK-306的5.09倍和YK-307的2.46倍。
YK-301、YK-302、YK-303、YK-304、YK-306和YK-307之间的活性差别也较大。YK-306和YK-307细胞转染效率均比SM-102要强,分别可达SM-102的1.37倍和2.84倍;YK-301和YK-303与SM-102相差不大,稍低一些,分别是其0.53倍和0.39倍;YK-302和YK-304的细胞转染效率最低,仅为SM-102的0.017倍和0.013倍。
用GraphPad Prism软件对数据进行分析,YK-305、YK-310、YK-312、YK-319和YK-318中的任一个,与YK-301、YK-302、YK-303、YK-304、YK-306和YK-307相比,均有显著差异,转染效率显著提高。
b.化学结构差别
此系列化合物与YK-305、YK-310、YK-312、YK-319和YK-318结构非常类似,只是G1、G2、G3、R1或R2基团稍有差别。此系列化合物之间也都非常类似(见表6)。
I.与YK-305结构区别
与YK-305相比,YK-304仅是R1基团和R2基团为直链结构,而YK-305为支链结构;其它结构完全相同,但细胞转染效率YK-305达到了YK-304的1324.99倍。
与YK-305相比,YK-302仅是G1基团少2个C;R1基团为直链结构,而YK-305为支链结构;R2基团单链多1个C,双链中每条单链少2个C;其它结构完全相同,但细胞转染效率YK-305达到了YK-302的986.71倍。
与YK-305相比,YK-303仅是R1基团为直链结构,而YK-305为支链结构;G2基团少2个C;R2基团单链多2个C,双链中每条单链多2个C;其它结构完全相同,但细胞转染效率YK-305是YK-303的43.76倍。
II.与YK-310结构区别
与YK-310相比,YK-304仅是G2基团多2个C;R2基团为直链结构,而YK-310为支链结构;G3基团中与N相连的基团少1个C;其它结构完全相同,但细胞转染效率YK-310达到了YK-304的1247.08倍。
与YK-310相比,YK-302仅是G1基团少2个C;R1基团少1个C;G2基团多2个C;R2基团单链少1个C,双链中每条单链少4个C;G3基团中与N相连的基团少1个C;其它结构完全相同,但细胞转染效率YK-310达到了YK-302的928.69倍。
与YK-310相比,YK-303仅是G3基团与N相连的基团少1个C;其它结构完全相同,但细胞转染效率YK-310是YK-303的41.19倍。
III.与YK-312结构区别
与YK-312相比,YK-304仅是R1基团和R2基团为直链结构,而YK-312为支链结构;G3基团与N相连的基团少1个C;其它结构完全相同,但细胞转染效率YK-312达到了YK-304的974.01倍。
与YK-312相比,YK-302仅是G1基团少2个C;R1基团为直链结构,而YK-312为支链结构;R2基团单链多1个C,双链中每条单链少2个C;G3基团中与N相连的基团少1个C;其它结构完全相同,但细胞转染效率YK-312达到了YK-302的725.34倍。
与YK-312相比,YK-303仅是R1基团为直链结构,而YK-312为支链结构;G2基团少2个C;R2基团单链多2个C,双链中每条单链多2个C;G3基团中与N相连的基团少1个C;其它结构完全相同,但细胞转染效率YK-312是YK-303的32.17倍。
IV.与YK-319结构区别
与YK-319相比,YK-304仅是G1基团和G2基团各少1个C;R1基团和R2基团为直链结构,而YK-319为支链结构;G3基团中与N相连的基团少1个羟甲基;其它结构完全相同,但细胞转染效率YK-319达到了YK-304的1182.82倍。
与YK-319相比,YK-302仅是G1基团少3个C;R1基团为直链结构,而YK-319为支链结构;G2基团少1个C;G3基团与N相连的基团少1个羟甲基;其它结构完全相同,但细胞转染效率YK-319达到了YK-302的880.83倍。
与YK-319相比,YK-306仅是G1基团和G2基团各少1个C;G3基团与N相连的基团少1个羟甲基;其它结构完全相同,但细胞转染效率YK-319为YK-306的11.14倍。
V.与YK-318结构区别
与YK-318相比,YK-304仅是R1基团和R2基团为直链结构,而YK-318为支链结构;G3基团中与N相连的基团少1个羟甲基;其它结构完全相同,但细胞转染效率YK-318达到了YK-304的540.95倍。
与YK-318相比,YK-302仅是G1基团少2个C;R1基团为直链结构,而YK-318为支链结构;G3基团与N相连的基团少1个羟甲基;其它结构完全相同,但细胞转染效率YK-318达到了YK-302的402.84倍。
与YK-318相比,YK-303仅是R1基团为直链结构,而YK-318为支链结构;G2基团少2个C;R2基团单链多3个C,双链中每条单链各多2个C;G3基团与N相连的基团少1个羟甲基;其它结构完全相同,但细胞转染效率YK-318为YK-303的17.87倍。
小结:
在我们设计的一系列结构非常类似的化合物中,与结构类似、G3基团为HO(CH2)2N(CH3)CH2CH(OH)CH2-的化合物相比,YK-305、YK-310、YK-312、YK-319和YK-318细胞转染效率最高。例如,YK-305可比YK-304提高1300倍,比YK-302提高900倍。
同时我们发现,化合物的结构和细胞内转染效率之间无对应关系,即使是结构非常类似的一组化合物,在细胞转染效率方面也极有可能差异非常大。
因此,从一系列结构非常相近的化合物中,筛选出具有高转染效率的阳离子脂质化合物非常困难,需要付出大量创造性劳动。
(4)YK-305、YK-310、YK-312、YK-319和YK-318,与结构类似、G3基团为HO(CH2)2N(CH2CH3)CH2CH(OH)CH2-的一系列化合物相比,细胞转染效率最高。例如,YK-305可达YK-309的200倍以上。
我们把结构类似、G3基团为HO(CH2)2N(CH2CH3)CH2CH(OH)CH2-的一系列化合物与YK-305、YK-310、YK-312、YK-319和YK-318进行了比较。这些化合物结构上的区别仅在于:G1、G2、G3、R1或R2基团稍有不同(见表8)。结果表明,此系列化合物活性差别非常大,其中YK-305、YK-310、YK-312、YK-319和YK-318的细胞转染效率最高,分别可达活性最低的YK-309的210倍、200倍、160倍、190倍和90倍,转染效率显著提高。
表8 设计的化合物化学结构
表9 Fluc-mRNA的荧光检测结果-3
a.细胞转染效率差别
虽然与YK-305、YK-310、YK-312、YK-319和YK-318相比,其它化合物只是G1、R1、G2、R2或G3基团有一些较小的区别(见表8),但对细胞转染效率的影响却非常大,相差可达到200倍以上。
具体来说,从表9可以看出,由YK-309制备的LNP制剂的荧光吸收值与YK-305、YK-310、YK-312、YK-319和YK-318差别非常大。
YK-305、YK-310、YK-312、YK-319和YK-318分别可达YK-309的218.62倍、205.77倍、160.71倍、195.16倍和89.26倍。
由YK-311、YK-313、YK-314和YK-315制备的LNP制剂的荧光吸收值与YK-305、YK-310、YK-312、YK-319和YK-318相比,转染效率相差很大。
YK-305为YK-311的13.96倍、YK-313的31.63倍、YK-314的倍50.07和YK-
315的17.27倍。
YK-310为YK-311的13.14倍、YK-313的29.77倍、YK-314的47.12倍和YK-315的16.25倍。
YK-312为YK-311的10.26倍、YK-313的23.25倍、YK-314的36.81倍和YK-315的12.69倍。
YK-319为YK-311的12.46倍、YK-313的28.24倍、YK-314的44.70倍和YK-315的15.42倍。
YK-318为YK-311的5.70倍、YK-313的12.91倍、YK-314的20.44倍和YK-315的7.05倍。
由YK-308制备的LNP制剂的荧光吸收值与YK-305、YK-310、YK-312、YK-319和YK-318相比,转染效率也相差较大。
YK-305、YK-310、YK-312、YK-318和YK-319分别为YK-308的5.44倍、5.12倍、4.00倍、4.86倍和2.22倍。
用GraphPad Prism软件对数据进行分析,YK-305、YK-310、YK-312、YK-319和YK-318中的任一个,与其它化合物均有显著差异,细胞转染效率显著提高。
b.化学结构差别
此系列化合物与YK-305、YK-310、YK-312、YK-319和YK-318结构非常类似,只是G1、G2、G3、R1或R2基团稍有差别。此系列化合物之间也都非常类似(见表8)。
I.与YK-305结构区别
与YK-305相比,YK-309仅是G1基团少2个C;R1基团为直链结构,而YK-305为支链结构;R2基团单链多1个C,双链中每条单链少2个C;G3基团与N相连的基团多1个C;其它结构完全相同,但细胞转染效率YK-305达到了YK-309的218.62倍。
与YK-305相比,YK-314仅是G1和G2基团各多2个C;R1和R2基团单链各少1个C;G3基团与N相连的基团多1个C;其它结构完全相同,但细胞转染效率YK-305达到了YK-314的50.07倍。
与YK-305相比,YK-313仅是R1和R2基团单链各少1个C;G3基团与N相连的基团多1个C;其它结构完全相同,但细胞转染效率YK-305达到了YK-313的31.63倍。
II.与YK-310结构区别
与YK-310相比,YK-309仅是G1基团少2个C;R1基团少1个C;G2基团多2个
C;R2基团单链少1个C,双链中每条单链少4个C;其它结构完全相同,但细胞转染效率YK-310达到了YK-309的205.77倍。
与YK-310相比,YK-314仅是G1基团多2个C;R1基团为支链结构,而YK-310为直链结构;G2基团多4个C;R2基团单链少3个C,双链中每条单链少2个C;其它结构完全相同,但细胞转染效率YK-310达到了YK-314的47.12倍。
与YK-310相比,YK-313仅是R1基团为支链结构,而YK-310为直链结构;G2基团多2个C;R2基团单链少3个C,双链中每条单链少2个C;其它结构完全相同,但细胞转染效率YK-310达到了YK-313的29.77倍。
III.与YK-312结构区别
与YK-312相比,YK-309仅是G1基团少2个C;R1基团为直链结构,而YK-312为支链结构;R2基团单链多1个C,双链中每条单链少2个C;其它结构完全相同,但细胞转染效率YK-312达到了YK-309的160.71倍。
与YK-312相比,YK-314仅是G1和G2基团各多2个C;R1和R2基团单链各少1个C;其它结构完全相同,但细胞转染效率YK-312达到了YK-314的36.81倍。
与YK-312相比,YK-313仅是R1和R2基团单链各少1个C;其它结构完全相同,但细胞转染效率YK-312达到了YK-313的23.25倍。
IV.与YK-319结构区别
与YK-319相比,YK-309仅是G1基团少3个C;R1基团为直链结构,而YK-319为支链结构;G2基团少1个C;G3基团中与N相连的基团少1个羟基;其它结构完全相同,但细胞转染效率YK-319达到了YK-309的195.16倍。
与YK-319相比,YK-314仅是G1和G2基团各多1个C;R1和R2基团单链各少2个C,双链中每条单链各多2个C;G3基团中与N相连的基团少1个羟基;其它结构完全相同,但细胞转染效率YK-319达到了YK-314的44.70倍。
与YK-319相比,YK-313仅是G1和G2基团各少1个C;R1和R2基团单链各少2个C,双链中每条单链各多2个C;G3基团中与N相连的基团少1个羟基;其它结构完全相同,但细胞转染效率YK-319达到了YK-313的28.24倍。
V.与YK-318结构区别
与YK-318相比,YK-309仅是G1基团少2个C;R1基团为直链结构,而YK-318为支链结构;G3基团中与N相连的基团少1个羟基;其它结构完全相同,但细胞转染效率YK-318达到了YK-309的89.26倍。
与YK-318相比,YK-314仅是G1和G2基团各少2个C;G3基团中与N相连的基团少1个羟基;其它结构完全相同,但细胞转染效率YK-318达到了YK-314的20.44倍。
与YK-318相比,YK-313仅是G3基团中与N相连的基团少1个羟基;其它结构完全相同,但细胞转染效率YK-318达到了YK-313的12.91倍。
小结:
在我们设计的一系列结构非常类似的化合物中,与结构类似、G3基团为HO(CH2)2N(CH2CH3)CH2CH(OH)CH2-的化合物相比,YK-305、YK-310、YK-312、YK-319和YK-318细胞转染效率最高。例如,YK-305和YK-310可比YK-309高200倍。
同时我们发现,化合物的结构和细胞内转染效率之间无对应关系,即使是结构非常类似的一组化合物,在细胞转染效率方面也极有可能差异非常大。
因此,从一系列结构非常相近的化合物中,筛选出具有高转染效率的阳离子脂质化合物非常困难,需要付出大量创造性劳动。
(5)YK-305、YK-310、YK-312、YK-319和YK-318,与结构类似、G3基团为(HO(CH2)2)2NCH2CH(OH)CH2-的一系列化合物相比,细胞转染效率最高。例如,YK-305可达YK-321的20倍。
YK-305、YK-310、YK-312、YK-319和YK-318,与结构相近、G3基团为(HO(CH2)2)2NCH2CH(OH)CH2-化合物相比(见表10),细胞转染效率最高。例如,YK-305可达YK-321的20倍。
表10 设计的化合物化学结构
表11 Fluc-mRNA的荧光检测结果-4
a.细胞转染效率差别
与结构相近、G3基团为(HO(CH2)2)2NCH2CH(OH)CH2-化合物(见表10)相比,YK-305、YK-310、YK-312、YK-319和YK-318细胞转染效率最高,例如,YK-305可达YK-321的20倍。
具体如下:
从表11可以看出,YK-321与YK-305、YK-310、YK-312、YK-318和YK-319相差很大。
YK-305、YK-310、YK-312、YK-319和YK-318分别为YK-321的19.53倍、18.38倍、14.36倍、17.43倍和7.97倍。
此外,YK-316、YK-317和YK-320与YK-305、YK-310、YK-312、YK-319和YK-318相比,均相差较大。
YK-305分别可达YK-316的5.70倍、YK-317的7.60倍和YK-320的10.14倍。
YK-310分别可达YK-316的5.36倍、YK-317的7.16倍和YK-320的9.54倍。
YK-312分别可达YK-316的4.19倍、YK-317的5.59倍和YK-320的7.45倍。
YK-319分别可达YK-316的5.09倍、YK-317的6.79倍和YK-320的9.05倍。
YK-318分别可达YK-316的2.33倍、YK-317的3.10倍和YK-320的4.14倍。
图7所示为由YK-305、YK-310、YK-320和YK-321制备的LNP制剂的荧光吸收图片,可以看出,同YK-305和YK-310相比,YK-320和YK-321的荧光吸收非常弱。
用GraphPad Prism软件对数据进行分析,YK-305、YK-310、YK-312、YK-319和YK-318中的任一个,与其它化合物均有显著差异,转染效率显著提高。
b.化学结构差别
此系列化合物与YK-305、YK-310、YK-312、YK-319和YK-318结构非常类似,只是G1、G2、G3、R1或R2基团稍有差别。此系列化合物之间结构也都非常类似。(见表10)
I.与YK-305结构区别
与YK-305相比,YK-321仅是G1和G2基团各少2个C;R1和R2基团单链各多2个C,双链中每条单链各多2个C;G3基团与N相连的基团多1个羟甲基;其它结构完全相同,但细胞转染效率YK-305达到了YK-321的19.53倍。
与YK-305相比,YK-320仅是G1和G2基团各多2个C;R1和R2基团单链各少1个C;G3基团与N相连的基团多1个羟甲基;其它结构完全相同,但细胞转染效率YK-305达到了YK-320的10.14倍。
与YK-305相比,YK-316仅是G3基团与N相连的基团多1个羟甲基;其它结构完全相同,但细胞转染效率YK-305达到了YK-316的5.70倍。
II.与YK-310结构区别
与YK-310相比,YK-321仅是G1基团少2个C;R1基团为支链结构,而YK-310为直链结构;G3基团与N相连的基团多1个羟基;其它结构完全相同,但细胞转染效率YK-310达到了YK-321的18.38倍。
与YK-310相比,YK-320仅是G1基团多2个C;R1基团为支链结构,而YK-310为直链结构;G2基团多4个C;R2基团单链少3个C,双链中每条单链各少2个C;G3基团与N相连的基团多1个羟基;其它结构完全相同,但细胞转染效率YK-310达到了YK-320的9.54倍。
与YK-310相比,YK-317仅是R1基团为支链结构,而YK-310为直链结构;G2基团多2个C;R2基团单链少1个C,双链中每条单链各少4个C;G3基团与N相连的基团多1个羟基;其它结构完全相同,但细胞转染效率YK-310达到了YK-317的7.16倍。
III.与YK-312结构区别
与YK-312相比,YK-321仅是G1和G1基团各少2个C;R1和R2基团单链各多2个C,双链中每条单链各多2个C;G3基团与N相连的基团多1个羟基;其它结构完全相同,但细胞转染效率YK-312达到了YK-321的14.36倍。
与YK-312相比,YK-320仅是G1和G1基团各多2个C;R1和R2基团单链各少1个C;G3基团与N相连的基团多1个羟基;其它结构完全相同,但细胞转染效率YK-312达到了YK-320的7.45倍。
与YK-312相比,YK-316仅是G3基团与N相连的基团多1个羟基;其它结构完全相同,但细胞转染效率YK-312达到了YK-316的4.19倍。
IV.与YK-319结构区别
与YK-319相比,YK-321仅是G1和G1基团各少3个C;R1和R2基团单链各多1个C,双链中每条单链各多4个C;其它结构完全相同,但细胞转染效率YK-319达到了YK-321的17.43倍。
与YK-319相比,YK-320仅是G1和G1基团各多1个C;R1和R2基团单链各少2个C,双链中每条单链各多2个C;其它结构完全相同,但细胞转染效率YK-319达到了YK-320的9.05倍。
与YK-319相比,YK-317仅是G1和G1基团各少1个C;它结构完全相同,但细胞转染效率YK-319达到了YK-317的6.79倍。
V.与YK-318结构区别
与YK-318相比,YK-321仅是G1和G2基团各少2个C;R1和R2基团单链各多3个C,双链中每条单链各多2个C;其它结构完全相同,但细胞转染效率YK-318达到了YK-321的7.97倍。
与YK-318相比,YK-320仅是G1和G2基团各多2个C;其它结构完全相同,但细胞转染效率YK-318达到了YK-320的4.14倍。
与YK-318相比,YK-316仅是R1和R2基团单链各多1个C;其它结构完全相同,但细胞转染效率YK-318达到了YK-316的2.33倍。
小结:
在我们设计的一系列结构非常类似的化合物中,与结构类似、G3基团为(HO(CH2)2)2NCH2CH(OH)CH2-的化合物相比,YK-305、YK-310、YK-312、YK-319和YK-318细胞转染效率最高。例如,YK-305可达YK-321的20倍。
同时我们发现,根据结构差别完全无法推测出不同化合物(无论结构相近还是差异巨大)之间细胞转染效率的差别,即使是结构上差别很小的一组化合物,在细胞转染效率方面也极有可能差异非常大。
因此,从一系列化学结构相近的化合物中,筛选出具有高转染效率的阳离
子脂质化合物非常困难,需要付出大量创造性劳动。
总结:
1)通过对化合物结构的多种设计和大量创造性劳动,我们设计并筛选出了具有高细胞转染效率的阳离子脂质化合物,例如YK-305、YK-310、YK-312、YK-319和YK-318。
设计的此系列化合物与现有技术中代表性阳离子脂质,例如SM-102、ALC-0315、化合物21、化合物23、HHMA和YK-009化学结构差异巨大,G3基团完全不同,其它部位也均有差别,因此在极性、酸碱性和亲水性等方面也会有很大差别。无法根据现有技术公开的上述阳离子脂质化合物,推测出由此系列化合物制备的LNP制剂的细胞转染效率、细胞毒性,以及在动物体内表达情况。
2)由YK-305、YK-310、YK-312、YK-319和YK-318制备的LNP制剂细胞转染效率最高,相比于现有技术中代表性阳离子脂质活性显著提高。例如,YK-305可达SM-102的17倍,化合物21的19倍,化合物23的20倍。
与结构类似、G3基团为HO(CH2)2N(CH3)CH2CH(OH)CH2-的化合物相比,YK-305、YK-310、YK-312、YK-319和YK-318细胞转染效率最高。例如,YK-305可比YK-304提高1300倍,比YK-302提高900倍。
与结构类似、G3基团为HO(CH2)2N(CH2CH3)CH2CH(OH)CH2-的化合物相比,YK-305、YK-310、YK-312、YK-319和YK-318细胞转染效率最高。例如,YK-305和YK-310均可比YK-309提高200倍。
与结构类似、G3基团为(HO(CH2)2)2NCH2CH(OH)CH2-的化合物相比,YK-305、YK-310、YK-312、YK-319和YK-318细胞转染效率最高。例如,YK-305可达YK-321的20倍。
3)化合物的结构和细胞内转染效率之间无对应关系,结构差异很小的化合物,在转染效率方面也极有可能差异非常大。因此,筛选出具有高转染效率的阳离子脂质化合物,需要进行多种设计,并付出大量创造性劳动。
2.细胞存活率测定
将含有1.5μg Fluc-mRNA的LNP制剂(LNP制剂载体组分为阳离子脂质、中性脂质、结构脂质和聚合物共轭脂质,摩尔比为49:10:39.5:1.5,其中阳离子脂质为表1中所列阳离子脂质)以及Lipofectamine 3000制剂加入96孔板的细胞培养液中,继续培养24小时后,向每孔中加入10μL CCK-8溶液,将培养板在培养箱中孵育1小时后,经酶标仪测定在450nm处的吸光度。结果见表12-15。
细胞存活率可以代表阳离子脂质对细胞的毒性,细胞存活率越高,表示对细胞的毒性越低。
实验结果:
(1)设计的一系列化合物中,由YK-305、YK-310、YK-312、YK-319和YK-318制备的LNP制剂,相比于现有技术中代表性阳离子脂质细胞毒性显著降低,细胞存活率显著提高。例如,YK-305和YK-310细胞存活率分别可比SM-102高12.73%和12.65%,分别比HHMA高15.71%和15.63%。
表12 细胞存活率-1
a.细胞存活率差别
表12列出了由不同阳离子脂质化合物制备的LNP制剂细胞毒性检测结果。其中YK-009在CN114044741B中公开(权利要求1),SM-102是WO2017049245A2中公开的化合物25(说明书第29页),ALC-0315是CN108368028B中公开的化合物3(说明书第24页),化合物21和化合物23在WO2021055833A1中公开(说明书第22页),HHMA为CN112979483B中公开的化合物1(说明书第12页);Lipofectamine3000是目前广泛应用的细胞转染试剂,具有较好的转染性能。
由表12可知,由YK-305、YK-310、YK-312、YK-319和YK-318制备的Fluc-mRNA的LNP制剂,细胞毒性最低,表现为细胞存活率分别可达82.18%、82.10%、76.96%、75.21%和75.56%。(图8)
YK-305比SM-102高12.73%,比ALC-0315高31.15%,比化合物21高11.97%,比化合物23高10.68%,比HHMA高15.71%,比Lipofectamine 3000高
57.17%。
YK-310比SM-102高12.65%,比ALC-0315高31.07%,比化合物21高11.89%,比化合物23高10.60%,比HHMA高15.63%,比Lipofectamine 3000高57.09%。
YK-312比SM-102高7.51%,比ALC-0315高25.93%,比化合物21高6.75%,比化合物23高5.46%,比HHMA高10.49%,比Lipofectamine 3000高51.95%。
YK-319比SM-102高5.76%,比ALC-0315高24.18%,比化合物21高5.00%,比化合物23高3.71%,比HHMA高8.74%,比Lipofectamine 3000高50.20%。
YK-318比SM-102高6.11%,比ALC-0315高24.53%,比化合物21高5.35%,比化合物23高4.06%,比HHMA高9.09%,比Lipofectamine 3000高50.55%。
用GraphPad Prism软件对数据进行分析,其中YK-305、YK-310、YK-312、YK-319和YK-318中的任一个,与SM-102、ALC-0315、化合物21、化合物23、HHMA和Lipofectamine 3000均具有显著差异,细胞毒性显著降低。
b.化学结构差别
YK-305、YK-310、YK-312、YK-319和YK-318与现有技术阳离子脂质相比,化学结构差别非常大,其中与HHMA结构差别最大,从化学结构图中可以看出,HHMA与中心N原子相连的基团,仅1个侧链与此系列结构的1个侧链相近,其它部分完全不同;与SM-102、ALC-0315、化合物21、化合物23和YK-009相比,G3基团完全不同,G1、R1、G2和R2基团也有巨大差别。
小结:
设计的一系列化合物中,由YK-305、YK-310、YK-312、YK-319和YK-318制备的LNP制剂细胞毒性最低,与现有技术中代表性阳离子脂质相比,细胞存活率显著提高。例如,YK-305和YK-310细胞存活率均可比ALC-0315高30%,比SM-102高12%,比HHMA高15%。
YK-305、YK-310、YK-312、YK-319和YK-318与现有技术中代表性阳离子脂质相比,化学结构差异巨大,G3基团完全不同,G1、R1、G2和R2基团也有巨大差别。
本申请首次设计的与现有技术阳离子脂质化学结构差异巨大的化合物,由其制备的LNP制剂,相比于现有技术阳离子脂质,细胞毒性显著降低,细胞存活率显著提高。
(2)YK-305、YK-310、YK-312、YK-319和YK-318,与结构类似、G3基团为HO(CH2)2N(CH3)CH2CH(OH)CH2-的一系列化合物相比,细胞毒性最低,细胞存活率显著提高。例如,YK-305和YK-310与YK-302相比,细胞存活率均提
高65%。
我们把YK-305、YK-310、YK-312、YK-319和YK-318与结构类似、G3基团为HO(CH2)2N(CH3)CH2CH(OH)CH2-的一系列化合物进行了比较,这些化合物仅是G1、G2、G3、R1或R2基团稍有差别。
结果表明,此系列化合物细胞毒性差异非常显著。其中YK-305、YK-310、YK-312、YK-319和YK-318细胞存活率最高,例如,YK-305和YK-310均可比YK-302提高65%。
表13 细胞存活率-2
a.细胞存活率差别
由表13可知,这些化合物制备的LNP制剂,细胞毒性差别很大,其中YK-302毒性最高,细胞存活率最低,仅为16.43%。(图9)
YK-305、YK-310、YK-312、YK-319和YK-318细胞存活率分别比YK-302提高达65.75%、65.67%、60.53%、58.78%和59.13%。
其它化合物与YK-305、YK-310、YK-312、YK-319和YK-318相比,细胞存活率也相差较大。
YK-305细胞存活率分别比YK-301高29.22%、比YK-303高18.86%、比YK-304高48.02%、比YK-306高39.99%、比YK-307高21.04%。
YK-310细胞存活率分别比YK-301高29.14%、比YK-303高18.78%、比YK-304高47.94%、比YK-306高39.91%、比YK-307高20.96%。
YK-312细胞存活率分别比YK-301高24.00%、比YK-303高13.64%、比YK-304高42.80%、比YK-306高34.77%、比YK-307高15.82%。
YK-319细胞存活率分别比YK-301高22.25%、比YK-303高11.89%、比YK-304高41.05%、比YK-306高33.02%、比YK-307高14.07%。
YK-318细胞存活率分别比YK-301高22.60%、比YK-303高12.24%、比YK-304高41.40%、比YK-306高33.37%、比YK-307高14.42%。
用GraphPad Prism软件对数据进行分析,其中YK-305、YK-310、YK-312、YK-319和YK-318中任一个,与其它化合物在细胞毒性上均具有显著差异,细胞毒性显著降低,细胞存活率显著提高。
b.化学结构差别
此系列化合物之间结构非常类似,只是个别基团稍有区别。YK-305、YK-310、YK-312、YK-319和YK-318,与其它化合物结构非常接近;其它化合物之间也都非常类似。
小结:
在我们设计的一系列结构非常类似的化合物中,与结构类似、G3基团为HO(CH2)2N(CH3)CH2CH(OH)CH2-的化合物相比,YK-305、YK-310、YK-312、YK-319和YK-318细胞毒性最低,细胞存活率显著提高。例如,YK-305和YK-310与YK-302相比,均可提高65%。
同时我们发现,化合物的结构与细胞毒性之间无对应关系,即使是结构最为类似的一组化合物,细胞毒性也有极有可能差异非常大。
因此,从一系列化学结构仅有很小差别的化合物中,筛选出具有低细胞毒性的阳离子脂质化合物非常困难,需要付出大量创造性劳动。
(3)YK-305、YK-310、YK-312、YK-319和YK-318,与结构类似、G3基团为HO(CH2)2N(CH2CH3)CH2CH(OH)CH2-的一系列化合物相比,细胞毒性最低,细胞存活率显著提高。例如,YK-305和YK-310细胞存活率,均可比YK-
309提高50%。
我们把YK-305、YK-310、YK-312、YK-319和YK-318,与结构类似、G3基团为HO(CH2)2N(CH2CH3)CH2CH(OH)CH2-的一系列化合物进行了比较,这些化合物仅是G1、G2、G3、R1或R2基团稍有差别。
结果表明,此系列化合物细胞毒性差异非常显著。其中YK-305、YK-310、YK-312、YK-319和YK-318细胞存活率最高,例如,YK-305和YK-310均可比YK-309提高50%。
表14 细胞存活率-3
a.细胞存活率差别
虽然与YK-305、YK-310、YK-312、YK-319和YK-318相比,其它化合物只是G1、G2、G3、R1或R2基团上一些较小的区别,但对细胞毒性的影响却非常大。细胞存活率YK-305、YK-310、YK-312、YK-319和YK-318最多可比其它化合物高50%。
从表14中可以看出,此系列化合物中,由YK-309制备的LNP制剂,细胞毒性最高,细胞存活率仅为31.61%。
YK-305、YK-310、YK-312、YK-319和YK-318细胞存活率分别比YK-309提高50.57%、50.49%、45.35%、43.60%和43.95%。
其它化合物与YK-305、YK-310、YK-312、YK-319和YK-318相比,也相差较大。
YK-305细胞存活率分别比YK-308高11.19%、比YK-311高12.12%、比YK-313高13.25%、比YK-314高14.30%、比YK-315高10.90%。
YK-310细胞存活率分别比YK-308高11.11%、比YK-311高12.04%、比YK-313高13.17%、比YK-314高14.22%、比YK-315高10.82%。
YK-312细胞存活率分别比YK-308高5.97%、比YK-311高6.90%、比YK-313高8.03%、比YK-314高9.08%、比YK-315高5.68%。
YK-319细胞存活率分别比YK-308高4.22%、比YK-311高5.15%、比YK-313高6.28%、比YK-314高7.33%、比YK-315高3.93%。
YK-318细胞存活率分别比YK-308高4.57%、比YK-311高5.50%、比YK-313高6.63%、比YK-314高7.68%、比YK-315高4.28%。(图10)
用GraphPad Prism软件对数据进行分析,其中YK-305、YK-310、YK-312、YK-319和YK-318中的任一个,与YK-308、YK-309、YK-311、YK-313、YK-314和YK-315在细胞毒性上均具有显著差异,细胞毒性显著降低,细胞存活率显著提高。
b.化学结构差别
此系列化合物之间结构非常类似,只是个别基团稍有区别。YK-305、YK-310、YK-312、YK-319和YK-318,与其它化合物结构非常接近;其它化合物之间也都非常类似。
小结:
在我们设计的一系列结构非常类似的化合物中,与结构类似、G3基团为HO(CH2)2N(CH2CH3)CH2CH(OH)CH2-的化合物相比,YK-305、YK-310、YK-312、YK-319和YK-318细胞毒性最低,细胞存活率显著提高。例如,YK-305和YK-310可比YK-302提高50%。
同时我们发现,化合物的结构与细胞毒性之间无对应关系,结构上仅存在很小的区别的化合物,细胞毒性也有极有可能差异非常大。
因此,从一系列仅在个别基团有一些较小区别的化合物中,筛选出具有低细胞毒性的阳离子脂质化合物非常困难,需要付出大量创造性劳动。
(4)YK-305、YK-310、YK-312、YK-319和YK-318,与结构类似、G3基团为(HO(CH2)2)2NCH2CH(OH)CH2-的一系列化合物相比,细胞毒性显著降低。例如,YK-305和YK-310细胞存活率比YK-317,均提高20%。
我们把YK-305、YK-310、YK-312、YK-319和YK-318,与结构类似、G3基团为(HO(CH2)2)2NCH2CH(OH)CH2-的一系列化合物进行了比较,这些化合物仅是G1、G2、G3、R1或R2基团稍有差别。结果表明,此系列化合物细胞毒性差异非常显著。其中YK-305、YK-310、YK-312、YK-319和YK-318细胞存活率最高,例如,YK-305和YK-310可比YK-317,均提高20%。
表15 细胞存活率-4
a.细胞存活率差别
虽然与YK-305、YK-310、YK-312、YK-319和YK-318相比,其它化合物只是G1、G2、G3、R1或R2基团上一些较小的区别,但细胞毒性的差别却非常大。例如,YK-305和YK-310细胞存活率比YK-317均提高20%。
从表15可以看出,此系列结构相近的化合物中,YK-317细胞毒性最大,细胞存活率仅为59.18%。
YK-305、YK-310、YK-312、YK-319和YK-318细胞存活率分别比YK-317高23.00%、22.92%、17.78%、16.03%和16.38%。
其它化合物与YK-305、YK-310、YK-312、YK-319和YK-318相比,也相差较大。
YK-305细胞存活率分别比YK-316高11.65%、比YK-320高11.11%、比YK-321高9.84%。
YK-310细胞存活率分别比YK-316高11.57%、比YK-320高11.03%、比YK-321高9.76%。
YK-312细胞存活率分别比YK-316高6.43%、比YK-320高5.89%、比YK-321高4.62%。
YK-319细胞存活率分别比YK-316高4.68%、比YK-320高4.14%、比YK-321高2.87%。
YK-318细胞存活率分别比YK-316高5.03%、比YK-320高4.49%、比YK-321高3.22%。(图11)
用GraphPad Prism软件对数据进行分析,其中YK-305、YK-310、YK-312、YK-319和YK-318中的任一个,与YK-316、YK-317、YK-320和YK-321均具有显著差异,细胞毒性显著降低,细胞存活率显著提高。
b.化学结构差别
此系列化合物之间结构非常类似,只是个别基团稍有区别。YK-305、YK-310、YK-312、YK-319和YK-318,与其它化合物结构非常接近;其它化合物之间也都非常类似。
小结:
在我们设计的一系列结构非常类似的化合物中,与结构类似、G3基团为(HO(CH2)2)2NCH2CH(OH)CH2-的化合物相比,YK-305、YK-310、YK-312、YK-319和YK-318细胞毒性最低,细胞存活率显著提高。例如,YK-305和YK-310可比YK-317提高20%。
同时我们发现,化合物的结构与细胞毒性之间无对应关系,即使仅是G3基团结构上有一些区别,细胞毒性也有极有可能差异非常大。
因此,从一系列仅在个别基团有一些较小的区别的化合物中,筛选出具有低细胞毒性的阳离子脂质化合物非常困难,需要付出大量创造性劳动。
总结:
1)我们对由设计的一系列化合物制备得到的LNP制剂进行细胞存活率测定,筛选出了相对于现有技术的阳离子脂质化合物,具有显著降低细胞毒性的
化合物,例如YK-305、YK-310、YK-312、YK-319和YK-318。
设计的此系列化合物与现有技术中代表性阳离子脂质,例如SM-102、化合物21、化合物23、HHMA和YK-009化学结构差异巨大,G3基团完全不同,其它部位也均有差别,因此在极性、酸碱性和亲水性等方面也会有很大差别。
2)由YK-305、YK-310、YK-312、YK-319和YK-318制备的LNP制剂细胞毒性最低,相比于现有技术中代表性阳离子脂质细胞存活率显著提高。例如,YK-305和YK-310细胞存活率均可比ALC-0315高30%,比SM-102高12%,比HHMA高15%。
与结构类似、G3基团为HO(CH2)2N(CH3)CH2CH(OH)CH2-的化合物相比,YK-305、YK-310、YK-312、YK-319和YK-318细胞毒性最低,细胞存活率显著提高。例如,YK-305和YK-310可比YK-302提高65%。
与结构类似、G3基团为HO(CH2)2N(CH2CH3)CH2CH(OH)CH2-的化合物相比,YK-305、YK-310、YK-312、YK-319和YK-318细胞毒性最低,细胞存活率显著提高。例如,YK-305和YK-310可比YK-302提高50%。
与结构类似、G3基团为(HO(CH2)2)2NCH2CH(OH)CH2-的化合物相比,YK-305、YK-310、YK-312、YK-319和YK-318细胞毒性最低,细胞存活率显著提高。例如,YK-305和YK-310可比YK-317提高20%。
3)化合物的结构和细胞毒性之间无对应关系,即使结构差异很小的化合物,在细胞毒性方面也极有可能差异非常大。因此无法根据化学结构预测其细胞毒性,筛选出具有低细胞毒性的阳离子脂质化合物非常困难,需要付出大量创造性劳动。
实施例7:体内验证阳离子脂质递送载体的性能
另外,我们也验证了设计的阳离子脂质递送的mRNA在小鼠体内的蛋白质表达和持续时间。体内实验进一步证明了我们的LNP递送载体能将mRNA有效地递送至体内,并高效持续地表达。
将含有10μg Fluc-mRNA的LNP制剂经肌肉注射至4-6周龄、重量为17-19g的雌性BALB/C小鼠体内,并在给药后特定的时间节点(6h、24h、48h和7d)对小鼠进行腹腔注射荧光成像底物,小鼠自由活动5分钟,然后经IVIS Spectrum小动物活体成像仪检测LNP所携带的mRNA在小鼠体内表达的蛋白质的平均辐射强度(对应于荧光表达强度)。
实验结果:
a.mRNA在小鼠体内的表达
LNP制剂中mRNA在小鼠体内表达的蛋白质的平均辐射强度检测结果见表
16-19和图12-14。
(1)设计的一系列化合物中,由YK-305、YK-310、YK-312、YK-319和YK-318制备的LNP制剂,mRNA在小鼠体内以极高程度表达,且持续表达,相比于现有技术中代表性阳离子脂质显著提高。例如,YK-305和YK-310均可达SM-102、化合物21和化合物23的30倍。mRNA在小鼠体内表达方面与细胞转染活性一致。
表16 小鼠活体成像实验数据-1
a.小鼠体内表达差别
表16列出了由不同阳离子脂质制备的含有Fluc-mRNA的LNP制剂,在小鼠体内不同时间mRNA的表达强度。其中YK-009在CN114044741B中公开(权利要求1),SM-102是WO2017049245A2中公开的化合物25(说明书第29页),ALC-0315是CN108368028B中公开的化合物3(说明书第24页),化合物21和化合物23在WO2021055833A1中公开(说明书第22页),HHMA为CN112979483B中公开的化合物1(说明书第12页),这些阳离子脂质可用来制备递送mRNA的载体。
由表12可知,由YK-305、YK-310、YK-312、YK-319和YK-318制备的含有Fluc-mRNA的LNP制剂,mRNA在小鼠体内以极高程度表达,且持续表达。
YK-305平均辐射强度,在6h为9239340,是SM-102的13.18倍、ALC-0315的10.70倍、化合物21的15.14倍、化合物23的15.68倍和HHMA的14.19倍;在24h为2823400,是SM-102的23.44倍、ALC-0315的14.82倍、化合物21的25.70倍、化
合物23的27.01倍和HHMA的23.54倍;在48h为1047720,是SM-102的32.19倍、ALC-0315的26.32倍、化合物21的33.82倍、化合物23的31.63倍和HHMA的32.18倍;在7d为127015,是SM-102的19.18倍、ALC-0315的18.02倍、化合物21的19.71倍、化合物23的20.35倍和HHMA的21.63倍。
YK-310平均辐射强度,在6h为9125240,是SM-102的13.01倍、ALC-0315的10.56倍、化合物21的14.95倍、化合物23的15.48倍和HHMA的14.02倍;在24h为2952310,是SM-102的24.51倍、ALC-0315的15.50倍、化合物21的26.88倍、化合物23的28.24倍和HHMA的24.61倍;在48h为981000,是SM-102的30.14倍、ALC-0315的24.64倍、化合物21的31.67倍、化合物23的29.62倍和HHMA的30.13倍;在7d为117462,是SM-102的17.74倍、ALC-0315的16.67倍、化合物21的18.23倍、化合物23的18.82倍和HHMA的20.01倍。
YK-312平均辐射强度,在6h为8009850,是SM-102的11.42倍、ALC-0315的9.27倍、化合物21的13.12倍、化合物23的13.59倍和HHMA的12.30倍;在24h为2278520,是SM-102的18.91倍、ALC-0315的11.96倍、化合物21的20.74倍、化合物23的21.80倍和HHMA的19.00倍;在48h为813200,是SM-102的24.98倍、ALC-0315的20.43倍、化合物21的26.25倍、化合物23的24.55倍和HHMA的24.98倍;在7d为105500,是SM-102的15.93倍、ALC-0315的14.97倍、化合物21的16.37倍、化合物23的16.91倍和HHMA的17.97倍。
YK-319平均辐射强度,在6h为8230500,是SM-102的11.74倍、ALC-0315的9.53倍、化合物21的13.49倍、化合物23的13.96倍和HHMA的12.64倍;在24h为2433960,是SM-102的20.20倍、ALC-0315的12.78倍、化合物21的22.16倍、化合物23的23.28倍和HHMA的20.29倍;在48h为887680,是SM-102的27.27倍、ALC-0315的22.30倍、化合物21的28.65倍、化合物23的26.80倍和HHMA的27.27倍;在7d为104860,是SM-102的15.84倍、ALC-0315的14.88倍、化合物21的16.27倍、化合物23的16.80倍和HHMA的17.86倍。
YK-318平均辐射强度,在6h为3325680,是SM-102的4.74倍、ALC-0315的3.85倍、化合物21的5.45倍、化合物23的5.64倍和HHMA的5.11倍;在24h为968540,是SM-102的8.04倍、ALC-0315的5.08倍、化合物21的8.82倍、化合物23的9.27倍和HHMA的8.08倍;在48h为356810,是SM-102的10.96倍、ALC-0315的8.96倍、化合物21的11.52倍、化合物23的10.77倍和HHMA的10.96倍;在7d为50659,是SM-102的7.65倍、ALC-0315的7.19倍、化合物21的7.86倍、化合物23的8.12倍和HHMA的8.63倍。
用GraphPad Prism软件对数据进行分析,YK-305、YK-310、YK-312、YK-
319和YK-318中的任一个,与SM-102、ALC-0315、化合物21、化合物23、HHMA和YK-009在各个时间均具有显著差异,表达量和持续时间均显著提高。
b.化学结构差别
YK-305、YK-310、YK-312、YK-319和YK-318,与现有技术中阳离子脂质,例如SM-102、ALC-0315、化合物21、化合物23、HHMA和YK-009相比,化学结构差别非常大。其中与HHMA结构差异最大,HHMA除了与中心N原子相连的1个铡链与YK-305、YK-310、YK-312、YK-319和YK-318的1个侧链相近,其它结构完全不同。与SM-102、ALC-0315、化合物21、化合物23和YK-009相比,YK-305、YK-310、YK-312、YK-319和YK-318的G3基团完全不同,G1、R1、G2和R2基团也有很大差别。
小结:
设计的一系列化合物中,由YK-305、YK-310、YK-312、YK-319和YK-318制备的LNP制剂,mRNA在小鼠体内表达量最高,且持续表达,在6h、24h、48h和7d表达量均比现有技术中代表性阳离子脂质显著提高。例如,YK-305和YK-310可达SM-102、化合物21和化合物23的30倍。mRNA在小鼠体内表达方面与与实施例6中细胞转染实验结果一致。
并且,YK-305、YK-310、YK-312、YK-319和YK-318,与现有技术中代表性阳离子脂质结构差别非常大,G3基团完全不同,G1、R1、G2和R2基团也有巨大差别。
本申请预料不到地发现,本申请首次设计的与现有技术阳离子脂质结构差异巨大的化合物,由其制备的LNP制剂,mRNA极高程度地表达,且持续表达。
(2)YK-305、YK-310、YK-312、YK-319和YK-318,与结构类似、G3基团为HO(CH2)2N(CH3)CH2CH(OH)CH2-的一系列化合物相比,在小鼠体内mRNA表达量最高,且持续时间最长。例如,YK-305表达量可达YK-302的1000倍以上。mRNA在小鼠体内表达方面与细胞转染活性一致。
为了比较由结构非常接近,仅G1、G2、G3、R1或R2基团稍有不同的化合物制备的递送载体,递送的mRNA在小鼠体内表达强度及持续时间的差别,我们把结构类似、G3基团为HO(CH2)2N(CH3)CH2CH(OH)CH2-的一系列化合物与YK-305、YK-310、YK-312、YK-319和YK-318进行了比较。
结果表明,此系列化合物制备的LNP制剂,mRNA在小鼠体内表达差别非常大,其中YK-305、YK-310、YK-312、YK-319和YK-318表达量最高,且持续时间最长,例如,YK-305表达量可达到YK-302的1000倍以上。
表17 小鼠活体成像实验数据-2
a.小鼠体内表达差别
由表17可以看出,与结构类似、G3基团为HO(CH2)2N(CH3)CH2CH(OH)CH2-的一系列化合物相比,由YK-305、YK-310、YK-312、YK-319和YK-318制备的LNP制剂,mRNA在小鼠体内的表达量和持续时间均最高。
YK-305在6h可达YK-302的633.70倍,在24h可达713.70倍,在48h可达1022.17倍,在7d为330.77倍。
YK-310在6h可达YK-302的625.87倍,在24h可达746.29倍,在48h可达957.07倍,在7d为305.89倍。
YK-312在6h可达YK-302的549.37倍,在24h可达575.97倍,在48h可达793.37倍,在7d为274.74倍。
YK-319在6h可达YK-302的564.51倍,在24h可达615.26倍,在48h可达866.03倍,在7d为273.07倍。
YK-318在6h可达YK-302的228.10倍,在24h可达244.83倍,在48h可达348.11倍,在7d为131.92倍。
用GraphPad Prism软件对数据进行分析,YK-305、YK-310、YK-312、YK-319和YK-318中任一个,与其它化合物在各个时间均具有显著差异,表达量和持续时间均显著提高。
b.化学结构差别
此系列化合物与YK-305、YK-310、YK-312、YK-319和YK-318结构非常类
似,只是G1、G2、G3、R1或R2基团稍有差别。
小结:
与结构类似、G3基团为HO(CH2)2N(CH3)CH2CH(OH)CH2-的化合物相比,由YK-305、YK-310、YK-312、YK-319和YK-318制备的LNP制剂,mRNA在小鼠体内表达强度最高,持续时间最长。例如,YK-305在48h可达YK-302的1000倍以上,在7d仍可达300倍以上。mRNA在小鼠体内表达方面与实施例6中细胞转染实验结果一致。
我们还发现,mRNA在小鼠体内表达方面与阳离子脂质结构之间无对应关系,即使是由结构非常类似,仅G1、G2、G3、R1或R2基团稍有差别的一组化合物制备的LNP制剂,mRNA在小鼠体内表达程度和持续时间也极有可能差异非常大。
因此,从一系列结构最类似的化合物中筛选出在动物体内以极高程度表达且持续表达的阳离子脂质化合物非常困难,需要付出大量创造性劳动。
(3)YK-305、YK-310、YK-312、YK-319和YK-318,与结构类似、G3基团为HO(CH2)2N(CH2CH3)CH2CH(OH)CH2-的一系列化合物相比,在小鼠体内mRNA表达量最高,且持续时间最长。例如,YK-305表达量可达YK-309的160倍。mRNA在小鼠体内表达方面与细胞转染活性一致。
我们比较了由结构类似、G3基团为HO(CH2)2N(CH2CH3)CH2CH(OH)CH2-的一系列化合物与YK-305、YK-310、YK-312、YK-319和YK-318制备的包含mRNA的LNP制剂,在小鼠体内表达方面的差别。结果表明,YK-305、YK-310、YK-312、YK-319和YK-318的表达量最高,且持续时间最长,显著高于其它化合物。例如,YK-305可达YK-309的160倍。
表18 小鼠活体成像实验数据-3
a.小鼠体内表达差别
由表18可以看出,在此系列化合物中,由YK-305、YK-310、YK-312、YK-319和YK-318制备的LNP制剂,mRNA在小鼠体内的表达量和持续时间均最高。
YK-305表达量,在6h为YK-309的140.67倍和YK-313的20.89倍,在24h可达YK-309的167.86倍和YK-313的27.04倍,在48h为YK-309的159.93倍和YK-313的40.99倍,在7d为YK-309的101.13倍和YK-313的39.26倍。
YK-310表达量,在6h为YK-309的138.93倍和YK-313的20.64倍,在24h可达YK-309的175.52倍和YK-313的28.27倍,在48h为YK-309的149.75倍和YK-313的38.38倍,在7d为YK-309的93.52倍和YK-313的36.31倍。
YK-312表达量,在6h为YK-309的121.95倍和YK-313的18.11倍,在24h可达YK-309的135.46倍和YK-313的21.82倍,在48h为YK-309的124.13倍和YK-313的31.82倍,在7d为YK-309的84.00倍和YK-313的32.61倍。
YK-319表达量,在6h为YK-309的125.31倍和YK-313的18.61倍,在24h可达YK-309的144.71倍和YK-313的23.31倍,在48h为YK-309的135.50倍和YK-313的34.73倍,在7d为YK-309的83.49倍和YK-313的32.41倍。
YK-319表达量,在6h为YK-309的50.63倍和YK-313的7.52倍,在24h可达YK-309的57.58倍和YK-313的9.27倍,在48h为YK-309的54.47倍和YK-313的13.96倍,在7d为YK-309的40.33倍和YK-313的15.66倍。
用GraphPad Prism软件对数据进行分析,YK-305、YK-310、YK-312、YK-
319和YK-318中任一个,与其它化合物在各个时间均具有显著差异,表达量和持续时间均显著提高。
b.化学结构差别
此系列化合物与YK-305、YK-310、YK-312、YK-319和YK-318结构非常类似,只是G1、G2、G3、R1或R2基团稍有差别。
小结:
与结构类似、G3基团为HO(CH2)2N(CH2CH3)CH2CH(OH)CH2-的化合物相比,由YK-305、YK-310、YK-312、YK-319和YK-318制备的LNP制剂,mRNA在小鼠体内表达强度最高,持续时间最长。例如,YK-305在48h可达YK-309的160倍,在7d仍可达100倍。mRNA在小鼠体内表达方面与实施例6中细胞转染实验结果一致。
我们还发现,mRNA在小鼠体内表达方面与阳离子脂质结构之间无对应关系,即使是由结构非常类似,仅G1、G2、G3、R1或R2基团稍有差别的一组化合物制备的LNP制剂,mRNA在小鼠体内表达程度和持续时间也极有可能差异非常大。
因此,从一系列结构最类似的化合物中筛选出在动物体内具有以极高程度表达且持续表达的阳离子脂质化合物非常困难,需要付出大量创造性劳动。
(4)YK-305、YK-310、YK-312、YK-319和YK-318,与结构类似、G3基团为(HO(CH2)2)2NCH2CH(OH)CH2-的一系列化合物相比,在小鼠体内mRNA表达量最高,且持续时间最长。例如,YK-310比YK-321提高29倍。mRNA在小鼠体内表达方面与细胞转染活性一致。
我们又比较了由结构类似、G3基团为(HO(CH2)2)2NCH2CH(OH)CH2-的一系列化合物与YK-305、YK-310、YK-312、YK-319和YK-318制备的包含mRNA的LNP制剂,在小鼠体内表达方面的差别。结果表明,YK-305、YK-310、YK-312、YK-319和YK-318的表达量最高,且持续时间最长,显著高于其它化合物。例如,YK-310可达YK-321的29倍。
表19 小鼠活体成像实验数据-4
a.小鼠体内表达差别
由表19可以看出,在此系列化合物中,由YK-305、YK-310、YK-312、YK-319和YK-318制备的LNP制剂,mRNA在小鼠体内的表达量和持续时间均最高。
YK-305表达量,在6h为YK-321的17.92倍,在24h为27.89倍,在48h为28.65倍,在7d为倍19.29。
YK-310表达量,在6h为YK-321的17.70倍,在24h为29.16倍,在48h为26.83倍,在7d为17.84倍。
YK-312表达量,在6h为YK-321的15.54倍,在24h为22.51倍,在48h为22.24倍,在7d为16.02倍。
YK-319表达量,在6h为YK-321的15.96倍,在24h为24.04倍,在48h为24.28倍,在7d为15.92倍。
YK-318表达量,在6h为YK-321的6.45倍,在24h为9.57倍,在48h为9.76倍,在7d为7.69倍。
用GraphPad Prism软件对数据进行分析,YK-305、YK-310、YK-312、YK-319和YK-318中任一个,与其它化合物在各个时间均具有显著差异,表达量和持续时间均显著提高。
b.化学结构差别
此系列化合物与YK-305、YK-310、YK-312、YK-319和YK-318结构非常类似,只是G1、G2、G3、R1或R2基团稍有差别。
小结:
与结构类似、G3基团为(HO(CH2)2)2NCH2CH(OH)CH2-的化合物相比,由YK-305、YK-310、YK-312、YK-319和YK-318制备的LNP制剂,mRNA在小鼠体内表达强度最高,持续时间最长。例如,YK-310在24h可达YK-321的29倍,在7d仍可达17倍。mRNA在小鼠体内表达方面与实施例6中细胞转染实验结果一致。
我们还发现,mRNA在小鼠体内表达方面与阳离子脂质结构之间无对应关系,即使是由结构非常类似,仅G1、G2、G3、R1或R2基团稍有差别的一组化合物制备的LNP制剂,mRNA在小鼠体内表达程度和持续时间也极有可能差异非常大。
因此,从一系列结构最类似的化合物中筛选出在动物体内具有极高程度表达且持续表达的阳离子脂质化合物非常困难,需要付出大量创造性劳动。
b.脂质体在小鼠体内的分布
小鼠活体成像结果显示,由不同化合物制备的脂质体,在小鼠体内的分布有较大差别,有一些在肝脏内有蛋白质表达,而有一些在肝脏内无蛋白质表达。
具体如下:在6h,一些阳离子脂质,例如ALC-0315、SM-102、化合物21、化合物23、HHMA、YK-305和YK-319,在肝脏内存在蛋白质表达,与ALC-0315和SM-102相比,YK-305和YK-319表达量减少;而一些化合物,例如YK-310和YK-313,在肝脏内无蛋白质表达。在24h,所有化合物制备的LNP制剂,在肝脏内已经代谢,无蛋白质表达。(图15)化合物21、化合物23和HHMA与SM-102相似,图未显示。
由此可知,与现有技术阳离子脂质相比,由我们设计的化合物制备的脂质体,在经过肌肉注射后,脂质体在肝脏表达目的蛋白量减少(YK-305和YK-319),或者不会在肝内停留并表达目的蛋白(YK-310和YK-313)。脂质体中携带的mRNA在肝内表达,表达的蛋白通过肝脏代谢,会增加肝脏的负担,因此,我们设计的一些化合物,相比于现有技术代表性阳离子脂质,会降低脂质体在肝脏的毒性。
小结:
与现有技术代表性阳离子脂质,例如SM-102、ALC-0315、化合物21、化合物23和HHMA相比,由我们设计的化合物制备的脂质体,在肝脏表达目的蛋白量减少,或不会在肝内停留并表达目的蛋白。因此相比于现有技术阳离子脂质,由我们设计的化合物制备的LNP制剂,对肝脏毒性降低或无毒性。
总结:
1)我们对由设计的一系列化合物制备得到的LNP制剂进行动物体内递送实验,筛选出了mRNA在小鼠体内具有以极高程度表达且持续表达的阳离子脂质化合物,例如YK-305、YK-310、YK-312、YK-319和YK-318。
设计的此系列化合物与现有技术中代表性阳离子脂质,例如SM-102、ALC-0315、化合物21、化合物23、HHMA和YK-009化学结构差异巨大,G3基团完全不同,其它部位也均有差别,因此在极性、酸碱性和亲水性等方面也会有很大差别。
2)由YK-305、YK-310、YK-312、YK-319和YK-318制备的LNP制剂,mRNA在小鼠体内以极高程度表达,且持续表达,与现有技术中代表性阳离子脂质相比显著提高。例如,YK-305和YK-310可达SM-102、化合物21和化合物23的30倍。
与结构类似、G3基团为HO(CH2)2N(CH3)CH2CH(OH)CH2-的化合物相比,由YK-305、YK-310、YK-312、YK-319和YK-318制备的LNP制剂,mRNA在小鼠体内表达强度最高,持续时间最长。例如,YK-305在48h可达YK-302的1000倍以上,在7d仍可达300倍以上。
与结构类似、G3基团为HO(CH2)2N(CH2CH3)CH2CH(OH)CH2-的化合物相比,由YK-305、YK-310、YK-312、YK-319和YK-318制备的LNP制剂,mRNA在小鼠体内表达强度最高,持续时间最长。例如,YK-305在48h可达YK-309的160倍,在7d仍可达100倍。
并且,与现有技术代表性阳离子脂质,例如SM-102、ALC-0315、化合物21、化合物23和HHMA相比,由我们设计的化合物制备的脂质体,在肝脏表达目的蛋白量减少,或不会在肝内停留并表达目的蛋白。因此相比于现有技术阳离子脂质,由我们设计的化合物制备的LNP制剂,对肝脏毒性降低或无毒性。
3)阳离子脂质的结构和递送的mRNA在小鼠体内的高表达及持续表达之间无对应关系,即使结构差异很小的阳离子脂质化合物,由其制备得到的LNP制剂中的mRNA在动物体内表达方面极有可能差异非常大。无法根据阳离子脂质化学结构预测mRNA在动物体内是否高表达和持续表达,筛选出具有mRNA以极高程度表达且持续表达的阳离子脂质化合物非常困难,需要付出大量创造性劳动。
结论:
1.设计的一系列化合物,包括YK-305、YK-310、YK-312、YK-319和YK-318,与现有技术阳离子脂质,例如SM-102、化合物21、化合物23、HHMA和YK-009化学结构差异巨大,G3基团完全不同,其它部位也均差别非常大,因此
在极性、酸碱性和亲水性等方面也会有很大差别。
在设计的此系列化合物中,由YK-305、YK-310、YK-312、YK-319和YK-318制备的LNP制剂,与现有技术中代表性的阳离子脂质相比,细胞转染效率显著提高,细胞毒性显著降低,mRNA在小鼠体内的表达量及持续时间均显著提高,在肝脏表达目的蛋白量减少,或不会在肝内停留并表达目的蛋白,对肝脏毒性降低或无毒性。例如,YK-305可达SM-102的17倍,化合物21的19倍,化合物23的20倍;细胞存活率YK-305和YK-310均可比ALC-0315高30%,比SM-102高12%,比HHMA高15%;mRNA在小鼠体内表达量,YK-305和YK-310均可达到SM-102、化合物21和化合物23的30倍。
在我们设计的化学结构差异很小的一系列化合物中,由YK-305、YK-310、YK-312、YK-319和YK-318制备的LNP制剂,同其它化合物相比,细胞转染效率显著提高,细胞毒性显著降低,mRNA在小鼠体内的表达量与持续时间均显著提高。
此系列化合物结构上与YK-305、YK-310、YK-312、YK-319和YK-318相比,仅是G1、G2、R1、R2或G3基团稍有差别,但是YK-305细胞转染效率可达YK-304的1300倍和YK-302的900倍,细胞毒性可比YK-302降低65%,mRNA在小鼠体内的表达量可达YK-302的1000倍。
2.阳离子脂质化合物的结构与细胞内转染效率、对细胞产生的毒性以及由其制备的LNP制剂中的mRNA在动物体内的高表达和持续表达之间无明显的对应关系。结构差异很小的化合物,在转染效率和/或对细胞的毒性、细胞内的表达方面极有可能差异非常大。
例如,与YK-305相比,YK-302仅是G1基团少2个C;R1基团为直链结构,而YK-305为支链结构;R2基团单链多1个C,双链中每条单链少2个C;其它结构完全相同,但细胞转染效率YK-305是YK-302的900倍,对转染细胞的毒性YK-305比YK-302降低65%,mRNA在小鼠体内的表达YK-305可达YK-302的1000倍;与YK-310相比,YK-303仅是G3基团与N相连的基团少1个C;其它结构完全相同,但细胞转染效率YK-310是YK-303的40倍,对转染细胞的毒性YK-310比YK-303降低了18%。
因此,筛选合适的阳离子脂质化合物,能同时具有高的转染效率和对细胞的低毒性、mRNA在小鼠体内的高表达及持续表达是非常困难的事情,需要付出大量创造性劳动。
3.本发明通过独特的设计和大量的筛选,发现了一些化合物,例如YK-305、YK-310、YK-312、YK-319和YK-318,相对于现有技术的其它化合物,能
够以显著提高的细胞转染效率、显著降低的细胞毒性以及在动物体内显著提高的表达量和持续时间来递送核酸,取得了预料不到的技术效果。
Claims (59)
- 一种式(I)化合物
或其N-氧化物、溶剂合物、药学上可接受的盐或立
体异构体,其中G1为C1~8亚烷基;G2为C2~8亚烷基;R1为C6~25直链或支链烷基;R2为C12~25直链或支链烷基;G3为:HO(CH2)2N(R3)CH2CH(OH)CH2-,其中R3为-CH3或-CH2CH3或-CH2CH2OH。 - 根据权利要求1所述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体,其中G1为未取代的C3~7亚烷基。
- 根据权利要求1或2所述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体,其中G1为未取代的C3亚烷基或C5亚烷基或C6亚烷基。
- 根据前述权利要求中任一项所述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体,其中G2为未取代的C3~7亚烷基。
- 根据前述权利要求中任一项所述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体,其中G2为未取代的C3亚烷基或C5亚烷基或C6亚烷基。
- 根据前述权利要求中任一项所述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体,其中R1为未取代的C11直链烷基或未取代的C12~24支链烷基。
- 根据权利要求6所述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体,其中R1为未取代的C18支链烷基或C15支链烷基或C24支链烷基或C17支链烷基。
- 根据权利要求7所述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体,其中R1为:
- 根据前述权利要求中任一项所述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体,其中R2为未取代的C11直链烷基或未取代的C14~24支链烷基。
- 根据权利要求9所述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体,其中R2为未取代的C18支链烷基或C24支链烷基或C15支链烷基或C17支链烷基。
- 根据权利要求10所述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体,其中R2为:
- 根据前述权利要求中任一项所述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体,其中所述式(I)化合物具有以下结构中的一种:
- 根据前述权利要求中任一项所述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体,其中所述式(I)化合物是具有以下结构的化合物YK-305:
- 根据权利要求1-12中任一项所述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体,其中所述式(I)化合物是具有以下结构的化合物YK-310:
- 根据权利要求1-12中任一项所述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体,其中所述式(I)化合物是具有以下结构的化合物YK-312:
- 根据权利要求1-12中任一项所述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体,其中所述式(I)化合物是具有以下结构的化合物YK-319:
- 根据权利要求1-12中任一项所述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体,其中所述式(I)化合物是具有以下结构的化合物YK-318:
- 一种组合物,其包含载体,所述载体包括阳离子脂质,所述阳离子脂质包括根据前述权利要求中任一项所述的式(I)化合物或其N-氧化物、溶剂合物、 药学上可接受的盐或立体异构体。
- 根据权利要求18所述的组合物,其中所述阳离子脂质占载体的摩尔比为25%~75%。
- 根据权利要求18-19中任一项所述的组合物,其中所述载体还包含中性脂质。
- 根据权利要求20所述的组合物,其中所述阳离子脂质与所述中性脂质的摩尔比为1:1~15:1,优选为4.5:1。
- 根据权利要求20-21中任一项所述的组合物,其中所述中性脂质包括磷脂酰胆碱、磷脂酰乙醇胺、鞘磷脂、神经酰胺、甾醇及其衍生物中的一种或多种。
- 根据权利要求20-22中任一项所述的组合物,其中所述中性脂质选自以下中的一种或多种:1,2-二亚油酰基-sn-甘油-3-磷酸胆碱(DLPC)、1,2-二肉豆蔻酰基-sn-甘油-磷酸胆碱(DMPC)、1,2-二油酰基-sn-甘油-3-磷酸胆碱(DOPC)、1,2-二棕榈酰基-sn-甘油-3-磷酸胆碱(DPPC)、1,2-二硬脂酰基-sn-甘油-3-磷酸胆碱(DSPC)、1,2-双十一烷酰基-sn-甘油-磷酸胆碱(DUPC)、1-棕榈酰基-2-油酰基-sn-甘油-3-磷酸胆碱(POPC)、1,2-二-O-十八碳烯基-sn-甘油-3-磷酸胆碱(18:0 Diether PC)、1-油酰基-2-胆固醇基半琥珀酰基-sn-甘油-3-磷酸胆碱(OChemsPC)、1-十六烷基-sn-甘油-3-磷酸胆碱(C16 Lyso PC)、1,2-二亚麻酰基-sn-甘油-3-磷酸胆碱、1,2-二花生四烯酰基-sn-甘油-3-磷酸胆碱、1,2-双二十二碳六烯酰基-sn-甘油-3-磷酸胆碱、1,2-二油酰基-sn-甘油-3-磷酸乙醇胺(DOPE)、1,2-二植烷酰基-sn-甘油-3-磷酸乙醇胺(ME 16.0 PE)、1,2-二硬脂酰基-sn-甘油-3-磷酸乙醇胺、1,2-二亚油酰基-sn-甘油-3-磷酸乙醇胺、1,2-二亚麻酰基-sn-甘油-3-磷酸乙醇胺、1,2-二花生四烯酰基-sn-甘油-3-磷酸乙醇胺、1,2-双二十二碳六烯酰基-sn-甘油-3-磷酸乙醇胺、1,2-二油酰基-sn-甘油-3-磷酸-rac-(1-甘油)钠盐(DOPG)、二棕榈酰基磷脂酰甘油(DPPG)、棕榈酰基油酰基磷脂酰乙醇胺(POPE)、二硬脂酰基-磷脂酰-乙醇胺(DSPE)、二棕榈酰基磷脂酰乙醇胺(DPPE)、二肉豆蔻酰基磷酸乙醇胺(DMPE)、1-硬脂酰基-2-油酰基-硬脂酰乙醇胺(SOPE)、1-硬脂酰基-2-油酰基-磷脂酰胆碱(SOPC)、鞘磷脂、磷脂酰胆碱、磷脂酰乙醇胺、磷脂酰丝氨酸、磷脂酰肌醇、磷脂酸、棕榈酰基油酰基磷脂酰胆碱、溶血磷脂酰胆碱、溶血磷脂酰乙醇胺(LPE)以及其混合物。
- 根据权利要求23所述的组合物,其中所述中性脂质是DOPE和/或DSPC。
- 根据权利要求18-24中任一项所述的组合物,其中所述载体还包含结构性脂质。
- 根据权利要求25所述的组合物,其中所述阳离子脂质与所述结构性脂质的摩尔比为0.6:1~3:1。
- 根据权利要求25-26中任一项所述的组合物,其中所述结构性脂质选自以下中的一种或多种:胆固醇、非甾醇、谷固醇、麦角固醇、菜油甾醇、豆甾醇、芸苔甾醇、番茄碱、番茄碱、熊果酸、α-生育酚、皮质类固醇。
- 根据权利要求27所述的组合物,其中所述结构性脂质是胆固醇。
- 根据权利要求18-28中任一项所述的组合物,其中所述载体还包含括聚合物共轭脂质。
- 根据权利要求29所述的组合物,其中所述聚合物共轭脂质占载体的摩尔比为0.5%~10%,优选为1.5%。
- 根据权利要求29-30中任一项所述的组合物,其中所述聚合物共轭脂质选自以下中的一种或多种:PEG修饰的磷脂酰乙醇胺、PEG修饰的磷脂酸、PEG修饰的神经酰胺、PEG修饰的二烷基胺、PEG修饰的二酰基甘油、PEG修饰的二烷基甘油。
- 根据权利要求31所述的组合物,其中所述聚合物共轭脂质选自以下中的一种或多种:二硬脂酰基磷脂酰乙醇胺聚乙二醇2000(DSPE-PEG2000),二肉豆蔻酰甘油-3-甲氧基聚乙二醇2000(DMG-PEG2000)和甲氧基聚乙二醇双十四烷基乙酰胺(ALC-0159)。
- 根据权利要求18-32中任一项所述的组合物,其中所述载体包括中性脂质、结构脂质以及聚合物共轭脂质,所述阳离子脂质、所述中性脂质、所述结构脂质、以及所述聚合物共轭脂质的摩尔比为(25~75):(5~25):(15~65):(0.5~10)。
- 根据权利要求33所述的组合物,其中所述阳离子脂质、所述中性脂质、所述结构脂质、以及所述聚合物共轭脂质的摩尔比为(35~49):(7.5~15):(35~55):(1~5)。
- 根据权利要求34所述的组合物,其中所述阳离子脂质、所述中性脂质、所述结构脂质、以及所述聚合物共轭脂质的摩尔比为45:10:43.5:1.5。
- 根据权利要求18-35中任一项所述的组合物,其中所述组合物为纳米颗粒制剂,所述纳米颗粒制剂的平均粒径为10nm~300nm;所述纳米颗粒制剂的多分散系数≤50%。
- 根据权利要求36所述的组合物,其中所述组合物为纳米颗粒制剂,所述纳米颗粒制剂的平均粒径为90nm~280nm;所述纳米颗粒制剂的多分散系数≤45%。
- 根据权利要求18-37中任一项所述的组合物,其中所述阳离子脂质还包括一种或多种其它可电离的脂质化合物。
- 根据权利要求18-38中任一项所述的组合物,其还包含治疗剂或预防剂。
- 根据权利要求39所述的组合物,其中所述载体与所述治疗剂或预防剂的质量比为10:1~30:1。
- 根据权利要求40所述的组合物,其中所述载体与所述治疗剂或预防剂的质量比为12.5:1~20:1。
- 根据权利要求41所述的组合物,其中所述载体与所述治疗剂或预防剂的质量比为15:1。
- 根据权利要求39-42中任一项所述的组合物,其中所述治疗剂或预防剂包括核酸分子、小分子化合物、多肽或蛋白质中的一种或多种。
- 根据权利要求39-42中任一项所述的组合物,其中所述治疗剂或预防剂是能够引起免疫响应的疫苗或化合物。
- 根据前述权利要求39-44中任一项所述的组合物,其中所述治疗剂或预防剂是核酸。
- 根据权利要求45所述的组合物,其中所述治疗剂或预防剂是核糖核酸(RNA)。
- 根据权利要求45所述的组合物,其中所述治疗剂或预防剂是脱氧核糖核酸(DNA)。
- 根据权利要求46所述的组合物,其中所述RNA选自由以下组成的组:小干扰RNA(siRNA)、不对称干扰RNA(aiRNA)、微RNA(miRNA)、Dicer-底物RNA(dsRNA)、小发夹RNA(shRNA)、信使RNA(mRNA)以及其混合物。
- 根据权利要求48所述的组合物,其中所述RNA是mRNA。
- 根据权利要求18-49中任一项所述的组合物,其中所述组合物还包括药物可用的赋形剂或稀释剂中的一种或多种。
- 根据前述权利要求1-17中任一项所述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体或者如前述权利要求18-50中任一项所述的组合物在制备核酸药物、基因疫苗、小分子药物、多肽或蛋白质药物中的用途。
- 一种如前述权利要求1-17中任一项所述的式(I)化合物或其N-氧化物、溶剂合物、药学上可接受的盐或立体异构体或者前述权利要求18-50中任一项所述的组合物在制备用于治疗有需要哺乳动物的疾病或病症的药物中的用途。
- 根据权利要求52所述的用途,其中所述疾病或病症以功能失常或异常的蛋白质或多肽活性为特征。
- 根据权利要求52-53中任一项所述的用途,其中所述疾病或病症选自由以下组成的组:感染性疾病、癌症和增生性疾病、遗传性疾病、自体免疫性疾病、糖尿病、神经退化性疾病、心血管和肾血管疾病以及代谢性疾病。
- 根据权利要求54所述的用途,其中所述感染性疾病选自:由冠状病毒、流感病毒或HIV病毒引起的疾病,小儿肺炎,裂谷热,黄热病,狂犬病,或多种疱疹。
- 根据权利要求52-55中任一项所述的用途,其中所述哺乳动物是人。
- 根据权利要求51-56中任一项所述的用途,其中所述组合物经静脉内、肌肉内、皮内、皮下、鼻内或通过吸入施用。
- 根据权利要求57所述的用途,其中所述组合物是皮下施用的。
- 根据权利要求51-58中任一项所述的用途,其中将约0.001mg/kg至约10mg/kg剂量的所述治疗剂或预防剂施用给所述哺乳动物。
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Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103380113A (zh) * | 2010-11-15 | 2013-10-30 | 生命科技公司 | 含胺的转染试剂及其制备和使用方法 |
CA2998810A1 (en) * | 2015-09-17 | 2017-03-23 | Modernatx, Inc. | Compounds and compositions for intracellular delivery of therapeutic agents |
CN108368028A (zh) * | 2015-10-28 | 2018-08-03 | 爱康泰生治疗公司 | 用于递送核酸的新型脂质和脂质纳米颗粒制剂 |
CN110325511A (zh) * | 2016-12-21 | 2019-10-11 | 阿克丘勒斯治疗公司 | 用于rna递送的可离子化阳离子脂质 |
CN110520409A (zh) * | 2017-03-15 | 2019-11-29 | 摩登纳特斯有限公司 | 用于细胞内递送治疗剂的化合物和组合物 |
US20210128488A1 (en) * | 2017-08-16 | 2021-05-06 | Acuitas Therapeutics, Inc. | Lipids for use in lipid nanoparticle formulations |
CN112979483A (zh) * | 2021-05-14 | 2021-06-18 | 苏州艾博生物科技有限公司 | 一种阳离子脂质化合物、包含其的组合物及应用 |
CN114044741A (zh) * | 2022-01-13 | 2022-02-15 | 北京悦康科创医药科技股份有限公司 | 一种阳离子脂质化合物、包含其的组合物及用途 |
CN114728887A (zh) * | 2019-09-19 | 2022-07-08 | 摩登纳特斯有限公司 | 用于治疗剂的细胞内递送的支链尾端脂质化合物和组合物 |
CN115745820A (zh) * | 2023-01-05 | 2023-03-07 | 北京悦康科创医药科技股份有限公司 | 长效低毒的新型阳离子脂质化合物及其组合物 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
BR112017014710B1 (pt) * | 2015-01-12 | 2022-06-14 | Stepan Company | Processo livre de solvente orgânico para a obtenção de uma composição compreendendo um ou mais ramnolipídeos (rls) e composições |
-
2023
- 2023-01-05 CN CN202310010912.6A patent/CN115745820B/zh active Active
- 2023-01-05 CN CN202310371271.7A patent/CN116375592A/zh active Pending
- 2023-01-19 WO PCT/CN2023/073230 patent/WO2024145965A1/zh unknown
Patent Citations (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103380113A (zh) * | 2010-11-15 | 2013-10-30 | 生命科技公司 | 含胺的转染试剂及其制备和使用方法 |
CA2998810A1 (en) * | 2015-09-17 | 2017-03-23 | Modernatx, Inc. | Compounds and compositions for intracellular delivery of therapeutic agents |
US20180273467A1 (en) * | 2015-09-17 | 2018-09-27 | Modernatx, Inc. | Compounds and compositions for intracellular delivery of therapeutic agents |
CN108368028A (zh) * | 2015-10-28 | 2018-08-03 | 爱康泰生治疗公司 | 用于递送核酸的新型脂质和脂质纳米颗粒制剂 |
CN110325511A (zh) * | 2016-12-21 | 2019-10-11 | 阿克丘勒斯治疗公司 | 用于rna递送的可离子化阳离子脂质 |
CN110520409A (zh) * | 2017-03-15 | 2019-11-29 | 摩登纳特斯有限公司 | 用于细胞内递送治疗剂的化合物和组合物 |
US20210128488A1 (en) * | 2017-08-16 | 2021-05-06 | Acuitas Therapeutics, Inc. | Lipids for use in lipid nanoparticle formulations |
CN114728887A (zh) * | 2019-09-19 | 2022-07-08 | 摩登纳特斯有限公司 | 用于治疗剂的细胞内递送的支链尾端脂质化合物和组合物 |
CN112979483A (zh) * | 2021-05-14 | 2021-06-18 | 苏州艾博生物科技有限公司 | 一种阳离子脂质化合物、包含其的组合物及应用 |
CN114044741A (zh) * | 2022-01-13 | 2022-02-15 | 北京悦康科创医药科技股份有限公司 | 一种阳离子脂质化合物、包含其的组合物及用途 |
CN114957027A (zh) * | 2022-01-13 | 2022-08-30 | 北京悦康科创医药科技股份有限公司 | 一种阳离子脂质化合物、包含其的组合物及用途 |
CN115745820A (zh) * | 2023-01-05 | 2023-03-07 | 北京悦康科创医药科技股份有限公司 | 长效低毒的新型阳离子脂质化合物及其组合物 |
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