Targeted therapeutic drug combining activated platelet-modified liposomes with the red blood cell hitchhiking technique

Abstract

The present invention provides a targeted drug co-delivery system that combines an activated platelet-modified liposome with a red blood cell hitchhiking technique; specifically, a composite liposome drug delivery carrier is provided, which is formed by the combination of a platelet membrane-modified liposome and a red blood cell. After loading drugs, this carrier can significantly improve the targeting property and blood half-life, achieve more effective drug sustained release and clinical treatment effects with a lower drug dose, and has broad application prospects.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and particularly relates to a targeted therapeutic drug combining activated platelet-modified liposomes with the hitchhiking technology of red blood cells. Background Art

[0002] The emergence and development of nanocarriers have provided a more effective treatment means than pure drugs for the diagnosis, treatment, prevention of diseases and reducing the burden on patients, and some nano-related drugs have been applied clinically. However, these nanocarriers still have deficiencies: 1. Nano-drugs are artificially synthesized foreign substances, which can cause immune rejection in the body after entering the body and will be quickly cleared by organs such as the liver and kidneys; 2. Some nanocarriers with special components are not easily degraded in the body and will accumulate in the liver, causing inflammation or toxic damage; 3. Untreated nano-drugs have no targeting property, and the drug delivery efficiency through blood circulation is low. Coupled with the clearance of the body's immune system, the amount of drug reaching the therapeutic effect is extremely low, and multiple administrations are required.

[0003] Platelets (PLT) are recognized as the body's own anucleate cells, the "band-aids" of blood vessels, with a diameter of about 1-3 mm. The lifespan of a single platelet is about 8-10 days, and the PLT concentration in human blood is approximately 100-400×10 9 cells / L. Its main functions are to maintain the integrity of blood vessels and stop bleeding for vascular injuries related to stroke, myocardial infarction and surgery; activated PLT also helps in wound healing. In addition to proteins that promote blood coagulation, PLT also contains a variety of growth factors, chemokines and cytokines, which can promote angiogenesis and the recruitment, proliferation and differentiation of regenerative cells. These characteristics make PLT an ideal carrier for renewable and safe drug therapy.

[0004] In 1970, the Hebden HF team found that PLT was the main carrier of vinblastine, and thus discovered that PLT could carry drugs to participate in disease treatment; the Hughes K team used electroporation to enable PLM to encapsulate fluorescent dyes and drugs for targeting macrophages. In 2015, the Hu CM team encapsulated docetaxel and vancomycin in PLM to form a nano-drug for the treatment of arterial stenosis and bacterial infection, which was the initial PLM-based nano-drug delivery system combined with drug loading. Since the p-selectin (CD62p) protein present on the surface of PLM can target and recognize the mucin CD44 on the surface of tumor cells, PLM-modified nano-carriers can actively target tumor cells, thereby increasing the accumulation of drugs at the tumor site and improving their anti-tumor efficacy. Based on the above excellent properties, PLM-modified nano-carriers have been designed and fabricated for a variety of biomedical applications. In addition, studies have also demonstrated that CTCs in the blood can recruit platelets to adhere to their surface as a camouflage coat, forming "platelet-CTC aggregates", thereby protecting CTCs to achieve immune escape and form tumor metastases. Therefore, neutralizing or eliminating CTCs may be an effective strategy for preventing tumor metastasis. Based on this, Zhang et al. prepared paclitaxel micelles modified with p-selectin targeting peptide (PSN), which could easily adhere to the surface of activated PLT, and then capture CTCs in the blood circulation, effectively inhibiting lung metastasis and reducing the incidence of liver metastasis. Professor Zhang Liangfang reported a biomimetic nano-delivery system based on platelet membrane-coated PLGA for delivering the anti-cancer drug docetaxel. This biomimetic nanoparticle completely retained the biological functions of the platelet membrane, and some nanoparticles could target and aggregate in the tumor area and inhibit tumor growth. In 2018, the Zhang X team used genetic engineering techniques to modify megakaryocytes so that the released PLT could express PD-1 and thus participate in cancer treatment. Currently, the PLT / PLM nano-drug delivery system can load different types of drugs and has achieved certain results in the treatment research of various diseases such as cancer, inflammation, and immune diseases.

[0005] Although the modification of nano-carriers with PLM can enhance the targeting ability of the carrier and extend its half-life to a certain extent, most of the PLM-nanoparticles still accumulate in the liver and spleen. In addition, to achieve the therapeutic effect, a large dose needs to be injected and the injection cycle needs to be shortened, which is likely to cause significant side effects on the liver and lead to drug resistance in target cells. Therefore, further research is needed to improve the efficiency of the existing PLM-nano-drug delivery system.

[0006] The red blood cell (RBC) drug delivery system is one of the most studied cell-based drug delivery systems. The advantages of the RBC drug delivery system mainly include: 1. RBCs are the most abundant cells in the blood, easy to obtain, without the need for in vitro culture. Mature RBCs have no nucleus and organelles, with high safety; 2. The polysaccharides and proteins on the surface of RBCs can effectively avoid clearance by the reticuloendothelial system (RES), thus circulating in the body for up to 120 days; 3. RBCs have a large specific surface area, which is conducive to loading various drug nanoparticles for delivery on their surface. Therefore, RBCs are an ideal drug delivery carrier. The red blood cell hitchhiking (RH) technique is a new and effective delivery method in recent years. The RH technique refers to attaching drug nanoparticles to the surface of RBCs through electrostatic force, van der Waals force, and hydrophobic interaction force, and then infusing RBC-nanoparticles through the intravenous or arterial route. When RBCs pass through capillaries smaller than their own size, the nanoparticles are squeezed off from the RBCs. This technique can enrich some nanocarriers in the lungs, effectively improve the hepatic and splenic uptake of nanodrug carriers, reduce adverse reactions, and improve the targeting of drugs to the lungs.

[0007] It can be seen that although both PLM modification and the RH technique have the advantage of enhancing drug targeting, they still have certain defects. It is difficult to predict what kind of impact the combined use of the two methods will have on their respective advantageous characteristics, and whether they can effectively complement or improve each other's defects. At present, there are no reports on related technologies. Summary of the Invention

[0008] The purpose of the present invention is to provide a targeted therapeutic drug by combining activated platelet-modified liposomes with the red blood cell hitchhiking technique.

[0009] The present invention provides a composite liposome drug delivery carrier, which is formed by combining platelet membrane-modified liposomes with red blood cells.

[0010] Further, the above-mentioned platelet membrane is wrapped on the surface of the liposome, and the platelet membrane-modified liposome adheres to the surface of the red blood cell membrane or fuses with the red blood cell membrane.

[0011] Further, the above-mentioned platelet membrane is an activated platelet membrane, and the activation degree is 30% - 50%.

[0012] Even further, the above-mentioned activated platelet membrane is prepared according to the following steps:

[0013] (1) Platelets are stored under shaking at 22°C ± 5°C for 7 days for natural activation;

[0014] (2) The naturally activated platelets are alternately frozen and thawed 6 - 8 times at 35°C - 40°C and -75°C - 85°C, centrifuged, resuspended, and sonicated to obtain the product.

[0015] Furthermore, the above liposome is prepared from one, two or more than two raw materials selected from egg yolk lecithin, 1-palmitoyl-2-oleoyl phosphatidylcholine, soybean phospholipid, dipalmitoyl phosphatidylcholine, dioleoyl phosphatidylcholine, dioleoyl phosphatidylethanolamine, dioleoyl phosphatidylcholine, distearoyl phosphatidylcholine and cholesterol;

[0016] Preferably, the liposome is prepared from the following raw materials in parts by weight: 50-60 parts of dipalmitoyl phosphatidylcholine and 1-5 parts of cholesterol;

[0017] Alternatively, the liposome is prepared from the following raw materials in parts by weight: 40-50 parts of dipalmitoyl phosphatidylcholine, 10-20 parts of dioleoyl phosphatidylethanolamine and 1-5 parts of cholesterol;

[0018] More preferably, the liposome is prepared from the following raw materials in parts by weight: 59.5 parts of dipalmitoyl phosphatidylcholine and 3.5 parts of cholesterol;

[0019] Alternatively, the liposome is prepared from the following raw materials in parts by weight: 46.2 parts of dipalmitoyl phosphatidylcholine, 13.4 parts of dioleoyl phosphatidylethanolamine and 3.5 parts of cholesterol.

[0020] Furthermore, the above platelet membrane-modified liposome is prepared by ultrasonic mixing of the platelet membrane and the liposome, and then passing through polycarbonate membranes with different pore sizes; preferably, the amounts of the platelet membrane and the liposome used are: 2-6 mg of liposome is mixed with 2×10 8 platelet membranes.

[0021] Furthermore, the above drug delivery carrier is prepared by co-incubating the platelet membrane-modified liposome with red blood cells; preferably, the co-incubation conditions are incubation at 35-40 °C for 0.5-1.5 hours.

[0022] The present invention also provides a preparation method of the above drug delivery carrier, comprising the following steps:

[0023] (1) Ultrasonic mixing of the platelet membrane and the liposome for 3-5 minutes, passing through polycarbonate membranes with pore sizes of 0.35-0.45 μm, 0.15-0.25 μm and 0.05-0.15 μm in sequence for 3-5 times each, centrifuging, and resuspending to obtain a platelet membrane-modified liposome solution;

[0024] (2) Mixing the platelet membrane-modified liposome solution with red blood cells, co-incubating at 35-40 °C for 0.5-1.5 hours, centrifuging, and removing the supernatant to obtain the product; preferably, the amounts of the platelet membrane-modified liposome solution and red blood cells used are: 100-200 μL of the platelet membrane-modified liposome solution is mixed with 3×10 8 red blood cells.

[0025] The present invention also provides a pharmaceutical preparation, which is obtained by loading a drug onto the above-mentioned drug delivery carrier.

[0026] Preferably, the drug is an anti-tumor, antibacterial, anti-inflammatory, anti-allergic or antiviral drug.

[0027] More preferably, the drug is paclitaxel, vincristine, dexamethasone or doxorubicin.

[0028] Furthermore, the method for loading the drug is as follows: adding the drug during the preparation of liposomes to prepare drug-loaded liposomes, and then the drug-loaded liposomes are prepared with platelet membranes and red blood cells according to the method described above.

[0029] Advantages of the present invention: The present invention selects platelet membranes activated at a specific ratio to modify liposomes. After binding with red blood cells, a drug carrier with tumor targeting is successfully constructed, realizing the effective combination of the platelet membrane-modified liposome technology and the red blood cell hitchhiking technology. It can significantly improve the targeting and blood half-life, achieve more effective drug slow release and clinical treatment effects with a lower drug dose, and has broad application prospects.

[0030] The "activation degree" of the platelet membrane in the present invention refers to the expression rate of platelet membrane CD62p (p-selectin) detected by flow cytometry.

[0031] Obviously, based on the above content of the present invention, according to the common general technical knowledge and conventional means in the art, without departing from the above basic technical idea of the present invention, various other forms of modifications, substitutions or changes can be made.

[0032] The following is a further detailed description of the above content of the present invention through specific embodiments in the form of examples. However, this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. All technologies implemented based on the above content of the present invention fall within the scope of the present invention. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 (A) Preparation of PTX-loaded liposomes by the thin film method; (B) Schematic diagram of the PLM extraction method; (C) Obtaining liposomes with active tumor targeting after the combination of PLM and liposomes.

[0034] Figure 2 Organ distribution of PLM-lipo and RBC-PLM-lipo in vivo.

[0035] Figure 3 (A) Anti-tumor treatment results of a mouse subcutaneous LLC xenograft model (PTX = 5 mg / kg), injected every two days; (B) After the treatment, the mice were sacrificed, and the tumors were dissected and photographed (n = 5).

[0036] Figure 4 (A) Body weight change trend graph of the mouse CTC model; (B) Anti-tumor treatment result graph of the mouse CTC model (PTX = 5 mg / kg, injected once every two days).

[0037] Figure 5 (A) Schematic diagram of the C57 mouse CTC lung metastasis model; (B) Lung bioluminescence signal change graph of the mouse CTC lung metastasis model; (C) Body weight change trend graph of the mouse CTC lung metastasis model. Detailed implementation manners

[0038] The raw materials and equipment used in the present invention are all known products and are obtained by purchasing commercially available products.

[0039] The method for establishing the animal model of the present invention is as follows: 1. Establish a mouse lung cancer circulating tumor (CTCs) model. By injecting 5x10 6 LLCs (Luciferase-labeled) via the tail vein, randomly divide C57 mice into 6 groups (n = 5), start treatment on the 2nd day, and inject PLM-DPPC-RBC (DPPC liposomes modified with platelet membrane adhered to RBC), PLM-DPPC (DPPC liposomes modified with platelet membrane), DPPC, PLM-DOPE-RBC (DOPE liposomes modified with platelet membrane adhered to RBC), PLM-DOPE (DOPE liposomes modified with platelet membrane), and DOPE via the tail vein respectively. The treatment dose of paclitaxel is 5 mg / kg, injected once every two days for 21 days.

[0040] 2. Establish a mouse lung cancer metastasis model. By injecting 5x10 6 LLC (Luciferase-labeled) via the tail vein, randomly divide C57 mice into 6 groups (n = 5), start treatment on the 8th day, and inject the above six groups of liposome delivery systems via the tail vein respectively. The treatment dose of paclitaxel is 5 mg / kg, injected once every two days for 21 days.

[0041] Example 1. Preparation of the pharmaceutical preparation of the present invention

[0042] 1. Preparation of drug-loaded liposomes

[0043] 1) Preparation of PTX-lipo-DPPC

[0044] Dissolve 59.5 g of dipalmitoyl phosphatidylcholine (DPPC) and 3.5 g of cholesterol (CHO) in 3 mL of chloroform, add 1.8 g of paclitaxel (PTX) and dissolve it. Then, perform vacuum rotary evaporation by the thin film method at 45 - 50 °C for 60 min. Subsequently, add 5 mL of phosphate buffer solution (PBS) with pH = 7.4 and hydrate it at 50 - 55 °C for 30 min. The hydrated product is passed through polycarbonate membranes with pore sizes of 0.4 μm, 0.2 μm, and 0.1 μm, each for 3 - 5 times, to obtain the PTX-loaded liposome solution.

[0045] 2) Preparation of PTX-lipo-DOPE

[0046] Dissolve 46.2 g of DPPC, 13.4 g of dioleoyl phosphatidylethanolamine (DOPE), and 3.5 g of cholesterol in 3 mL of chloroform, add 1.8 g of PTX and dissolve it. Then, perform vacuum rotary evaporation by the thin film method at 45 - 50 °C for 60 min. Subsequently, add 5 mL of phosphate buffer solution (PBS) with pH = 7.4 and hydrate it at 50 - 55 °C for 30 min. The hydrated product is passed through polycarbonate membranes with pore sizes of 0.4 μm, 0.2 μm, and 0.1 μm, each for 3 - 5 times, to obtain the PTX liposome solution containing DOPE.

[0047] Table 1 PTX encapsulation efficiency of PTX-lipo (Lipo-DPPC / DOPE)

[0048]

[0049] 3) Preparation of vincristine-lipo-DPPC liposome

[0050] Put DPPC:CHO = 9:1 plus 1.8 mg of vincristine in a round-bottom flask. Rotate and evaporate at 37 °C for 60 min to obtain a transparent film. Hydrate it for 30 min under the hydration condition of 37 °C. The hydrated product is passed through polycarbonate membranes with pore sizes of 0.4 μm, 0.2 μm, and 0.1 μm, each for 3 - 5 times, to obtain the vincristine liposome solution.

[0051] 4) Preparation of vincristine-lipo-DOPE liposome

[0052] Put DPPC:DOPE:cholesterol = 7:2:1 plus 1.8 mg of vincristine in a round-bottom flask. Rotate and evaporate at 37 °C for 60 min to obtain a transparent film. Hydrate it for 30 min under the hydration condition of 37 °C. The hydrated product is passed through polycarbonate membranes with pore sizes of 0.4 μm, 0.2 μm, and 0.1 μm, each for 3 - 5 times, to obtain the vincristine liposome solution.

[0053] 2. Extraction of PLM from activated platelets by freeze-thaw method

[0054] The platelets separated and concentrated from whole blood were placed in a special platelet storage bag and stored with shaking at 22°C ± 5°C for 7 days to allow the platelets to be naturally activated, and the activation degree was about 30% - 50% (represented by the expression rate of CD62p (p-selectin) detected by flow cytometry; the activation rate on day D0 was less than 5%); the naturally activated platelets (stored for 7 days) were taken out from the -80°C refrigerator and repeatedly frozen and thawed 6 - 8 times between 37°C and -80°C. Centrifugation (20000g, 5 min) was used to remove the plasma, and the platelets were resuspended in PBS (5 mL) with pH = 7.4 and sonicated in an ultrasonic cell disruptor for 4 min (750W, 40s).

[0055] 3. Preparation of PLM-liposomes

[0056] The PLM prepared in step 2 and any one of the liposomes prepared in step 1 were sonicated together in an ultrasonic cell disruptor for 4 min (750W, 40s) (4 mg of liposomes and 2×10 8 PLMs), and passed through polycarbonate membranes with pore sizes of 0.4 μm, 0.2 μm, and 0.1 μm 3 - 5 times in sequence, and then centrifuged (20000g, 20 min) and resuspended in 300 μL of PBS to obtain PLM-liposomes (PLM-DPPC, PLM-DOPE).

[0057] Table 2 PTX encapsulation rate of PLM-lipo

[0058]

[0059] 4. Binding of activated PLM-liposomes to RBCs

[0060] The obtained PLM-liposome solution was resuspended in PBS buffer (pH = 7.4). 150 μL of the PLM-liposome solution prepared in 4) was incubated with RBCs (3×10 8 RBCs) (37°C, 1 h), and then centrifuged (500g, 10 min) three times to separate the RBCs that did not fuse with liposomes from the RBCs that fused with liposomes. The supernatant was removed to obtain the RBC drug carrier preparation combined with liposomes, named RBC-PLM-DPPC and RBC-PLM-DOPE.

[0061] The schematic diagram of the preparation process is as Figure 1 shown.

[0062] The beneficial effects of the present invention are demonstrated by the following experimental examples. The following experiments were all carried out using Lipo-DPPC, Lipo-DOPE, PLM-DPPC, PLM-DOPE, RBC-PLM-DPPC, and RBC-PLM-DOPE loaded with paclitaxel.

[0063] Experimental Example 1, In vivo distribution of the pharmaceutical preparation of the present invention

[0064] Lipo-DPPC and Lipo-DOPE were labeled by lipophilic fluorescent dye staining to establish an orthotopic metastatic tumor model of LLC lung cancer in C57 mice. Six groups of samples (Lipo-DPPC, Lipo-DOPE, PLM-DPPC, PLM-DOPE, RBC-PLM-DPPC, and RBC-PLM-DOPE) were injected via the tail vein respectively. After 1 h, the mice were sacrificed and the organs were dissected. The enrichment of fluorescently labeled liposomes in the organs was detected by small animal in vivo imaging. The results showed that the liposomes prepared with DOPE were significantly enriched in the lungs (i.e., the tumor site), which was due to the sensitivity of DOPE to acidic conditions. When PLM was fused with the liposomes, the enrichment degree in the lungs was enhanced, proving that PLM indeed had natural targeting to tumor cells; after RBC was combined with PLM, the targeting to the lungs was further enhanced; therefore, when the DOPE liposomes were fused with PLM and then combined with RBC, they had the characteristics of RH technology (able to squeeze off PLM-lipo at the pulmonary capillaries), and had the best pulmonary targeting among the six groups in the lungs, proving that the PLM drug delivery system combined with RH technology could greatly improve the pulmonary targeting of drugs. At the same time, due to CD47 on the RBC membrane, it could also be well avoided from being cleared by the immune system, achieving the effect of enhancing the therapeutic effect( Figure 2 ).

[0065] Experimental Example 2, Therapeutic effect of the pharmaceutical preparation of the present invention on transplanted lung tumors

[0066] An LLC transplanted tumor model was established in C57 mice. When the tumor size was about 100 mm3, the above six groups of samples were injected via the tail vein respectively. The results showed that the anti-tumor effects of the RBC-PLM group were better than those of the liposome group or the PLM-liposome group, and the results of the DOPE group were better than those of the DPPC group. Figure 3 All proved that the RBC-PLM-DOPE group could effectively inhibit the growth of subcutaneous transplanted tumors, which was because DOPE and PLM could enhance tumor targeting simultaneously, and the RH technology could effectively increase the half-life of the nanocarrier in the blood.

[0067] Experimental Example 3, Therapeutic effect of the pharmaceutical preparation of the present invention on circulating tumor cells (CTCs)

[0068] Establish a C57 mouse CTC model and inject the above 6 groups of samples via the tail vein respectively. Administer the drug once every other day (5 mg / kg), and detect the bioluminescence signal in the lungs every 5 days to explore the effects of PLM-lipo and RBC-PLM-lipo on the occurrence and development of CTC. The results show that there is no significant difference in the body weights of the mice in each group within 20 days, proving that the drug administration method of the present invention has no significant toxic effect on the mice. Figure 4 A); The anti-CTC effects of the RBC-PLM group are better than those of the liposome (lipo) group or the PLM-liposome (PLM-lipo) group, and the results of the DOPE group are better than those of the DPPC group. Figure 4 B). The results prove that the RBC-PLM-DOPE group can effectively inhibit the development of CTC and its metastasis to the lungs. This is because DOPE can target tumor sites, and at the same time PLM can effectively bind CTC in the blood.

[0069] Experimental Example 4. Therapeutic effect of the pharmaceutical preparation of the present invention on lung metastatic tumors of circulating tumor cells

[0070] Establish a C57 mouse CTC lung metastasis model and inject the above 6 groups of samples via the tail vein respectively. Administer the drug once every other day (5 mg / kg, Figure 5 A), and detect the bioluminescence signal in the lungs every 5 days to explore the effects of PLM-lipo and RBC-PLM-lipo on lung metastatic tumors caused by CTC.

[0071] The results show that there are significant differences in the body weights of the mice in each group within 20 days, proving that the drug administration methods of RBC-PLM-DPPC and RBC-PLM-DOPE of the present invention can reduce the toxic effects of chemotherapy. Figure 5 C); The anti-tumor effects of the RBC-PLM group are better than those of the liposome (lipo) group or the PLM-liposome (PLM-lipo) group, and the results of the DOPE group are better than those of the DPPC group. Figure 5 B). The results prove that the RBC-PLM-DOPE group can effectively inhibit the development of the lesions after the metastasis of CTC to the lungs. This is because DOPE can target tumor sites, PLM can effectively bind CTC in the blood, and at the same time the red blood cell hitchhiking technology can improve the enrichment of nanoparticles in the lungs, further improve the enrichment of drugs in the lungs, and reduce liver and spleen clearance and related side effects.

[0072] In summary, the present invention provides a targeted therapeutic drug that combines an activated platelet-modified liposome with a specific activation degree and the red blood cell hitchhiking technology; it can effectively combine the advantages of PLM modification and RH technology, significantly improve the targeting and blood half-life, achieve more effective drug slow release and clinical therapeutic effects with a lower drug dose, and has broad application prospects.

Claims

1. A composite liposome drug delivery carrier, characterized in that, It is formed by the combination of platelet membrane-modified liposomes and red blood cells; The platelet membrane coats the surface of the liposome, and the platelet membrane-modified liposome adheres to the surface of the red blood cell membrane or fuses with the red blood cell membrane; The platelet membrane is an activated platelet membrane, and the activation degree is 30% - 50%; The activated platelet membrane is prepared according to the following steps: (1) Platelets are stored under shaking at 22°C ± 5°C for 7 days for natural activation; (2) The naturally activated platelets are alternately frozen and thawed 6 - 8 times at 35°C - 40°C and -75°C - 85°C, centrifuged, resuspended, and ultrasonicated to obtain the product.

2. The drug delivery carrier according to claim 1, wherein The liposome is prepared from the following raw materials in the following weight ratio: 50 - 60 parts of dipalmitoyl phosphatidylcholine, 1 - 5 parts of cholesterol; Or, the liposome is prepared from the following raw materials in the following weight ratio: 40 - 50 parts of dipalmitoyl phosphatidylcholine, 10 - 20 parts of dioleoyl phosphatidylethanolamine, 1 - 5 parts of cholesterol.

3. The drug delivery carrier according to claim 2, wherein The liposome is prepared from the following raw materials in the following weight ratio: 59.5 parts of dipalmitoyl phosphatidylcholine, 3.5 parts of cholesterol; Or, the liposome is prepared from the following raw materials in the following weight ratio: 46.2 parts of dipalmitoyl phosphatidylcholine, 13.4 parts of dioleoyl phosphatidylethanolamine, 3.5 parts of cholesterol.

4. The drug delivery carrier according to claim 1, characterized in that, The platelet membrane-modified liposome is obtained by ultrasonicating the mixture of the platelet membrane and the liposome, and then passing through polycarbonate membranes with different pore sizes.

5. The drug delivery carrier according to claim 4, wherein The dosages of the platelet membrane and the liposome are as follows: 2×10 platelet membranes are mixed with every 2 - 6 mg of liposome. 8 ​ 6. The drug delivery carrier according to claim 1, characterized in that, It is prepared by co-incubating platelet membrane-modified liposomes with red blood cells.

7. The drug delivery vehicle according to claim 6, characterized in that, The conditions for the co-incubation are incubation at 35 - 40°C for 0.5 - 1.5 hours.

8. A method for preparing the drug delivery carrier according to any one of claims 1 to 7, characterized in that, It includes the following steps: (1) The platelet membrane and the liposome are mixed and ultrasonicated for 3 - 5 minutes, and then passed through polycarbonate membranes with pore sizes of 0.35 - 0.45 μm, 0.15 - 0.25 μm, and 0.05 - 0.15 μm respectively, 3 - 5 times each, centrifuged, and resuspended to obtain a platelet membrane-modified liposome solution; (2) The platelet membrane-modified liposome solution is mixed with red blood cells, co-incubated at 35 - 40°C for 0.5 - 1.5 hours, centrifuged, and the supernatant is removed to obtain the product.

9. The preparation method according to claim 8, characterized in that, The dosage of the platelet membrane-modified liposome solution and red blood cells is as follows: 3×10 8 red blood cells are mixed with every 100 - 200 μL of the platelet membrane-modified liposome solution.

10. A pharmaceutical preparation, characterized in that, It is obtained by loading a drug into the drug delivery carrier according to any one of claims 1 - 7; the drug is paclitaxel, vincristine, dexamethasone or doxorubicin.

11. The pharmaceutical preparation according to claim 10, characterized in that, The method for loading the drug is: adding the drug during the preparation of the liposome to prepare a drug-loaded liposome, and then the drug-loaded liposome, the platelet membrane, and the red blood cells are prepared according to the method described in any one of claims 8 - 9.

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