Tertiary amine oxidation type zwitterionic lipid, lipid nano-delivery particle and application of tertiary amine oxidation type zwitterionic lipid and lipid nano-delivery particle

Abstract

The invention relates to tertiary amine oxidation type zwitterionic lipid, lipid nano-delivery particles and application of the tertiary amine oxidation type zwitterionic lipid and the lipid nano-delivery particles. The invention provides tertiary amine oxidation type zwitterionic lipid which is proper in size and special in structure. The tertiary amine oxidation type zwitterionic lipid can deliver hydrophilic / hydrophobic organic / inorganic contents. The lipid nano-delivery particles are prepared on the basis of the tertiary amine oxidation type zwitterionic lipid, and various contents including hydrophilic drugs, hydrophobic drugs and inorganic nano-particles can be encapsulated by regulating and controlling the ratio of the tertiary amine oxidation type zwitterionic lipid to the lipid without the tertiary amine oxidation type group. The formed lipid nanoparticles are uniform in size, stably exist in different solutions, do not agglomerate, have long blood circularity of up to at least 60 hours, have very high specific affinity to tumors, are gathered in the tumors in quantity, do not cause any obvious damage to main organs, and can be used for preparing the lipid nanoparticles. The bioavailability of the content and the cancer treatment effect are obviously improved.

Description

Technical Field

[0001] This invention belongs to the field of biomedical technology, and in particular relates to a tertiary amine oxidized zwitterionic lipid, lipid nanoparticles and their applications. Background Technology

[0002] Lipid nanodelivery systems are an important platform in the field of modern drug delivery, and their successful application in COVID-19 mRNA vaccines demonstrates their enormous clinical potential. Traditional liposomal drugs, such as Doxil (doxorubicin liposome) and Onivyde (irinotecan liposome), have been widely used in the treatment of diseases such as cancer. These formulations, by encapsulating the drug, can improve its pharmacokinetic behavior to some extent, reducing early leakage and promoting rapid clearance.

[0003] However, traditional liposomes composed of conventional phospholipids still have significant limitations. Studies have shown that they have low accumulation efficiency in target tissues and poor penetration into tumor tissues, resulting in limited therapeutic effects (Zhou et al., Biomaterials, 2020, 240, 119902). The root cause is that traditional liposomes are prone to non-specific protein adsorption on their surface, leading to rapid recognition and clearance by the immune system, making efficient delivery difficult.

[0004] To overcome these challenges, the design of novel lipid materials has become a research focus. In recent years, materials modified with tertiary amine oxidation groups have shown unique advantages. Studies have shown that these materials can form a strong hydration layer, effectively resisting non-specific protein adsorption and endowing nanocarriers with long-term cycling capabilities (Chen et al., Nature Biomedical Engineering, 2021, 5, 1019). More importantly, the tertiary amine oxidation structure has a high affinity for cell membrane phospholipids, which can not only promote the efficient internalization of the carrier by cells, but also target the Golgi apparatus, actively triggering transcellular transport pathways, thereby significantly enhancing tissue penetration and deep tumor accumulation.

[0005] However, these existing nanodelivery systems carrying tertiary amine oxidation groups (where the nitrogen atom connects two short saturated fatty chains or is in a heterocyclic ring) still do not perform ideally in terms of tumor-specific selection, tending to accumulate in major organs such as the liver, spleen, and intestines, which does not show a significant advantage compared to traditional liposomes. Therefore, developing a tumor-highly selective nanodelivery system based on novel tertiary amine oxidation group-functionalized lipids has important clinical translational value for improving the delivery efficiency, bioavailability, and efficacy of the contents. Summary of the Invention

[0006] Addressing the problem that existing nanodelivery systems carrying tertiary amine oxidation groups tend to aggregate in major organs such as the liver, spleen, and intestines, this invention provides a novel tertiary amine oxidation zwitterionic lipid, lipid nanodelivery particles, and their applications.

[0007] The tertiary amine oxidized zwitterionic lipids provided by this invention can be combined with one or more auxiliary lipids to encapsulate various hydrophilic / hydrophobic and organic / inorganic contents to form nanoparticles. The resulting nanoparticles are uniform in size, stable in different solutions and do not aggregate. They can evade phagocytosis by the mononuclear phagocytic system in vivo, achieve long circulation, have excellent biocompatibility, and can specifically aggregate inside tumors while rarely remaining in other major organs.

[0008] The objective of this invention can be achieved through the following technical solutions: In a first aspect, the present invention provides a tertiary amine oxidized zwitterionic lipid with the chemical structure shown in Formula I: , In Formula I, R is selected from C1-C6 alkyl groups, and X and Y are each independently selected from hydrophobic units with a number average molecular weight ≥142.

[0009] In Formula I, the nitrogen atom is simultaneously connected to a short-chain alkyl group (i.e., the R structure) and two larger hydrophobic units.

[0010] In some embodiments of the present invention, X and Y in the structure shown in Formula I independently contain linking bonds and lipid-soluble molecular residues.

[0011] In some embodiments of the present invention, the tertiary amine oxidized zwitterionic lipid has the chemical structure shown in Formula II: In Formula II, R is selected from C1-C6 alkyl groups; n is an integer from 1 to 3; L is a linking group, including but not limited to ester bonds, carbonate bonds, amide bonds, carbamate bonds, urea bonds, and disulfide bonds; R 1 and R 2 Each is independently selected from lipid-soluble molecular residues.

[0012] More preferably, in the structure shown in Formula II, R 1 and R 2 They are independently selected from cholesterol residues, bile acid residues, fat-soluble vitamin residues, steroid hormone residues, and hydrophobic signal molecule residues.

[0013] Fat-soluble vitamins include, but are not limited to, vitamins A, D, E, and K. Steroid hormones include, but are not limited to, testosterone, estrogen, and cortisol. Hydrophobic signaling molecules include, but are not limited to, prostaglandins and leukotrienes.

[0014] More preferably, in the structure shown in Formula II, R 1 and R 2 They are selected independently from saturated fatty acid chains or unsaturated fatty acid chains.

[0015] Furthermore, the tertiary amine oxidized zwitterionic lipid is selected from one of the following structures: .

[0016] Regarding the tertiary amine oxidized zwitterionic lipid structures provided above, these structures are obtained by further synthesizing tertiary amine oxidized zwitterionic lipids using bifunctional tertiary amine compounds as the backbone. The bifunctional tertiary amine compounds include, but are not limited to, the following structures: .

[0017] Furthermore, the tertiary amine oxidized zwitterionic lipid is selected from the following structures: .

[0018] Secondly, the present invention provides a lipid nanocarrier containing tertiary amine oxidized zwitterionic lipids, wherein the lipid nanocarrier is prepared from the above-mentioned tertiary amine oxidized zwitterionic lipids and lipids without tertiary amine oxidized groups.

[0019] The lipid nanocarrier shell is electrically neutral and has good hydrophilicity, biocompatibility, and stealth properties (avoiding clearance by mononuclear phagocytic systems).

[0020] In one embodiment of the present invention, lipids that do not contain tertiary amine oxidation groups include, but are not limited to, one or more of cationic lipids, anionic lipids, uncharged lipids, phospholipids, phospholipid-polyethylene glycol, vitamin E polyethylene glycol succinate, or cholesterol.

[0021] In some embodiments of the present invention, the mass ratio of the tertiary amine oxidized zwitterionic lipid to the lipid without tertiary amine oxidized groups is 1-20:1.

[0022] Thirdly, the present invention provides a lipid nanodelivery particle, comprising the lipid nanodelivery carrier and contents described in the second aspect of the present invention.

[0023] In some embodiments of the present invention, the mass ratio of the contents to the lipid nanodelivery carrier is 0.01-100:1.

[0024] In some embodiments of the present invention, the contents are hydrophobic or hydrophilic.

[0025] In some embodiments of the present invention, the contents include, but are not limited to, hydrophobic drugs, hydrophilic drugs, proteins, peptides, DNA, RNA, inorganic nanoparticles, organic / inorganic hybrid nanoparticles, and nanoscale metal-organic frameworks.

[0026] In some embodiments of the present invention, the hydrophobic drug includes, but is not limited to, sorafenib, itraconazole, lovastatin, phenytoin, dexamethasone, ibuprofen, etc.

[0027] In some embodiments of the present invention, the hydrophilic drug includes, but is not limited to, penicillin, atenolol, levodopa, metformin, 5-fluorouracil, oseltamivir, etc.

[0028] In some embodiments of the present invention, the proteins include, but are not limited to, bevacizumab, insulin, interferon, streptokinase, coagulation factors, hepatitis B vaccine, etc.

[0029] In some embodiments of the present invention, the polypeptide includes, but is not limited to, telpolide, nesiritide, leuprolide, polymyxin B / E, teriparatide, etc.

[0030] In some embodiments of the present invention, the DNA / RNA includes, but is not limited to, plasmids, mRNA, siRNA, etc.

[0031] In some embodiments of the present invention, the inorganic nanoparticles include, but are not limited to, barium titanate, cerium oxide, iron tetroxide, calcium phosphate, magnesium sulfate, etc.

[0032] In some embodiments of the present invention, the organic / inorganic hybrid nanoparticles include, but are not limited to, hydroxyapatite, calcium citrate, manganese citrate, etc.

[0033] In some embodiments of the present invention, the nanoscale metal-organic framework includes, but is not limited to, MOF-5, UiO-66, ZIF-67, etc.

[0034] Fourthly, a method for preparing the lipid nanoparticles is provided. When the contents are hydrophobic, the lipid nanoparticles are prepared as follows: tertiary amine oxidized zwitterionic lipids, lipids without tertiary amine oxidized groups, and hydrophobic contents are dissolved or dispersed in an organic solvent to obtain an organic phase, which is then added to a stirred aqueous phase or a microfluidic device is used to mix the organic phase and the aqueous phase to obtain nanoparticles containing hydrophobic contents. When the contents are hydrophilic, the lipid nanoparticles are prepared as follows: tertiary amine oxidized zwitterionic lipids or lipids without tertiary amine oxidized groups are dissolved or dispersed in an organic solvent to obtain an organic phase; then added to a stirred aqueous phase containing hydrophilic contents, or a microfluidic device is used to mix the organic phase with the aqueous phase containing hydrophilic contents to obtain nanoparticles containing hydrophilic contents.

[0035] In some embodiments of the present invention, the volume ratio of the organic phase to the aqueous phase is 1:2-20.

[0036] Fifthly, the application of the lipid nanoparticles is provided, wherein the lipid nanoparticles are formulated as one or more of the following: intravenous injection, intraperitoneal injection, intramuscular injection, intratumoral injection, intradermal injection, or subcutaneous injection.

[0037] That is, nanoparticles can be delivered to the human body via one or more of the following methods: intravenous injection, intraperitoneal injection, intramuscular injection, intratumoral injection, intradermal injection, and subcutaneous injection.

[0038] Compared with the prior art, the present invention has the following advantages and beneficial effects: This application provides a tertiary amine oxidized zwitterionic lipid with a suitable size and a unique structure, which is capable of delivering hydrophilic / hydrophobic, organic / inorganic contents.

[0039] This application also prepared lipid nanoparticles based on tertiary amine oxidized zwitterionic lipids. These lipid nanoparticles are exempt from clearance by the mononuclear phagocytic system and the kidneys and can selectively guide the nanoparticles to accumulate in tumors. The negligible cytotoxicity and hemolysis rate of the nanoparticles themselves will not cause systemic toxicity during their long-term blood circulation.

[0040] This application enables the encapsulation of various contents, including hydrophilic drugs, hydrophobic drugs, and inorganic nanoparticles, by adjusting the ratio of zwitterionic lipids with tertiary amine oxidation groups to lipids without tertiary amine oxidation groups. The resulting lipid nanoparticles are uniform in size, stable in different solutions, and do not aggregate. They exhibit long blood circulation of up to at least 60 hours, have a high specific affinity for tumors, and accumulate in large quantities inside the tumor without causing any significant damage to major organs. This significantly improves the bioavailability of the contents and the efficacy of cancer treatment. Attached Figure Description

[0041] To make the objectives, technical solutions, and beneficial effects of this invention clearer, the following figures are provided: Figure 1 This is a diagram of the TAO synthesis pathway in Example 1; Figure 2TAO-CeO in Example 3 2-x Particle size distribution of nanoparticles; Figure 3 TAO-CeO in Example 3 2-x Potential diagram of nanoparticles; Figure 4 TAO-CeO in Example 4 2-x Particle size stability diagram of nanoparticles; Figure 5 TAO-CeO in Example 4 2-x Distribution stability diagram of nanoparticles; Figure 6 TAO-CeO in Example 5 2-x Average fluorescence intensity of nanoparticles uptake by cells; Figure 7 TAO-CeO in Example 6 2-x Hemolysis rate diagram of nanoparticles; Figure 8 TAO-CeO in Example 7 2-x Cytotoxicity diagram of nanoparticles; Figure 9 TAO-CeO in Example 8 2-x In vivo imaging of nanoparticles accumulating within a tumor over time.

[0042] Figure 10 TAO-CeO in Example 8 2-x In vivo imaging of the distribution of nanoparticles in a mouse. Detailed Implementation

[0043] The preferred embodiments of the present invention will now be described in detail with reference to the accompanying drawings.

[0044] In this invention, unless otherwise specified, all raw materials and equipment used are commercially available or commonly used in the field. The methods described in the following embodiments are conventional methods in the field, unless otherwise specified.

[0045] Example 1 Synthesis of zwitterionic lipids with tertiary amine oxidation (taking TAO as an example).

[0046] In this embodiment, the TAO synthesis path is as follows: Figure 1 As shown, the specific steps are as follows: N,N'-carbonyldiimidazole (CDI) (14.41 g, 88.86 mmol), N-methyldiethanolamine (1.7 mL, 14.81 mmol), triethylamine (12.5 mL, 89.93 mmol), and 190 mL of anhydrous tetrahydrofuran (THF) were added sequentially to a reaction flask, and the mixture was stirred at room temperature for 12 hours. The product 1 was obtained by washing several times with dilute hydrochloric acid and saturated brine, and then drying. Add 5.22 g (19.52 mmol) of oleylamine to a 30 mL flask containing product 1 (2 g, 6.51 mmol) of anhydrous THF. React the product in a water bath at 30 °C for 48 hours under light-protected conditions with stirring. After the reaction is complete, purify the product by column chromatography (MeOH:DCM = 1:15) to obtain product 2. Weigh 400 mg of product 2, dissolve it in 2.5 mL of anhydrous ethanol, add 5 mL of 30% hydrogen peroxide solution (H2O2), react at room temperature for 6 hours, and freeze dry to obtain the final product, namely TAO.

[0047] Example 2 Preparation of nanoparticles (taking inorganic cerium oxide nanoparticles as an example): The following ingredients were added in a mass ratio of 4:1:1:0.8: TAO (prepared in Example 1), phospholipid-polyethylene glycol 2000 (DSPE-PEG2000), cholesterol (Chol), and cerium oxide (CeO) 2-x A stock solution of 200 μg / mL (based on the concentration of TAO) was prepared by dispersing TAO in dichloromethane. 100 μL of the stock solution was then added to 1 mL of vigorously stirred ddH₂O and stirred for 30 min to obtain TAO-CeO₂. 2-x Nanoparticles.

[0048] In this embodiment, cerium oxide (CeO) is used. 2-x In CeO, x represents the proportion of oxygen atoms missing, typically ranging from 0 < x ≤ 0.5, reflecting the oxygen defect content. 2-x This indicates that Ce is in a +3 or +4 oxidation state. Ideal cerium oxide is stoichiometric CeO2, but under reducing atmospheres (such as H2, CO) or high-temperature conditions, some Ce... 4+ It will be reduced to Ce 3+ To maintain electroneutrality, oxygen vacancies are created in the crystal lattice, resulting in an oxygen content below 2, forming CeO. 2-x It is also commonly referred to as cerium oxide nanoparticles, and is described in patents such as CN113388874A.

[0049] This application provides a cerium oxide (CeO) 2-x The preparation method of ) (sol-gel method) is as follows: CeO with a particle size of 3 nanometers was synthesized via a non-hydrolyzed sol-gel reaction. 2-x Nanoparticles. In brief, 12 mmol oleylamine, 1 mmol cerium acetate, and 15 mL xylene were mixed in a 50 mL three-necked flask. The resulting solution was sonicated at room temperature for 30 min, followed by stirring for 2 h. The solution was then heated to 90 °C under vacuum at a heating rate of 2 °C / min. After stirring at 90 °C for 20 min, 1 mL of deionized water was rapidly added to the mixture, and the mixture was stirred vigorously. The solution gradually changed color from grayish-white to pale yellow via a sol-gel reaction. The reaction mixture was aged at 90 °C for 3 h and cooled to room temperature to obtain a clear yellow colloidal solution. The synthesized CeO₂ was precipitated by adding 100 mL of acetone. 2-x Nanoparticles. Collected CeO 2-x The nanoparticles were washed with ethanol and acetone by centrifugation (15,000 rpm, 20 minutes), vacuum dried, and then resuspended in dichloromethane for later use.

[0050] Of course, CeO in this application 2-x Nanoparticles are materials that can be prepared using existing technologies. Those skilled in the art may obtain them not only by the methods described above, but also by other methods or by purchasing them from other sources.

[0051] Example 3 TAO-CeO in Example 2 2-x Nanoparticle size distribution and surface potential analysis: TAO-CeO 2-x Nanoparticles were uniformly dispersed in ultrapure water, and the TAO-CeO in the solution was analyzed using dynamic light scattering technology. 2-x The nanoparticles were subjected to particle size distribution analysis, and their surface Zeta potential in ultrapure water was measured. For example... Figure 2 , 3 As shown, the nanoparticles have a particle size of about 120 nm and a potential of about -4 mV.

[0052] Example 4 TAO-CeO in Example 2 2-x Dispersion and stability studies of nanoparticles: Prepare TAO-CeO at concentrations of 20–200 µg / mL respectively. 2-x The particle size distribution of nanoparticles in aqueous solutions and physiological saline solutions was monitored for three consecutive days at 4, 8, 12, 24, 36, 48, and 72 hours using a nanoparticle size analyzer. Figure 4 , 5As shown, the particle size did not change significantly within 72 hours, and the PDI value remained stable at around 0.2, indicating that TAO-CeO 2-x Nanoparticles maintain good dispersibility in both deionized water and physiological saline, and are not prone to aggregation or precipitation.

[0053] Example 5 TAO-CeO in Example 2 2-x Cellular uptake of nanoparticles: Referring to the method for synthesizing tertiary amine oxidized zwitterionic lipids in Example 1, oleylamine was labeled with Cy5.5 (Sulfo-Cyanine5.5) to obtain TAO. cy5.5 .

[0054] Referring again to the nanoparticle preparation method in Example 2, TAO was replaced with TAO cy5.5 Obtain TAO cy5.5 -CeO 2-x Fluorescent nanoparticles.

[0055] TAO cy5.5 -CeO 2-x Fluorescent nanoparticles are used in cellular uptake experiments.

[0056] Hepa1-6 cells were divided into 3×10 5 Cells were evenly seeded at a density of 1 cell / well in 6-well cell culture plates and incubated in a cell culture incubator for 24 hours. When the cells had completely adhered and grown to a density of approximately 70%–80%, 50 μg / mL (cy5.5eq: 1 μg / mL) of TAO was added to each well. cy5.5 -CeO 2-x Nanoparticles were co-incubated for 2 h, 4 h, 8 h, 10 h, and 12 h. Cells were then digested with trypsin and collected. The fluorescence intensity of nanoparticle uptake by cells at different time points was measured using flow cytometry. Figure 6 As shown, the fluorescence intensity of cell uptake reaches its maximum at 10 h, indicating that the nanoparticles have good cell internalization properties.

[0057] Example 6 TAO-CeO in Example 2 2-x Cell hemolysis experiment using nanoparticles.

[0058] A healthy C57BL / 6 black mouse was selected, and blood samples were obtained via ocular sampling. The blood-containing tubes were placed in a low-temperature centrifuge at 1000 rpm / min for 5 min at a constant temperature of 4°C. The supernatant was discarded, and the remaining blood cells were resuspended and washed with physiological saline until the supernatant was clear and colorless. The centrifuged red blood cells were diluted with physiological saline to prepare a 4% red blood cell suspension for later use. During the experiment, 500 μL of the 4% red blood cell physiological saline solution was mixed with 500 μL of deionized water as a positive control; mixed with 500 μL of physiological saline as a negative control; and mixed with 500 μL of TAO-CeO4 at different concentrations as a negative control. 2-x Nanoparticle solutions (20, 50, 100, and 200 μg / mL) were mixed to form experimental groups. All samples were incubated at 37°C for 12 hours, followed by centrifugation at 3000 rpm / min for 5 min using a low-temperature centrifuge. After centrifugation, 100 μL of the supernatant was transferred to a 96-well plate, and the absorbance of the supernatant at 541 nm was measured to assess the amount of hemoglobin released into the supernatant during hemolysis.

[0059] The formula for calculating the percentage of hemolysis is as follows: like Figure 7 As shown, no obvious hemolysis was observed after the nanoparticles of different concentrations were exposed to blood for 12 hours, proving that the material has good blood compatibility.

[0060] Example 7 TAO-CeO in Example 2 2-x Cytotoxicity of nanoparticles: Hepa1-6 cells were administered at a rate of 1×10⁻⁶. 4 The cells were seeded evenly into 96-well cell culture plates at a density of [number] cells / well and incubated for approximately 24 hours until the cell density reached 70-80%. Then, TAO-CeO3 was added to the plates at different concentrations (20 μg / mL, 50 μg / mL, 100 μg / mL, 200 μg / mL). 2-x Cells were cultured in DMEM complete medium containing nanoparticles for another 24 h, and cell viability was determined using the standard MTT assay. 100 μL of 10% MTT (MTT powder prepared as a 1.5 mg / mL stock solution in PBS) in DMEM complete medium was added to each well under light-protected conditions. The cells were incubated in a cell culture incubator under light-protected conditions for 4 h. The supernatant was discarded, and 100 μL of DMSO was added. The absorbance of each well was measured at 570 nm using a microplate reader, and the cell viability percentage was calculated. The formula for calculating the cell viability percentage is as follows: The results are as follows Figure 8 As shown, cells maintained nearly 100% viability across a wide range of nanoparticle concentrations, demonstrating the effectiveness of TAO-CeO. 2-x The nanoparticles themselves do not have the ability to kill cancer cells, which means that the nanoparticles have quite good cell safety.

[0061] Example 8 TAO-CeO in Example 2 2-x In vivo imaging of small animals using nanoparticles.

[0062] Referring to the method for synthesizing tertiary amine oxidized zwitterionic lipids in Example 1, oleylamine was labeled with Cy5.5 (Sulfo-Cyanine5.5) to obtain TAO. cy5.5 .

[0063] Referring again to the nanoparticle preparation method in Example 2, TAO was replaced with TAO cy5.5 Obtain TAO cy5.5 -CeO 2-x Fluorescent nanoparticles.

[0064] TAO cy5.5 -CeO 2-x Fluorescent nanoparticles are used for in vivo imaging of small animals.

[0065] A subcutaneous tumor model in mice was established using Hepa1-6 cells and 5-6 week old female C57BL / 6 mice. When the Hepa1-6 cell density reached 80%–90%, the cells were digested with trypsin, and the resulting cells were resuspended in PBS to form a single-cell suspension. 6 Hepa1-6 cells were inoculated subcutaneously into the right buttock of C57BL / 6 female black mice at a density of / mice.

[0066] The tumor volume can be maintained at 60 mm 3 The inoculation is considered successful if the tumor continues to grow without regressing. The inoculation is considered successful when the tumor reaches a size of 400 mm. 3 Tumor-bearing mice were randomly divided into two groups of three mice each for subsequent in vivo imaging studies. The control group received a tail vein injection of 100 µL of PBS, while the experimental group received a tail vein injection of 100 µL of TAO. cy5.5 -CeO 2-xFluorescent nanoparticles (concentration of 20 μg / g in mice). Following injection, the fluorescence signal intensity in the tumor region was monitored and recorded using an in vivo imaging system at multiple time points: 4 h, 8 h, 12 h, 24 h, 36 h, 48 h, and 60 h. After 60 h of imaging, the mice were euthanized, and rapid dissection was performed to collect major organs such as the heart, liver, spleen, lungs, and kidneys, as well as tumor tissue. Fluorescence signals from each site were detected to comprehensively assess the distribution dynamics of the fluorescent nanoparticles in vivo and their enrichment in the tumor region. Figure 9 As shown, after 2 hours, the fluorescence signal at the tumor site was significantly enhanced compared to the PBS group, indicating that nanoparticles began to accumulate at the tumor site. The fluorescence signal peaked at 24 hours and remained relatively stable at the tumor site for approximately 60 hours. Figure 10 As shown, the fluorescence intensity of the tumor is much higher than that of other organs, indicating that the nanoparticles mainly aggregate within the tumor and have high tumor selectivity.

[0067] The above description of the embodiments is provided to enable those skilled in the art to understand and use the invention. It will be apparent to those skilled in the art that various modifications can be made to these embodiments, and the general principles described herein can be applied to other embodiments without inventive effort. Therefore, the present invention is not limited to the above embodiments, and any improvements and modifications made by those skilled in the art based on the disclosure of the present invention without departing from the scope of the invention should be within the protection scope of the present invention.

Claims

1. A zwitterionic lipid of tertiary amine oxidation type, characterized in that, The chemical structure is shown in Formula I: ， In Formula I, R is selected from C1-C6 alkyl groups, and X and Y are each independently selected from hydrophobic units with a number average molecular weight ≥142.

2. The zwitterionic lipid of tertiary amine oxidation according to claim 1, characterized in that, Tertiary amine oxidized zwitterionic lipid, chemical structure as shown in Formula II: In Formula II, R is selected from C1-C6 alkyl groups; n is an integer from 1 to 3; L is a linking group, selected from ester bonds, carbonate bonds, amide bonds, carbamate bonds, urea bonds or disulfide bonds; R 1 and R 2 Each residue is independently selected from lipid-soluble molecular residues, preferably R 1 and R 2 Individually selected from cholesterol residues, bile acid residues, fat-soluble vitamin residues, steroid hormone residues, and hydrophobic signal molecule residues, more preferably, R 1 and R 2 They are selected independently from saturated fatty acid chains or unsaturated fatty acid chains.

3. The zwitterionic lipid of tertiary amine oxidation according to claim 2, characterized in that, The tertiary amine oxidized zwitterionic lipid is selected from one of the following structures: 。 4. A lipid nanocarrier containing zwitterionic lipids of tertiary amine oxidation, characterized in that, The lipid nanodelivery carrier is prepared from any one of the tertiary amine oxidized zwitterionic lipids according to claims 1-3 and lipids without tertiary amine oxidized groups.

5. The lipid nanocarrier containing tertiary amine oxidized zwitterionic lipids according to claim 4, characterized in that, Lipids that do not contain tertiary amine oxidation groups are selected from one or more of cationic lipids, anionic lipids, uncharged lipids, phospholipids, phospholipid-polyethylene glycol, vitamin E polyethylene glycol succinate, or cholesterol. The mass ratio of the tertiary amine oxidized zwitterionic lipid to the lipid without tertiary amine oxidized groups is 1-20:

1.

6. A lipid nanoparticle delivery system, characterized in that, It includes the lipid nanodelivery carrier and contents as described in claim 4 or 5; the mass ratio of the contents to the lipid nanodelivery carrier is 0.01-100:

1.

7. The lipid nanodelivery particle according to claim 6, characterized in that, The contents are selected from one of the following: hydrophobic drugs, hydrophilic drugs, proteins, peptides, DNA / RNA, inorganic nanoparticles, organic / inorganic hybrid nanoparticles, or nanoscale metal-organic frameworks.

8. The lipid nanoparticle according to claim 7, characterized in that, The hydrophobic drug is selected from one or more of sorafenib, itraconazole, lovastatin, phenytoin, dexamethasone, or ibuprofen; The hydrophilic drug is selected from one or more of penicillin, atenolol, levodopa, metformin, 5-fluorouracil, or oseltamivir; The protein is selected from one or more of bevacizumab, insulin, interferon, streptokinase, coagulation factors, or hepatitis B vaccine; The polypeptide is selected from one or more of telpolide, nesiritide, leuprolide, polymyxin B / E or teriparatide. The DNA / RNA is selected from one or more of plasmids, mRNA or siRNA; The inorganic nanoparticles are selected from one or more of barium titanate, cerium oxide, iron oxide, calcium phosphate, or magnesium sulfate. The organic / inorganic hybrid nanoparticles are selected from one or more of hydroxyapatite, calcium citrate, or manganese citrate. The nanoscale metal-organic framework is selected from one or more of MOF-5, UiO-66, or ZIF-67.

9. A method for preparing lipid nanoparticles according to any one of claims 6-8, characterized in that, When the contents are hydrophobic, the lipid nanoparticles are prepared as follows: tertiary amine oxidized zwitterionic lipids, lipids without tertiary amine oxidized groups, and hydrophobic contents are dissolved or dispersed in an organic solvent to obtain an organic phase, which is then added to a stirred aqueous phase or a microfluidic device is used to mix the organic phase and the aqueous phase to obtain nanoparticles containing hydrophobic contents. When the contents are hydrophilic, the lipid nanoparticles are prepared as follows: tertiary amine oxidized zwitterionic lipids or lipids without tertiary amine oxidized groups are dissolved or dispersed in an organic solvent to obtain an organic phase; then added to a stirred aqueous phase containing hydrophilic contents, or a microfluidic device is used to mix the organic phase with the aqueous phase containing hydrophilic contents to obtain nanoparticles containing hydrophilic contents. The volume ratio of the organic phase to the aqueous phase is 1:2-20.

10. The application of the lipid nanoparticles according to any one of claims 6-8, characterized in that, The lipid nanoparticles are formulated as one or more of the following: intravenous injection, intraperitoneal injection, intramuscular injection, intratumoral injection, intradermal injection, or subcutaneous injection.

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