Lipoic acid derivative-based lipid compound, carrier and preparation method and application of nanoparticle composition entrapping nucleic acid medicine

Abstract

The invention provides a preparation method and application of lipid nanoparticles based on lipoic acid derivatives. The lipoic acid derivative provided by the invention depends on a cyclopentane structure and a disulfide bond of lipoic acid, so that a lipid compound is more easily internalized by cells, and the effectiveness of nucleic acid delivery is improved. The lipid nanoparticles have excellent spleen targeting performance, and drugs are preferentially delivered to the spleen.

Description

Technical Field

[0001] This invention belongs to the field of biomedicine, specifically relating to a method for preparing a lipid compound, carrier, and nanoparticle composition for encapsulating nucleic acid drugs based on thioctic acid derivatives, and its application. Background Technology

[0002] In recent years, nucleic acid drugs have attracted widespread attention in the pharmaceutical industry due to their ability to target gene regulation, particularly in tumor treatment, genetic disease repair, and antiviral vaccines, demonstrating great potential. However, nucleic acid drugs are unstable under physiological conditions and are easily degraded by nucleases, leading to drug inactivation. Furthermore, negatively charged nucleic acids have difficulty penetrating the equally negatively charged cell membrane. Therefore, selecting a suitable delivery system to deliver nucleic acid drugs to cells is crucial. Non-viral vectors are currently a research hotspot in nucleic acid drug delivery systems. Compared with viral vectors, non-viral vectors have lower immunogenicity and higher safety, among which lipid nanoparticles (LNPs) delivery systems show great application potential.

[0003] Lipid nanoparticles typically consist of four components: ionizable cationic lipids (ILs), neutral phospholipids, cholesterol, and PEGylated lipids. Among these, ionizable cationic lipids serve as the core functional component. Their head polar groups can provide a positive charge through protonation, efficiently binding negatively charged nucleic acid molecules via electrostatic interactions and mediating cellular uptake and endosome escape. However, existing LNP systems still face a critical bottleneck—insufficient endosome escape efficiency during nucleic acid drug delivery restricts release, severely limiting their therapeutic potential. Therefore, developing novel ionizable cationic lipids with highly efficient endosome escape capabilities is crucial for improving the delivery efficiency and targeting of nucleic acid drugs.

[0004] To address this challenge, structural optimization of ionizable cationic lipids is a key strategy for overcoming delivery bottlenecks. Lipoic acid (LNP) is a natural disulfide compound. Its ring strain makes it readily react with thiol groups on the cell surface, promoting LNP adhesion to the cell membrane and enhancing endocytosis efficiency. Furthermore, the disulfide bond can be cleaved in the high-concentration glutathione (GSH) environment within the cell, enabling rapid release of nucleic acid drugs.

[0005] In view of this, the present invention designs a novel ionizable cationic lipid derivative by modifying lipoic acid, and optimizes the nucleic acid loading capacity, cellular uptake efficiency and endosome escape performance of the lipid molecule, aiming to build a next-generation LNP delivery system with both high delivery efficiency and organ targeting. Summary of the Invention

[0006] The purpose of this invention is to overcome the shortcomings of existing technologies and provide a method for preparing lipid compounds based on lipoic acid derivatives and their applications. The lipid compounds based on lipoic acid derivatives possess highly efficient nucleic acid delivery capabilities.

[0007] The present invention also provides a method for preparing a lipid compound carrier based on the above-mentioned thioctic acid derivative and a nanoparticle composition encapsulating a nucleic acid drug, and its application.

[0008] To achieve the above objectives, the present invention adopts the following technical solution:

[0009] In a first aspect, the present invention provides a lipid compound based on a lipoic acid derivative, said lipid compound having the structure shown in Formula I:

[0010]

[0011] R1 is independently selected from at least one group selected from straight-chain alkyl, straight-chain alkenyl, cycloalkyl, straight-chain alkyl containing heteroatoms, branched alkyl containing heteroatoms, branched alkylene containing heteroatoms, alkyl containing heteroatom rings, alkyl containing heteroatoms and aromatic rings, alkyl containing hydroxyl groups, alkyl containing ester groups, alkyl containing ether groups, and alkyl containing sulfonate groups.

[0012] R2 is independently selected from at least one group selected from straight-chain alkyl, branched-chain alkyl, straight-chain alkenyl, branched-chain alkenyl, substituted alkynyl, cycloalkyl, phenyl, and heteroatom-containing aromatic groups;

[0013] R3 is independently selected from at least one group selected from straight-chain alkyl, branched alkyl, straight-chain alkenyl, cycloalkyl, straight-chain alkyl containing heteroatoms, branched alkyl containing heteroatoms, branched alkylene containing heteroatoms, alkyl containing heteroatom rings, alkyl containing heteroatoms and aromatic rings, alkyl containing hydroxyl groups, alkyl containing ester groups, alkyl containing ether groups, and alkyl containing sulfonate groups.

[0014] Specifically, in the lipid compound based on lipoic acid derivatives described in this invention, preferably, R1 is selected from any one of the following groups; wherein, Representative group connection positions:

[0015]

[0016] Preferably, R2 is selected from any one of the following groups; wherein Representative group connection positions:

[0017]

[0018] Preferably, R3 is selected from any one of the following groups; wherein Represents the location of the group connection;

[0019]

[0020] As a preferred embodiment, the lipid compound based on lipoic acid derivatives of the present invention includes any one of the following compounds:

[0021]

[0022]

[0023] This invention also provides the application of the above-mentioned lipid compounds based on thioctic acid derivatives in the preparation of drug carriers.

[0024] Secondly, the present invention provides a lipid nanoparticle composition carrier, which includes one or more of the following: lipid compounds based on lipoic acid derivatives, polyethylene glycol lipids, cholesterol, and neutral phospholipids. The neutral phospholipids are preferably distearylphosphatidylcholine (DSPC), 1,2-dioleoyl-sn-glycerol-3-phosphoethanolamine (DOPE), dioleoylphosphatidylcholine (DOPC), lecithin (ESM), etc.

[0025] Furthermore, the lipid nanoparticle composition carrier comprises, in molar percentage, 10%–70% of a lipid compound based on lipoic acid derivatives, 0.1%–25% of polyethylene glycol lipids, 10%–50% of cholesterol, and 5%–30% of neutral phospholipids.

[0026] The present invention also provides the application of the above-mentioned lipid nanoparticle composition carrier in the preparation of nucleic acid-loaded drugs.

[0027] Thirdly, the present invention provides a method for preparing a nanoparticle composition encapsulating a nucleic acid drug, specifically comprising the following steps:

[0028] 1) The lipid compound based on lipoic acid derivative, neutral phospholipid, polyethylene glycol lipid and cholesterol are dissolved in ethanol to obtain an organic phase liposome solution, wherein the concentration of the lipoic acid derivative lipid compound is 0.01-100 mg / mL, the concentration of the neutral phospholipid is 0.01-100 mg / mL, the concentration of the polyethylene glycol lipid is 0.01-100 mg / mL, and the concentration of cholesterol is 0.01-100 mg / mL;

[0029] 2) Dissolve the nucleic acid drug in citric acid / sodium citrate buffer to obtain an aqueous nucleic acid drug solution;

[0030] 3) The organic phase liposome solution and the aqueous phase nucleic acid drug solution are mixed and dialyzed using a dialysis bag with a molecular weight cutoff of 1000 to obtain a nanoparticle composition loaded with nucleic acid drugs.

[0031] Specifically, the pH of the citric acid / sodium citrate buffer solution is 3 to 7.

[0032] Furthermore, in the aqueous nucleic acid drug solution, the concentration of the nucleic acid drug is 0.01-1.00 mg / mL.

[0033] Preferably, the volume ratio of the organic phase liposome solution to the aqueous phase nucleic acid drug solution during mixing is 1:2 to 1:5.

[0034] The present invention also provides a nanoparticle composition for encapsulating nucleic acid drugs prepared by the above preparation method.

[0035] Fourthly, the present invention also provides the application of the above-mentioned nanoparticle composition encapsulating nucleic acid drugs as an antitumor drug.

[0036] Compared with the prior art, the present invention has the following advantages and beneficial effects:

[0037] 1) The compound provided by the present invention is a novel lipid compound based on lipoic acid derivatives, which has excellent spleen targeting, preferentially delivers drugs to the spleen, and has good biocompatibility.

[0038] 2) The lipids based on lipoic acid derivatives described in this invention have a cyclopentane structure of lipoic acid and disulfide bonds. This structure makes the lipid compounds easier to be internalized by cells, resulting in excellent cell infection efficiency and significantly improving the effectiveness of nucleic acid delivery.

[0039] 3) This invention designs a novel ionizable cationic lipid derivative by modifying lipoic acid, and optimizes the nucleic acid loading capacity, cellular uptake efficiency and endosomal escape performance of the lipid molecule, thus constructing a next-generation LNP delivery system that combines high delivery efficiency and organ targeting. Attached Figure Description

[0040] To more clearly illustrate the specific embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained from these drawings without creative effort.

[0041] Figure 1 This is the hydrogen NMR spectrum of A4I18R2 in Example 1 of this invention;

[0042] Figure 2 This is the mass spectrum of A4I18R2 in Example 1 of the present invention;

[0043] Figure 3 This is the hydrogen NMR spectrum of A4I16R2 in Example 2 of this invention;

[0044] Figure 4 This is the mass spectrum of A4I16R2 in Example 2 of the present invention;

[0045] Figure 5 This is the hydrogen NMR spectrum of A4I12R2 in Example 3 of the present invention;

[0046] Figure 6 This is the mass spectrum of A4I12R2 in Example 3 of the present invention;

[0047] Figure 7 The hydrogen NMR spectrum of AlI12R2 in Example 4 of this invention;

[0048] Figure 8 This is the mass spectrum of A1I112R2 in Example 4 of the present invention;

[0049] Figure 9 The image shows an in vivo imaging study of A4I18R2 after intravenous injection in Example 1 of this invention; (left) shows the bioluminescence intensity of A4I18R2 after intravenous injection in Example 1, and (right) shows the bioluminescence intensity of each organ in vitro.

[0050] Figure 10 The images show in vivo imaging after intraperitoneal injection of A4I16R2 in Example 2 of this invention; (left) shows the bioluminescence intensity of in vivo A4I16R2 after intraperitoneal injection in Example 2; (right) shows the bioluminescence intensity of each organ in vitro. Detailed Implementation

[0051] To better illustrate the purpose, technical solution, and advantages of this application, the following description will be provided in conjunction with the accompanying drawings and specific embodiments, but the scope of protection of this invention is not limited thereto.

[0052] In the following embodiments, unless otherwise specified, the experimental methods used are conventional methods in the art, and the materials and reagents used are commercially available unless otherwise specified.

[0053] Ionizable cationic lipid analogs were synthesized using a general chemical reaction formula, and the general structural formula of the product is as follows:

[0054]

[0055] The specific preparation method is as follows:

[0056] At room temperature, 1.1 mmol of an aldehyde compound and 1.1 mmol of an amine compound were added to 3 mL of ethanol, and reacted at 30 °C for 6–12 h. Then, 1.0 mmol of an isocyanate compound was added, and the reaction was continued at 30 °C for 30 min. Then, 1.0 mmol of lipoic acid was added, and the reaction was continued at 45 °C for 12 h. After the reaction, the product was purified by silica gel chromatography, using a mixture of methanol and dichloromethane as the eluent. The solvent was removed by rotary evaporation, and the product was dried under vacuum overnight at room temperature. 1 Chemical structure characterization was performed using 1H NMR and mass spectrometry.

[0057] The general formula for the synthesis of Equation I is:

[0058]

[0059] Among them, the aldehyde compounds are selected as A1, A2, A3, and A4; the amine compound is R2; and the isocyanate compounds are I12, I16, I18, I11-2, and I17-2.

[0060] The general structural formula of the isocyanate is:

[0061] R3-NC

[0062] Formula II

[0063] The isocyanate compounds in this invention are synthesized by the following method:

[0064] 50 mmol of amine was refluxed in 1300 mmol of ethyl formate for 20 h, and then concentrated to dryness under reduced pressure. The resulting product was dissolved in 60 mL of dry dichloromethane, and then 43 mmol of triethylamine was added, denoted as solvent A. 150 mmol of phosphorus oxychloride was dissolved in 40 mL of dichloromethane to prepare solution B, which was then added dropwise to solution A over 30 min at -20 °C. The resulting reaction mixture was slowly heated to room temperature and stirred overnight. Thin-layer chromatography was used to confirm the completion of the reaction. The resulting mixture was poured into 200 mL of cold water and extracted twice with 100 mL of dichloromethane. The organic layer was washed with 100 mL of saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Subsequently, it was purified by column chromatography (petroleum ether:ethyl acetate = 30:1, v / v) to obtain the isocyanate product.

[0065] In the above synthesis process, the amine is selected according to R3. For example, if dodecylamine is selected as the starting material, the corresponding isocyanate product is dodecyl isocyanate (I12); if hexadecylamine is selected as the starting material, the corresponding isocyanate product is hexadecyl isocyanate (I16); if octadecylamine is selected as the starting material, the corresponding isocyanate product is octadecyl isocyanate (I18); if 9-amino-17-alkane is selected as the starting material, the corresponding isocyanate product is 9-isocyan-17-alkane (I17-2); if 6-amino-11-alkane is selected as the starting material, the corresponding isocyanate product is 6-isocyan-11-alkane (I11-2).

[0066] In a preferred embodiment, the lipoic acid-modified lipid compound includes any one of the following compounds:

[0067]

[0068]

[0069] Example 1

[0070] This embodiment provides a lipid compound based on a lipoic acid derivative, the structural formula of which is shown below as A4I8R2:

[0071]

[0072] Preparation of A4I18R2:

[0073] At room temperature, 3-dimethylaminopropylamine (112.4 mg, 1.1 mmol) and 2-ethylhexanal (141.0 mg, 1.1 mmol) were dissolved in ethanol (3 mL), and the mixture was stirred at 30 °C for 12 h. Octadecyl isocyanate (279.5 mg, 1 mmol) was added, and the mixture was stirred at 30 °C for another 30 min. Thioctic acid (206.3 mg, 1 mmol) was then added, and the mixture was reacted at 45 °C for 12 h. After the reaction was complete, the product was purified by column chromatography (dichloromethane:methanol = 20:1, v / v), the solvent was removed by rotary evaporation, and the product was dried under vacuum overnight at room temperature to obtain product A4I18R2 (1H NMR spectrum shown below). Figure 1 As shown, the mass spectrum is as follows Figure 2 (As shown). 1H NMR(400MHz,Chloroform-d)δ4.45(s,1H),3.65-3.53(m,1H),3.44-3.07(m,6H),2.54-2.19(m,12H),1.98-1. 86(m,1H),1.83-1.59(m,6H),1.54-1.37(m,4H),1.37-1.14(m,40H),1-0.83(m,9H).MS:m / z:[M+H]+calcdfor C40H79N3O2S2,698.21; found,698.70.

[0074] Example 2

[0075] This embodiment provides a lipid compound based on a lipoic acid derivative, the structural formula of which is shown in the following diagram: A4I16R2.

[0076]

[0077] Preparation of A4I16R2:

[0078] At room temperature, 3-dimethylaminopropylamine (112.4 mg, 1.1 mmol) and 2-ethylhexanal (141.0 mg, 1.1 mmol) were dissolved in ethanol (3 mL), and the mixture was stirred at 30 °C for 12 h. Hexadecanoic acid (251.3 mg, 1 mmol) was added, and the mixture was stirred at 30 °C for another 30 min. Thioctic acid (206.3 mg, 1 mmol) was then added, and the mixture was reacted at 45 °C for 12 h. After the reaction was complete, the product was purified by column chromatography (dichloromethane:methanol = 20:1, v / v), the solvent was removed by rotary evaporation, and the product was dried under vacuum overnight at room temperature to obtain product A4I16R2 (1H NMR spectrum shown below). Figure 3 As shown, the mass spectrum is as follows Figure 4 (As shown). ¹H NMR (400 MHz, Chloroform-d) δ 4.41 (s, ¹H), 3.64–3.50 (m, ¹H), 3.41–3.28 (m, 2H), 3.20–

[0079] 3.04(m,4H),2.52-2.38(m,2H),2.36-2.21(m,9H),1.91-1.84(m,1H),1.78-1 .59(m,6H),1.52-1.38(m,5H),1.31-1.04(m,36H),0.87(m,9H).MS:m / z:calcd forC38H76N3O2S2,670.53; found,670.53.

[0080] Example 3

[0081] This embodiment provides a lipid compound based on a lipoic acid derivative, the structural formula of which is shown below as A4I12R2:

[0082]

[0084] Preparation of A4I12R2:

[0085] At room temperature, 3-dimethylaminopropylamine (112.4 mg, 1.1 mmol) and 2-ethylhexanal (141.0 mg, 1.1 mmol) were dissolved in ethanol (3 mL), and the mixture was stirred at 30 °C for 12 h. Dodecanoic acid (195.2 mg, 1 mmol) was added, and the mixture was stirred at 30 °C for another 30 min. Thioctic acid (206.3 mg, 1 mmol) was then added, and the mixture was reacted at 45 °C for 12 h. After the reaction was complete, the product was purified by column chromatography (dichloromethane:methanol = 20:1, v / v), the solvent was removed by rotary evaporation, and the product was dried under vacuum overnight at room temperature to obtain product A4I12R2 (1H NMR spectrum shown below). Figure 5 As shown, the mass spectrum is as follows Figure 6 shown). 1HNMR(400MHz,Chloroform-d)δ4.59-4.23(s,1H),3.63-3.50(m,1H),3.41-3.25(m,2H),3.23-3.06(m,4H),2.52-2.19(m, 14H),1.96-1.84(m,1H),1.76-1.60(m,6H),1.54-1.37(m,5H),1.34-1.17(m,26H),0.94-0.82(m,9H).MS:m / z:[M+H]+calcd for C34H68N3O2S2,614.47;

[0086] Found, 614.47.

[0087] Example 4

[0088] This embodiment provides a lipid compound based on a lipoic acid derivative, the structural formula of which is shown below as A1I12R2.

[0089]

[0090] Preparation of A1I12R2:

[0091] At room temperature, 3-dimethylaminopropylamine (112.4 mg, 1.1 mmol) and isobutyraldehyde (72 mg, 1.1 mmol) were dissolved in ethanol (3 mL), and the mixture was stirred at 30 °C for 12 h. Dodecaisocyanate (195.2 mg, 1 mmol) was added, and the mixture was stirred at 30 °C for another 30 min. Then, thioctic acid (206.3 mg, 1 mmol) was added, and the mixture was reacted at 45 °C for 12 h. After the reaction was complete, the product was purified by silica gel chromatography (dichloromethane:methanol = 20:1, v / v), the solvent was removed by rotary evaporation, and the product was dried under vacuum overnight at room temperature to obtain product A1I12R2 (1H NMR spectrum shown below). Figure 7 As shown, the mass spectrum is as follows Figure 8 shown). 1H NMR(400MHz,Chloroform-d)δ4.31-3.93(s,1H),3.64-3.52(m,1H),3.41-3.28(m,2H),3.24-3.05(m,4H),2.52-2.19(m,12H),1.95-1.85(m,1H) ),1.80-1.58(m,6H),1.54-1.39(m,4H),1.32-1.19(m,18H),0.98-0.91(d,3H),0.89-0.85(t,3H),0.84-0.77(d,3H).MS(ESI)m / z:[M+H]+calcd forC30H60N3O2S2,558.41; found,558.41.

[0092] Application Example 1

[0093] This application example provides a nanoparticle composition encapsulating a nucleic acid drug, which is prepared by the following steps:

[0094] 1) Lipoic acid derivative (the lipoic acid derivative-based lipid compound shown in A4I18R2 prepared in Example 1), cholesterol, neutral phospholipid (DSPC), and polyethylene glycol (PEG2000) were dissolved in ethanol to prepare 10.00 mg / mL ethanol solutions. They were then mixed in a molar ratio of 60.0%:30.8%:8.0%:1.2%, and a certain amount of ethanol was added to 20 μL to obtain an organic phase liposome mixed solution. At this time, the concentration of the lipoic acid derivative lipid compound was 2.75 mg / mL, the concentration of cholesterol was 0.78 mg / mL, the concentration of neutral phospholipid was 0.42 mg / mL, and the concentration of polyethylene glycol lipid was 0.16 mg / mL.

[0095] 2) The reporter gene encoding the firefly luciferase protein was selected (Firefly Luciferase-mRNA, catalog number: 17101ES, purchased from Yisheng Biotechnology Co., Ltd.), and dissolved and diluted with citric acid / sodium citrate buffer at pH 4 to obtain an aqueous solution with an mRNA concentration of 5 μg / 60 μL.

[0096] 3) The organic phase liposome mixture was added dropwise to the aqueous phase solution at a volume ratio of 1:3. The resulting system had an ionizable lipid to mRNA mass ratio of 11:1, with 5 μg of mRNA. The mixture was then dialyzed at 4°C for 2 hours using a dialysis bag with a molecular weight cutoff of 1000 to remove ethanol, yielding a lipid nanoparticle composition containing lipoic acid and loaded with mRNA.

[0097] Application Example 2

[0098] This application example provides a nanoparticle composition encapsulating a nucleic acid drug. The only difference from Application Example 1 is that A4I18R2 is replaced with an equal concentration of A4I16R2. All other steps are exactly the same as in Example 1.

[0099] Application Example 3

[0100] This application example provides a nanoparticle composition encapsulating a nucleic acid drug. The only difference from Application Example 1 is that A4I18R2 is replaced with an equal concentration of A4I12R2. All other steps are exactly the same as in Example 1.

[0101] Application Example 4

[0102] This application example provides a nanoparticle composition encapsulating a nucleic acid drug. The only difference from Application Example 1 is that A4I18R2 is replaced with an equal concentration of A1I12R2. All other steps are exactly the same as in Example 1.

[0103] Test Example 1

[0104] Evaluation of the in vivo delivery performance of firefly luciferase mRNA.

[0105] Test sample: The lipid nanoparticle composition carrying nucleic acid drugs provided in the above application example.

[0106] Test method:

[0107] Tail vein administration: The lipid nanoparticle composition prepared by tail vein injection was administered at a dose of 5 μg mRNA per mouse. The molar ratio of lipoic acid lipids, DSPC, cholesterol, and DMG-PEG2000 was 60%:8%:30.8%:1.2%; the mass ratio of lipoic acid lipids to mRNA was 11:1. Six hours later, 200 μL of D-firefly luciferase substrate at a concentration of 15 mg / ml was injected intraperitoneally into each mouse for subsequent in vivo imaging. Fifteen minutes later, the mice were placed under an in vivo imaging system to observe and photograph the bioluminescence intensity of the mouse body and isolated organs.

[0108] Intraperitoneal administration: The lipid nanoparticle composition prepared for intraperitoneal injection was administered at a dose of 5 μg mRNA per mouse. The molar ratio of lipoic acid lipids, DSPC, cholesterol, and DMG-PEG2000 was 60%:8%:30.8%:1.2%; the mass ratio of lipoic acid lipids to mRNA was 11:1. Six hours later, 200 μL of D-firefly luciferase substrate at a concentration of 15 mg / ml was injected intraperitoneally into each mouse for subsequent in vivo imaging. Fifteen minutes later, the mice were placed under an in vivo imaging system to observe and photograph the bioluminescence intensity of the mouse body and isolated organs.

[0109] The test results are shown in Table 1 below. Figure 8 and Figure 9 As shown.

[0110] Table 1. In vivo luminescence intensity of different lipid nanoparticles under different injection methods

[0111] sample vein abdominal cavity A1I12R2 <![CDATA[5.595×10 5 ]]> <![CDATA[4.604×10 5 ]]> A4I12R2 <![CDATA[3.553×10 5 ]]> <![CDATA[5.581×10 4 ]]> A4I16R2 <![CDATA[8.822×10 5 ]]> <![CDATA[2.002×10 6 ]]> A4I18R2 <![CDATA[9.855×10 5 ]]> <![CDATA[2.674×10 6 ]]>

[0112] As shown in Table 1, different injection methods produce different delivery effects. Among them, A4I18R2 has a good delivery effect in both intravenous and intraperitoneal injection.

[0113] Figure 8 The left image shows the bioluminescence intensity of intravenous injection of Example 1A4I18R2 in vivo, while the right image shows the bioluminescence intensity of various organs in vitro. Figure 8 It can be seen that intravenous injection of A4I18R2 can efficiently deliver the spleen.

[0114] Figure 9 The left image shows the bioluminescence intensity of A4I16R2 injected intraperitoneally in Example 2; the right image shows the bioluminescence intensity of various organs in vitro. Figure 9 It can be seen that intraperitoneal injection of A4I16R2 can efficiently deliver it to the spleen.

[0115] In summary, when the lipoic acid-derived lipids provided by this invention are used as delivery carriers for nucleic acid drugs, the disulfide bonds within the compound are cleaved by intracellular glutathione, leading to compound degradation. This not only ensures the timely release of the nucleic acid drug but also significantly reduces cytotoxicity caused by intracellular compound accumulation, demonstrating excellent biocompatibility. Furthermore, the lipid nanoparticle composition of this invention, when used as a carrier for delivering nucleic acid drugs, exhibits excellent delivery efficiency and superior spleen targeting, preferentially delivering nucleic acid drugs to the spleen.

[0116] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of the present invention.

Claims

1. A lipid compound based on a lipoic acid derivative, characterized in that, The lipid compound based on lipoic acid derivatives has the structure shown in Formula I: Formula I R1 is independently selected from at least one group selected from straight-chain alkyl, straight-chain alkenyl, cycloalkyl, straight-chain alkyl containing heteroatoms, branched alkyl containing heteroatoms, branched alkylene containing heteroatoms, alkyl containing heteroatom rings, alkyl containing heteroatoms and aromatic rings, alkyl containing hydroxyl groups, alkyl containing ester groups, alkyl containing ether groups, and alkyl containing sulfonate groups. R2 is independently selected from at least one group selected from straight-chain alkyl, branched-chain alkyl, straight-chain alkenyl, branched-chain alkenyl, substituted alkynyl, cycloalkyl, phenyl, and heteroatom-containing aromatic groups; R3 is independently selected from at least one group selected from straight-chain alkyl, branched alkyl, straight-chain alkenyl, cycloalkyl, straight-chain alkyl containing heteroatoms, branched alkyl containing heteroatoms, branched alkylene containing heteroatoms, alkyl containing heteroatom rings, alkyl containing heteroatoms and aromatic rings, alkyl containing hydroxyl groups, alkyl containing ester groups, alkyl containing ether groups, and alkyl containing sulfonate groups.

2. The lipid compound based on lipoic acid derivatives according to claim 1, characterized in that, R1 is selected from any one of the following groups; wherein, Representative group connection positions: The R2 is selected from any one of the following groups; wherein Representative group connection positions: The R3 is selected from any one of the following groups; wherein Represents the location of the group connection; 。 3. The lipid compound based on lipoic acid derivatives according to claim 1, characterized in that, The lipid compounds based on lipoic acid derivatives include any one of the following compounds: 。 4. The use of the lipid compound based on thioctic acid derivatives according to any one of claims 1 to 3 in the preparation of drug carriers.

5. A lipid nanoparticle composition carrier, characterized in that, It includes one or more of the following: lipid compounds based on lipoic acid derivatives as described in any one of claims 1 to 3, polyethylene glycol lipids, cholesterol, and neutral phospholipids.

6. The lipid nanoparticle composition carrier according to claim 5, characterized in that, The lipid nanoparticle composition carrier comprises, by molar percentage, 10%–70% lipid compounds based on lipoic acid derivatives, 0.1%–25% polyethylene glycol lipids, 10%–50% cholesterol, and 5%–30% neutral phospholipids.

7. The use of the lipid nanoparticle composition carrier according to claim 5 or 6 in the preparation of nucleic acid-loaded drugs.

8. A method for preparing a nanoparticle composition encapsulating a nucleic acid drug, characterized in that, Includes the following steps: 1) Dissolve the lipid compound based on lipoic acid derivative, neutral phospholipid, polyethylene glycol lipid and cholesterol according to any one of claims 1 to 3 in ethanol to obtain an organic phase liposome solution; 2) Dissolve the nucleic acid drug in citric acid / sodium citrate buffer to obtain an aqueous nucleic acid drug solution; 3) The organic phase liposome solution and the aqueous phase nucleic acid drug solution are mixed and dialyzed to obtain a nanoparticle composition loaded with nucleic acid drugs.

9. A nanoparticle composition containing a nucleic acid drug prepared by the preparation method of claim 8.

10. The use of the nanoparticle composition of claim 9 containing nucleic acid drugs as an antitumor drug.

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