CN112716915A - Bionic nano-carrier and application thereof in preparing medicament for treating brain glioma - Google Patents
Bionic nano-carrier and application thereof in preparing medicament for treating brain glioma Download PDFInfo
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Abstract
The invention discloses a bionic nano-carrier and application thereof in preparing a medicament for treating brain glioma, belonging to the technical field of medicaments. The bionic nano-carrier comprises a long-circulating liposome and a hybrid cell membrane, wherein the long-circulating liposome is an inner core, and the hybrid cell membrane is an outer shell and is coated outside the long-circulating liposome; the hybrid cell membrane is formed by mixing immune cell membranes and tumor cell membranes. The nano carrier takes the long-circulating liposome as an inner core, the outer of the inner core is coated with a hybrid cell membrane of immune cells and tumor cells, the hybrid cell membrane moves through a blood brain barrier through the interaction of surface protein of the immune cells and receptors on brain endothelial cells, and simultaneously, the enhanced tumor targeting capability is realized through the homologous targeting and homing effects, the targeted treatment of brain glioma is realized, and the chemotherapy effect is improved.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a bionic nano-carrier and application thereof in preparation of a medicament for treating brain glioma.
Background
Malignant brain glioma belongs to primary brain tumor, and is mainly caused by canceration of astrocyte or oligodendrocyte and other glial cells in brain and spinal cord. In adults, glioblastomas account for more than half of all gliomas and are the most common malignant primary brain tumors. The treatment of brain glioma mainly comprises chemotherapy and radiotherapy mainly based on operation, and comprehensive means such as targeted therapy and the like. Because of the wide infiltration of brain glioma and the high complexity of the nervous system, the surgical treatment has the characteristics of incomplete excision, high recurrence rate and the like, and the postoperative adjuvant therapy is usually required to be continued. However, due to the existence of the blood brain barrier, the application of chemotherapeutic drugs to the treatment of brain glioma is often greatly limited, and the chemotherapeutic drugs cannot effectively reach the target site, thereby causing great toxic and side effects in vivo. Researchers have now used nasal administration, transient disruption of blood-brain barrier integrity, receptor-mediated delivery of drugs to the brain.
With the wide application of nanotechnology in the biomedical fields of treatment, diagnosis and the like, the development of new formulations and new carriers by utilizing the technology also becomes an intense research field. The current research idea is mainly based on specific application, and the nano materials are synthesized into a proper preparation through reasonable design. However, most of the traditional synthetic nano preparations are exogenous substances, and are easily identified and removed by mononuclear macrophages or reticuloendothelial systems when entering the body, and in addition, the nano preparations are easily adhered by nonspecific proteins (plasma proteins) and biomolecules to form Protein crowns (Protein crowns) when being exposed in a body fluid environment, so that the change of the surface performance of the nanoparticles is caused, and the exertion of the effect of the nanoparticles is hindered. Therefore, the concept of bionic modification is introduced on the basis of chemical structure modification of the traditional nano preparation. Among a plurality of bionic Materials, the cell membrane has higher biocompatibility, and simultaneously has the characteristics of low toxicity, degradability and the like, and the cell membrane is fused on the surface of the nanoparticle, so that the nano preparation simultaneously comprises the complex and unique biological function of a natural biological membrane and the physicochemical property of the nanoparticle, thereby achieving the effective delivery of the drug [ Fang R H, Advanced Materials,2014,14(4): 2181-one 2188 ]. For example, CN109893660A discloses a biomimetic nanocarrier for brain glioma treatment and a preparation method thereof, the nanocarrier Ang-RBCm-CA/siRNA consists of an erythrocyte membrane (Ang-RBCm) modified by Angiopep-2(Ang) polypeptide and a composition (CA/siRNA) of citraconic anhydride grafted polylysine and polyethyleneimine-siRNA; CN110859826A discloses a brain tumor cell-targeted adriamycin-loaded polyglutamic acid bionic nanoparticle coated by a human brain glioma U87 cell membrane, a preparation method thereof and application thereof in medicines for treating brain tumor diseases.
In the current design of the bionic nano preparation, the characteristic that erythrocyte membranes can circulate for a long time in vivo or the homologous targeting effect of tumor cell membranes are mainly and singly utilized to enhance the utilization efficiency of the medicament in vivo. The specific functional characteristics of different cell membranes are flexibly combined by the provision of the hybrid cell membrane bionic nano preparation, reasonable carrier design is carried out according to the requirements of disease treatment, the biological function of parent cell membranes of the nano preparation is endowed, the multifunctional and multi-task processing capability of nano particles is improved, the nano preparation is more suitable for the complexity of a biological system, and simultaneously, the step-by-step targeting effect is played, and great convenience is provided in the aspect of individually designing the nano preparation.
At present, no report of adopting a bionic nano-carrier hybridized by an immune cell membrane and a brain glioma cell membrane for treating the brain glioma exists, and the bionic nano-carrier is designed by means of the characteristics of blood brain barrier passing of immune cells, long-term circulation and homologous targeting characteristics of brain glioma cells according to the pathological characteristics and treatment requirements of the brain glioma, and can be used as an ideal drug delivery system for treating the brain glioma.
Disclosure of Invention
The invention aims to provide a bionic nano-carrier, which takes a long-circulating liposome as an inner core, wherein the inner core is coated with a hybrid cell membrane of immune cells and tumor cells, the nano-carrier can move through a blood brain barrier through the interaction of surface proteins of the immune cells and receptors on brain endothelial cells, and simultaneously, the enhanced tumor targeting capability is realized through the homologous targeting and homing effects, so that the targeted treatment of brain glioma is realized, and the chemotherapy effect is improved.
In order to achieve the purpose, the invention adopts the following technical scheme:
a bionic nano-carrier comprises a long-circulating liposome and a hybrid cell membrane, wherein the long-circulating liposome is an inner core, and the hybrid cell membrane is an outer shell and is coated outside the long-circulating liposome;
the hybrid cell membrane is formed by mixing immune cell membranes and tumor cell membranes.
Specifically, the immune cell membrane and the brain glioma cell membrane in the hybrid cell membrane provide great flexibility for realizing customization of personalized nano-drugs through different proportions, and balance of long blood circulation, blood brain barrier passing and active targeting of the nanoparticles in vivo can be realized through different proportions so as to expect to achieve optimal tumor part accumulation efficiency.
Further, the long-circulating liposome is made of phospholipid and cholesterol, and chemotherapeutic drugs are loaded in the long-circulating liposome.
Specifically, the phospholipids include, but are not limited to: (1) natural phospholipids, such as lipo-yolk lecithin PC-98T, yolk lecithin PL-100M, yolk phosphatidylglycerol, soybean lecithin; and (2) synthetic phospholipids such as hydrogenated soybean phosphatidylcholine, erucylphosphatidylcholine, dioleoylphosphatidylcholine, dimyristoylphosphatidylcholine, 1-palmitoyl-2-oleoyl phosphatidylcholine, distearoylphosphatidylcholine, dipalmitoylphosphatidylcholine, dipalmitoylphosphatidylserine, dioleoylphosphatidylserine, dipalmitoylphosphatidylethanolamine, dioleoylphosphatidylglycerol, egg phosphatidylglycerol, 1-palmitoyl-2-oleoylphosphatidylglycerol, 1, 2-palmitoylphosphatidylglycerol, distearoylphosphatidylglycerol, dimyristoylphosphatidylglycerol, dipalmitoylphosphatidylethanolamine-methoxypolyethylene glycol, dipalmitoylphosphatidylcholine, phosphatidylethanolamine-methoxypolyethylene glycol, phosphatidylethanolamine, phosphatidyl, Distearoylphosphatidylethanolamine-polyethylene glycol, (2, 3-dioleoyl-propyl) -trimethylamine, and the like.
In the present invention, a mixture of soybean phospholipids and DSPE-PEG2000 is preferable.
The chemotherapeutics suitable for the bionic nano-carrier of the invention include but are not limited to one or a combination of carfilzomib, bortezomib, paclitaxel, docetaxel, adriamycin and the like. The non-toxic and anti-tumor nano-carrier can prolong the half-life period in blood, penetrate through the blood brain barrier, improve the targeting property of the chemotherapeutic drugs and induce the apoptosis of brain glioma cells.
Suitable immune cell membranes for the biomimetic nanocarriers of the present invention include, but are not limited to: one or more of macrophagy/monocyte membrane, T cell membrane, NK cell membrane and neutrophilic granulocyte membrane. The immune cell membrane can carry a preparation to pass through a blood brain barrier, can target an inflammation part, realizes the delivery of a cancer medicament, reduces the opsonization of an antibody and the adsorption of serum protein, and avoids immune surveillance.
In the present invention, macrophagy/monocyte membranes are preferred.
The tumor cell membrane of the bionic nano-carrier is mainly from homologous brain glioma cells. Cancer cells are easily cultured in vitro and membrane material is obtained. The cancer cell also has the characteristics of self-targeting and the like, and can be used for the delivery of cancer drugs and the imaging purpose.
In one embodiment of the invention, the tumor cell membrane is a human malignant brain glioma U87 cell membrane.
In the present invention, the hybrid cell membrane of the biomimetic nanocarrier should be derived from an immune cell of the same biological species as the cancer subject and a tumor cell membrane of the same biological species as the cancer subject. The coating of immune cell membranes of different biological species is easy to cause immunogenicity, and the elimination of the bionic nano-carrier by an immune system is promoted; the coating of tumor cell membranes of different biological species can dilute the tumor antigen pool, introduce ineffective foreign proteins, and even trigger immunogenicity.
In the invention, the mass ratio of the hybrid cell membrane to the inner core long-circulating liposome of the bionic nano-carrier is 1:15-1: 5. The potential of the bionic nano-carrier obtained by adopting the mass ratio is consistent with that of the hybridized cell membrane, complete coating can be realized, and the mass ratio of the hybridized cell membrane to the kernel long-circulating liposome of the bionic nano-carrier is preferably 1:10 for economic consideration and the control of the particle size of the carrier.
In the invention, the average particle size of the long-circulating liposome of the inner core is 80-120 nm, the final particle size is 120-180 nm after the hybrid cell membrane is coated, compared with the cell with micron scale, the specific surface area is larger, the function of the membrane structure can be more efficiently exerted, the nano carrier (less than 1000nm) is easier to pass through the blood brain barrier, the problems that the nano carrier is easy to be identified and removed by an immune system and the blood circulation time is short when the size is larger (more than 250nm) are avoided, and the preparation is beneficial to the penetration at the tumor part and long-acting retention in the organism.
On the other hand, the invention also provides a preparation method of the bionic nano-carrier.
In a specific embodiment, the preparation method of the bionic nano-carrier comprises the following steps:
(1) precisely weighing soybean lecithin, DSPE-PEG2000, cholesterol and chemotherapeutic drugs according to the prescription amount, placing the mixture into an eggplant-shaped bottle, adding a proper amount of trichloromethane to dissolve the mixture, and performing reduced pressure rotary evaporation at 40 ℃ until organic solvents are completely removed. After a layer of uniform film is formed on the bottle wall, adding a proper amount of PBS preheated to the same temperature into a water bath at 40 ℃ for shaking and hydrating, and placing the obtained suspension under a probe for ultrasonic treatment to obtain the product.
(2) Digesting the tumor cells and the immune cells with good growth state respectively, washing with PBS three times, washing the components in the cells such as culture medium, serum, pancreatin and the like, and collecting the cells. Treating cells with hypotonic solution and protease inhibitor, standing at 4 deg.C for 2 hr, fully lysing the cells, and breaking the cell lysis solution in an ultrasonic cell disruptor. Centrifuging 3,200g of the lysed cell solution for 5min, collecting the supernatant, suspending the precipitate with a proper amount of hypotonic solution precooled to 4 ℃ and a protease inhibitor, repeating the cell lysis operation, centrifuging 3200g of the solution for 5min, and combining the supernatants. The supernatant was centrifuged at 20,000g for 20min, the pellet was discarded, and the supernatant was collected again. The supernatant was centrifuged at 100,000g for 60min to enrich the cell membranes.
(3) Mixing the immune cell membrane and the tumor cell membrane obtained in the step (2) according to a certain mass ratio, and then co-extruding the mixture to pass through a 400nm carbonate membrane.
(4) And (3) mixing the drug-loaded long-circulating liposome obtained in the step (1) with the hybrid cell membrane obtained in the step (3) according to a certain proportion, respectively and circularly co-extruding carbonate membranes of 400nm and 200nm for certain times, and purifying to obtain the drug-loaded long-circulating liposome.
In order to optimize the preparation scheme, the specific measures adopted further comprise:
the mass ratio of the long-circulating liposome to the chemotherapeutic drug in the step (1) is 10: 1-25: 1, preferably 15: 1.
The probe ultrasound in the step (1) specifically refers to that the power is 300W, the total time is 3min, the mode is over 3s, the stop is 2s, ice bath ultrasound is carried out, and the drug leakage and the reduction of the encapsulation efficiency caused by the temperature rise can be avoided under the condition.
The specific ratio of the hypotonic lysate to the protease inhibitor in the step (2) is as follows: 8000 ten thousand cells were treated with 50. mu.L protease inhibitor in 5mL of cell lysate.
The ultrasonic probe in the step (2) specifically means that the power is 65W, the total time is 1min, the mode is over 2s, and the operation is stopped for 5 s.
The mass ratio of the tumor cell membrane to the immune cell membrane in the step (3) is 1: 1.
The number of times of circulating extrusion in the step (4) is 10-50, and preferably 20.
The invention also protects the application of the prepared bionic nano-carrier in the preparation of targeted therapeutic drugs for brain glioma.
The invention innovatively provides the capability of step-by-step targeting and long-acting circulation of the core nanoparticles by adopting the heterozygosis of two cell membranes, combining the functions of enabling immune cell membranes to penetrate through a blood brain barrier and prolonging the in-vivo circulation time of a preparation and the homologous targeting function of tumor cell membranes.
The invention has the beneficial effects that:
the invention provides a drug-loaded bionic nano-carrier coated by immune cells and tumor cells and application thereof. Under the inflammatory microenvironment of brain tumor, the secreted matrix metalloprotease (MMP-2, MMP-9), Vascular Endothelial Growth Factor (VEGF), TNF-alpha, gamma-interferon and other inflammatory mediators destroy the integrity of blood brain barrier, and the glioma secretes monocyte chemotactic protein-3 (MCP-3) which can simultaneously chemotact microglia in brain and immune cells in circulating blood to reach the periphery of the tumor through the damaged blood brain barrier. Integrin α 4 β 1 on the surface of leukocytes forms a firm adhesion to ICAM-1 receptors on endothelial cells, and locally released chemokines potentiate integrin binding and cause direct leukocyte migration across the blood-brain barrier. After an immune cell membrane plays a role of crossing a blood brain barrier, galectin-3 (galectin-3) on homologous tumor cells is combined with carcinoembryonic antigen (CEA) on tumor-related transmembrane mucin MUC-1 under an anchorage-independent condition to induce the MUC-1 to polarize on the cell surface, expose epithelial cell adhesion molecules (E-Ca mucin) and induce the tumor cells to homotype aggregate to reach a brain glioma part. Based on the high targeting ability to homologous tumors, the application range of the kit is expanded, which shows that various cancers can be accurately diagnosed or treated by adjusting the sources of tumor cell membranes.
Drawings
FIG. 1 is a particle size and potential statistical chart of non-enveloped drug-loaded liposome (PTX @ L) and hybrid bionic drug-loaded liposome (PTX @ C-MMCL).
FIG. 2 is a TEM image of drug-loaded liposomes (PTX @ L) and hybrid biomimetic drug-loaded liposomes (PTX @ C-MMCL).
FIG. 3 is a graph of the release profiles of free paclitaxel, drug-loaded liposomes (PTX @ L) and hybrid biomimetic drug-loaded liposomes (PTX @ C-MMCL) under 1M sodium salicylate in PBS buffer (pH 5.0,6.8, 7.4).
FIG. 4 shows SDS-PAGE detection results of non-enveloped liposomes, macrophage membrane-enveloped liposomes (PTX @ MMCL), tumor cell membrane-enveloped liposomes (PTX @ CMCL), hybrid biomimetic liposomes, tumor cell membranes, macrophage membranes and mixed membranes.
FIG. 5 shows WB detection results of non-enveloped liposomes, macrophage membrane-enveloped liposomes (PTX @ MMCL), tumor cell membrane-enveloped liposomes (PTX @ CMCL), hybrid biomimetic liposomes, tumor cell membranes, macrophage membranes and mixed membranes.
FIG. 6 shows the results of hemolysis experiments with non-enveloped liposomes, enveloped liposomes and taxol solvent.
FIG. 7 shows the results of cytotoxicity experiments with nonenveloped liposomes and empty carriers of enveloped liposomes.
FIG. 8 is a flow cytometer used to quantitatively determine the uptake of non-enveloped liposome (C6@ L), wrapped macrophage membrane liposome (C6@ MMCL), wrapped tumor cell membrane liposome (C6@ CMCL) and hybrid bionic liposome (C6@ C-MMCL) carrying coumarin 6 by brain glioma cells.
FIG. 9 shows the conditions of macrophage uptake of non-enveloped liposome (C6@ L) carrying coumarin 6, macrophage-enveloped liposome (C6@ MMCL), tumor-enveloped cell membrane liposome (C6@ CMCL) and hybrid biomimetic liposome (C6@ C-MMCL) by using an inverted fluorescence microscope
FIG. 10 shows the injection of different formulations (Free-Dir, Dir @ L, Dir @ MMCL, Dir @ CMCL, Dir @ C-MMCL) into tumor-bearing nude mice via the tail vein and in vivo imaging at 0.5h, 2h, 4h, 8h, 24h after administration.
FIG. 11 is a photograph showing fluorescence images of Dir in each organ 24 hours after injecting various preparations (Free-Dir, Dir @ L, Dir @ MMCL, Dir @ CMCL, Dir @ C-MMCL) into tumor-bearing nude mice via the tail vein.
Detailed Description
The invention is described in further detail below with reference to the figures and the specific examples, which should not be construed as limiting the invention. Modifications or substitutions to methods, procedures, or conditions of the invention may be made without departing from the spirit and scope of the invention. The experimental methods and reagents of the formulations not specified in the examples are in accordance with the conventional conditions in the art.
Example 1
The preparation method of the bionic nano carrier comprises the following steps:
(1) according to the prescription amount, soybean lecithin, DSPE-PEG2000, cholesterol and chemotherapeutic drugs PTX are placed in an eggplant-shaped bottle according to the mass ratio of 12:5:4:1, appropriate amount of trichloromethane is added for dissolving, and the mixture is subjected to reduced pressure rotary evaporation at 40 ℃ until organic solvents are completely removed. After a layer of uniform film is formed on the bottle wall, adding a proper amount of PBS preheated to the same temperature into a water bath at 40 ℃ for shaking and hydrating, and placing the obtained suspension under a probe for ultrasonic treatment to obtain the product. The ultrasonic treatment specifically refers to ultrasonic treatment in ice bath with power of 300W, total time of 3min, mode of over 3s and stop 2 s.
(2) Respectively digesting human malignant brain glioma U87 cells and macrophage/mononuclear cells with good growth state, washing with PBS three times, washing culture medium, serum, pancreatin and other components in the cells, and collecting the cells. Treating cells with hypotonic solution and protease inhibitor, treating 8000 ten thousand cells with 5mL of cell lysis solution and 50 μ L of protease inhibitor, standing at 4 deg.C for 2 hr, fully lysing the cells, and breaking the cell lysis solution in an ultrasonic cell breaker (ultrasonic means power of 65W, total time of 1min, mode of 2s or more, and stopping for 5 s). Centrifuging 3,200g of the lysed cell solution for 5min, collecting the supernatant, suspending the precipitate with a proper amount of hypotonic solution precooled to 4 ℃ and a protease inhibitor, repeating the cell lysis operation, centrifuging 3200g of the solution for 5min, and combining the supernatants. The supernatant was centrifuged at 20,000g for 20min, the pellet was discarded, and the supernatant was collected again. The supernatant was centrifuged at 100,000g for 60min to enrich the cell membranes.
(3) Mixing the macrophage/mononuclear cell membrane obtained in the step (2) with the human malignant brain glioma U87 cell membrane according to the mass ratio of 1:1, and then co-extruding the mixture to pass through a 400nm carbonate membrane.
(4) And (3) mixing the drug-loaded long-circulating liposome obtained in the step (1) with the hybrid cell membrane obtained in the step (3) according to a certain proportion, respectively and circularly co-extruding carbonate membranes with the diameters of 400nm and 200nm for 20 times, and purifying to obtain the drug-loaded long-circulating liposome.
The prepared bionic nano-carrier is characterized in detail as follows, including: in vitro characterization, in vitro drug release performance, hybrid membrane component detection, safety research, ingestion performance and targeting detection.
1. In vitro characterization of biomimetic nanocarriers
The particle size distribution of the non-coated drug-loaded liposome (PTX @ L) and the hybrid bionic drug-loaded liposome (PTX @ C-MMCL) and the Zeta potential of the non-coated drug-loaded liposome (PTX @ L), the hybrid bionic drug-loaded liposome (PTX @ C-MMCL), the U87 cell membrane (U87-m), the RAW cell membrane (RAW-m) and the hybrid cell membrane (U87-RAW-m) are respectively measured by a Malvern particle sizer. The particle size of the enveloped liposome is about 140nm, and the particle size of the non-enveloped liposome is about 120nm, which proves that the particle size is increased probably because the outer layer of the liposome is wrapped by a cell membrane structure of about 20 nm. The surface potential of the non-enveloped liposome is about-40 mV, while the surface potential of the enveloped liposome is similar to the potential of a tumor cell membrane, a macrophage membrane and a mixed membrane, which are all about-25 mV, and the outer layer of the liposome is also verified to wrap the cell membrane structure. The results of particle size and potential distribution are shown in FIG. 1. With TEM, morphological features of PTX @ L and PTX @ C-MMCL were photographed, respectively, and the results are shown in FIG. 2.
2. In vitro drug release performance of bionic nano carrier
In vitro release studies were performed using PTX @ L, PTX @ C-MMCL and paclitaxel free drug, using 1M sodium salicylate in PBS buffer (pH 5.0,6.8,7.4) as the release medium, and the results are shown in FIG. 3. According to results, the PTX free drug shows a quick release result under three pH conditions, the release platform is basically reached within about 20 hours, and the accumulated release amount reaches about 90%; the paclitaxel-loaded coated liposome and the non-coated liposome show uniform and slow release in the whole drug release process, the cumulative release amount reaches 75-85% in 96h, and the cumulative release amount of the liposome is slightly lower than the release under the other pH conditions at pH7.4, but the statistical difference is not significant. Experiments prove that the paclitaxel liposome can play a role in sustained release of the drug, has uniform speed in the release process, and avoids the risk of burst release.
3. Hybrid membrane component detection of biomimetic nanocarriers
The non-enveloped liposome, the macrophage membrane liposome (PTX @ MMCL), the tumor cell membrane liposome (PTX @ CMCL), the hybrid bionic liposome, the tumor cell membrane, the macrophage membrane and the mixed membrane are characterized by SDS-PAGE and WB, and the results are shown in figure 4 and figure 5. As is clear from the SDS-PAGE results, no protein was present in the non-enveloped liposomes, and no band was extracted. The PTX @ MMCL is consistent with a band of a macrophage membrane, the PTX @ CMCL is consistent with a band of a tumor cell membrane, and the PTX @ C-MMCL is consistent with a band of a mixed membrane, so that the tumor cell membrane, the macrophage membrane and the mixed membrane can be coated on the surface of the liposome and stably exist. From WB results, it is known that the surfaces of macrophages and the liposome wrapped by the macrophage membrane contain Integrin-alpha 4, and the surfaces of tumor cell membranes, the macrophage membrane and the enveloped liposome contain Galectin-3, and therefore, the fact that functional proteins Integrin-alpha 4 and Galectin-3 of the two cell membranes exist on the surface of the liposome is proved, and the liposome has the functions of penetrating through BBB and targeting to homologous tumor cells. The results show that Galectin-3 is expressed on tumor cell membranes and macrophage membranes, because Galectin-3 is expressed on various cells, but the functions of the Galectin-3 are different, the Galectin-3 mainly plays the roles of mediating the mutual adhesion of homologous tumor cells and tumor metastasis on the surfaces of the tumor cells and mainly mediates the occurrence of immune reactions on the surfaces of immune cells such as macrophages and the like.
4. Safety study of biomimetic nanocarriers
The non-enveloped liposome, the enveloped liposome and the taxol solvent are respectively taken for hemolysis experiment investigation, and the result is shown in figure 6. From the results, both liposomes produced a great improvement in hemolysis compared to Taxol solvent, and at a concentration of 10mg/ml, the hemolysis rate of unencapsulated liposomes was about 8.07%, the hemolysis rate of encapsulated liposomes was 4.56% (the hemolysis rate was less than 10%, generally considered to be non-toxic), and the safety of encapsulated liposomes was higher. Probably because the biocompatibility of the cell membrane on the surface of the enveloped liposome is better, the safety of the preparation is improved.
According to the general rule 0632 osmolality determination method in the four parts of China pharmacopoeia 2020 edition, the osmolality of a normal human body is 285-310 mOsmol/kg. In order to ensure the safe and controllable quality of the injection and reduce the medication risk, the osmotic pressure molar concentration of the injection needs to be controlled. The results of the measurements of osmolality of the non-enveloped liposomes and the enveloped liposome solution are shown in Table 1. From the results, the osmolality of both liposomes was within an acceptable range.
TABLE 1 osmolality
Taking U87-Luc cells in a logarithmic growth phase, adjusting the concentration of the cell suspension, adding the cells into a 96-well plate according to 200 mu L per well to ensure that the number of the cells in each well is 8,000-10,000, and culturing in an incubator. Respectively adding non-enveloped liposome and enveloped liposome solution which are not loaded with chemotherapeutic drugs and have different concentrations, and inspecting the toxicity of the blank carrier by adopting an MTT method. The results are shown in FIG. 7. From the results, it is known that the blank vector has a significant nourishing effect on the growth of tumor cells and the membrane-coated liposome has a stronger nourishing effect than the control group (only the blank medium is added). The liposome carrier is proved to be safe and nontoxic.
5. Detection of cell uptake performance by bionic nano-carrier
The uptake of non-enveloped liposome (C6@ L) carrying coumarin 6, enveloped macrophage membrane liposome (C6@ MMCL), enveloped tumor cell membrane liposome (C6@ CMCL) and hybrid bionic liposome (C6@ C-MMCL) by brain glioma cells is quantitatively determined by a flow cytometer, and the result is shown in figure 8. From the results, it was found that the uptake of cells was time-dependent, the amount of cellular uptake was the least at 0.5h for each preparation group, and the difference between the groups was small. With increasing time, the cellular uptake increased gradually and the difference increased gradually, and by 4h, the uptake of free coumarin 6 by the cells was minimal, and the uptake of the C6@ CMCL, C6@ MMCL, C6@ C-MMCL group was significantly higher than that of the C6@ L group, with statistically significant differences (P < 0.001). Indicating that the homologous tumor cells enhance the cellular uptake effect.
The uptake of non-enveloped liposome (C6@ L) carrying coumarin 6, enveloped macrophage membrane liposome (C6@ MMCL), enveloped tumor cell membrane liposome (C6@ CMCL) and hybrid bionic liposome (C6@ C-MMCL) by macrophages is photographed by an inverted fluorescence microscope, and the result is shown in figure 9. The results show that the macrophage has higher uptake of C6@ L, C6@ CMCL, and probably because the macrophage has the function of recognizing and swallowing a foreign body, the macrophage can take exogenous C6@ L, C6@ CMCL more easily. In comparison, the uptake of C6@ MMCL and C6@ C-MMCL is low, probably because macrophage membranes are coated on the surfaces of the MMCL and are not phagocytized after being recognized by macrophages, so that the clearance effect of an immune system is avoided, and the circulation time in a body is prolonged.
6. In vivo biodistribution and tumor targeting detection of bionic nano-carrier
In order to evaluate the in vivo targeting performance of the preparation, a 5-week-old Balb/c nude mouse glioma model is selected, and a fluorescent dye Dir is used as a fluorescent probe. Different preparations (Free-Dir, Dir @ L, Dir @ MMCL, Dir @ CMCL, Dir @ C-MMCL) are injected into tumor-bearing nude mice through tail veins, and living body imaging shooting is carried out at 0.5h, 2h, 4h, 8h and 24h after administration, and the result is shown in figure 10. After Dir @ L, Dir @ CMCL administration, the concentration is also concentrated in liver and kidney parts, but the retention time is obviously longer than that of free Dir, and the in vivo fluorescence intensity is still maintained at a higher level within 24 h. After Dir @ MMCL and Dir @ C-MMCL are administrated, except the liver and kidney parts are gathered, the brain part has obvious distribution, and the brain part rapidly reaches the brain part at 0.5h, and the fluorescence intensity of the brain part gradually increases and then decreases along with the increase of time.
The nude mice are sacrificed 24h after administration, heart, liver, spleen, lung, kidney and brain tissues are respectively taken out and photographed in a living body imager, and the fluorescence intensity is calculated, the result is shown in figure 11, only the Dir @ MMCL and Dir @ C-MMCL groups can photograph the fluorescence of the brain tissues, the preparation enters the brain and is detained, and the Dir @ C-MMCL detains more in the brain by the quantitative calculation of the fluorescence intensity and the fluorescence value. In addition, the fluorescence intensity of the liver and kidney was higher in the preparation group compared to the free Dir group, probably due to the longer circulation time of the preparation in vivo, and the preparation was more easily enriched in the tissues with abundant blood vessels. The two cell membranes of macrophage membrane and tumor cell membrane are simultaneously encapsulated, so that the preparation can pass through the blood brain barrier and stay at the part of brain glioma.
Claims (7)
1. A bionic nano-carrier is characterized in that: the hybrid cell membrane is a shell and is coated outside the long-circulating liposome;
the hybrid cell membrane is formed by mixing immune cell membranes and tumor cell membranes.
2. The biomimetic nanocarrier of claim 1, wherein: the mass ratio of the hybrid cell membrane to the long-circulating liposome is 1:15-1: 5.
3. The biomimetic nanocarrier of claim 1, wherein: the long-circulating liposome is prepared from phospholipid and cholesterol, and chemotherapy drugs are loaded in the long-circulating liposome.
4. The biomimetic nanocarrier of claim 1, wherein: the long-circulating liposome is prepared from soybean phospholipid, DSPE-PEG2000 and cholesterol; the hybrid cell membrane is formed by mixing an immune cell membrane and a brain glioma cell membrane.
5. The biomimetic nanocarrier of claim 4, wherein: the mass ratio of the hybrid cell membrane to the long-circulating liposome is 1: 10.
6. The method for preparing a biomimetic nanocarrier according to claim 1, wherein: the method comprises the following steps:
step 1, preparing a long-circulating liposome by adopting a thin film method;
step 2, preparation of immune cell membranes and tumor cell membranes: respectively cracking and purifying immune cells and tumor cells to obtain immune cell membranes and tumor cell membranes;
step 3, preparation of hybrid cell membrane: mixing the immune cell membrane and the tumor cell membrane obtained in the step 2, and ultrasonically extruding to obtain a hybrid cell membrane;
step 4, preparing the bionic nano carrier: and (3) mixing the long-circulating liposome obtained in the step (1) and the hybrid cell membrane obtained in the step (3), extruding, and purifying to obtain the liposome.
7. The use of the biomimetic nanocarrier of claim 1 in the preparation of a medicament for targeted therapy of brain glioma.
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