WO2018177420A1 - 一种生物膜包载药物纳米晶体的制备方法及其用途 - Google Patents
一种生物膜包载药物纳米晶体的制备方法及其用途 Download PDFInfo
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Definitions
- the invention belongs to the field of pharmacy, relates to a preparation method of biofilm-coated drug nanocrystals, and the application of the method in biofilm-coated nanocrystals to construct a nano drug delivery system. Specifically, the invention relates to a method for preparing a nano drug delivery system of a biofilm coated drug nanocrystal by coating a nanocrystal of a drug directly as a rigid support skeleton, and coating the nano film of the biofilm coated nanocrystal. Application in the delivery system.
- the biofilm-coated nano-delivery system is a drug delivery system formed by coating a biofilm on a rigidly supported nanoparticle, and the supported nanoparticle is usually formed of an organic polymer material or an inorganic material.
- biofilm-coated nano-delivery systems have the following advantages: 1) good biocompatibility and high safety; 2) systemic circulation time Long; 3) Compared with the traditional long-circulating nano-formulation, it has no PEGylation modification and low immunogenicity.
- biofilm-coated nano-drug delivery systems may also have targeted functions through homologous tropism or modification of surface target molecules.
- the biofilm-coated nano-drug delivery system can be carried by adsorbing a drug onto a biofilm or encapsulating it in a support matrix.
- the drug-loading method adsorbed on the membrane is generally used for substances which have specific adsorption to the biofilm, such as the natural adsorption of the erythrocyte membrane by the bacterial toxin, and the erythrocyte membrane coated with the nanoparticle to adsorb the toxin for immunoprevention and treatment, However, this method does not apply to most drugs.
- the method of loading the drug on the support skeleton is to first package the drug in the nanoparticle formed by the organic polymer carrier (commonly used PLGA) or the inorganic carrier (mesoporous material), and then packaged by extrusion or ultrasonic method. Covering the biofilm to form a drug-loaded biofilm-coated nano-drug delivery system.
- PLGA nanoparticles are often due to poor compatibility of drug molecules with carriers, resulting in low drug loading; drug loading by inorganic mesoporous materials, although with high drug-loading capacity, is not biodegradable due to inorganic carriers, biological phase Poor tolerance, so limited in practical applications.
- Drug nanocrystals refer to the formation of nanometer-scale and rigid drug crystals during the crystallization of drug molecules. As a drug intermediate for improving drug dissolution and improving drug bioavailability, it has been widely used in the research and development of oral preparations. In addition, the drug exists in the form of nanocrystals, which have a sustained release function.
- the invention provides a method for preparing a biofilm-coated nano drug delivery system using rigid drug nanocrystals as a support skeleton.
- the method replaces the commonly used PLGA or inorganic mesoporous materials in the biofilm-coated nano-delivery system with the nanocrystal of the drug, and provides the support structure required for the biofilm-coated nano drug delivery system, and also realizes Drug loading.
- the nano-delivery system of biofilm coated drug nanocrystals constructed by the method has many advantages: 1) large drug loading amount, which can meet the dosage requirements of clinical drugs; 2) avoiding the use of carrier materials and improving the delivery system Biocompatibility and safety; 3) Reduce the specific surface energy of the drug nanocrystals and increase the stability of the drug nanocrystals; 4) Both the sustained release properties of the drug nanocrystals and the biofilm coated nano drug delivery The advantage of long circulation in the system. Therefore, this method has great potential application value.
- the invention provides a preparation method of biofilm coated drug nanocrystals.
- RGD refers to a polypeptide having a high binding activity to integrin.
- VAP refers to a polypeptide having a high binding activity to the glucose regulator protein GRP78.
- WVAP refers to a polypeptide that has high binding activity to both the quorum sensing receptor and the glucose regulator protein GRP78.
- A7R refers to a polypeptide which has high binding activity to both vascular endothelial growth factor receptor 2 and neuropilin-1.
- CDX refers to a polypeptide having a high binding activity to an acetylcholine receptor.
- U87 cell refers to: human malignant glioma U87 cells.
- PLGA means: a polylactic acid-glycolic acid copolymer.
- F127 means: poloxamer, a polyoxyethylene polyoxypropylene ether block copolymer.
- PEG polyethylene glycol
- DSPE refers to: distearoylphosphatidylethanolamine.
- PBS refers to a phosphate buffered saline solution.
- FBS means: fetal bovine serum
- a first aspect of the present invention provides a nano drug delivery system comprising: a drug nanocrystal coated with a biofilm, wherein the drug directly acts as a rigid support skeleton in a physical form of nanocrystals, Filled in biofilm.
- the nano drug delivery system according to the first aspect of the present invention wherein the drug nanocrystal is both a skeleton material and a drug reservoir.
- nano drug delivery system according to the first aspect of the present invention, wherein the drug nanocrystal is a nanoscale crystal formed by treatment of a drug by physical or chemical means.
- the nano drug delivery system according to the first aspect of the present invention wherein the drug nanocrystal has a particle diameter of 10 nm to 1000 nm, preferably 10 nm to 200 nm.
- nano drug delivery system according to the first aspect of the invention, wherein the drug is a therapeutic drug and/or a diagnostic drug.
- the therapeutic drug is selected from one or more of the following: an antitumor drug, an anti-infective drug, an anti-cardiovascular disease drug, an anti-lymphatic disease drug, and an anti-infective drug which can be prepared into a nanocrystal by physical or chemical methods.
- an antitumor drug an anti-infective drug, an anti-cardiovascular disease drug, an anti-lymphatic disease drug, and an anti-infective drug which can be prepared into a nanocrystal by physical or chemical methods.
- an antitumor drug an anti-infective drug, an anti-cardiovascular disease drug, an anti-lymphatic disease drug, and an anti-infective drug which can be prepared into a nanocrystal by physical or chemical methods.
- Immune system disease drugs analgesic drugs;
- the anti-tumor drug is selected from the group consisting of: taxanes such as paclitaxel, anthracyclines such as doxorubicin, camptothecins, vincristines, zidomines such as bortezomib, and cis.
- a platinum-based drug such as platinum, irinotecan and/or parthenolide
- the anti-infective drug is selected from the group consisting of: ceftriaxone, cefoxitin, aztreonam, streptomycin, amphotericin B, and vancomycin , tigecycline, teicoplanin, morpholinium, adenosine and acyclic glucoside
- the anti-cardiovascular disease drug is selected from the group consisting of: ganglioside, ferulic acid, ligustrazine And troxerutin and sodium ozagrel
- the anti-lymphatic system disease drug is pabisstat
- the anti-immune system disease drug is selected from the group consisting of: methylprednisolone and cyclosporine
- the analgesic drug is selected from the group consisting of: Morphine and methadone
- the drug is irinotecan or docetaxel or cabazitaxel.
- the diagnostic drug is selected from one or more of the following: a fluorescent substance, a near-infrared dye, a magnetic resonance imaging agent which can be prepared into a nanocrystal by physical or chemical means.
- biofilm is a membrane structure having a lipid bilayer
- the biofilm is selected from a natural cell membrane or an artificial biofilm
- the natural cell membrane is selected from one or more of the following: an erythrocyte membrane, a platelet membrane, a macrophage membrane, a leukocyte membrane, a tumor cell membrane, and the artificial biofilm is a liposome membrane;
- the biofilm is selected from one or more of the following: an erythrocyte membrane, a platelet membrane, a tumor cell membrane.
- nano drug delivery system according to the first aspect of the present invention, wherein the nano drug delivery system surface is further modified by a targeting molecule to construct the nano drug delivery system as a biofilm coating having an active targeting function Nano-delivery system for nanocrystals;
- the targeting molecule is selected from a polypeptide target molecule
- polypeptide target molecule is selected from one or more of the group consisting of RGD, VAP, WVAP, A7R, CDX.
- a second aspect of the present invention provides a method for preparing a nano drug delivery system according to the first aspect of the present invention, wherein the method comprises: filling a drug into a biofilm directly in a physical form of the nanocrystal as a rigid support skeleton.
- a third aspect of the invention provides the use of the nano-delivery system of the first aspect of the invention for the preparation of an in vivo therapeutic and/or diagnostic product for use in a medicament.
- a fourth aspect of the invention provides a method of treating and/or diagnosing a disease in vivo, wherein a nano-drug delivery system according to the first aspect of the invention is administered to a subject in need thereof.
- the present invention provides the use of the inventive method in the preparation of nanofilm delivery systems for biofilm coated nanocrystals.
- the method for preparing a biofilm-coated drug nanocrystal is to prepare a nanometer of a biofilm-coated drug nanocrystal by constructing a drug into a nanocrystal and then directly coating the biofilm as a rigid support skeleton. Delivery system.
- the nanocrystals of the drug can be obtained by physical or chemical treatment, and the obtained nanocrystal particle diameter is controlled to be 10 nm to 1000 nm, preferably 10 nm to 200 nm.
- Drug nanocrystals are composed of therapeutic drugs or diagnostic drugs.
- the therapeutic drug is an antitumor drug which can be prepared into nanocrystals by physical or chemical methods (such as taxanes such as paclitaxel, anthracyclines such as doxorubicin, camptothecins, vincristine, and bortezole).
- taxanes such as paclitaxel
- anthracyclines such as doxorubicin, camptothecins, vincristine, and bortezole.
- Sami drugs such as rice, platinum drugs such as cisplatin, irinotecan, parthenolide, etc.), anti-infective drugs (such as ceftriaxone, cefoxitin, aztreonam, streptomycin, amphiphilic B, vancomycin, tigecycline, teicoplanin, morpholinium, adenosine, acyclic glycosides, etc.), anti-cardiovascular disease drugs (such as gangliosides, awei Acid, ligustrazine, troxerutin, sodium ozagrel, etc.), anti-lymphatic diseases drugs (such as pabisstat, etc.), anti-immune system diseases (such as methylprednisolone, cyclosporine, etc.), town Pain medications (such as morphine, methadone, etc.).
- anti-infective drugs such as ceftriaxone, cefoxitin, aztreonam, streptomycin, amphi
- Diagnostic drugs are fluorescent substances (such as Fluorescein, Rhodamine, etc.) that can be prepared into nanocrystals by physical or chemical methods, near-infrared dyes (such as cy5.5, IR820, DiR, etc.), and magnetic resonance imaging agents (such as Gd agents, iron oxides). Wait).
- the selected biofilm is a membrane structure with a lipid bilayer, which may be a natural cell membrane such as an erythrocyte membrane, a platelet membrane, a macrophage membrane, a leukocyte membrane, a tumor cell membrane, or an artificial biofilm, such as a liposome membrane. Wait.
- the nano-delivery system of erythrocyte membrane, platelet membrane coated irinotecan nanocrystal, erythrocyte membrane coated docetaxel nanocrystal nano-drug system, RGD modified erythrocyte membrane coated Dorsey was constructed by the method provided by the invention. He competes in the nano-delivery system of nanocrystals.
- the erythrocyte membrane of the invention and the nano-delivery system of the RGD-modified red blood cell membrane coated with docetaxel nanocrystals can be used for tumor-targeted delivery in vivo for anti-tumor treatment.
- the invention provides a preparation method of a biofilm-coated drug nanocrystal, and the application of the method in constructing a biofilm-coated nanocrystal nano-drug system, and the erythrocyte membrane and the RGD modified erythrocyte membrane package constructed by the method
- the nano-delivery system of docetaxel nanocrystals serves as the basis for tumor therapy.
- the test results of the present invention indicate that the nano drug delivery system of the biofilm coated drug nanocrystal prepared by the method of the invention has a clear nuclear-membrane structure by TEM, and the stability of the drug nanocrystal is significantly improved.
- Nanocrystals were successfully coated by biofilm; in vitro release showed that the nano-delivery system coated with biofilm coated drug nanocrystals had obvious drug release properties; in vivo pharmacokinetics showed that biofilm-coated nanocrystals of drug nanocrystals have The advantage of long circulation significantly prolongs the circulation time of the drug in vivo; biofilm coating and targeted molecular modification biofilm coated nanocrystal delivery system of drug nanocrystals can be enriched in tumor tissue by passive or active targeting, Stronger inhibition of tumor growth. In addition, nano-drug delivery systems coated with biofilms of biofilms are safer than commercially available formulations and drug nanocrystals.
- the preparation method of the biofilm-coated drug nanocrystal provided by the invention can be used for preparing the nano drug delivery system of the biofilm coated drug nanocrystal, and compared with the existing nanofilm delivery system for constructing the biofilm coating.
- the drug-loading method has greater advantages, so its application prospect is good.
- Modification of RGD or VAP or WVAP or A7R or CDX by first modifying streptavidin by lipid insertion into the surface of a nanocarrier system coated with erythrocyte membrane coated docetaxel nanocrystals, followed by biotinylation Incubation of RGD or biotinylated VAP or biotinylated WVAP or biotinylated A7R or biotinylated CDX to obtain nanoparticles of RGD or VAP or WVAP or A7R or CDX modified erythrocyte membrane coated docetaxel nanocrystals Delivery system.
- the in vitro release of the drug was determined by the dialysis bag method.
- ICR mice were given a commercial docetaxel injection, docetaxel nanocrystals, a red cell membrane coated docetaxel nanocrystal nano-delivery system, and an RGD-modified red blood cell membrane coated with docetaxel nanocrystals.
- the nano drug delivery system takes blood at a certain time, and the concentration of the drug in the blood is determined by HPLC method, and the pharmacokinetic curve is plotted.
- U87 subcutaneous xenograft model or U87 intracerebral in situ tumor model nude mice were given a commercial docetaxel injection, erythrocyte membrane coated docetaxel nanocrystal nano-drug system and RGD modified erythrocyte membrane coating
- the nano-drug system of the Sithasai nanocrystals takes tissue organs and whole blood at a certain time, and the tissue and blood drug concentrations are determined by HPLC.
- U87 subcutaneous xenograft model nude mice were injected with normal saline, commercially available docetaxel injection, docetaxel nanocrystals, erythrocyte membrane coated docetaxel nanocrystal nano-delivery system and RGD modified erythrocyte membrane.
- the nano-drug system coated with docetaxel nanocrystals was used to evaluate the anti-tumor effect in vivo by using tumor volume and survival time as indicators.
- the U8 brain in situ tumor model was injected into the tail vein of nude mice with physiological saline, commercial docetaxel injection, erythrocyte membrane coated docetaxel nanocrystal nano-drug system and RGD modified erythrocyte membrane coated docetaxel.
- the nano-delivery system of Nanocrystals evaluated the anti-tumor effect in vivo based on the survival time.
- mice Normal nude mouse tail vein injection of normal saline, commercial docetaxel injection, erythrocyte membrane coated docetaxel nanocrystal nano-delivery system and RGD modified erythrocyte membrane coated docetaxel nanocrystal nano-drug In vivo, the safety of the body was evaluated by the leukocyte level of whole blood and the creatinine clearance rate of mice.
- Figure 1 shows an electron micrograph of a nano-delivery system of erythrocyte membrane and platelet membrane coated irinotecan nanocrystals:
- the irinotecan nanocrystal (A) is rod-shaped; the erythrocyte membrane (B) and the platelet membrane (C) coated with irinotecan nanocrystals have a spherical nanoparticle delivery system with a particle size of about 40 nm.
- Figure 2 shows an electron micrograph of a nano-delivery system of erythrocyte membrane coated docetaxel nanocrystals:
- the docetaxel nanocrystal (A) is spherical and has a particle size of about 30 nm;
- the nano drug delivery system (B) coated with docetaxel nanocrystals in the erythrocyte membrane is spherical and has a distinct nuclear-membrane.
- the structure has a particle size of about 70 nm.
- Figure 3 shows the in vitro release profile of the nanocarrier system of erythrocyte membrane and RGD modified erythrocyte membrane coated docetaxel nanocrystals:
- the picture shows docetaxel nanocrystals (DTX NCs), erythrocyte membrane coated docetaxel nanocrystal nano-delivery system (RBC/DTX NCs) and RGD modified erythrocyte membrane coated docetaxel nanocrystals. Release of the drug system (RGD-RBC/DTX NCs) in PBS (pH 7.4) solution.
- DTX NCs docetaxel nanocrystals
- RGD-RBC/DTX NCs erythrocyte membrane coated docetaxel nanocrystal nano-delivery system
- RGD-RBC/DTX NCs RGD modified erythrocyte membrane coated docetaxel nanocrystals
- Figure 4 shows the in vivo pharmacokinetic profile and parameter table of the nano drug delivery system of erythrocyte membrane and RGD modified erythrocyte membrane coated docetaxel nanocrystals:
- FIG. 5 is a bar graph showing the tissue distribution of the erythrocyte membrane and the RGD-modified erythrocyte membrane-coated docetaxel nanocrystal nano-delivery system in a U87 subcutaneous xenograft model mouse:
- the nano-delivery system (RBC/DTX NCs) coated with docetaxel nanocrystals in erythrocyte membranes, regardless of whether or not there is RGD modification, is distributed in the liver of mice compared with the commercially available docetaxel injection (DTX).
- DTX docetaxel injection
- Figure 6 is a bar graph showing the tissue distribution of erythrocyte membrane and RGD-modified red blood cell membrane coated docetaxel nanocrystal nano-delivery system in mice bearing U87 brain in situ tumor model:
- the nano-delivery system (RBC/DTX NCs) coated with docetaxel nanocrystals in red blood cell membranes is distributed in the liver of mice regardless of RGD modification.
- RGD modification Reduced, increased blood distribution, and targeted molecular modification can carry the nano-delivery system across the blood-brain tumor barrier and significantly increase the accumulation of drugs in the brain tumor site.
- Figure 7 shows the in vitro anti-U87 cell activity curve of the nanocarrier system of erythrocyte membrane and RGD modified erythrocyte membrane coated with docetaxel nanocrystals:
- U87 cells are separately marketed with docetaxel injection (DTX), docetaxel nanocrystals (DTX NCs), and erythrocyte membrane coated docetaxel nanocrystal nanodispensing system (RBC/DTX NCs).
- DTX docetaxel injection
- DTX NCs docetaxel nanocrystals
- RGD/DTX NCs erythrocyte membrane coated docetaxel nanocrystal nanodispensing system
- Figure 8 shows the evaluation of the anti-U87 subcutaneous tumor of the nano drug delivery system coated with erythrocyte membrane and RGD modified erythrocyte membrane coated with docetaxel nanocrystals:
- Figure A is a graph showing the tumor volume of U87 subcutaneously transplanted nude mice with time;
- Figure B is the survival curve of U87 subcutaneous transplanted nude mice;
- Figure C is the comparison of tumor inhibition rates of each group on the 28th day after administration;
- D is a comparison of the tumor inhibition rates at the median survival of each group after administration.
- DTX NCs docetaxel nanocrystals
- RBC/DTX NCs erythrocyte membrane coating
- PBS normal saline
- the nanocarrier delivery system (RBC/DTX NCs) of erythrocyte membrane coated docetaxel nanocrystals was significantly higher.
- the survival time of the model nude mice was prolonged (median survival time 42 days), and the survival time of the RGD-modified erythrocyte membrane coated docetaxel nanocrystal nano-delivery system (RGD-RBC/DTX NCs) group was the most significant ( The median survival time is 47 days).
- the tumor inhibition rates of the groups were 89.18 ⁇ 6.75% in the RBC/DTX NCs group and 97.28 ⁇ 2.46% in the RGD-RBC/DTX NCs group, which were significantly higher than those in the DTX group (53.28 ⁇ 19.79). %).
- the tumor inhibition rates of the groups after the median survival were 33.76% ⁇ 6.37% in the RBC/DTX NCs group and 77.24% ⁇ 6.58% in the RGD-RBC/DTX NCs group, which were also significantly higher than the DTX group. Tumor inhibition rate (4.93% ⁇ 2.52%). The results indicated that RGD-RBC/DTX NCs had the best antitumor effect in vivo.
- Figure 9 shows the evaluation of anti-U87 in situ tumors of the nano-delivery system of erythrocyte membrane and RGD-modified red blood cell membrane coated with docetaxel nanocrystals:
- Figure U87 Survival curves of nude mice in situ in the brain. The results showed that compared with and with saline (PBS) (median survival 32 days), commercial docetaxel injection (DTX) (median survival 32.5 days) and erythrocyte membrane coated docetaxel nanoparticles Crystals (RBC/DTX NCs) (median survival 34.5 days), RGD modified erythrocyte membrane coated docetaxel nanocrystal nano-delivery system (RGD-RBC/DTX NCs) significantly prolonged mouse survival time (median) The survival period is 62 days).
- PBS saline
- DTX commercial docetaxel injection
- RRC/DTX NCs erythrocyte membrane coated docetaxel nanoparticles Crystals
- RGD-RBC/DTX NCs RGD modified erythrocyte membrane coated docetaxel nanocrystal nano-delivery system
- Figure 10 shows the in vivo safety evaluation of the nano drug delivery system of erythrocyte membrane and RGD modified erythrocyte membrane coated docetaxel nanocrystals:
- Figure A shows the change in the number of white blood cells in whole blood within 12 days after administration in normal nude mice.
- the results show that the commercially available docetaxel injection (DTX) significantly reduces the level of leukocytes in mice, reaching a minimum value 5 days after administration.
- erythrocyte membrane coated docetaxel nanocrystal nano-delivery system RBC/DTX NCs
- RGD modified erythrocyte membrane coated docetaxel nanocrystal nano-drug system
- Figure B shows the creatinine clearance after 12 days of normal nude mice administration.
- the results showed that DTX significantly reduced creatinine clearance in mice, with nephrotoxicity, RBC/DTX NCs, There was no significant difference in creatinine clearance between RGD-RBC/DTX NCs and saline groups.
- Example 1 Erythrocyte membrane, platelet membrane, tumor cell membrane coated with irinotecan, cabazitaxel Preparation and characterization of nano-delivery system for race nanocrystals
- Tumor cells (U87) were transferred to buffer (20.5 g mannitol, 13 g sucrose dissolved in 500 mL Tris buffer, pH 7.5), centrifuged at 800 g/min for 5 minutes, and the supernatant was discarded.
- the preparation method is the same as the erythrocyte membrane, the platelet membrane, and the tumor cell membrane coated with the nano delivery system of irinotecan nanocrystals.
- Example 2 Erythrocyte membrane and RGD, VAP, WVAP, A7R, CDX modified red Preparation and characterization of nano drug delivery system coated with docetaxel nanocrystals
- the basic preparation process is the same as the erythrocyte membrane coated docetaxel nanocrystal nano-delivery system, the RGD modification method is: 40 ⁇ L streptavidin-PEG 3400- DSPE in PBS solution (5mg/mL) and from 100 ⁇ L The erythrocyte membrane vesicles obtained in the blood were incubated in a 37 ° C water bath for 30 minutes to obtain streptavidin-erythrocyte membrane vesicles.
- streptavidin-erythrocyte membrane vesicles were mixed with docetaxel nanocrystals and ultrasonicated to obtain a nano-delivery system of surface-modified streptavidin-coated erythrocyte membrane-coated nanocrystals, and then 100 ⁇ L of biotin was added.
- PEG 3500- RGD in PBS (0.1 mg/mL) was incubated in a 37 ° C water bath for 10 minutes to obtain a nano-delivery system of RGD-modified red blood cell membrane coated docetaxel nanocrystals.
- the preparation method is the same as the nano drug delivery system of RGD modified red blood cell membrane coated with docetaxel nanocrystals.
- Example 3 Erythrocyte membrane and RGD modified erythrocyte membrane coated docetaxel nanocrystal delivery In vitro release test of drug system
- the in vitro release was determined by the dialysis bag method. 0.3 mL of docetaxel nanocrystals (DTX NCs), erythrocyte membrane coated docetaxel nanocrystal nanodispensing system (RBC/DTX NCs) and RGD modified erythrocyte membrane coated with docetaxel nanocrystals
- the nano drug delivery system (RGD-RBC/DTX NCs) was sealed in a dialysis bag (molecular weight cutoff 7kDa) and placed in 6mL PBS solution (containing 1% sodium dodecyl sulfate) in pH 7.4, shaken at 37 ° C , at 15 and 30 min, 1, 1.5, 2, 4, 8, 24, 48, and 72 h, respectively, take 0.2 mL of the release medium, and add the same volume of fresh medium, the diluted solution is appropriately diluted, and the determination of docetaxel by HPLC The concentration of the game was plotted and the release curve was plotted. The results are shown in Figure 3.
- Example 4 Erythrocyte membrane and RGD modified erythrocyte membrane coated with docetaxel nanocrystals In vivo pharmacokinetic test of nano drug delivery system
- ICR mice were injected with 150 ⁇ L of commercial docetaxel injection (DTX), docetaxel nanocrystals (DTX NCs), and erythrocyte membrane coated docetaxel nanocrystal nano-drug system (RBC/DTX).
- NCs docetaxel injection
- DTX NCs docetaxel nanocrystals
- RGD-RBC/DTX NCs RGD modified erythrocyte membrane coated docetaxel nanocrystal nano-delivery systems
- Example 5 Erythrocyte membrane and RGD modified erythrocyte membrane coated with docetaxel nanocrystals Tissue distribution test in nano drug delivery system
- U87 subcutaneous tumor or orthotopic tumor model was constructed, and 150 ⁇ L of commercial docetaxel injection (DTX), erythrocyte membrane coated docetaxel nanocrystal nano drug delivery system (RBC/DTX NCs) and RGD were respectively injected into the tail vein.
- the nano-drug system (RGD-RBC/DTX NCs) modified with erythrocyte membrane coated with docetaxel nanocrystals was taken.
- the tissues and whole blood were taken at 2h and 24h respectively.
- the homogenate was treated with diethyl ether/tetrahydrofuran (1:4) solution.
- the mixture was extracted twice, evaporated, and reconstituted with acetonitrile, followed by HPLC analysis. The results are shown in Figures 5 and 6.
- Example 6 Erythrocyte membrane and RGD modified erythrocyte membrane coated with docetaxel nanocrystals In vitro pharmacodynamic test of nano drug delivery system
- Example 7 Erythrocyte membrane and RGD modified erythrocyte membrane coated with docetaxel nanocrystals In vivo pharmacodynamic evaluation of nano drug delivery system
- the U87 subcutaneous tumor animal model was constructed, and the tumor size was observed regularly. When the tumor size was 150 mm 3 , the test was performed in groups. Intravenous injection of PBS (pH 7.4), commercial docetaxel injection (DTX), docetaxel nanocrystals (DTX NCs), erythrocyte membrane coated docetaxel nanocrystal nano-drug system (RBC) /DTX NCs) and RGD modified erythrocyte membrane coated docetaxel nanocrystal nanodispensing systems (RGD-RBC/DTX NCs). Docetaxel is administered at a total dose of 25 mg/kg in a single dose. The survival time of nude mice was recorded (Fig.
- V tumor volume 0.5 (a ⁇ b 2 )
- Tumor inhibition rate (%) (1-V experimental group tumor volume / V control tumor volume ) ⁇ 100
- U8 in situ tumor model was constructed. After 10 days of tumor implantation, PBS (pH 7.4), commercial docetaxel injection (DTX), docetaxel nanocrystals (DTX NCs), and erythrocyte membrane coating were injected into the tail vein. Nano-delivery systems (RBC/DTX NCs) and RGD-modified red blood cell membrane coated docetaxel nanocrystal nanodispensing systems (RGD-RBC/DTX NCs). Docetaxel is administered at a total dose of 25 mg/kg in a single dose. The survival time of nude mice was recorded (Fig. 9).
- Example 8 Erythrocyte membrane and RGD modified erythrocyte membrane coated with docetaxel nanocrystals Nano drug delivery system safety evaluation
- mice Normal nude mice were injected with normal saline, commercial docetaxel injection (DTX), erythrocyte membrane coated docetaxel nanocrystal nano-delivery system (RBC/DTX NCs) and RGD modified erythrocyte membrane coating. Nano-delivery systems for the West Indiana nanocrystals (RGD-RBC/DTX NCs). Docetaxel is administered at a total dose of 25 mg/kg in a single dose. Whole blood was measured for white blood cell counts on days 1, 3, 5, 7, 9, and 11 after administration (Fig. 10A), and serum was taken on day 12 after administration to determine creatinine clearance (Fig. 10B).
- DTX erythrocyte membrane coated docetaxel nanocrystal nano-delivery system
- RGD-RBC/DTX NCs Nano-delivery systems for the West Indiana nanocrystals
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Abstract
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Claims (13)
- 一种纳米递药系统,其特征在于,所述纳米递药系统包括:由生物膜包覆的药物纳米晶体,其中,所述药物以纳米晶体的物理形态直接作为刚性支撑骨架,填充于生物膜中。
- 根据权利要求1所述的纳米递药系统,其特征在于,所述药物纳米晶体既是骨架材料,又是药物贮体。
- 根据权利要求1或2所述的纳米递药系统,其特征在于,所述的药物纳米晶体是由药物通过物理或化学方法处理而形成的纳米尺度结晶。
- 根据权利要求1至3任一项所述的纳米递药系统,其特征在于,所述的药物纳米晶体粒径为10nm~1000nm,优选为10nm~200nm。
- 根据权利要求1至3任一项所述的纳米递药系统,其特征在于,所述药物为治疗药物和/或诊断药物。
- 根据权利要求5所述的纳米递药系统,其特征在于,所述治疗药物选自以下一种或多种:可通过物理或化学方法制备成纳米晶体的抗肿瘤药物、抗感染药物、抗心脑血管系统疾病药物、抗淋巴系统疾病药物、抗免疫系统疾病药物、镇痛药物;优选地:所述抗肿瘤药物选自:紫杉醇等紫杉烷类药物、阿霉素等蒽环类药物、喜树碱类药物、长春新碱类药物、硼替佐米等佐米类药物、顺铂等铂类药物、伊利替康和/或小白菊内酯类药物;所述抗感染药物选自:头孢曲松、头孢西丁、氨曲南、链霉素、两性霉素B、万古霉素、替加环素、替考拉宁、吗啉呱、阿糖腺苷和无环茑苷;所述抗心脑血管系统疾病药物选自:神经节苷脂、阿魏酸、川穹嗪、曲克芦丁和奥扎格雷钠;所述抗淋巴系统疾病药物为帕比司他;所述抗免疫系统疾病药物选自:甲泼尼龙和环孢素;所述镇痛药物选自:吗啡和美沙酮等;最优选地,所述药物为伊立替康或多西他赛或卡巴他赛。
- 根据权利要求5所述的纳米递药系统,其特征在于,所述诊断药物选自以下一种或多种:可通过物理或化学方法制备成纳米晶体 的荧光物质、近红外染料、磁共振影像剂。
- 根据权利要求1-7任一项所述的纳米递药系统,其特征在于,所述的生物膜是具有脂质双层的膜结构;优选地,所述生物膜选自天然的细胞膜或人工生物膜;更优选地,所述天然的细胞膜选自以下一种或多种:红细胞膜、血小板膜、巨噬细胞膜、白细胞膜、肿瘤细胞膜,所述人工生物膜为脂质体膜;进一步优选地,所述生物膜选自以下一种或多种:红细胞膜、血小板膜、肿瘤细胞膜。
- 根据权利要求1-8任一项所述的纳米递药系统,其特征在于,所述纳米递药系统表面进一步被靶向分子修饰,从而将所述纳米递药系统构建为具有主动寻靶功能的生物膜包覆纳米晶体的纳米递药系统;优选地,所述靶向分子选自多肽靶分子;更优选地,所述多肽靶分子选自以下一种或多种:RGD、VAP、WVAP、A7R、CDX。
- 根据权利要求1-9任一项所述的纳米递药系统的制备方法,其特征在于,所述方法包括:将药物以纳米晶体的物理形态直接作为刚性支撑骨架,填充于生物膜中。
- 根据权利要求1-9任一项所述的纳米递药系统在制备用于药物的体内治疗和/或诊断产品中的应用。
- 一种药物体内治疗和/或诊断疾病的方法,其特征在于,向有需要的受试者给予根据权利要求1-8任一项所述的纳米递药系统。
- 根据权利要求11所述的应用或根据权利要求12所述的方法,其特征在于,所述药物体内治疗和/或诊断为药物的体内靶向治疗和/或药物的体内靶向诊断。
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CN115920081A (zh) * | 2022-11-02 | 2023-04-07 | 重庆大学 | 红细胞膜自发定向包被ros响应的纳米前药及其应用 |
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JP2020515642A (ja) | 2020-05-28 |
US11260032B2 (en) | 2022-03-01 |
EP3603625A4 (en) | 2020-12-16 |
EP3603625A1 (en) | 2020-02-05 |
JP7014886B2 (ja) | 2022-02-01 |
US20200069601A1 (en) | 2020-03-05 |
CN108653236A (zh) | 2018-10-16 |
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