CN116602965A - Carrier-free nano-drug and preparation method and application thereof - Google Patents
Carrier-free nano-drug and preparation method and application thereof Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a carrier-free nano-drug, a preparation method and application thereof, wherein the preparation method comprises the following steps: the modified hydrophobic anticancer drug and the alpha-TOS are self-assembled together to prepare the carrier-free nano-drug; wherein the modified hydrophobic anticancer drug is a hydrophobic anticancer drug containing a protecting group. The carrier-free nano-drug provided by the invention has the advantages of simple preparation method, high drug loading capacity, good stability and no potential carrier material toxicity, and solves the problems of low drug loading capacity, large use of inactive carriers, potential toxicity of carriers and the like in the traditional nano-delivery system; solves the problem that the existing carrier-free nano system still uses a small amount of inert materials for enhancing the stability of the nano particles; solves the universality problem of the hydrophobic anticancer drugs in the formation of carrier-free nano systems.
Description
Technical Field
The invention relates to the technical field of biological medicine, in particular to a carrier-free nano-drug, a preparation method and application thereof.
Background
Cancer remains one of the major diseases threatening human health, and although treatments for cancer continue to advance with the development of the pharmaceutical field, chemotherapy remains the current major treatment in clinic. However, the traditional chemotherapeutic drugs have the defects of poor water solubility, lack of targeting, serious side effects, easiness in causing multi-drug tolerance and the like, so that the treatment effect is seriously weakened. The nano carrier not only enhances the stability and bioavailability of the anticancer drug, but also reaches the tumor part through various targeting strategies, enhances the deep penetration of the tumor, and reduces the toxic and side effects and tolerance. Despite the advantages of nano-drug delivery systems, there are still problems of low drug loading (typically less than 10%), undefined metabolic mechanism of carrier materials in vivo, potential toxicity, complex and cumbersome carrier preparation process, large batch-to-batch differences, etc., which greatly limit the clinical transformation of carrier drug delivery systems.
In order to solve the defects of nano-carriers, carrier-free nano-drugs formed by self-assembly of small-molecule drugs or prodrugs are generated. The carrier system is usually nanoparticles formed by assembling one or more drugs through non-covalent acting force under the condition of no or least using inert materials, not only has the advantages of a carrier delivery system, but also solves the problems of low drug loading rate, complicated preparation process, large batch-to-batch variability and the like of the nano carrier system, eliminates the potential toxicity of the carrier to organisms, and shows great potential of the carrier-free nano drug delivery system as a drug delivery platform. However, the existing carrier-free nano-drug is limited by the physical and chemical properties of drug molecules, such as crystallinity, rigidity and the like, so that the problems of poor stability, low drug loading, uncontrollable particle size or morphology and the like are caused, or the nano-carrier formed by self-assembly of a single drug is easy to generate drug resistance to tumors and the like, so that the further clinical application of the nano-drug is limited. Therefore, developing a nano-carrier with high co-self-assembly efficiency is important to improving the curative effect of the carrier-free nano-drug on tumor treatment.
Disclosure of Invention
In order to solve the defects in the prior art, the invention aims to provide a carrier-free nano-drug and a preparation method and application thereof, so as to solve the problem that the existing drug is difficult to self-assemble or cannot co-self-assemble to form nano-carriers.
The technical scheme for solving the technical problems is as follows: the preparation method of the carrier-free nano-drug comprises the following steps: co-self-assembling the modified hydrophobic anticancer drug with alpha-TOS (alpha-tocopheryl succinate) to prepare carrier-free nano-drug; wherein the modified hydrophobic anticancer drug is a hydrophobic anticancer drug containing a protecting group, namely, the modified hydrophobic anticancer drug is prepared by reacting the hydrophobic anticancer drug with the protecting group to reduce the crystallinity of molecules.
The beneficial effects of the invention are as follows: the hydrophobic anticancer drug molecules are difficult to self-assemble by themselves or cannot co-self-assemble with alpha-TOS to form nano carriers due to the structural problems of the molecules such as strong molecular crystallinity, and the hydrophobic molecules are modified by adding a protecting group to modify, so that charge distribution conditions around polar groups are influenced, the capability and the speed of agglomeration among molecules in water are reduced, so that the molecules cannot be agglomerated quickly, and precipitation is generated. The flexible long-chain molecular structure of the alpha-TOS further prevents the aggregation state among hydrophobic anticancer drug molecules from growing, furthermore, the benzene ring structure of the alpha-TOS participates in the aggregation of the hydrophobic anticancer drug molecules, and the ordered aggregation of the original drug molecules is changed, so that the modified hydrophobic anticancer drug can be self-assembled with the alpha-TOS to prepare the carrier-free nano drug.
Based on the technical scheme, the invention can also be improved as follows:
further, the preparation method of the carrier-free nano-drug comprises the following steps: dissolving the modified hydrophobic anticancer drug in an organic solvent to obtain a solution A; dissolving alpha-TOS in a solvent to obtain a solution B; and mixing the solution A and the solution B uniformly, then slowly dripping the mixed solution into water under the stirring condition, and finally removing the organic solvent to prepare the carrier-free nano-drug.
Further, the hydrophobic anticancer drug is 7-ethyl-10 hydroxycamptothecin (SN 38), paclitaxel (PTX), methotrexate, camptothecin, etc.
Further, the modified hydrophobic anticancer drug is BOC protected 7-ethyl-10 hydroxycamptothecin or BOC protected paclitaxel.
Further, the BOC protected 7-ethyl-10 hydroxycamptothecin is prepared by the following method: adding 7-ethyl-10 hydroxycamptothecin into dichloromethane solvent under inert gas atmosphere, mixing, sequentially adding di-tert-butyl dicarbonate and pyridine, reacting for 12h at normal temperature, cleaning, collecting organic layer, drying, and concentrating.
Further, BOC-protected paclitaxel was prepared by the following method: and (3) adding paclitaxel into a dichloromethane solvent under an inert gas atmosphere, uniformly mixing, sequentially adding di-tert-butyl dicarbonate and pyridine, reacting for 12 hours at normal temperature, cleaning, collecting an organic layer, drying and concentrating to obtain the taxol.
Further, after the solution A and the solution B are mixed, the mass ratio of the modified hydrophobic anticancer drug to the alpha-TOS is 1:1-5, and preferably the mass ratio of the modified hydrophobic anticancer drug to the alpha-TOS is 1:3.
Further, water was added thereto and stirred at room temperature for 8 to 15 minutes.
Further, the organic solvent is removed by means of dialysis.
The carrier-free nano-drug prepared by the method can be used for preparing anticancer drugs.
The invention has the following beneficial effects:
(1) The invention uses alpha-TOS as an active material for constructing the carrier-free nano-drug, has anticancer activity, and avoids the aim of solubilization, transportation and maintenance of in vivo half-life of the drug by using a large amount of carrier materials without drug activity in the traditional nano-drug carrying system.
(2) The invention modifies the hydrophobic anticancer drugs such as 7-ethyl-10 hydroxycamptothecin, taxol and the like in a mode of protecting by a protecting group, for example, protecting by a BOC and the like.
(3) The carrier-free nano-drug provided by the invention has the advantages of simple preparation method, high drug loading capacity, good stability and no potential carrier material toxicity, and solves the problems of low drug loading capacity, large use of inactive carriers, potential toxicity of carriers and the like in the traditional nano-delivery system; solves the problem that the existing carrier-free nano system still uses a small amount of inert materials for enhancing the stability of the nano particles; solves the universality problem of the hydrophobic anticancer drugs in the formation of carrier-free nano systems.
Drawings
FIG. 1 is a synthetic route diagram of modified SN 38.
Fig. 2 is a synthetic route pattern of the modified PTX.
FIG. 3 is a mass spectrum of modified SN 38.
Fig. 4 is a mass spectrum of the modified PTX.
FIG. 5 is a nuclear magnetic resonance spectrum of modified SN 38.
FIG. 6 is a nuclear magnetic pattern of modified PTX.
FIG. 7 is a TEM image of BOC-SN38 forming nanometers with alpha-TOS.
FIG. 8 is a TEM image of BOC-PTX forming nanometers with alpha-TOS.
FIG. 9 shows the particle sizes of unsupported nanoparticles prepared with varying ratios of BOC-PTX to alpha-TOS.
FIG. 10 shows the results of the time-dependent particle size change of the unsupported nanoparticles prepared with varying ratios of BOC-SN38 to alpha-TOS in example 1; wherein each group of bar graphs respectively represent the proportional relations of 1:3, 1:5 and 1:7 from left to right.
FIG. 11 shows the results of the time-dependent particle size change of the unsupported nanoparticles prepared in example 2 with varying ratios of BOC-PTX to alpha-TOS; wherein each group of bar graphs respectively represent the proportional relations of 1:3, 1:5 and 1:7 from left to right.
FIG. 12 shows the results of antitumor activity of SN38 and BOC-SN38 free drug.
FIG. 13 shows the results of antitumor activity of BOC-SN38 after nanoparticle formation with alpha-TOS.
FIG. 14 shows the results of antitumor activity of PTX and BOC-PTX free drug.
FIG. 15 shows the results of antitumor activity of BOC-PTX after nanoparticle formation with alpha-TOS.
Detailed Description
The examples given below are only intended to illustrate the invention and are not intended to limit the scope thereof. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
Example 1: self-assembly behavior of modified SN38 and TOS and anticancer activity
(1) Synthesis of modified SN38
7-ethyl-10 hydroxycamptothecin (SN-38) (0.5 g) was weighed into a flask, vacuum was applied, a dry dichloromethane solvent was added under a nitrogen atmosphere, and after stirring uniformly using magnetic force, di-tert-butyl dicarbonate (0.27 g) and pyridine (2.8 mL) were added in sequence to react for 12h at normal temperature. After the completion of the reaction, the reaction mixture was washed with a saturated aqueous ammonium chloride solution and a saturated brine alternately three times, and the lower organic layer was collected, dried over anhydrous magnesium sulfate, and then the filtrate was collected by filtration. The filtrate was concentrated using a rotary evaporator and then the product was isolated by column chromatography eluting with methanol/dichloromethane (1/10, v/v). The reaction scheme is shown in FIG. 1. The mass spectrum of the modified SN38 is shown in FIG. 3, and the nuclear magnetic spectrum of the modified SN38 is shown in FIG. 5.
(2) Preparation of modified SN38 and alpha-TOS unsupported nanoparticles
Accurately weighing a certain mass of modified SN38 (BOC-SN 38), and preparing a 30mg/mL solution by using a DMSO solvent; a mass of alpha-TOS (alpha-tocopheryl succinate) was accurately weighed and formulated to 90mg/mL using DMSO solvent. Accurately sucking 84 mu L of DMSO solution of BOC-SN38 into a 1.5mL EP tube, sucking 84 mu L of 90mg/mL of DMSO solution of alpha-TOS into the EP tube, supplementing DMSO solvent again, and fully mixing the solution with the total solvent volume of 0.6 mL. The solution was added dropwise to 5mL of deionized water under magnetic stirring, and after the addition was completed, stirring was continued for 10min. After the stirring was completed, the obtained solution was dialyzed using a 2kDa dialysis bag, and the dialysis process was continued for 12 hours, during which time deionized water was replaced three times. And (3) after the dialysis is finished, obtaining the carrier-free nano solution with the modified SN38 and the alpha-TOS concentration of 1:3.
The carrier-free nano-solution with the modified SN38 and the alpha-TOS concentration of 1:5 and 1:7 is prepared according to the same method.
The obtained unsupported nanoparticles were characterized and their properties were determined as follows:
(1) Particle size, potential and morphology characterization of unsupported nanoparticles
The particle size and potential of the solution of unsupported nanoparticles obtained in example 1 above were measured by Dynamic Light Scattering (DLS), wherein the dispersion medium was water.
As can be seen from fig. 10, the carrier-free nanoparticle sizes of modified SN38 and α -TOS at concentrations of 1:3, 1:5, and 1:7 were 75.12 ±4.87nm, 72.15 ±0.38nm, and 66.89±3.26nm, respectively, and the potentials were: -26.00.+ -. 1.97mV, -25.60.+ -. 1.10mV, -25.10.+ -. 1.50mV.
As can be seen from FIG. 7, the unsupported nanoparticles prepared by modifying SN38 and alpha-TOS have a bilayer structure.
(2) Drug loading rate of carrier-free nanoparticles
The drug loading of BOC-SN38 in the unsupported nanoparticles prepared in example 1 was determined as follows:
the drug-loaded nanoparticles were diluted to a suitable concentration using a mobile phase (acetonitrile/water phase=65/35, v/v; water phase is 36mmol/L sodium dihydrogen phosphate and 4mmol/L sodium heptanesulfonate, ph=4.8), the peak area of the sample was determined by HPLC, and the BOC-SN38 content in the nanoparticles was calculated. The HPLC detection wavelength was 380nm, and the flow rate was 0.5mL/min.
The nanoparticles were additionally diluted to an appropriate concentration using methanol and the content of α -TOS in the nanoparticles was determined by HPLC. Determination conditions for HPLC: the mobile phase was methanol/glacial acetic acid=625/4, v/v; detection wavelength 284nm; the flow rate was 1mL/min. And according to the test result, calculating: the BOC-SN38 drug loading is 78.09% and the alpha-TOS drug loading is 88.03%.
(3) Stability test of unsupported nanoparticles
BOC-SN38@α -TOS unsupported nanoparticles prepared in various proportions according to the preparation method in example 1 above were placed in a refrigerator at 4℃and the particle size change thereof was measured by dynamic light scattering at predetermined time points (0 day, 31 day and 70 day). As a result, as shown in fig. 10, the prepared nano-particles had good stability, and the particle size was stable in the stability test for 70 days.
(4) Cytotoxicity of unsupported nanoparticles
The cytotoxicity of the constructed unsupported nanoparticles to 4T1 cells is determined by adopting an MTT method, and the specific process is as follows:
preparing single cell suspension from 4T1 cells in good state, counting, diluting to 5×10 with fresh culture solution 4 cells mL -1 . After mixing, 100. Mu.L of cell suspension is added to the 96-well plate in sequence, shaking is carried out gently, and the mixture is placed in an incubator for incubation for 24 hours. After the cells are completely adhered, 100 mu L of culture medium and different concentrations of SN38 and BOC-SN38 which are diluted in an equal gradient manner are respectively added for 48 hours of incubation. After incubation, the 96-well plate was removed and 5 mg/mL diluted ten times with serum-free medium was added to each well -1 100. Mu.L of MTT solution was placed again in the incubator and incubated for 4h. After incubation, the 96-well plate was removed, after sufficient pipetting of the plate with a pipettor, 100 μl DMSO was added to each well, and the wells were shaken on an shaker to fully dissolve the formazan, and then the absorbance values for each well were determined using an enzyme-linked immunosorbent assay at 490nm wavelength. Cytotoxicity of SN38 drugs to 4T1 cells before and after modification was also determined using the MTT method.
As can be seen from the MTT test results, the molecular weight of the sample was 0.019. Mu.M-1.87X10 -5 In the μM concentration range, SN38 was comparable to 48h cytotoxicity of 4T1 cells before and after modification (FIG. 12), and IC50 values were obtained at 9.56X10, respectively -4 Mu M and 6.84×10 -4 Mu M; as can be seen from the MTT assay results for 48h (drug concentration is calculated as BOC-SN 38), the BOC-SN38@alpha-TOS nanoparticles showed lower cell viability than the free drug BOC-SN38 at concentrations of BOC-SN38 above 1.77 μg/ml over the defined dosing concentration rangeIndicating its cytotoxicity superior to single drug (figure 13). When the concentration of BOC-SN38 is below 1.77. Mu.g/ml, the effect of BOC-SN38@α -TOS nanoparticles is comparable to that of free BOC-SN 38. This may be due to the nanoparticle delayed drug release process. Meanwhile, the inhibition capacity of free BOC-SN38 is obviously increased under the condition of low BOC-SN38 concentration after the combination of alpha-TOS, and the synergistic effect between the two medicines is further shown.
Example 2: self-assembly behavior of PTX and TOS after modification and anticancer activity
(1) Synthesis of modified PTX (BOC-PTX)
PTX 0.5g was placed in a flask, the flask was evacuated, a dry methylene chloride solvent was added under a nitrogen atmosphere, and after stirring uniformly using a magnetic force, di-tert-butyl dicarbonate (0.14 g) and pyridine (1.41 mL) were added in this order, and reacted at room temperature for 12 hours. After the completion of the reaction, the reaction mixture was washed with a saturated aqueous ammonium chloride solution and a saturated brine alternately three times, and the lower organic layer was collected, dried over anhydrous magnesium sulfate, and then the filtrate was collected by filtration. The filtrate was concentrated and then subjected to column chromatography, and the eluent was ethyl acetate/petroleum ether (1/1, v/v). The reaction scheme is shown in FIG. 2. The mass spectrum of the modified PTX is shown in FIG. 4, and the nuclear magnetic spectrum of the modified PTX is shown in FIG. 6.
(2) Preparation of modified PTX and alpha-TOS unsupported nanoparticles
Accurately weighing BOC-PTX with a certain mass, and preparing into a 90mg/mL solution by using a DMSO solvent; accurately weighing a certain mass of alpha-TOS, and preparing 30mg/mL solution by using DMSO solvent. Accurately sucking 31 mu L of DMSO solution of BOC-PTX into a 1.5mL EP tube, sucking 93 mu L of 30mg/mL of DMSO solution of alpha-TOS into the EP tube, supplementing DMSO solvent again, and fully mixing the solution with the total solvent volume of 0.6 mL. The solution was added dropwise to 5mL of deionized water under magnetic stirring, and after the addition was completed, stirring was continued for 10min. After the stirring was completed, the obtained solution was dialyzed using a 2kDa dialysis bag, and the dialysis process was continued for 12 hours, during which time deionized water was replaced three times. And (3) after the dialysis is finished, obtaining the carrier-free nano solution with the BOC-PTX and alpha-TOS concentration of 1:3.
The same method is used for preparing the carrier-free nano solution with BOC-PTX and alpha-TOS concentration of 1:1, 1:3 and 1:5.
The obtained unsupported nanoparticles were characterized and their properties were determined as follows:
(1) Particle size, potential and morphology characterization of unsupported nanoparticles
The particle size and potential of the solution of unsupported nanoparticles obtained in example 2 above were measured by Dynamic Light Scattering (DLS), wherein the dispersion medium was water.
As can be seen from FIG. 11, the carrier-free nanoparticle sizes of BOC-PTX and alpha-TOS at concentrations of 1:1, 1:3 and 1:5 were 63.31.+ -. 1.71nm, 100.80.+ -. 3.77nm and 104.60.+ -. 4.06nm, respectively, and the potentials were: 32.50.+ -. 0.95mV, -28.70.+ -. 0.81mV, -28.00.+ -. 1.13mV.
As can be seen from FIG. 8, the unsupported nanoparticles prepared from BOC-PTX and alpha-TOS have a bilayer structure.
(2) Drug loading rate of carrier-free nanoparticles
The drug loading of BOC-PTX in the unsupported nanoparticles prepared in example 2 was determined as follows:
the unsupported nanoparticles were diluted to a suitable concentration using a mobile phase (acetonitrile/water=3/2, v/v), the peak area of the sample was determined by HPLC, and the BOC-PTX content in the nanoparticles was calculated. The detection wavelength of HPLC was 227nm and the flow rate was 1ml/min.
In addition, the method for determining the content of alpha-TOS was as described in example 1.
And according to the test result, calculating: the BOC-PTX drug loading was 91.20% and the alpha-TOS drug loading was 96.67%.
(3) Stability test of unsupported nanoparticles
BOC-PTX@α -TOS unsupported nanoparticles prepared in various ratios according to the preparation method in example 2 above were stored in a refrigerator at 4℃and their particle size change was measured by dynamic light scattering at predetermined time points (0 day, 36 day and 56 day). The results are shown in fig. 11, and the prepared nanoparticle size remained stable in the stability test for 56 days.
(4) Cytotoxicity of unsupported nanoparticles
The cytotoxicity of the constructed unsupported nanoparticles to 4T1 cells is determined by adopting an MTT method, and the specific process is as follows:
preparing single cell suspension from 4T1 cells in good state, counting, diluting to 5×10 with fresh culture solution 4 cells mL -1 . After mixing, 100. Mu.L of cell suspension is added to the 96-well plate in sequence, shaking is carried out gently, and the mixture is placed in an incubator for incubation for 24 hours. After the cells were completely adherent, different concentrations of PTX and BOC-PTX solutions were added to 100. Mu.L of each well plate and incubated for 48h. After incubation, the 96-well plate was removed and 5 mg/mL diluted ten times with serum-free medium was added to each well -1 100. Mu.L of MTT solution was placed again in the incubator and incubated for 4h. After incubation, the 96-well plate was removed, after sufficient pipetting of the plate with a pipettor, 100 μl DMSO was added to each well, and shaking on a shaker was sufficient to dissolve the formazan, followed by measurement of the absorbance values for each well at 490nm using an enzyme-linked immunosorbent assay.
The cytotoxicity results are shown in FIG. 14, which shows that the MTT assay was performed for 48h at 4.39X10 -3 μM-4.29×10 -6 The toxicity of the free drug PTX and the modified PTX to 4T1 cells is equivalent in the concentration range of mu M, and the IC50 values are respectively 1.20 multiplied by 10 -5 Mu M and 1.68X10 -5 Mu M, it can be seen that the hydroxyl groups of PTX remain quite cytotoxic after BOC protection. The 48h cytotoxicity results of modified PTX and α -TOS on 4T1 after nanoparticle formation are shown in FIG. 15, when the dose is higher than 0.029 μg/mL (BOC-PTX concentration), BOC-PTX@α -TOS has similar toxicity on 4T1 cells as free BOC-PTX, but when the dose is lower than 0.029 μg/mL, BOC-PTX@α -TOS shows better cytotoxicity; at a concentration of 0.007 μg/mL, the 4T1 cell viability of the BOC-PTX experimental group reached 93.25%, whereas the 4T1 cell viability of the BOC-PTX@α -TOS experimental group was only 65.93%.
The foregoing description of the preferred embodiments of the invention is not intended to limit the invention to the precise form disclosed, and any such modifications, equivalents, and alternatives falling within the spirit and scope of the invention are intended to be included within the scope of the invention.
Claims (10)
1. The preparation method of the carrier-free nano-drug is characterized by comprising the following steps of: the modified hydrophobic anticancer drug and the alpha-TOS are self-assembled together to prepare the carrier-free nano-drug; wherein the modified hydrophobic anticancer drug is a hydrophobic anticancer drug containing a protecting group.
2. The method for preparing the carrier-free nano-drug according to claim 1, comprising the steps of: dissolving the modified hydrophobic anticancer drug in an organic solvent to obtain a solution A; dissolving alpha-TOS in a solvent to obtain a solution B; mixing the solution A and the solution B, stirring uniformly, adding into water, stirring, and finally removing the organic solvent to obtain the aqueous emulsion.
3. The method for preparing the carrier-free nano-drug according to claim 1 or 2, wherein the hydrophobic anticancer drug is 7-ethyl-10 hydroxycamptothecin, paclitaxel, methotrexate or camptothecin.
4. The method of preparing a carrier-free nano-drug according to claim 3, wherein the modified hydrophobic anticancer drug is BOC-protected 7-ethyl-10 hydroxycamptothecin or BOC-protected paclitaxel.
5. The method for preparing the carrier-free nano-drug according to claim 4, wherein the BOC-protected 7-ethyl-10 hydroxycamptothecin or the BOC-protected paclitaxel is prepared by the following method: adding 7-ethyl-10 hydroxycamptothecin or taxol into dichloromethane solvent under inert gas atmosphere, mixing, sequentially adding di-tert-butyl dicarbonate and pyridine, reacting at normal temperature for 12 hr, cleaning, collecting organic layer, drying, and concentrating.
6. The method for preparing the carrier-free nano-drug according to claim 2, wherein the mass ratio of the modified hydrophobic anticancer drug to the alpha-TOS is 1:1-5 after the solution a and the solution B are mixed.
7. The method for preparing the carrier-free nano-drug according to claim 2, wherein the water is added and stirred at room temperature for 8-15min.
8. The method for preparing the carrier-free nano-drug according to claim 2, wherein the organic solvent is removed by means of dialysis.
9. A carrier-free nano-drug prepared by the preparation method of any one of claims 1 to 8.
10. Use of the carrier-free nano-drug according to claim 9 for the preparation of an anticancer drug.
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