CN114848594A - Lipid nano-carrier loaded with anticancer drug and preparation method and application thereof - Google Patents
Lipid nano-carrier loaded with anticancer drug and preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of nano medicaments, and discloses a lipid nano carrier loaded with an anticancer medicament, and a preparation method and application thereof. The preparation method comprises the following steps: dissolving 1, 2-dioleoyl-3-phosphoethanolamine, cholesterol, 1, 2-dimyristoyl-sn-glycero-3-methoxypolyethylene glycol and an anticancer drug in absolute ethyl alcohol, and adding a solution containing a fourth phospholipid to obtain a phospholipid ethyl alcohol solution; and (3) rapidly mixing the phospholipid ethanol solution with pure water, incubating at room temperature for 10min, and dialyzing for 3h to obtain the solid lipid nanoparticle solution loaded with the anticancer drug. The lipid nano-carrier prepared by the preparation method of the invention has a lipophilic shell formed by a single layer of phospholipid and can wrap hydrophobic drugs; the potential changes with the change in the mole percentage of the fourth phospholipid; can prolong the blood circulation time of the medicine in vivo and improve the bioavailability of the medicine; liver tissue can be targeted in vivo. Can be applied to the treatment of relevant liver diseases.
Description
Technical Field
The invention relates to the technical field of nano medicaments, in particular to a lipid nano carrier loaded with anticancer drugs and a preparation method and application thereof.
Background
Statistically, the incidence of neurodegenerative diseases, cancer, cardiovascular diseases and other related diseases is greatly increasing in recent years, and cancer has become the second leading cause of death worldwide, which poses a great threat to human life. To date, there are many cancer treatments, and conventional clinical treatments include surgical resection, drug therapy, radiotherapy, etc., and the intervention or treatment of tumor diseases by using chemical drugs is one of the more common methods. Single drug therapy indexes are narrow, requiring multiple administrations, often resulting in organ intolerance to drugs, and therefore, people focus on developing nanocarrier formulations. The nano carrier is a nano-scale conveying system, has extremely wide application, and plays a key role in the nano medical field of multi-mode imaging, drug delivery, targeted therapy and the like of human diseases. Compared with free drug molecules, the nano-carrier can improve the solubility of various drugs, reduce the toxic and side effects of the drugs, improve the treatment effect, reduce the administration times and the like. According to the difference of nano-carrier materials, the nano-carrier can be divided into a polymer nano-carrier, a lipid nano-carrier, a metal nano-carrier and an inorganic nano-carrier. These different types of nano-carriers have been widely used to study drug delivery, and lipid nano-carriers are a novel drug delivery system using lipid with good biocompatibility as a material.
Common lipid nanocarriers for drug delivery can be divided into: liposomes (lipomes), non-ionic surfactant Liposomes (niosomes), Solid Lipid Nanoparticles (SLNs), and Nanostructured Lipid Carriers (NLCs). It is reported that the action mechanism of the coronavirus infectious disease vaccine developed in 2019 is to utilize solid lipid nanoparticles to transfer mRNA to pathological tissues for treatment. Among the different lipid delivery systems, solid lipid nanoparticles made of solid lipids at room temperature and body temperature are one of the materials that have been studied earlier and are the most representative lipid nanosystems. SLNs are spherical particles with a particle size between 50 and 1000nm, and encapsulation of anticancer drugs in SLNs has also been studied intensively. In addition, SLNs have better release characteristics, higher bioavailability of the drug and long-term stability in vivo than nanoemulsions, liposomes and inorganic nanoparticles.
Disclosure of Invention
The invention aims to provide a lipid nano-carrier loaded with an anticancer drug, and a preparation method and application thereof. The prepared lipid nano-carrier has a lipophilic shell formed by a single layer of phospholipid and can wrap hydrophobic drugs; the potential changes with the change in the mole percentage of the fourth phospholipid; can prolong the blood circulation time of the medicine in vivo and improve the bioavailability of the medicine; liver tissue can be targeted in vivo. Can be applied to the treatment of relevant liver diseases.
In order to solve the above problems, the present invention provides a method for preparing a lipid nanocarrier loaded with an anticancer drug, comprising the steps of:
1) dissolving 1, 2-dioleoyl-3-phosphoethanolamine, cholesterol, 1, 2-dimyristoyl-sn-glycerol-3-methoxypolyethylene glycol and an anticancer drug in absolute ethyl alcohol, adding a solution containing a fourth phospholipid, and uniformly mixing to obtain a phospholipid ethyl alcohol solution; the solution containing the fourth phospholipid is 1, 2-dioleoyl-sn-glycero-3-phosphate dissolved by tetrahydrofuran or 1, 2-dioleoyl-3- (dimethylamino) propane dissolved by absolute ethyl alcohol;
2) and (3) rapidly mixing the phospholipid ethanol solution with pure water, incubating at room temperature for 10min, transferring into a dialysis bag, and dialyzing with pure water for 3h under the stirring condition to remove the unencapsulated anticancer drug to obtain the solid lipid nanoparticle solution loaded with the anticancer drug, namely the lipid nano-carrier loaded with the anticancer drug.
Further, the molar ratio of the 1, 2-dioleoyl glycerol-3-phosphoethanolamine in the step 1) to the cholesterol, the 1, 2-dimyristoyl-sn-glycerol-3-methoxypolyethylene glycol and the fourth phospholipid is 69: 40: 4: x and X are 0, 12.6 or 48.4.
Further, the mass ratio of the anticancer drug to the total amount of the four phospholipids in the step 1) is 1: 4, the four phospholipids are 1, 2-dioleoyl glycerol-3-phosphoethanolamine, cholesterol, 1, 2-dimyristoyl-sn-glycerol-3-methoxypolyethylene glycol and a fourth phospholipid;
further, the anti-cancer drug is adriamycin or docetaxel.
Further, the volume ratio of the phospholipid ethanol solution to the pure water in the step 2) is 1: 3.
Further, the molecular weight cut-off of the dialysis bag in step 2) is 14000.
The invention also provides the lipid nano-carrier loaded with the anticancer drugs, which is prepared by the preparation method.
Further, the hydration particle size of the lipid nano-carrier loaded with the anticancer drug is 120-170 nm.
The invention also provides application of the lipid nano-carrier loaded with the anticancer drug in preparation of a targeted liver anticancer drug.
Compared with the prior art, the invention has the following beneficial effects:
1. the lipid nano-carrier can change the charging condition and the charge size of the surface charge of particles by fixing the molar ratio of three lipids in the components and changing the species and the molar ratio of the added fourth phospholipid, thereby improving the capability of passively targeting tissues by the lipid nano-carrier.
2. The lipid nano-carrier can prevent aggregation among particles, reduce the combination of the particles and plasma protein in vivo, prolong the blood circulation time of the medicament and improve the bioavailability of the medicament in the lipid nano-carrier.
3. The lipid nano-carrier can target the liver, so that more medicaments can be accumulated in the liver.
4. The biocompatibility of the lipid nano-carrier is higher than that of other nano-carriers, the drug release and targeting can be controlled, and the lipid nano-carrier has biodegradability and low immunogenicity. In addition, the preparation is simple and convenient, the surface is easy to modify, and the rapid large-scale production can be realized.
Drawings
FIG. 1 is a graph of the unloaded neutral solid lipid nanoparticles (0% SLNs) provided in examples 1-1, the unloaded 10% anionic and cationic solid lipid nanoparticles (10% DOPA/DODAP SLNs) provided in examples 1-2, the unloaded 30% anionic and cationic solid lipid nanoparticles (30% DOPA/DODAP SLNs) provided in examples 1-3, the anticancer drug-loaded neutral solid lipid nanoparticles (0% SLNs-DOX, 0% SLNs-DTX) provided in examples 2-1 and 3-1, the anticancer drug-loaded 10% anionic and cationic solid lipid nanoparticles (10% DOPA/DONs SLX, 10% DOPA/DODAP Ns-DTX) provided in examples 2-2 and 3-2, Hydrated particle size histograms for 30% anionic and cationic solid lipid nanoparticles loaded with anticancer drug (30% DOPA/DODAP SLNs-DOX, 30% DOPA/DODAP SLNs-DTX) provided in examples 2-3 and 3-3, for 50% anionic and cationic solid lipid nanoparticles unloaded provided in comparative example 1-1 (50% DOPA/DODAP SLNs), for 50% anionic and cationic solid lipid nanoparticles loaded with anticancer drug (50% DOPA/DODAP SLNs-DOX, 50% DOPA/DODAP SLNs-DTX) provided in comparative examples 1-2 and 1-3; in FIG. 1, A is a graph showing the hydrated particle sizes of the unloaded SLNs and the anticancer drug-loaded SLNs measured after changing the mole percentage of 1, 2-dioleoyl-sn-glycero-3-phosphate (DOPA), and B is a graph showing the hydrated particle sizes of the unloaded SLNs and the anticancer drug-loaded SLNs measured after changing the mole percentage of 1, 2-dioleoyl-3- (dimethylamino) propane (DODAP).
FIG. 2 is a graph of the unloaded neutral solid lipid nanoparticles (0% SLNs) provided in examples 1-1, the unloaded 10% anionic and cationic solid lipid nanoparticles (10% DOPA/DODAP SLNs) provided in examples 1-2, the unloaded 30% anionic and cationic solid lipid nanoparticles (30% DOPA/DODAP SLNs) provided in examples 1-3, the anticancer drug-loaded neutral solid lipid nanoparticles (0% SLNs-DOX, 0% SLNs-DTX) provided in examples 2-1 and 3-1, the anticancer drug-loaded 10% anionic and cationic solid lipid nanoparticles (10% DOPA/DONs SLX, 10% DOPA/DODAP Ns-DTX) provided in examples 2-2 and 3-2, Potential change statistical graphs of 30% anionic and cationic solid lipid nanoparticles loaded with anticancer drugs (30% DOPA/DODAP SLNs-DOX, 30% DOPA/DODAP SLNs-DTX) provided in examples 2-3 and 3-3, 50% anionic and cationic solid lipid nanoparticles (50% DOPA/DODAP SLNs) unloaded provided in comparative example 1-1, 50% anionic and cationic solid lipid nanoparticles (50% DOPA/DODAP SLNs) loaded with anticancer drugs (50% DOPA/DODAP SLNs-DOX, 50% DOPA/DODAP SLNs-DTX) provided in comparative examples 1-2 and 1-3; in FIG. 1, A is a graph showing potential values of unloaded SLNs and anticancer drug-loaded SLNs measured after changing the mole percentage of 1, 2-dioleoyl-sn-glycero-3-phosphate (DOPA), and B is a graph showing potential values of unloaded SLNs and anticancer drug-loaded SLNs measured after changing the mole percentage of 1, 2-dioleoyl-3- (dimethylamino) propane (DODAP).
FIG. 3 is a graph showing anticancer drug-loaded neutral solid lipid nanoparticles (0% SLNs-DOX, 0% SLNs-DTX) provided in examples 2-1 and 3-1, anticancer drug-loaded 10% anionic and cationic solid lipid nanoparticles (10% DOPA/DODASLNs-DOX, 10% DOPA/DODASLNs-DTX) provided in examples 2-2 and 3-2, anticancer drug-loaded 30% anionic and cationic solid lipid nanoparticles (30% DOPA/DODANs-DOX, 30% DOPA/DODASLNs-DTX) provided in examples 2-3 and 3-3, anticancer drug-loaded 50% anionic and cationic solid lipid nanoparticles (50% DOPA/DODAPS SLNs-DOX, 30% DOPA/DODAPS SLNs-DTX) provided in comparative examples 1-2 and 1-3, 50% DOPA/DODAP SLNs-DTX); in fig. 3, a is a graph showing the encapsulation efficiency of SLNs loaded with different mole percentages of Doxorubicin (DOX), and B is a graph showing the encapsulation efficiency of SLNs loaded with different mole percentages of Docetaxel (DTX).
FIG. 4 is a transmission electron micrograph of unloaded neutral solid lipid nanoparticles (0% SLNs) provided in example 1-1.
Figure 5 is a docetaxel release profile under normoxic conditions for docetaxel, docetaxel-loaded neutral solid lipid nanoparticles provided in examples 3-1 (0% SLNs-DTX), docetaxel-loaded 50% anionic and cationic solid lipid nanoparticles provided in comparative examples 1-3 (50% DOPA/DODAP SLNs-DTX);
FIG. 6 is the results of the distribution of docetaxel, docetaxel-loaded neutral solid lipid nanoparticles provided in examples 3-1 (0% SLNs-DTX), docetaxel-loaded 10% anionic and cationic solid lipid nanoparticles provided in examples 3-2 (10% DOPA/DODAP SLNs-DTX), docetaxel-loaded 30% anionic and cationic solid lipid nanoparticles provided in examples 3-3 (30% DOPA/DODAP SLNs-DTX), docetaxel-loaded 50% anionic and cationic solid lipid nanoparticles provided in comparative examples 1-3 (50% DOPA/DODAP SLNs-DTX) in the major organs in vivo; in fig. 6, panel a is the drug amount per gram of tissue measured at 6h post-dose for various mole percent DOPA SLNs loaded with docetaxel, after removal of the heart, liver, spleen, lung and kidney; panel B is the percent of drug per gram of tissue measured at 6h post dose for docetaxel loaded DODAP SLNs as a percentage of total drug injected after removal of the heart, liver, spleen, lung and kidney.
Figure 7 is the drug concentration in the blood of mice measured at different time points for docetaxel, docetaxel-loaded neutral solid lipid nanoparticles provided in examples 3-1 (0% SLNs-DTX), docetaxel-loaded 50% anionic and cationic solid lipid nanoparticles provided in comparative examples 1-3 (50% DOPA/DODAP SLNs-DTX).
FIG. 8 is a schematic structural diagram of an anticancer drug loaded lipid nanocarrier prepared by the present invention.
Detailed Description
For a further understanding of the invention, reference will now be made in detail to the preferred embodiments of the invention with reference to the following examples, but it is to be understood that the description is intended to illustrate further features and advantages of the invention, and not to limit the scope of the claims.
All starting materials for the present invention, without particular limitation as to their source, may be purchased commercially or prepared according to conventional methods well known to those skilled in the art.
Examples 1 to 1
Preparation of unloaded neutral solid lipid nanoparticles:
dissolving 2.57mg (69 equivalents) of 1, 2-dioleoyl glycerol-3-phosphoethanolamine (DOPE), 0.77mg (40 equivalents) of Cholesterol (CHOL), 0.5mg (4 equivalents) of 1, 2-dimyristoyl-sn-glycerol-3-methoxypolyethylene glycol (DMG-PEG) in absolute ethanol, adding 0mg (0 equivalent) of 1, 2-dioleoyl-sn-glycerol-3-phosphate (DOPA) dissolved in tetrahydrofuran, and uniformly mixing to obtain a phospholipid ethanol solution; mixing phospholipid ethanol solution with triple distilled water at a volume ratio of 1:3, incubating at room temperature for 10min, transferring the solution to a dialysis bag (MW 14000), and dialyzing with pure water for 3h under stirring to obtain unloaded neutral solid lipid nanoparticle solution (0% SLNs).
The particle size of the unloaded solid lipid nanoparticle solution is tested, and the result is shown in FIG. 1, wherein the particle size of the solid lipid nanoparticle is between 120-170 nm; as shown in fig. 2, the potential of the solid lipid nanoparticle is nearly neutral, which indicates that the construction of the unloaded solid lipid nanoparticle is successful.
Putting unloaded neutral solid lipid nanoparticles on a copper mesh, sucking redundant liquid by using filter paper, dyeing by using a 1% phosphotungstic acid solution, continuously washing for 3 times by using clear water after dyeing for 1-2 min, sucking redundant liquid by using the filter paper, observing the shape by using a transmission electron microscope (TEM, JEM-1230, Japan) after air drying, and taking the transmission electron microscope image of the unloaded neutral solid lipid nanoparticle solution (0% SLNs) as shown in figure 4.
Examples 1 to 2
Preparation of unloaded 10% anionic and cationic solid lipid nanoparticles:
(1) 2.22mg (69 equiv.) of 1, 2-dioleoyl glycerol-3-phosphoethanolamine (DOPE), 0.67mg (40 equiv.) of Cholesterol (CHOL), 0.43mg (4 equiv.) of 1, 2-dimyristoyl-sn-glycero-3-methoxypolyethylene glycol (DMG-PEG) were dissolved in absolute ethanol, and 0.52mg (12.6 equiv.) of 1, 2-dioleoyl-sn-glycero-3-phosphate (DOPA) dissolved in tetrahydrofuran was added, and the rest of the procedure was the same as in example 1-1 (except for transmission observation), to obtain an unloaded solution of anionic solid lipid nanoparticles (10% DOPA SLNs).
(2) Dissolving 2.32mg (69 equivalents) of 1, 2-dioleoyl glycerol-3-phosphoethanolamine (DOPE), 0.7mg (40 equivalents) of Cholesterol (CHOL), 0.451mg (4 equivalents) of 1, 2-dimyristoyl-sn-glycerol-3-methoxypolyethylene glycol (DMG-PEG) and 0.369mg (12.6 equivalents) of 1, 2-dioleoyl-3- (dimethylamino) propane (DODAP) in absolute ethanol, and uniformly mixing to obtain a phospholipid ethanol solution; the rest of the procedure was the same as in example 1-1 (except for transmission observation), to obtain an unloaded cationic solid lipid nanoparticle solution (10% DODAP SLNs).
The particle size of the unloaded 10% anionic solid lipid nanoparticle and cationic solid lipid nanoparticle solutions was tested, and the results are shown in FIG. 1, wherein the particle size of the 10% anionic solid lipid nanoparticle and cationic solid lipid nanoparticle is between 120-170 nm; as shown in fig. 2, the potential of the 10% anionic solid lipid nanoparticle is negatively charged and the potential of the 10% cationic solid lipid nanoparticle is positively charged, indicating that the construction of the unloaded 10% anionic solid lipid nanoparticle and the cationic solid lipid nanoparticle is successful.
Examples 1 to 3
Preparation of unloaded 30% anionic and cationic solid lipid nanoparticles:
(1) 1.6mg (69 equiv.) of 1, 2-dioleoyl glycerol-3-phosphoethanolamine (DOPE), 0.48mg (40 equiv.) of Cholesterol (CHOL), 0.31mg (4 equiv.) of 1, 2-dimyristoyl-sn-glycero-3-methoxypolyethylene glycol (DMG-PEG) were dissolved in absolute ethanol, and 1.45mg (48.4 equiv.) of 1, 2-dioleoyl-sn-glycero-3-phosphate (DOPA) dissolved in tetrahydrofuran was added, and the rest of the procedure was the same as in example 2-1 (except for transmission observation), to obtain an unloaded solution of anionic solid lipid nanoparticles (30% DOPA SLNs).
(3) Dissolving 1.83mg (69 equivalents) of 1, 2-dioleoyl glycerol-3-phosphoethanolamine (DOPE), 0.55mg (40 equivalents) of Cholesterol (CHOL), 0.36mg (4 equivalents) of 1, 2-dimyristoyl-sn-glycerol-3-methoxypolyethylene glycol (DMG-PEG) and 1.1mg (48.4 equivalents) of 1, 2-dioleoyl-3- (dimethylamino) propane (DODAP) in absolute ethanol, and uniformly mixing to obtain a phospholipid ethanol solution; the rest of the procedure was the same as in example 2-1 (except for transmission observation), to obtain an unloaded cationic solid lipid nanoparticle solution (30% DODAP SLNs).
The particle size of the unloaded 30% anionic solid lipid nanoparticle and cationic solid lipid nanoparticle solution is tested, and the results are shown in FIG. 1, wherein the particle size of the 30% anionic solid lipid nanoparticle and cationic solid lipid nanoparticle is between 120-170 nm; as shown in fig. 2, the potential of the 30% anionic solid lipid nanoparticle is negatively charged and the potential of the 30% cationic solid lipid nanoparticle is positively charged, indicating that the construction of the unloaded 30% anionic solid lipid nanoparticle and the cationic solid lipid nanoparticle is successful.
Example 2-1
Preparation of doxorubicin-loaded neutral solid lipid nanoparticles:
in example 1-1, 0.96mg of Doxorubicin (DOX) was added, and the procedure was otherwise the same as in example 1-1. And (4) obtaining neutral solid lipid nanoparticles (0% SLNs-DOX) loaded with the adriamycin after dialysis.
The particle size of the doxorubicin-loaded neutral solid lipid nanoparticle solution is obtained through testing, and the result is shown in fig. 1, wherein the particle size of the doxorubicin-loaded neutral solid lipid nanoparticle is between 120-170 nm; as shown in FIG. 2, the electric potential of the doxorubicin-loaded neutral solid lipid nanoparticle is neutral, which indicates that the doxorubicin-loaded neutral solid lipid nanoparticle is successfully constructed.
Examples 2 to 2
Preparation of doxorubicin-loaded 10% anionic solid lipid nanoparticles and cationic solid lipid nanoparticles:
in steps (1) and (2) of example 1-2, 0.96mg of Doxorubicin (DOX) was added, respectively, and the rest of the steps were the same as in example 1-2. After dialysis, 10% anionic solid lipid nanoparticles and cationic solid lipid nanoparticles (10% DOPA SLNs-DOX, 10% DODAP SLNs-DOX) loaded with adriamycin are obtained.
The particle size of the adriamycin-loaded 10% anionic solid lipid nanoparticle and cationic solid lipid nanoparticle solution is tested, and the result is shown in figure 1, wherein the particle size of the adriamycin-loaded 10% anionic solid lipid nanoparticle and cationic solid lipid nanoparticle is between 120-170 nm; as shown in fig. 2, the electric potential of the doxorubicin-loaded 10% anionic solid lipid nanoparticle is negatively charged, and the electric potential of the doxorubicin-loaded 10% cationic solid lipid nanoparticle is positively charged, which indicates that the doxorubicin-loaded 10% anionic solid lipid nanoparticle and the doxorubicin-loaded cationic solid lipid nanoparticle are successfully constructed.
Examples 2 to 3
Preparation of doxorubicin-loaded 30% anionic solid lipid nanoparticles and cationic solid lipid nanoparticles:
in steps (1) and (2) of examples 1 to 3, 0.96mg of Doxorubicin (DOX) was added, respectively, and the rest of the steps were the same as in examples 1 to 3. And (3) dialyzing to obtain adriamycin-loaded 30% anionic solid lipid nanoparticles and cationic solid lipid nanoparticles (30% DOPA SLNs-DOX and 30% DODAP SLNs-DOX).
The particle size of the solution of the adriamycin-loaded 30% anionic solid lipid nanoparticle and the cationic solid lipid nanoparticle is tested, and the result is shown in figure 1, wherein the particle size of the adriamycin-loaded 30% anionic solid lipid nanoparticle and the cationic solid lipid nanoparticle is between 120-170 nm; as shown in fig. 2, the electric potential of the doxorubicin-loaded 30% anionic solid lipid nanoparticle is negatively charged, and the electric potential of the doxorubicin-loaded 30% cationic solid lipid nanoparticle is positively charged, which indicates that the doxorubicin-loaded 30% anionic solid lipid nanoparticle and the doxorubicin-loaded cationic solid lipid nanoparticle are successfully constructed.
Example 3-1
Preparation of docetaxel-loaded neutral solid lipid nanoparticles:
0.96mg of Docetaxel (DTX) was added to example 1-1, and the rest was the same as in example 1-1. Neutral solid lipid nanoparticles (0% SLNs-DTX) loaded with docetaxel are obtained after dialysis.
Fig. 8 shows a schematic structural diagram of a neutral solid lipid nanoparticle loaded with docetaxel in this embodiment, and it can be seen from fig. 8 that the neutral solid lipid nanoparticle is a spherical nanoparticle having a solid lipid core and a monolayer phospholipid shell, and a hydrophobic drug is wrapped inside the nanoparticle.
The particle size of the neutral solid lipid nanoparticle solution loaded with docetaxel is obtained through a test, and the result is shown in fig. 1, wherein the particle size of the neutral solid lipid nanoparticle loaded with docetaxel is between 120-170 nm; as shown in fig. 2, the potential of the neutral solid lipid nanoparticle loaded with docetaxel is neutral, which indicates that the neutral solid lipid nanoparticle loaded with docetaxel is successfully constructed.
Examples 3 to 2
Preparation of docetaxel-loaded 10% anionic solid lipid nanoparticles and cationic solid lipid nanoparticles:
in example 1-2, 0.96mg of Docetaxel (DTX) was added in steps (1) and (2), respectively, and the rest of the procedure was the same as in example 1-2. After dialysis, docetaxel-loaded 10% anionic solid lipid nanoparticles and cationic solid lipid nanoparticles (10% DOPA SLNs-DTX, 10% DODAP SLNs-DTX) were obtained.
The particle size of the solution of the 10% anionic solid lipid nanoparticle and the cationic solid lipid nanoparticle loaded with docetaxel is tested, and the result is shown in fig. 1, wherein the particle size of the 10% anionic solid lipid nanoparticle and the cationic solid lipid nanoparticle loaded with docetaxel is between 120 and 170 nm; as shown in fig. 2, the potential of the 10% anionic solid lipid nanoparticle loaded with docetaxel is negatively charged, and the potential of the 10% cationic solid lipid nanoparticle loaded with docetaxel is positively charged, which indicates that the 10% anionic solid lipid nanoparticle and the cationic solid lipid nanoparticle loaded with docetaxel are successfully constructed.
Examples 3 to 3
Preparation of docetaxel-loaded 30% anionic solid lipid nanoparticles and cationic solid lipid nanoparticles:
in examples 1-3, 0.96mg of Docetaxel (DTX) was added in steps (1) and (2), respectively, and the rest of the procedure was the same as in examples 1-3. After dialysis, 30% anionic solid lipid nanoparticles and cationic solid lipid nanoparticles (30% DOPA SLNs-DTX, 30% DODAP SLNs-DTX) loaded with docetaxel were obtained.
The particle size of the solution of the 30% anionic solid lipid nanoparticle and the cationic solid lipid nanoparticle loaded with docetaxel is tested, and the result is shown in fig. 1, wherein the particle size of the 30% anionic solid lipid nanoparticle and the cationic solid lipid nanoparticle loaded with docetaxel is between 120 and 170 nm; as shown in fig. 2, the potential of the 30% anionic solid lipid nanoparticle loaded with docetaxel is negatively charged, and the potential of the 30% cationic solid lipid nanoparticle loaded with docetaxel is positively charged, which indicates that the 30% anionic solid lipid nanoparticle and the cationic solid lipid nanoparticle loaded with docetaxel are successfully constructed.
Comparative examples 1 to 1
Preparation of unloaded 50% anionic and cationic solid lipid nanoparticles:
(1) 1.07mg (69 equiv.) of 1, 2-dioleoyl glycerol-3-phosphoethanolamine (DOPE), 0.32mg (40 equiv.) of Cholesterol (CHOL), 0.21mg (4 equiv.) of 1, 2-dimyristoyl-sn-glycerol-3-methoxypolyethylene glycol (DMG-PEG) were dissolved in absolute ethanol, and 2.24mg (113 equiv.) of 1, 2-dioleoyl-sn-glycerol-3-phosphate (DOPA) dissolved in tetrahydrofuran were added, and the rest of the procedure was the same as in example 2-1 (except for transmission observation), to obtain a solution of unloaded anionic solid lipid nanoparticles (50% DOPA SLNs).
(2) Dissolving 1.31mg (69 equivalents) of 1, 2-dioleoyl glycerol-3-phosphoethanolamine (DOPE), 0.39mg (40 equivalents) of Cholesterol (CHOL), 0.26mg (4 equivalents) of 1, 2-dimyristoyl-sn-glycerol-3-methoxypolyethylene glycol (DMG-PEG) and 1.88mg (48.4 equivalents) of 1, 2-dioleoyl-3- (dimethylamino) propane (DODAP) in absolute ethanol, and uniformly mixing to obtain a phospholipid ethanol solution; the rest of the procedure was the same as in example 2-1 (except for transmission observation), to obtain an unloaded cationic solid lipid nanoparticle solution (50% DODAP SLNs).
The particle size of the unloaded 50% anionic solid lipid nanoparticle and cationic solid lipid nanoparticle solution is tested, and the result is shown in FIG. 1, wherein the particle size of the 50% anionic solid lipid nanoparticle and cationic solid lipid nanoparticle is between 120-170 nm; as shown in fig. 2, the 50% anionic solid lipid nanoparticle potential is negatively charged and the 50% cationic solid lipid nanoparticle potential is positively charged, indicating that the construction of the unloaded 50% anionic solid lipid nanoparticle and the cationic solid lipid nanoparticle is successful.
Comparative examples 1 to 2
Preparation of doxorubicin-loaded 50% anionic solid lipid nanoparticles and cationic solid lipid nanoparticles:
in comparative example 1-1, 0.96mg of Doxorubicin (DOX) was added in steps (1) and (2), respectively, and the remaining steps were the same as in comparative example 1-1. After dialysis, 50% anionic solid lipid nanoparticles and cationic solid lipid nanoparticles (50% DOPA SLNs-DOX, 50% DODAP SLNs-DOX) loaded with adriamycin are obtained.
The particle size of the doxorubicin-loaded 50% anionic solid lipid nanoparticle and cationic solid lipid nanoparticle solution is tested, and the result is shown in fig. 1, wherein the particle size of the doxorubicin-loaded 50% anionic solid lipid nanoparticle and cationic solid lipid nanoparticle is between 120-170 nm; as shown in fig. 2, the potential of the doxorubicin-loaded 50% anionic solid lipid nanoparticle is negatively charged, and the potential of the doxorubicin-loaded 50% cationic solid lipid nanoparticle is positively charged, which indicates that the doxorubicin-loaded 50% anionic solid lipid nanoparticle and the doxorubicin-loaded cationic solid lipid nanoparticle are successfully constructed.
Comparative examples 1 to 3
Preparation of docetaxel-loaded 50% anionic solid lipid nanoparticles and cationic solid lipid nanoparticles:
in comparative example 1-1, 0.96mg of Docetaxel (DTX) was added in steps (1) and (2), respectively, and the remaining steps were the same as in comparative example 1-1. After dialysis, 50% anionic solid lipid nanoparticles and cationic solid lipid nanoparticles (50% DOPA SLNs-DTX, 50% DODAP SLNs-DTX) loaded with docetaxel were obtained.
The particle size of the solution of 50% anionic solid lipid nanoparticle and cationic solid lipid nanoparticle loaded with docetaxel is tested, and the result is shown in fig. 1, wherein the particle size of the 50% anionic solid lipid nanoparticle and cationic solid lipid nanoparticle loaded with docetaxel is between 120-170 nm; as shown in fig. 2, the potential of the 50% anionic solid lipid nanoparticle loaded with docetaxel is negatively charged, and the potential of the 50% cationic solid lipid nanoparticle loaded with docetaxel is positively charged, which indicates that the 50% anionic solid lipid nanoparticle and the cationic solid lipid nanoparticle loaded with docetaxel are successfully constructed.
Example 4
DTX, 0% SLNs-DTX, 50% DODASLNs-DTX in vitro drug release profile measurements under normoxic conditions:
docetaxel, solid lipid nanoparticles (0% SLNs-DTX) loaded with docetaxel obtained in example 3-1, and 50% cationic solid lipid nanoparticles (50% DODAP SLNs-DTX) loaded with docetaxel obtained in comparative example 1-3 were mixed well and then left to stand, 0.2ml of supernatant was taken after time periods of 0h, 0.05h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 12h and 24h, and the same volume of fresh PBS solution was added while taking 0.2ml of supernatant each time, so that the volume of the whole system was kept constant. Then, it was added to 3ml of methanol solution, and the content of DTX in the solution was detected by High Performance Liquid Chromatography (HPLC), thereby calculating the amount of cumulative release of DTX.
DTX Release profiles As shown in FIG. 5, it can be seen from FIG. 5 that 0% SLNs-DTX released less drug at the same time than the other two groups, indicating that 0% SLNs-DTX could prolong the release time of the drug and that 0% SLNs-DTX release rate was lower than the free drug group, which was statistically significant.
Example 5
Distribution of DTX, different mole percent solid lipid nanoparticles loaded with docetaxel in different organs:
ICR mice were randomly divided into 8 groups of 3 mice each, each group was injected caudal vein with 5mg/kg body weight of free docetaxel, docetaxel-loaded solid lipid nanoparticles obtained in example 3-1 (0% SLNs-DTX), docetaxel-loaded 10% anionic and cationic solid lipid nanoparticles obtained in example 3-2 (10% DOPA SLNs-DTX, 10% DODAP SLNs-DTX), docetaxel-loaded 30% anionic and cationic solid lipid nanoparticles obtained in example 3-3 (30% DOPA SLNs-DTX, 30% DODAP SLNs-DTX), docetaxel-loaded 50% anionic and cationic solid lipid nanoparticles obtained in comparative examples 1-3 (50% DOPA SLNs-DTX, D X, B-D, C-D, C-D, C, 50% DODAP SLNs-DTX). After 6 hours of administration, chloral hydrate was injected into the abdominal cavity to anesthetize the mice, followed by perfusion with physiological saline, and the tissues of the heart, liver, spleen, lung, kidney, etc. were taken out, respectively. The tissue was weighed and homogenized using a homogenizer. Adding 5ml of mixed solution (chloroform: methanol is 4:1) into the homogenized tissue, crushing, performing ultrasonic treatment for 10min, centrifuging for 10min at 8000r/min, taking out the lower layer of chloroform solution, performing spin drying, adding 3ml of methanol solution for redissolution, centrifuging for 10min at 8000r/min, measuring the content of the drug in different tissues in the supernatant by using HPLC, wherein the statistics of the percentage of the drug in the body tissue in each gram of tissue in the total injected drug is shown in FIG. 6.
As can be seen from FIG. 6, SLNs are mainly distributed in the liver, and the drug content in the liver is higher than that of the free drug and 50% of SLNs drug-loaded drug group, which indicates that the prepared SLNs have better liver targeting function when the molar percentage of DOPA or DODAP accounts for 0% -30% of the total phospholipid.
Example 6
DTX, 0% SLNs-DTX, 50% DODASLNs-DTX pharmacokinetics:
healthy BALB/c mice were randomly divided into 3 groups of 3 mice each, and each group was treated with 5mg/kg body weight of docetaxel injected into the tail vein (control group 1), docetaxel-loaded solid lipid nanoparticles obtained in example 3-1 (0% SLNs-DTX), docetaxel-loaded 50% cationic solid lipid nanoparticles obtained in comparative examples 1-3 (50% DODAP SLNs-DTX, control group 2). Collecting blood from orbit at 0.05h, 0.5h, 1h, 2h, 4h, 6h, 12h, and 24h after tail vein administration to obtain 1ml blood, standing at 4 deg.C, centrifuging at 3000r/min for 5min, and collecting 0.2ml upper layer serum. Adding the extract into 0.2ml PBS solution and 3ml chloroform solution, vortexing for 5min, centrifuging at 5500r/min for 10min, taking out chloroform layer liquid, adding 2ml methanol for redissolving after the chloroform is spun off, centrifuging at 8000r/min for 10min, and measuring the drug content in different tissues in the supernatant by using HPLC.
According to fig. 7, the DTX concentration-time profiles in the plasma were measured at different time points within 24h of the administration of ICR mice. Compared with the control group 1-2, the 0% SLNs-DTX has long half-life and slow clearance rate in vivo, can prolong the blood circulation time of the drug in vivo and simultaneously improve the bioavailability of the drug in vivo.
Fluorescence spectrophotometer and HPLC measurements of anticancer drug-loaded neutral solid lipid nanoparticles (0% SLNs-DOX, 0% SLNs-DTX) provided in examples 2-1 and 3-1, anticancer drug-loaded 10% anionic and cationic solid lipid nanoparticles (10% DOPA/DODAPS SLNs-DOX, 10% DOPA/DODAPS SLNs-DTX) provided in examples 2-2 and 3-2, anticancer drug-loaded 30% anionic and cationic solid lipid nanoparticles (30% DOPA/DODTX SLNs-DOX, 30% DOPA/DODAPS-DTN-DTX) provided in examples 2-3 and 3-3, anticancer drug-loaded 50% anionic and cationic solid lipid nanoparticles (50% DOPA/DODAP SLNs-DOX, 30% DOPA/DOSLNs-DOWN-provided in comparative examples 1-2 and 1-3), and anticancer drug-loaded 50% anionic and cationic solid lipid nanoparticles (50% DOPA/DODAP SLNs-DOX, 50% DOPA/DODAP SLNs-DTX), a statistical plot of the encapsulation efficiency is shown in FIG. 3. According to fig. 3, the encapsulation efficiency of the DTX-loaded solid lipid nanoparticles is higher than that of the DOX-loaded solid lipid nanoparticles, which indicates that the DTX-loaded solid lipid nanoparticles can reduce the administration frequency and are more suitable for treatment.
While there have been shown and described what are at present considered the fundamental principles and essential features of the invention and its advantages, it will be apparent to those skilled in the art that the invention is not limited to the details of the foregoing exemplary embodiments, but is capable of other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that changes, modifications, substitutions and alterations can be made in these embodiments without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (8)
1. A preparation method of an anticancer drug loaded lipid nano-carrier is characterized in that the anticancer drug loaded lipid nano-carrier is an anticancer drug loaded solid lipid nano-particle solution, and the preparation method comprises the following steps:
1) dissolving 1, 2-dioleoyl-3-phosphoethanolamine, cholesterol, 1, 2-dimyristoyl-sn-glycerol-3-methoxypolyethylene glycol and an anticancer drug in absolute ethyl alcohol, adding a solution containing a fourth phospholipid, and uniformly mixing to obtain a phospholipid ethyl alcohol solution; the solution containing the fourth phospholipid is 1, 2-dioleoyl-sn-glycero-3-phosphate dissolved by tetrahydrofuran or 1, 2-dioleoyl-3- (dimethylamino) propane dissolved by absolute ethyl alcohol;
2) and (3) rapidly mixing the phospholipid ethanol solution with pure water, incubating at room temperature for 10min, transferring into a dialysis bag, and dialyzing with pure water for 3h under the stirring condition to remove the unencapsulated anticancer drug, thereby obtaining the solid lipid nanoparticle solution loaded with the anticancer drug.
2. The method according to claim 1, wherein the molar ratio of 1, 2-dioleoyl glycerol-3-phosphoethanolamine to cholesterol, 1, 2-dimyristoyl-sn-glycerol-3-methoxypolyethylene glycol, and the fourth phospholipid in step 1) is 69: 40: 4: x and X are 0, 12.6 or 48.4.
3. The method according to claim 1, wherein the mass ratio of the anticancer drug to the total amount of the four phospholipids in step 1) is 1: 4, the four phospholipids are 1, 2-dioleoyl glycerol-3-phosphoethanolamine, cholesterol, 1, 2-dimyristoyl-sn-glycerol-3-methoxypolyethylene glycol and a fourth phospholipid, and the anticancer drug is adriamycin or docetaxel.
4. The method according to claim 1, wherein the volume ratio of the phospholipid ethanol solution to the pure water in step 2) is 1: 3.
5. The method of claim 1, wherein the dialysis bag in step 2) has a molecular weight cut-off of 14000.
6. The anticancer drug loaded lipid nano-carrier prepared by the preparation method of any one of claims 1 to 5.
7. The anticancer drug-loaded lipid nano-carrier of claim 6, wherein the hydration particle size of the anticancer drug-loaded lipid nano-carrier is 120-170 nm.
8. The use of the anticancer drug-loaded lipid nanocarrier of claim 7 in the preparation of a liver-targeting anticancer drug.
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| CN101653414A (en) * | 2008-08-19 | 2010-02-24 | 中国科学院上海药物研究所 | Long-circulating solid lipid docetaxel nanoparticles and preparation method thereof |
| WO2011043532A1 (en) * | 2009-10-07 | 2011-04-14 | 건일제약 주식회사 | Lipid nanoparticles for oral administration, and method for preparing same |
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| WO2019135715A1 (en) * | 2018-01-05 | 2019-07-11 | Nanyang Technological University | Lipid-polymer hybrid nanoparticles |
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| CN101653414A (en) * | 2008-08-19 | 2010-02-24 | 中国科学院上海药物研究所 | Long-circulating solid lipid docetaxel nanoparticles and preparation method thereof |
| WO2011043532A1 (en) * | 2009-10-07 | 2011-04-14 | 건일제약 주식회사 | Lipid nanoparticles for oral administration, and method for preparing same |
| CN103976950A (en) * | 2014-05-21 | 2014-08-13 | 华中科技大学 | Adriamycin nano drug delivery system as well as preparation method and application thereof |
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