CN117017947A - Tumor cell membrane coated fullerene nano material and preparation method and application thereof - Google Patents
Tumor cell membrane coated fullerene nano material and preparation method and application thereof Download PDFInfo
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- CN117017947A CN117017947A CN202311067890.3A CN202311067890A CN117017947A CN 117017947 A CN117017947 A CN 117017947A CN 202311067890 A CN202311067890 A CN 202311067890A CN 117017947 A CN117017947 A CN 117017947A
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- fullerene
- cancer
- cell membrane
- amino
- tumor
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Classifications
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- A61K41/00—Medicinal preparations obtained by treating materials with wave energy or particle radiation ; Therapies using these preparations
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Abstract
The application discloses a nano material of fullerene coated by tumor cell membrane, a preparation method and application thereof. The nano material comprises a cell membrane and a medicine carrying inner core; the medicine carrying inner core comprises fullerene derivatives and lactic acid-glycolic acid copolymers; the cell membrane is wrapped on the surface of the medicine carrying inner core. The application combines the advantages of amino fullerene, PLGA nanosphere and tumor cell membrane to form a nanomaterial with stability, charge capacity and targeted delivery capacity. The nano material synthesized by the application can more easily increase the aggregation degree of the nano material at the tumor part through the EPR effect and the targeting effect of tumor cell membranes, and improve the use efficiency of the medicine.
Description
Technical Field
The application relates to the field of biological medicine, in particular to a nano material of fullerene coated by tumor cell membrane, a preparation method and application thereof.
Background
Tumors are a common and serious disease that creates a tremendous burden on global health. Currently, treatment methods for tumors include surgical excision, radiation therapy, chemotherapy, and the like, but these methods have some limitations such as poor therapeutic effects, large side effects of drugs, and drug resistance problems. Therefore, finding new tumor treatment strategies is of great clinical importance.
In recent years, nanotechnology has received a great deal of attention in the field of tumor therapy. Nanomaterials can play an important role at the cellular and molecular level due to their unique physical and chemical properties. They have a large specific surface area and excellent charge capacity, and are capable of carrying and releasing various therapeutic substances, thereby improving therapeutic effects and reducing side effects.
Fullerene is a special carbon nanomaterial with a spherical structure and many excellent properties. The preparation method has the characteristics of high stability, strong oxidation resistance, good biocompatibility and the like, so that the preparation method becomes an ideal biological nano material. The fullerene has a large surface area and rich functional groups, and can chemically react with different types of substances, so that the fullerene has wide application prospects in aspects of drug delivery, biological imaging, phototherapy and the like.
Disclosure of Invention
In order to solve the technical problems, the application provides the following technical scheme:
a nanomaterial comprising a cell membrane and a drug-loaded core; the drug-loaded core comprises fullerene derivatives and lactic-glycolic acid copolymers (PLGA); the cell membrane is wrapped on the surface of the medicine carrying inner core.
According to an embodiment of the application, the cell membrane is selected from the cell membranes of tumor cells, preferably colorectal cancer cells, such as MC38 colorectal cancer cells (also called MC38 tumor cells).
According to an embodiment of the present application, the mass ratio of the fullerene derivative to the lactic acid-glycolic acid copolymer in the drug-loaded core is (1-10): 1, for example, 5:1.
According to an embodiment of the application, the lactic acid-glycolic acid copolymer is alternatively commercially available, for example from the microphone reagent.
According to an embodiment of the application, the lactic acid-glycolic acid copolymer has a molecular weight ranging from 1000 to 20000, for example 5000, 10000, 15000.
According to an embodiment of the present application, the lactic acid-glycolic acid copolymer has a nanosphere structure.
According to an embodiment of the application, the nanospheres have a particle size of 10-200nm, for example 20nm, 30nm, 40nm, 50nm, 60nm, 70nm, 80nm, 90nm, 100nm, 150nm, 200nm.
According to an embodiment of the present application, the fullerene derivative is selected from amino fullerene derivatives having a structure represented by formula (I);
wherein F is a fullerene selected from at least one of a hollow fullerene, a metal fullerene, a heterocyclic fullerene and an endohedral fullerene;
wherein R is an amino modified group of the fullerene, one end of R is combined with the fullerene through a nitrogen-containing group, phenyl and mercapto, and the other end of R is any nitrogen-containing group, and the nitrogen-containing group comprises any one or more of primary ammonia, tertiary amine, secondary amine and quaternary amine;
wherein m is selected from integers of 1-12, preferably 3, 4, 5, 6, 10.
According to an embodiment of the application, R is-NR 1 -R'-NR 2 R 3 Wherein R is 1 ，R 2 ，R 3 Independently or simultaneously hydrogen, or optionally substituted C1-C6 alkyl, cycloalkyl, heteroatom-containing alkyl, heterocycloalkyl, aryl, heteroaryl, or R 1 And R is 2 And/or R 3 Together forming a cyclized substituent;
r' is optionally substituted C1-C6 alkyl, cycloalkyl, heteroatom-containing alkyl, heterocycloalkyl, aryl, heteroaryl, or R 1 And R' together form a cyclized substituent; wherein when R is 1 And R is 2 And/or R 3 R' is absent when taken together to form the cyclized substituent.
Further, R 2 、R 3 And is hydrogen.
According to an embodiment of the application, in the amino fullerene derivative, the fullerene is at least one of a hollow fullerene, a metal fullerene, a heterocyclic fullerene and an endohedral fullerene, preferably the fullerene is selected from C 2n 、M@C 2n 、M2@C 2n 、MA@C 2n 、M 3 N@C 2n 、M 2 C 2 @C 2n 、M 2 S@C 2n 、M 2 O@C 2n And M x A 3-x N@C 2n Any one or a mixture of the above, wherein M and A are metal elements, and M and A are selected from any one of Sc, Y and lanthanide metal elements; preferably, the fullerene is selected from C-containing compounds 2n Wherein 2n is the number of carbon atoms, and n is more than or equal to 30 and less than or equal to 60; preferably, the fullerene is selected from one or more of C60, C70, C76, C78, C80, C84; more preferably, the fullerene is selected from one or more of C60, C70.
According to an embodiment of the present application, in the amino fullerene derivative, the amino modification group R of the fullerene is one or several selected from (2-aminoethyl) amino, (3-aminopropyl) amino, (4-aminobutyl) amino, (5-aminopentyl) amino, (2-aminophenyl) amino, (3-aminophenyl) amino, (4-amino) piperidinyl, piperazinyl, 4-aminophenyl, (4-aminomethyl) phenyl, (4-aminophenyl) mercapto, (4-aminocyclohexyl) mercapto, 4-piperidinylmercapto, (1-aminoethyl) mercapto, (1-aminopropyl) mercapto, (1-aminobutyl) mercapto, (1-aminopentyl) mercapto.
The inventors found that tumor cell membrane is an important biological membrane structure with different properties from normal cell membrane. Specific antigens and surface receptors on tumor cell membranes make them markers for tumor cells, which provides an opportunity to target tumors. The tumor cell membrane is used for wrapping the nano material, so that the specific recognition and targeted delivery of the tumor can be realized. The main component of tumor cell membrane is lipid bilayer, which contains abundant membrane proteins. These proteins can bind to the corresponding ligands, thereby achieving specific recognition and binding to tumor cells. By wrapping the tumor cell membrane on the surface of the nanomaterial, the nanomaterial can have external characteristics similar to those of tumor cells, so that the nanomaterial can better interact with the tumor cells in vivo. The coating layer of the tumor cell membrane can provide a protective effect on the nano material and enhance the stability of the nano material. In addition, through the specific recognition and combination of tumor cell membranes, the nano material can accurately target tumor tissues, so that the treatment effect is improved, and the damage to normal cells is reduced.
The application also provides a preparation method of the nano material, which comprises the following steps:
s1, preparing lactic acid-glycolic acid copolymer nanospheres;
s2, preparing a medicine carrying inner core: loading fullerene derivatives onto the lactic acid-glycolic acid copolymer nanospheres to obtain the drug-loaded inner core;
s3, preparing cell membranes;
and S4, mixing the medicine carrying inner core obtained in the step S2 with the cell membrane obtained in the step S3, and coating the cell membrane on the medicine carrying inner core to obtain the nano material.
According to an embodiment of the present application, in step S1, the specific steps of the preparation are as follows: and dissolving PLGA in an organic solvent to obtain PLGA solution, dropwise dripping the PLGA solution into water after dissolving, stirring, ultrafiltering, and then re-suspending in water to prepare the lactic acid-glycolic acid copolymer nanospheres.
Preferably, the organic solvent is selected from acetone, dichloromethane, ethyl acetate, and the like.
Preferably, the volume ratio of the dropwise addition of water to the PLGA solution is 1-5:1, for example 3:1.
According to an embodiment of the present application, in step S2, the specific steps of the load are as follows: under the ultrasonic condition, adding the lactic acid-glycolic acid copolymer nanospheres into the solution of the fullerene derivative, stirring and filtering to obtain the product. In the present application, the stirring and filtration may be performed by any method known in the art, for example, ultrafiltration after stirring for 48 hours.
According to an embodiment of the present application, the solution of the fullerene derivative includes a fullerene derivative and a solvent.
According to an embodiment of the application, the concentration of the fullerene derivative in the solution of the fullerene derivative is 0.1-10mg/mL, for example 1mg/mL.
According to an embodiment of the application, the solvent is selected from at least one of ethanol, water, methanol, ethyl acetate, for example a 4% aqueous ethanol solution.
According to embodiments of the present application, the ultrasound may be selected using conditions known in the art, for example at 100W ultrasound power.
According to an embodiment of the application, in step S2, the mass ratio of the lactic acid-glycolic acid copolymer nanospheres to the fullerene derivative is (1-10): 1, for example 5:1.
According to an embodiment of the application, in step S3, the cell membrane is selected from the above mentioned tumor cell membranes, e.g. MC38 tumor cells.
According to an embodiment of the present application, in step S3, the steps for preparing a cell membrane are as follows: and (3) after the tumor cells are collected by digestion and centrifugation, adding hypotonic solution, and then obtaining the cell membrane by gradient centrifugation.
According to an embodiment of the application, the gradient centrifugation specifically comprises: centrifugal for a period of time at a first centrifugal force, at a second centrifugal force and at a third centrifugal force, respectively. Preferably, the first centrifugal force is (100-1000) x g, for example 500 x g. Preferably, the second centrifugal force is (5000-20000) x g, for example 10000 x g. Preferably, the third centrifugal force is (50000-200000) x g, for example 100000 x g. Illustratively, the gradient centrifugation comprises: centrifugation was performed at 500 Xg for 10 minutes, 10000 Xg for 10 minutes, 100000 Xg for 60 minutes, respectively.
According to an embodiment of the application, the hypotonic solution comprises: tris-HCl solution, KCl solution, mgCl 2 Solution, protease inhibitor tablet.
According to an embodiment of the present application, the cell membrane may be further resuspended in a buffer solution to obtain a cell membrane buffer. In the present application, the buffer solution may be selected from buffer solutions known in the art, for example, PBS buffer solution.
According to an embodiment of the application, in step S4, the mass ratio of the drug-loaded core to the cell membrane is 0.5-2:1, for example 1:1.
According to an embodiment of the application, in step S4, the coating may be performed by methods known in the art, for example using a film extruder.
In step S4, according to an embodiment of the present application, filtration may be performed after coating. The filtration may be performed by methods known in the art, for example, filtration with 400nm filters.
According to an embodiment of the present application, the present application provides a nanomaterial prepared by the above-described preparation method, the nanomaterial having the meaning as described above.
The application also provides application of the nanomaterial in preparation of a medicine for blocking a tumor cell cycle, wherein preferably the medicine for blocking the tumor cell cycle is a medicine for degrading Cyclin, and more preferably the Cyclin is selected from Cyclin D1.
The application also provides application of the nanomaterial in preparing CDK inhibitor medicines; preferably, the CDK is selected from one or more of CDK4, CDK 6.
The application also provides application of the nano material in preparing medicines for up-regulating tumor cell autophagy activator proteins; preferably, the autophagy activating protein is selected from one or more of PSAP, CTSL, CTSD or an intermediate or mature protein thereof.
In any of the above nanomaterial applications of the present application, the tumor is selected from one or more of liver cancer, lung cancer, colorectal cancer, kidney cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, stomach cancer, oral cancer, nasal cancer, laryngeal cancer, bile duct cancer, cervical cancer, uterine cancer, testicular cancer, meningioma, skin cancer, melanoma, lymphoma, glioma, leukemia or sarcoma; preferably, the tumor is selected from one or more of non-small cell lung cancer, breast cancer, brain glioma, liver cancer and prostate cancer.
In any of the above nanomaterial applications of the present application, the drug includes one or more of the nanomaterial and a pharmaceutically acceptable carrier, preferably, the preparation form of the drug is selected from one or more of solution, granule, lyophilized powder, emulsion, suspension, oil, and nano-preparation; preferably, the solution is an injection.
In any of the above nanomaterial applications of the present application, the drug may further include at least one or more antitumor drugs, and the antitumor drugs may be selected from antitumor drugs known in the art.
Advantageous effects
In the application, the novel nanomaterial is formed by wrapping the PLGA nanospheres loaded with the amino fullerene by using tumor cell membranes, wherein the tumor cell membranes provide a highly stable wrapping layer to protect the amino fullerene and the PLGA nanospheres from the external environment. Meanwhile, the antigen and the receptor on the tumor cell membrane can realize specific recognition and targeted delivery of the tumor cells, and improve the pertinence and the curative effect of treatment. The research of the nano material has important clinical application prospect.
The application can combine the advantages of amino fullerene, PLGA nanospheres and tumor cell membranes through reasonable design and preparation, and form a nanomaterial with stability, charge capacity and targeted delivery capacity.
When the nano material is prepared, particularly when the drug is loaded to the nano material, polyvinyl alcohol is not required to be added, the particle size of the synthesized nano material is about 100nm, the aggregation degree of the nano material at the tumor part is increased more easily through the EPR effect and the targeting effect of tumor cell membranes, and the use efficiency of the drug is improved.
Definition and description of terms
The term "pharmaceutically acceptable" refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
The term "treating" includes inhibiting, alleviating, preventing or eliminating one or more symptoms or side effects associated with the disease, condition or disorder being treated.
The terms "reduce", "inhibit", "reduce" or "reduce" are used relative to a control. One skilled in the art will readily determine the appropriate controls for each experiment. For example, a reduced response in a subject or cell treated with a compound is compared to a response in a subject or cell not treated with the compound.
As used herein, the term "effective amount" or "therapeutically effective amount" refers to a dosage sufficient to treat, inhibit or alleviate one or more symptoms of the disease state being treated or otherwise provide the desired pharmacological and/or physiological effect. The precise dosage will vary depending on a variety of factors, such as subject-dependent variables (e.g., age, immune system health, etc.), disease or disorder, and the treatment being administered. The effect of an effective amount may be relative to a control. These controls are known in the art and discussed herein, and may be, for example, the condition of the subject prior to or without administration of the drug or combination of drugs, or in the case of a combination of drugs, the combined effect may be compared to the effect of administration of only one drug.
The term "excipient" is used herein to include any other compound that is not a therapeutically or biologically active compound that may be contained in or on a microparticle. Thus, the excipient should be pharmaceutically or biologically acceptable or relevant, e.g., the excipient is generally non-toxic to the subject. "excipient" includes a single such compound, and is also intended to include multiple compounds.
The term "pharmaceutical composition" means a composition comprising an amino fullerene derivative and, depending on the mode of administration and the nature of the dosage form, at least one pharmaceutically acceptable ingredient selected from the group consisting of, but not limited to: carriers, diluents, adjuvants, excipients, preservatives, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, antibacterial agents, antifungal agents, lubricants, dispersing agents, temperature sensitive materials, temperature adjusting agents, adhesives, stabilizers, suspending agents, and the like.
As used herein, the term "fullerene" is a series of spheroidal cluster molecules consisting of an even number of carbon atoms, with 12 five-membered rings and the remainder being six-membered rings. The fullerene comprises hollow fullerene and embedded fullerene, wherein the embedded fullerene is formed by embedding metal or metal atom clusters in a carbon cage structure of the fullerene.
The terms "metallofullerene" and "endohedral fullerene" refer to a class of compounds having specific structures and properties, commonly referred to as endohedral fullerenes, typically using M@C, formed by incorporating various metals or metal clusters into the carbon cage structure of the fullerene 2n The form is represented, wherein M represents a metal element.
The term "amino fullerene derivative" refers to a fullerene modified by amination, wherein the outside of the modified fullerene comprises one or more identical or different amino-containing substituent groups, and the modification methods can be modified according to the methods disclosed in the prior art.
As used herein, the term "tumor" refers to or describes a physiological condition of a mammal, particularly a human, which is typically characterized by unregulated growth of cells. Examples of tumors include, but are not limited to, solid tumors, carcinomas (carpinoma), lymphomas, blastomas, sarcomas, and leukemias.
As used herein, the term "cell cycle" refers to the overall process that a cell undergoes from the completion of one division to the end of the next division, divided into two phases, the interphase and the division phase. The middle stage is divided into three stages, namely, the early stage of DNA synthesis (G1 stage), the DNA synthesis stage (S stage) and the late stage of DNA synthesis (G2 stage). The regulation of the cell cycle is mainly realized by the retention of the G1 phase, wherein the G0 phase refers to the state that the cells are in retention, and the G0 phase is a phase which is separated from the cell cycle and temporarily stops dividing, but can enter the cycle under a certain proper stimulus.
As used herein, the term "Cyclin D1" refers to G1/S-specific Cyclin-D1, which is a Cyclin. "cyclin" refers to proteins that are elevated in a periodic concentration in synchronization with the cell cycle of eukaryotic cells, including cyclin A, B, D, E, G and H. They bind to key protein kinases (cyclin-dependent kinases, cyclin dependent kinases, CDKs) and regulate their enzymatic activity, helping to drive and coordinate the progression of the cell cycle.
As used herein, the term "autophagy" refers to or describes the process of transporting intracellular damaged, denatured or senescent proteins and organelles to lysosomes for digestion degradation. Under normal physiological conditions, autophagy is beneficial to maintaining the cells in a self-stable state; in the event of stress, autophagy prevents accumulation of toxic or carcinogenic damaged proteins and organelles, inhibiting canceration of cells. During autophagy, lysosomes are involved in autophagy regulation. CTSL (Cathepsin L) and CTSD (CathepsinD) are lysosomal proteases responsible for degrading proteins and activating enzymatic precursors. PSAP (Prosaposin) isolates the lipid substrate from the membrane surroundings, making the soluble degrading enzymes more accessible. Both CTSL and CTSD may stimulate activation of autophagy, whereas PSAP deficiency may cause dysfunction of autophagy.
Drawings
Fig. 1 shows the molecular structure of an amino fullerene TAPC;
FIG. 2 shows a transmission electron microscope TEM image of a nanomaterial;
FIG. 3 shows the Zeta potential of the nanomaterial;
FIG. 4 shows a gel electrophoresis staining image of cell membrane surface antigens;
fig. 5 shows photographs of various groups of tumors after treatment;
FIG. 6 shows the mass of each group of tumors after treatment;
Detailed Description
The technical scheme of the application will be further described in detail below with reference to specific embodiments. It is to be understood that the following examples are illustrative only and are not to be construed as limiting the scope of the application. All techniques implemented based on the above description of the application are intended to be included within the scope of the application.
Unless otherwise indicated, the starting materials and reagents used in the following examples were either commercially available or may be prepared by known methods.
Example 1: amino fullerene nano material wrapped by synthetic tumor cell membrane
The preparation method of the PLGA nano material coated by tumor cell membranes and loaded with amino fullerene comprises the following specific steps:
s1, synthesizing PLGA nanospheres, preparing 40mL of PLGA acetone solution with the concentration of 1mg/mL, fully dissolving and mixing, dripping into 120mL of water, stirring overnight, ultrafiltering for 10 minutes by using a 10k ultrafiltration tube 6000X rpm, and collecting the product to obtain the PLGA nanospheres.
S2, loading amino fullerene onto PLGA nanospheres, dissolving amino fullerene TAPC (the amino fullerene has a structure shown in figure 1, and the preparation method is shown in the example 1 of the patent document CN 112516164A) into 4% ethanol water solution to prepare TAPC solution with the concentration of 1mg/mL, adding PEG-PO macromolecule auxiliary materials (the mole ratio of PEG-PO to TAPC is 10:1) for increasing the stability of the amino fullerene, and uniformly mixing with the TAPC solution. Subsequently, 2mg/mL of PLGA solution was added dropwise at an ultrasonic power of 100W, stirred for 48 hours, and ultrafiltered to obtain an amino fullerene-loaded PLGA core, designated TAPC-PLGA.
S3, collecting MC38 tumor cell membranes on a large scale, and performing cell separation onAfter MC38 tumor cells (MC 38 tumor cells are purchased from national biomedical experimental cell resource library) are digested, centrifugally collected, hypotonic solution (hypotonic solution comprises 20mM Tris-HCl solution, 10mM KCl solution and 2mM MgCl) 2 Solution, one tablet of protease inhibitor tablet), gradient centrifugation (500×g, centrifugation for 10 min to collect supernatant; 10000 Xg, centrifuging for 10 min to obtain supernatant; 100000 Xg, centrifuging for 60 min to obtain MC38 cell membrane, and re-suspending the obtained MC38 cell membrane in PBS buffer solution to obtain MC38 cell membrane buffer solution, wherein the mass volume ratio of MC38 cell membrane to PBS buffer solution is 1:50 (g: mL).
S4, mixing TAPC-PLGA obtained in the step S2 with the MC38 cell membrane buffer solution obtained in the step S3, wherein the mass ratio of the TAPC-PLGA to the MC38 cell membrane is 1:1, coating the TAPC-PLGA and the MC38 cell membrane by using a membrane extruder, and filtering the coated membrane by using a 400nm filter membrane to obtain the amino fullerene-loaded PLGA nano material coated by the tumor cell membrane, which is marked as TPM.
Comparative example 1
The comparative example uses PEG-PO as an adjuvant control, and an aqueous solution at a concentration of 10mM is designated PEG-PO.
Comparative example 2
In the comparative example, a cell membrane-coated PLGA nanomaterial was prepared as a cell membrane comparative group, and the preparation method was the same as in example 1, except that in step S4, PLGA obtained in step S1 was mixed with MC38 cell membrane buffer solution obtained in step S3, wherein the mass ratio of PLGA to MC38 cell membrane was 1:1, PLGA and MC38 cell membrane were coated with a membrane extruder, and the membrane-coated PLGA nanomaterial was obtained by passing through a 400nm filter membrane, and was designated as PM.
Comparative example 3
TAPC is used as a fullerene derivative comparison group in the comparison example, and the preparation method is that TAPC is prepared into an aqueous solution with the concentration of 1mM, and PEG-PO auxiliary material with the molar ratio of 10 times is added, and the mixture is uniformly mixed and marked as TAPC.
Example 2: nanomaterial TPM topography testing
The morphology and structure of the nanomaterial TPM were observed and analyzed using a transmission electron microscope (TEM, model HT 7700), as follows:
(1) The nanomaterial TPM is dissolved in water to prepare a sample solution.
(2) The carbon film was placed on the sample holder, and the sample solution was dropped on the carbon film so as to uniformly cover the sample solution.
(3) After the solvent volatilizes, the carbon film covering the sample is subjected to transmission electron microscopy test, and a clear particle image is obtained, as shown in fig. 2.
Conclusion: the nano material TPM synthesized in the embodiment 1 is spherical and has the particle size of about 100 nm; and the tumor cell membrane is completely wrapped on the outer surface of TAPC-PLGA.
Example 3: zeta potential test
1. Preparing a sample solution:
control group: respectively dispersing PLGA, TAPC-PLGA and MC38 cell membranes prepared in the example 1 into aqueous solution, and marking the PLGA group, the TAPC-PLGA group and the cell membrane group;
experimental group: the nanomaterial TPM of example 1 was dispersed in an aqueous solution and designated as a TPM group.
The above-mentioned sample solutions to be measured of each group were left to stand so that the particles were sufficiently dispersed and stabilized.
2. The potential test steps were as follows:
the sample solutions are respectively injected into a measuring cell of the Zeta potential measuring instrument by using a Zeta potential measuring instrument (model NanoZS Zen 3600), so that the injected sample solution is ensured to fill the measuring cell, and bubbles are removed as much as possible to obtain an accurate measuring result. The measurement process is initiated through the control panel or software interface of the instrument. The measurement procedure was completed according to the instruction manual of the instrument, and the test results are shown in fig. 3.
Conclusion: the Zeta potential of PLGA, TAPC-PLGA, cell membrane and cell membrane coated nanometer material (TPM) is-20.0 mV,5.6mV, -8.1mV and-15.5 mV respectively. It was found that the potential of the fullerene derivative was changed from positive to negative after the film coating, and the nonspecific binding to proteins in blood was reduced.
Example 4: surface protein expression test
1. Tumor cell sample: MC38 colorectal cancer cells (purchased from national biomedical experimental cell resource library).
2. Preparing a sample: dispersing MC38 cell membranes prepared in example 1 into PBS buffer solution to serve as a blank control group; the TPM nanomaterial prepared in example 1 was dispersed in PBS buffer solution as an experimental group.
3. Surface protein expression test:
coomassie brilliant blue staining detects membrane protein levels:
1) Tumor cell samples were collected, tumor cell membranes were lysed using RIPA cell lysate, and proteins within tumor cells were released. The tumor cell lysate was centrifuged and the supernatant was collected, which contained the extracted tumor cell holoprotein. The concentration of extracted tumor cell holoprotein was measured using a protein quantification method. Mixing the extracted tumor cell whole protein with a protein loading buffer solution, wherein the dosage ratio of the tumor cell whole protein to the protein loading buffer solution (commercial) is 1:4, obtaining a tumor cell protein sample.
2) Heating tumor cell protein samples, and respectively adding 30 mug of tumor cell protein samples of a control group and an experimental group to a prefabricated polyacrylamide gel electrophoresis pore canal. Electrophoresis was performed by adding electrophoresis buffer (specifically SDS-PAGE Running Buffer) under 130V for 75 minutes.
3) After electrophoresis, the gel was transferred to a staining cassette and covered with coomassie brilliant blue dye solution. Dyeing time was 10 minutes. The gel was removed and washed with wash buffer (specifically TBST solution). The stained gel was observed, and the position and intensity of the protein bands were recorded and analyzed, and the results are shown in fig. 4.
Conclusion: compared with the protein strips of the control group, the protein strips of the experimental group are basically consistent, which indicates that the membrane protein of the TPM of the nano material is expressed completely, and is beneficial to exerting the advantages of antigen presentation and homotypic targeting of tumor cell membranes.
Example 5: the tumor inhibition rate of animal experiments exceeds 60 percent
Animal strain: balb/c female mice, 5 weeks, weight between 16-20 g.
Tumor model: MC38 colorectal cancer subcutaneous tumor model (tumor model was obtained using cell seeding in the examples above).
Experimental grouping:
the Control group was a normal saline group (designated as Control), the adjuvant of comparative example 1 was taken as a PEG-PO group (concentration: 10mM, designated as PEG-PO), the PM nanomaterial prepared in comparative example 2 was taken as a blank tumor cell membrane-coated PLGA group (designated as PM), and the TAPC prepared in comparative example 3 was taken as a TAPC group (TAPC concentration: 1mM, designated as TAPC);
experimental group: the nanomaterial TPM prepared in example 1 was used as a membrane-coated nanomaterial set (referred to as TPM set, containing 1mM TAPC).
The administration mode is as follows: 0.1mL was intravenously injected.
The experimental method comprises the following steps: subcutaneous inoculation 100. Mu.L of 2X 10 concentration 6 After two days of inoculation of/ml MC38 colorectal cancer cells, 100 mu L of TPM material is injected intravenously, an equal dose of physiological saline and PEG-PO, PM, TAPC is injected intravenously in a control group, the administration is continued for a plurality of days, the tumor size is measured after the administration is started, the inhibition condition of the treatment group on the tumor is observed, and the inhibition results are shown in figures 5 and 6.
Experimental results: comparing the experimental group with the control group, the tumor size (figure 5) and weight (figure 6) of the TPM group after treatment are obviously smaller than those of the 3 control groups, which proves that the TPM group has obvious tumor inhibition effect and the tumor inhibition rate is more than 60 percent. Therefore, the nano material TPM has better tumor inhibiting effect and obviously exceeds the treatment effect of adopting a single component.
The above description of exemplary embodiments of the application has been provided. However, the scope of the present application is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, or the like, which are within the spirit and principles of the present application, should be made by those skilled in the art, and are intended to be included within the scope of the present application.
Claims (10)
1. A nanomaterial characterized in that the nanomaterial comprises a cell membrane and a drug-loaded core; the medicine carrying inner core comprises fullerene derivatives and lactic acid-glycolic acid copolymers; the cell membrane is wrapped on the surface of the medicine carrying inner core.
2. The nanomaterial of claim 1, wherein the cell membrane is selected from the group consisting of cell membranes of tumor cells.
Preferably, in the drug-carrying inner core, the mass ratio of the fullerene derivative to the lactic acid-glycolic acid copolymer is (1-10): 1.
Preferably, the lactic acid-glycolic acid copolymer has a molecular weight ranging from 1000 to 20000.
Preferably, the lactic acid-glycolic acid copolymer has a nanosphere structure.
Preferably, the particle size of the nanospheres is 10-200nm.
3. The nanomaterial according to claim 1 or 2, characterized in that the fullerene derivative is selected from amino fullerene derivatives having the structure represented by formula (I);
wherein F is a fullerene selected from at least one of a hollow fullerene, a metal fullerene, a heterocyclic fullerene and an endohedral fullerene;
wherein R is an amino modified group of the fullerene, one end of R is combined with the fullerene through a nitrogen-containing group, phenyl and mercapto, and the other end of R is any nitrogen-containing group, and the nitrogen-containing group comprises any one or more of primary ammonia, tertiary amine, secondary amine and quaternary amine;
wherein m is selected from integers from 1 to 12.
Preferably, R is-NR 1 -R'-NR 2 R 3 Wherein R is 1 ，R 2 ，R 3 Independently or simultaneously hydrogen, or optionally substituted C1-C6 alkyl, cycloalkyl, heteroatom-containing alkyl, heterocycloalkyl, aryl, heteroaryl, or R 1 And R is 2 And/or R 3 Together forming a cyclized substituent;
r' is optionally substituted C1-C6 alkyl, cycloalkyl, heteroatom-containing alkyl, heterocycloalkyl, arylRadicals, heteroaryl, or R 1 And R' together form a cyclized substituent; wherein when R is 1 And R is 2 And/or R 3 R' is absent when taken together to form the cyclized substituent.
Further, R 2 、R 3 And is hydrogen.
4. A nanomaterial according to any of claims 1-3, characterized in that in the amino fullerene derivative the fullerene is at least one of a hollow fullerene, a metallic fullerene, a heterocyclic fullerene and an endohedral fullerene, preferably the fullerene is selected from C 2n 、M@C 2n 、M2@C 2n 、MA@C 2n 、M 3 N@C 2n 、M 2 C 2 @C 2n 、M 2 S@C 2n 、M 2 O@C 2n And M x A 3-x N@C 2n Any one or a mixture of the above, wherein M and A are metal elements, and M and A are selected from any one of Sc, Y and lanthanide metal elements; preferably, the fullerene is selected from C-containing compounds 2n Wherein 2n is the number of carbon atoms, and n is more than or equal to 30 and less than or equal to 60; preferably, the fullerene is selected from one or more of C60, C70, C76, C78, C80, C84.
Preferably, in the amino fullerene derivative, the amino modification group R of the fullerene is one or several selected from (2-aminoethyl) amino, (3-aminopropyl) amino, (4-aminobutyl) amino, (5-aminopentyl) amino, (2-aminophenyl) amino, (3-aminophenyl) amino, (4-amino) piperidinyl, piperazinyl, 4-aminophenyl, (4-aminomethyl) phenyl, (4-aminophenyl) mercapto, (4-aminocyclohexyl) mercapto, 4-piperidinylmercapto, (1-aminoethyl) mercapto, (1-aminopropyl) mercapto, (1-aminobutyl) mercapto, (1-aminopentyl) mercapto.
5. The method for preparing a nanomaterial according to any one of claims 1 to 4, wherein the method comprises:
s1, preparing lactic acid-glycolic acid copolymer nanospheres;
s2, preparing a medicine carrying inner core: loading fullerene derivatives onto the lactic acid-glycolic acid copolymer nanospheres to obtain the drug-loaded inner core;
s3, preparing cell membranes;
and S4, mixing the medicine carrying inner core obtained in the step S2 with the cell membrane obtained in the step S3, and coating the cell membrane on the medicine carrying inner core to obtain the nano material.
6. The preparation method according to claim 5, wherein in step S1, the specific steps of the preparation are as follows: and dissolving PLGA in an organic solvent to obtain PLGA solution, dropwise dripping the PLGA solution into water after dissolving, stirring, ultrafiltering, and then re-suspending in water to prepare the lactic acid-glycolic acid copolymer nanospheres.
Preferably, the organic solvent is selected from acetone, dichloromethane, ethyl acetate, and the like.
Preferably, the volume ratio of the dropwise added water to the PLGA solution is 1-5:1.
7. The method according to claim 5 or 6, wherein in step S2, the loading is performed as follows: under the ultrasonic condition, adding the lactic acid-glycolic acid copolymer nanospheres into the solution of the fullerene derivative, stirring and filtering to obtain the product.
Preferably, the solution of fullerene derivative comprises fullerene derivative and solvent.
Preferably, the concentration of the fullerene derivative in the solution of the fullerene derivative is 0.1-10mg/mL.
Preferably, the solvent is at least one selected from ethanol, water, methanol, ethyl acetate.
Preferably, in step S2, the mass ratio of the lactic acid-glycolic acid copolymer nanospheres to the fullerene derivative is (1-10): 1.
8. The method according to any one of claims 5 to 7, wherein in step S3, the cell membrane is selected from the group consisting of tumor cell membranes.
Preferably, in step S3, the step of preparing a cell membrane is as follows: and (3) after the tumor cells are collected by digestion and centrifugation, adding hypotonic solution, and then obtaining the cell membrane by gradient centrifugation.
Preferably, the gradient centrifugation specifically includes: centrifugal for a period of time at a first centrifugal force, at a second centrifugal force and at a third centrifugal force, respectively. Preferably, the first centrifugal force is (100-1000) ×g. Preferably, the second centrifugal force is (5000-20000) ×g. Preferably, the third centrifugal force is (50000-200000) ×g.
Preferably, in step S4, the mass ratio of the drug-loaded inner core to the cell membrane is 0.5-2:1.
9. Use of a nanomaterial according to any of claims 1 to 4 in the manufacture of a medicament for blocking a tumor cell cycle, a CDK inhibitor medicament, or a medicament for up-regulating autophagy activating proteins of a tumor cell.
10. The use according to claim 9, wherein the drug that blocks the tumor cell cycle is a drug that degrades cyclin.
Preferably, the CDK is selected from one or more of CDK4, CDK 6.
Preferably, the autophagy activating protein is selected from one or more of PSAP, CTSL, CTSD or an intermediate or mature protein thereof.
Preferably, the tumor is selected from one or more of liver cancer, lung cancer, colorectal cancer, kidney cancer, pancreatic cancer, bone cancer, breast cancer, ovarian cancer, prostate cancer, esophageal cancer, stomach cancer, oral cancer, nasal cancer, laryngeal cancer, bile duct cancer, cervical cancer, uterine cancer, testicular cancer, meningioma, skin cancer, melanoma, lymphoma, glioma, leukemia or sarcoma; preferably, the tumor is selected from one or more of non-small cell lung cancer, breast cancer, brain glioma, liver cancer and prostate cancer.
Preferably, the medicament comprises one or more of the nanomaterials and a pharmaceutically acceptable carrier, preferably the medicament is in the form of a formulation selected from one or more of solutions, granules, freeze-dried powders, emulsions, suspensions, oils, nano-formulations.
Preferably, the medicament further comprises at least one or more antineoplastic agents.
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