CN119431176B - An ionizable cationic lipid, its preparation method and application - Google Patents
An ionizable cationic lipid, its preparation method and applicationInfo
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- CN119431176B CN119431176B CN202411569986.4A CN202411569986A CN119431176B CN 119431176 B CN119431176 B CN 119431176B CN 202411569986 A CN202411569986 A CN 202411569986A CN 119431176 B CN119431176 B CN 119431176B
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Abstract
本发明提供了一种可电离阳离子脂质及其制备方法和应用，涉及生物医药技术领域。本发明公开了一种新结构的可电离阳离子脂质，所述可电离阳离子脂质的示例如下。与目前最高效的脂质纳米粒子——DLin‑MC3‑DMA相比，本发明公开的脂质纳米粒子不仅制备过程更简单，而且递送效率更高。 This invention provides an ionizable cationic lipid, its preparation method, and its applications, relating to the field of biomedical technology. This invention discloses a novel ionizable cationic lipid structure, examples of which are shown below. Compared to the most efficient lipid nanoparticle currently available—DLin-MC3-DMA—the lipid nanoparticles disclosed in this invention not only have a simpler preparation process but also higher delivery efficiency.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and relates to an ionizable cationic lipid, a preparation method and application thereof.
Background
Nucleic acid drugs including DNA drugs, mRNA drugs and small nucleic acid drugs mainly face the problems of how to enter target cells efficiently, release to cytoplasm, and play roles efficiently and for a long time. High-efficiency, safe and accurate targeting and improvement of stability are key points of technological breakthroughs. Currently, nucleic acid in vivo delivery vectors are largely divided into viral vectors and non-viral vectors. The virus vector has very high delivery efficiency and can ensure the long-term expression of genes, but the defects of complex preparation process, high cost, easiness in causing immune response of organisms, involved biosafety problems, limited size of target gene fragments and the like limit the application of the virus vector. Compared with viral vectors, nonviral lipid-based delivery systems (e.g., lipid nanoparticles, LNP) are becoming key tools for nucleic acid vaccines and therapies due to their advantages of safety, tolerability, ability to repeat administration, and cargo carrying capacity of large numbers of genes.
LNP is typically composed of four components, ionizable cationic lipids, phospholipids, cholesterol, and pegylated lipids. Each component plays a crucial role in LNP stability, transfection efficiency and safety. For mRNA-LNP formation, the different lipids and mRNA are typically dissolved in ethanol and acidic aqueous phases, respectively. Then, ethanol and water phase are mixed with the microfluidic device in a volume ratio of 1:3, and the self-assembly process is completed. During formation, the ionizable cationic lipid is positively charged by protonation and then binds to negatively charged mRNA by electrostatic interactions, thereby encapsulating the mRNA within the LNP. Meanwhile, other helper lipids, including phospholipids, cholesterol, and pegylated lipids, self-assemble thereon to stabilize the mRNA-LNP formed. Subsequently, the mRNA-LNP solution is adjusted to neutral pH by buffer displacement, during which the ionizable lipid becomes uncharged, making it stable at physiological pH and less toxic. The LNP has the advantages of definite structure of each component, good reproducibility, favorable quality supervision, longer in vivo circulation time, good biocompatibility and the like. After entering cells, the nanoparticles need to escape from endosomes/lysosomes to release RNA in cytoplasm, so that the RNA can be expressed to generate target proteins. Thus, endosome/lysosomal escape is a critical step affecting nucleic acid delivery.
Chinese patent CN118388370a discloses a quaternary ammonium salt type cationic lipid analogue, and a composition and application thereof, which are prepared by chemically modifying or modifying an ionizable cationic lipid analogue, and replacing auxiliary phospholipid components in conventional four-component lipid nanoparticles with the quaternary ammonium salt type cationic lipid analogue, so as to form a novel LNP delivery system for targeted mRNA delivery of organs/tissues. However, this patent only investigated the targeted mRNA delivery performance of the novel LNP delivery system for organs/tissues and did not address endosome/lysosomal escape rates of the novel LNP delivery system.
DLin-MC3-DMA (1, 2-diol loxy 3-dimethyl-miniopane) is a synthetic cationic lipid that has been widely studied for gene therapy and mRNA vaccine due to its efficient nucleic acid delivery capacity. DLin-MC3-DMA has unique pH dependent charge variable properties of being electropositive under acidic conditions and electrically neutral under physiological pH conditions. Thus, the nucleic acid is encapsulated under acidic conditions, and the liposomes formed have a very low positive charge density in the blood, i.e. very low cytotoxicity. Although DLin-MC3-DMA cationic liposomes can increase lysosomal escape of particles in vivo due to electropositivity, only 1% -4% of RNA escapes endosomes/lysosomes.
In view of this, there is a need for an LNP delivery system that has both good nucleic acid entrapment and high endosome/lysosomal escape capabilities.
Disclosure of Invention
The invention aims to overcome the defects existing in the previous research and provides an ionizable cationic lipid, a preparation method and application thereof. The LNP delivery system composed of the ionizable cationic lipid prepared by the invention has good nucleic acid entrapment capacity, higher endosome/lysosome escape capacity, simple preparation method and great research significance and practical requirements.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
first, the present invention provides an ionizable cationic lipid having a structure selected from any one of formula (1), formula (2), formula (3), formula (4), and formula (5),
In the formula (1), the components are as follows,
a=1-5,b=1-6,
R 1、R2、R3、R4、R5 is each independently selected from hydrogen, (C 1-C6) alkyl, (C 1-C6) alkyl-COO- (C 5-C12) alkyl;
in the formula (2), the amino acid sequence of the compound,
c=1-6,
R 6、R7、R8、R9、R10、R11 is each independently selected from (C 1-C6) alkyl, (C 1-C6) alkyl-COO- (C 5-C12) alkyl;
In the formula (3), the amino acid sequence of the compound,
d=1-5,e=1-6,f=1-6,
R 12 is (C 1-C6) alkyl-COO- (C 5-C12) alkyl;
In the formula (4), the amino acid sequence of the compound,
R 13 is (C 1-C6) alkyl-COO- (C 5-C12) alkyl;
In the formula (5), the amino acid sequence of the compound,
R 14 is (C 1-C6) alkyl-COO- (C 5-C12) alkyl.
Preferably, the method comprises the steps of,
In the above-mentioned formula (1),
a=2-4,b=2-5,
R 1、R2、R3、R4、R5 is each independently selected from hydrogen, (C 1-C4) alkyl, (C 2-C4) alkyl-COO- (C 7-C10) alkyl;
In the above-mentioned formula (2),
c=1-5,
R 6、R7、R8、R9、R10、R11 is each independently selected from (C 1-C4) alkyl, (C 2-C4) alkyl-COO- (C 7-C10) alkyl;
in the above-mentioned formula (3),
d=2-4,e=2-5,f=2-5,
R 12 is (C 2-C4) alkyl-COO- (C 7-C10) alkyl;
in the above-mentioned formula (4),
R 13 is (C 2-C4) alkyl-COO- (C 7-C10) alkyl;
in the above-mentioned formula (5),
R 14 is (C 2-C4) alkyl-COO- (C 7-C10) alkyl.
It is further preferred that the composition comprises,
In the above-mentioned formula (1),
a=2-3,b=2-4,
R 1、R2、R3、R4、R5 is each independently selected from hydrogen, (C 1-C2) alkyl, (C 2-C3) alkyl-COO- (C 8-C9) alkyl;
In the above-mentioned formula (2),
c=1-4,
R 6、R7、R8、R9、R10、R11 is each independently selected from (C 1-C2) alkyl, (C 2-C3) alkyl-COO- (C 8-C9) alkyl;
in the above-mentioned formula (3),
d=2-3,e=2-4,f=2-4,
R 12 is (C 2-C3) alkyl-COO- (C 8-C9) alkyl;
in the above-mentioned formula (4),
R 13 is (C 2-C3) alkyl-COO- (C 8-C9) alkyl;
in the above-mentioned formula (5),
R 14 is (C 2-C3) alkyl-COO- (C 8-C9) alkyl.
Still further preferably the method comprises the steps of,
In the above-mentioned formula (1),
a=2-3,b=2-4,
R 1、R2、R3、R4、R5 is each independently selected from the group consisting of-H, -CH 3,
-CH2CH2COOCH2CH(CH2CH3)CH2CH2CH2CH3、
-CH2CH2COOCH2CH2CH2CH2CH2CH(CH3)2、
-CH2CH2COOCH2CH2CH2CH2CH2CH2CH(CH3)2;
In the above-mentioned formula (2),
c=1-3,
R 6、R7、R8、R9、R10、R11 are each independently selected from the group consisting of-CH 3,
-CH2CH2COOCH2CH(CH2CH3)CH2CH2CH2CH3、
-CH2CH2COOCH2CH2CH2CH2CH2CH(CH3)2、
-CH2CH2COOCH2CH2CH2CH2CH2CH2CH(CH3)2;
In the above-mentioned formula (3),
d=2-3,e=2-4,f=2-4,
R 12 is selected from -CH2CH2COOCH2CH(CH2CH3)CH2CH2CH2CH3、
-CH2CH2COOCH2CH2CH2CH2CH2CH(CH3)2、
-CH2CH2COOCH2CH2CH2CH2CH2CH2CH(CH3)2;
In the above-mentioned formula (4),
R 13 is selected from -CH2CH2COOCH2CH2CH2CH2CH2CH(CH3)2、
-CH2CH2COOCH2CH2CH2CH2CH2CH2CH(CH3)2;
In the above-mentioned formula (5),
R 14 is selected from -CH2CH2COOCH2CH(CH2CH3)CH2CH2CH2CH3、
-CH2CH2COOCH2CH2CH2CH2CH2CH(CH3)2、
-CH2CH2COOCH2CH2CH2CH2CH2CH2CH(CH3)2.
Still more preferably, the structure of the ionizable cationic lipid is selected from any one of formula (6), formula (7), formula (8), formula (9), formula (10), formula (11), formula (12), formula (13),
Still more preferably, the structure of the ionizable cationic lipid is selected from any one of formula (6), formula (7), formula (12), and formula (13).
Still more preferably, the structure of the ionizable cationic lipid is selected from any one of formula (6), formula (7), and formula (12).
Finally, preferably, the ionizable cationic lipid has the structure of formula (7).
Secondly, the invention provides a preparation method of the ionizable cationic lipid, comprising the following steps of mixing a raw material 1 and a raw material 2, and then reacting at 70-90 ℃;
the structure of the raw material 1 is selected from any one of a formula (14), a formula (15), a formula (16), a formula (17) and a formula (18),
In the formula (14), the amino acid sequence of the compound,
g=1-5,h=1-6,
Each R 15、R16、R17、R18、R19 is independently selected from hydrogen, (C 1-C6) alkyl;
in the formula (15), the amino acid sequence of the compound,
j=1-6,
Each R 20、R21、R22、R23、R24、R25 is independently selected from hydrogen, (C 1-C6) alkyl;
in the formula (16), the amino acid sequence of the compound,
k=1-5,m=1-6,n=1-6;
The raw material 2 is (C 5-C12) alkyl-COO- (C 1-C6) olefin.
Preferably, the starting materials 1 and 2 are reacted at 80 ℃.
Preferably, the molar ratio of the raw material 1 to the raw material 2 is 1:5-9.
Preferably, the preparation method further comprises a purification step of purifying the product by chromatography, wherein the eluent is a mixed solution of dichloromethane, methanol and ammonia water.
Further preferably, the mass ratio of the dichloromethane to the methanol to the ammonia water is 75:22:3.
Still more preferably, the ammonia water has an ammonia content of 27%.
Furthermore, the present invention provides a lipid nanoparticle comprising the above-described ionizable cationic lipid, phospholipid, cholesterol, and pegylated lipid.
Preferably, the phospholipid is phosphorylcholine (DSPC) or dioleoyl phosphatidylethanolamine (DOPE).
Preferably, the pegylated lipid is dimyristoylglycerol-polyethylene glycol (DMG-PEG).
Preferably, the volume ratio of the ionizable cationic lipid, phospholipid, cholesterol, and pegylated lipid is 10:5:10:3.
Finally, the present invention provides the use of the above-described ionizable cationic lipids or the above-described lipid nanoparticles as a targeted mRNA delivery vehicle.
Compared with the prior art, the invention has the following beneficial effects:
(1) Compared with the most efficient lipid nanoparticle-DLin-MC 3-DMA at present, the preparation process of the lipid nanoparticle disclosed by the invention is simpler and has lower cost.
(2) Compared with the most efficient lipid nanoparticle-DLin-MC 3-DMA at present, the lipid nanoparticle disclosed by the invention has higher delivery efficiency, and the delivery efficiency of the lipid nanoparticle with the optimal structure is 8.2 times that of the lipid nanoparticle with the optimal structure.
Detailed Description
The following non-limiting examples will enable those of ordinary skill in the art to more fully understand the invention and are not intended to limit the invention in any way. The following is merely exemplary of the scope of the invention as claimed and many variations and modifications of the invention will be apparent to those skilled in the art in light of the disclosure, which are intended to be within the scope of the invention as claimed.
The invention is further illustrated by means of the following specific examples. The various drugs used in the examples of the present invention are commercially available from conventional sources unless otherwise specified.
Example 1-starting materials of example 48
TABLE 1
Example 1-method of preparation of example 48
TABLE 2
Example 49
The reaction temperature of example 1 was changed from 80 ℃ to 70 ℃ and the rest of the preparation process was the same as example 1.
In a 50mL round bottom flask, starting material 1 (145.25 mg,1 mmol) and starting material 2 (921.4 mg,5 mmol) were added and reacted at 70℃for 48h to give the crude product. The product was then purified by column chromatography using a solution of dichloromethane, methanol and aqueous ammonia (27% ammonia) in a mass ratio of 75:22:3, and the desired fraction was collected to give the final product as example 49.
Example 50
The reaction temperature of example 1 was changed from 80 ℃ to 90 ℃ and the rest of the preparation process was the same as example 1.
In a 50mL round bottom flask, starting material 1 (145.25 mg,1 mmol) and starting material 2 (921.4 mg,5 mmol) were added and reacted at 90℃for 48h to give the crude product. The product was then purified by column chromatography using a solution of dichloromethane, methanol and aqueous ammonia (27% ammonia) in a mass ratio of 75:22:3, and the desired fraction was collected to give the final product as example 50.
Example 51
Preparation of mRNA/LNP:
(1) A1.5 mL EP tube was prepared with 300. Mu.L of solution in 216. Mu.L of ethanol followed by 9. Mu.L of DMG-PEG, 30. Mu.L of cholesterol, 15. Mu.L of DSPC and 30. Mu.L of ionizable cationic lipid in the volume ratio (3:10:5:10) in that order (prepared in example 4).
(2) In another 1.5mL of EP, 60ug of mRNA was dissolved in 10mM citrate buffer (pH 3.0) to prepare 900uL of mRNA solution;
(3) The 2 solutions were sucked into a threaded syringe, and the samples were collected by microfluidic synthesis at a rate of 12 mL/min.
(4) Concentrating the sample, namely concentrating the collected sample in a concentrated acid tube with 100Kd, centrifuging for 10min at 3000g, adding PBS with 2 times of the volume of the residual solution, centrifuging again, and collecting the concentrated solution for later use.
Example 52
30. Mu.L of the ionizable cationic lipid of example 51 (prepared in example 4) was replaced with 30. Mu.L of the ionizable cationic lipid (prepared in example 7), and the remaining raw materials and procedures were the same as in example 51.
Example 53
30. Mu.L of the ionizable cationic lipid of example 51 (prepared in example 4) was replaced with 30. Mu.L of the ionizable cationic lipid (prepared in example 10), and the remaining raw materials and procedures were the same as in example 51.
Example 54
30. Mu.L of the ionizable cationic lipid of example 51 (prepared in example 4) was replaced with 30. Mu.L of the ionizable cationic lipid (prepared in example 11), and the remaining raw materials and procedures were the same as in example 51.
Example 55
30. Mu.L of the ionizable cationic lipid of example 51 (prepared in example 4) was replaced with 30. Mu.L of the ionizable cationic lipid (prepared in example 13), DSPC was replaced with DOPE, and the rest of the raw materials and the procedure were the same as in example 51.
Example 56
30. Mu.L of the ionizable cationic lipid of example 51 (prepared in example 4) was replaced with 30. Mu.L of the ionizable cationic lipid (prepared in example 19), DSPC was replaced with DOPE, and the rest of the raw materials and the procedure were the same as in example 51.
Example 57
30. Mu.L of the ionizable cationic lipid of example 51 (prepared in example 4) was replaced with 30. Mu.L of the ionizable cationic lipid (prepared in example 20), DSPC was replaced with DOPE, and the rest of the raw materials and the procedure were the same as in example 51.
Example 58
30. Mu.L of the ionizable cationic lipid of example 51 (prepared in example 4) was replaced with 30. Mu.L of the ionizable cationic lipid (prepared in example 37), DSPC was replaced with DOPE, and the rest of the raw materials and the procedure were the same as in example 51.
Result detection
Cell experiment
1. Hela cell transfection
100. Mu.L of freshly resuspended HeLa cell fluid (1X 10 4 cells) was passaged overnight in 96-well plates and the mRNA/LNP prepared in examples 51-58 was diluted to 0.2ug/mL in fresh medium (1.5 mL EP tube) the next day, the old medium was discarded and 100uL fresh medium was added for 24h. After the incubation, the dead and alive state of the cells is primarily observed under a microscope, the culture solution is discarded, and the cells are detected by a firefly luciferase reporter gene detection kit. DLin-MC3-DMA was used as a positive control for comparison.
2. Fluorescence detection
(1) Cells were lysed by adding reporter cell lysate at 100 μl per well. After sufficient lysis, 10,000-15,000Xg was centrifuged for 3-5min and the supernatant was used for assay;
(2) Melting firefly luciferase detection reagent and reaching room temperature;
(3) Starting a chemiluminescent instrument or a multifunctional enzyme-labeled instrument with a chemiluminescent detection function according to instrument operation specifications, and setting interval time and measurement time according to the requirements of various instrument devices;
(4) 100 mu L of sample and 100 mu L of firefly luciferase detection reagent are added into each hole respectively, and the mixture is uniformly mixed by an enzyme-labeled instrument vibration plate for 60 seconds to measure the fluorescence intensity.
Technical effect detection
1. Example 1 Nuclear magnetic resonance results for the products of example 50
TABLE 3 Table 3
2. Results of cell experiments
Cell experiments were performed on examples 51-58, and the fluorescence intensity values of each example were counted as shown in Table 4:
TABLE 4 Table 4
| Examples numbering | Fluorescence intensity |
| Example 51 | 27518 |
| Example 52 | 48912 |
| Example 53 | 40000 |
| Example 54 | 160579 |
| Example 55 | 185750 |
| Example 56 | 24238 |
| Example 57 | 24238 |
| Example 58 | 29150 |
| Control (DLin-MC 3-DMA) | 22514 |
As can be seen from Table 4, the fluorescence intensities of examples 51 to 58 were all higher than DLin-MC3-DMA, with example 52 having the highest fluorescence intensity being 8.2 times that of DLin-MC3-DMA and example 56 having the lowest fluorescence intensity being 1.07 times that of DLin-MC 3-DMA. The above results demonstrate that the ionizable cationic lipids (48 compounds total) disclosed in the present invention are a highly efficient delivery mRNA vector.
Finally, it should be noted that the above description is only for illustrating the technical solution of the present invention, and not for limiting the scope of the present invention, and that the simple modification and equivalent substitution of the technical solution of the present invention can be made by those skilled in the art without departing from the spirit and scope of the technical solution of the present invention.
Claims (7)
1. An ionizable cationic lipid, characterized in that the cationic lipid has a structure represented by formula (6):
2. A process for producing an ionizable cationic lipid according to claim 1, comprising the steps of mixing raw material 1 and raw material 2 represented by the following structures, and then reacting at 70 to 90 ℃.
3. The preparation method according to claim 2, wherein the preparation method comprises the steps of adding 1mmol of raw material 1 and 5mmol of raw material 2 into a 50mL round bottom flask, reacting at 80 ℃ for 48 hours to obtain a crude product, purifying the product by column chromatography, eluting with a solution prepared by mixing dichloromethane, methanol and ammonia water with the ammonia content of 27% in a mass ratio of 75:22:3, and collecting the required fraction.
4. A lipid nanoparticle comprising the ionizable cationic lipid of claim 1, a phospholipid, cholesterol, and a pegylated lipid.
5. The lipid nanoparticle according to claim 4, it is characterized in that the method comprises the steps of,
The phospholipid is phosphorylcholine or dioleoyl phosphatidylethanolamine;
The pegylated lipid is dimyristoyl glycerol-polyethylene glycol.
6. The lipid nanoparticle of claim 5, wherein the volume ratio of ionizable cationic lipid, phospholipid, cholesterol, and pegylated lipid is 10:5:10:3.
7. Use of an ionizable cationic lipid of claim 1 or a lipid nanoparticle of any one of claims 4-6 in the preparation of a targeted mRNA delivery vehicle.
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| WO2019036028A1 (en) * | 2017-08-17 | 2019-02-21 | Acuitas Therapeutics, Inc. | Lipids for use in lipid nanoparticle formulations |
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