CN114191549A - Intestinal SGLT1 targeted docetaxel-curcumin solid lipid nanoparticle and preparation method and application thereof - Google Patents
Intestinal SGLT1 targeted docetaxel-curcumin solid lipid nanoparticle and preparation method and application thereof Download PDFInfo
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Abstract
The invention belongs to the technical field of medicines, and particularly relates to a docetaxel-curcumin solid lipid nanoparticle targeted by intestinal SGLT1, and a preparation method and application thereof. The raw materials are as follows by mass ratio: 200-400mg of glycerin monostearate, 100-300mg of lecithin, 10-25mg of docetaxel, 10-25mg of curcumin, 5-40mg of targeting material and 240-450mg of dodecyl maltoside. The nano-particle of the invention loads docetaxel and curcumin (photosensitizer) into the galactose modified solid lipid nano-particle together, thus not only solving the problems of serious adverse reaction and low oral bioavailability of the docetaxel and curcumin, but also realizing chemotherapy and photodynamic therapy and high-efficiency synergistic antitumor effect.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a docetaxel-curcumin solid lipid nanoparticle targeted by intestinal SGLT1, and a preparation method and application thereof.
Background
The oral administration route has the advantages of convenience, high safety and good patient compliance. However, oral administration is limited due to the presence of multiple absorption barriers in the gastrointestinal tract. The Solid Lipid Nanoparticles (SLN) can improve the stability of the medicament and break through the physiological barrier of the gastrointestinal tract through different transportation modes, thereby effectively improving the oral absorption of the medicament and having good development prospect. However, SLN is cleared during interaction with the gastrointestinal mucosa as mucus is refreshed, reducing its oral bioavailability. The cell surface of the alimentary canal mucosa layer has a plurality of transporters which can specifically recognize specific molecules in the gastrointestinal tract, thereby realizing the transportation and absorption of the substance. The SLN is subjected to surface modification, so that the intestinal epithelial cell uptake efficiency of the nano drug delivery system can be further improved, and the oral bioavailability of the drug can be effectively improved.
Sodium-glucose cotransporter 1(SGLT1) belongs to the family of membrane proteins that facilitate the transport of galactose and various ions through the intestinal epithelium. After galactose is modified on the surface of the nanoparticle, the cell uptake efficiency of the nanoparticle can be improved through the route-mediated endocytosis.
Docetaxel is a specific drug in M phase cycle, promotes the polymerization of small tubes into stable microtubules, inhibits the depolymerization of the microtubules, and retards cells in M phase, thereby inhibiting the mitosis and proliferation of cancer cells. Has good curative effect on advanced breast cancer, ovarian cancer and non-small cell lung cancer. However, docetaxel often has limited use due to severe adverse effects, and timely combination of docetaxel can lead to higher survival benefit of patients, such as chemotherapy combined with photodynamic therapy (PDT). Curcumin is a phenolic pigment extracted from Curcuma rhizome of Zingiberaceae, and has antiinflammatory, antioxidant, and antitumor effects. Curcumin is a commonly used photosensitizer in PDT to induce apoptosis. However, curcumin is poorly soluble in water, is easily hydrolyzed under neutral and alkaline conditions, has a biological half-life period, causes low bioavailability, and limits the clinical application of the compound.
At present, curcumin and docetaxel are jointly applied to anti-tumor research, for example, the curcumin and docetaxel are jointly encapsulated in PLGA nanoparticles, small peptide modified carboxymethyl chitosan and liposome, and the like. Related research has made certain progress in the synergistic antitumor aspect. However, the concentration of curcumin for exerting the tumor chemotherapy effect needs to reach millimole level, and the current research cannot meet the requirement, so that the synergistic anti-cancer effect and clinical transformation of curcumin and chemotherapeutic drugs are limited. PDT relies on a photosensitizer to transfer energy, generate active oxygen and kill tumors. The photosensitizer itself is not degraded and consumed during PDT, so a good anti-tumor effect can still be achieved with low tumor accumulation.
Based on the above problems, the present invention aims to use targeted SLN as a carrier, to encapsulate docetaxel and curcumin, and to use chemotherapy in combination with PDT for the treatment of non-small cell lung cancer, pancreatic cancer or breast cancer.
Disclosure of Invention
The invention provides a docetaxel-curcumin solid lipid nanoparticle targeted by intestinal SGLT1 and a preparation method and application thereof, aiming at solving the problems of low oral bioavailability of the solid lipid nanoparticle, serious adverse reaction of docetaxel monotherapy and poor curative effect. The nanoparticles of the invention load docetaxel and curcumin (photosensitizer) into galactose modified solid lipid nanoparticles together, thus not only solving the problems of serious adverse reaction and low oral bioavailability of docetaxel and curcumin, but also realizing the combined PDT treatment of chemotherapy, and e, the docetaxel and curcumin have high-efficiency synergistic anti-tumor effect.
In order to achieve the purpose, the intestinal SGLT1 targeted docetaxel-curcumin solid lipid nanoparticle provided by the invention comprises the following raw materials in percentage by mass: 200-400mg of glycerin monostearate, 100-300mg of lecithin, 10-25mg of docetaxel, 10-25mg of curcumin, 5-40mg of targeting material and 240-450mg of dodecyl maltoside.
The targeting material is DSPE-PEG2000-Galactose, stearoyl Galactose or oleoyl Galactose.
The glyceryl monostearate is used as a lipid material.
In order to achieve the purpose, the invention also provides a preparation method of the intestinal SGLT1 targeted docetaxel-curcumin solid lipid nanoparticle, which specifically comprises the following steps: weighing glyceryl monostearate, lecithin, targeting material, docetaxel and curcumin according to the mass ratio, adding ethanol, heating to completely dissolve, and preparing into an oil phase; in addition, weighing 30ml of dodecyl maltoside aqueous solution with the mass concentration of 1.3%, heating in water bath to the same temperature (70 ℃) as the oil phase to form a water phase; injecting the oil phase into the water phase in 70 deg.C water bath at stirring speed of 1000r/min, continuously stirring for 1 hr to volatilize organic solvent, concentrating to 30ml, mixing well, ultrasonic emulsifying with probe for 10min to obtain transparent nano emulsion, and cooling the obtained nano emulsion in ice water bath.
Preferably, the targeting material is DSPE-PEG2000-Galactose, and the addition amount is 32 mg.
Before the oil phase is added to the aqueous phase, the aqueous phase is heated to the same temperature as the oil phase (70 ℃).
The intestinal SGLT1 targeted docetaxel-curcumin solid lipid nanoparticle is used for combined photodynamic therapy of non-small cell lung cancer, pancreatic cancer or breast cancer chemotherapy.
The invention has obvious technical effect.
The invention can load the insoluble docetaxel and curcumin into the SLN at the same time, thus improving the water solubility of the docetaxel and curcumin, reducing the toxic and side effects and increasing the stability of gastrointestinal tract, and can increase the interaction between the SLN and intestinal mucosa by targeting the intestinal SGLT1, reduce the mucus clearance and further improve the membrane permeability; in addition, the dodecyl maltoside added into the system can open tight connection among cells, and further increase the membrane permeability of SLN. Both mechanisms synergistically enhance the oral bioavailability of SLN.
Laser irradiation of curcumin produces active oxygen, destroys tumor cell membranes and membranes of internal organelles, increases tumor cell membrane permeability of SLN, and promotes tumor cell apoptosis. Meanwhile, the sensitizing chemotherapeutic drug docetaxel and chemotherapy are combined with photodynamic therapy, and the high-efficiency synergistic antitumor effect is achieved.
Drawings
Fig. 1 targets SLN particle size and point location distribution.
Fig. 2 shows the inhibition rate (a) of a549 cells and the cellular reactive oxygen species production (b) of targeted SLN nanoparticles and their components (mean ± SD) × compared to docetaxel + curcumin group; # compared to the targeted SLN group;&compared to the Laser + docetaxel + curcumin group; the laser is 660nm, and the irradiation frequency is 0.6w/cm2The irradiation time was 10 min.
Fig. 3 drug concentration-time curves (administration dose 20mg/kg, n is 6) of docetaxel (a) and curcumin (b) after oral administration of bulk drug, non-targeted SLN nanoparticles and targeted SLN nanoparticles.
Fig. 4 shows the concentration-time curves of docetaxel (a) and curcumin (b) drugs after oral administration of targeted SLN nanoparticles and DSPE-PEG2000-Galactose together (both doses are 20mg/kg, n is 6).
Fig. 5 shows the drug concentration-time curves of docetaxel (a) and curcumin (b) after oral administration of SLN nanoparticles with different target material dosages (both the administration dosages are 20mg/kg, and n is 6).
Detailed description of the invention
The technical solution of the present invention is further described in detail with reference to the accompanying drawings and the detailed description. Unless otherwise specified, the technical means used in the examples are conventional means well known to those skilled in the art, and the raw materials used are commercially available products.
Example 1.
Respectively weighing 300mg of glyceryl monostearate, 150mg of lecithin, DSPE-PEG2000-Galactose8mg, 12.5mg of docetaxel and 12.5mg of curcumin, adding 15ml of ethanol, heating to completely dissolve the materials, and preparing into an oil phase; in addition, 30ml of dodecyl maltoside aqueous solution with the concentration of 1.3% is weighed, the mixture is heated in a water bath to the same temperature (70 ℃) as the oil phase to form a water phase, the oil phase is injected into the water phase in the water bath with the temperature of 70 ℃ and the stirring speed of 1000r/min, the organic solvent is volatilized by continuously stirring for 1h, the volume is concentrated to 30ml, the transparent nano emulsion can be obtained by ultrasonic emulsification for 10min through a probe after uniform mixing, and the obtained nano emulsion is cooled in an ice water bath.
Example 2.
This example differs from example 1 in that the amount of DSPE-PEG2000-Galactose added was 16mg, which was otherwise the same as in example 1.
Example 3.
This example differs from example 1 in that the amount of DSPE-PEG2000-Galactose added was 32mg, and the other examples are the same as those of example 1.
Example 4.
This example differs from example 1 in that the targeting material is stearoyl galactose, and the amount added is 8mg, otherwise the same as in example 1.
Example 5.
This example differs from example 1 in that the targeting material is stearoyl galactose, and the amount added is 16mg, otherwise the same as in example 1.
Example 6.
This example differs from example 1 in that the targeting material is stearoyl galactose, added in an amount of 32mg, and is otherwise the same as in example 1.
Example 7.
The difference between the embodiment and the embodiment 1 is that the target material is oleoyl galactose, the addition amount is 8mg, and the other steps are the same as the embodiment 1.
Example 8.
The difference between the embodiment and the embodiment 1 is that the target material is oleoyl galactose, the addition amount is 16mg, and the other steps are the same as the embodiment 1.
Example 9.
The difference between the embodiment and the embodiment 1 is that the target material is oleoyl galactose, the addition amount is 32mg, and the other steps are the same as the embodiment 1.
Example 10.
Process research of drug-containing solid lipid nanoparticles
1.1 selection of surfactants
And (3) by taking the encapsulation efficiency and the drug loading capacity as indexes, keeping other components unchanged, and respectively investigating the influence of three surfactants, namely Pluronic F-68, Tween 80 and dodecyl maltoside, on the preparation of the SLN.
Pluronic F-68, dodecyl maltoside, and Tween 80450 mg were weighed out to make 1.5% aqueous phase solvent. Weighing 300mg of glyceryl monostearate, 300mg of lecithin, 25mg of curcumin, 25mg of docetaxel and 8mg of DSPE-PEG2000-Galactose, and adding 15ml of ethanol to prepare an oil phase; the organic phase and the water phase are 1:2, and the ultrasonic time is 1 min; the results of the three surfactant SLNs preparation are shown in table 1.
Table 1 results of the effect of the kind of surfactant on the SLN drug loading (LE%) and the encapsulation efficiency (EE%) (n ═ 3).
The results show that: the encapsulation efficiency and the drug-loading rate of the dodecyl maltoside are higher than those of Pluronic F-68 and Tween 80, so that the dodecyl maltoside is selected as the surfactant.
1.2 the amount of the surfactant.
And (3) taking the encapsulation efficiency and the drug loading capacity as indexes, keeping other components unchanged, and respectively inspecting the influence of different dosages of dodecyl maltoside on the preparation of the SLN. 240mg,300mg, 400mg and 450mg of dodecyl maltoside are respectively weighed to prepare 0.8 percent, 1.0 percent, 1.3 percent and 1.5 percent of aqueous phase solvent. 300mg of glyceryl monostearate, 300mg of lecithin, 25mg of curcumin, 25mg of docetaxel and 8mg of DSPE-PEG2000-Galactose are weighed, and 15ml of ethanol is added to prepare an oil phase. Oil phase, aqueous phase 1: 2. The ultrasonic treatment time is 1 min. The results of the different surfactant levels SLN preparation are shown in Table 2.
Table 2 results of the effect of surfactant usage on SLN drug loading (LE%) and encapsulation efficiency (EE%) (n ═ 3).
The results show that the encapsulation efficiency and the drug loading rate are increased and then decreased with the increase of the dosage of the dodecyl maltoside, so that the dosage of the dodecyl maltoside is 400 mg.
1.3 drug to lipid ratio
And (3) taking the encapsulation efficiency and the drug loading capacity as indexes, keeping other components unchanged, and respectively inspecting the influence of the drug-to-lipid ratio ((docetaxel + curcumin)/glyceryl monostearate) of 1:4, 1:6, 1:8 and 1:10 on the preparation of the SLN. Respectively weighing docetaxel and curcumin according to different medicine-to-lipid ratios, wherein the ratio of the docetaxel to the curcumin is 1: 1. The amount of glyceryl monostearate was 300 mg. In addition, 400mg of dodecyl maltoside was weighed out to prepare a 1.3% aqueous phase solvent. Weighing 300mg of lecithin and 8mg of DSPE-PEG2000-Galactose, and adding 15ml of ethanol to prepare an oil phase. Organic phase and aqueous phase 1: 2. The ultrasonic treatment time is 1 min. The results of the preparation of SLN with different drug-to-lipid ratios are shown in Table 3.
Table 3 results of the effect of drug-lipid ratio on SLN drug loading (LE%) and encapsulation efficiency (EE%) (n ═ 3).
| Ratio of drug to fat | EE% (dox) | EE% (curcumin) | LE% (doxycycline) | LE% (curcumin) |
| 1:6 | 78.48±6.30 | 73.79±4.31 | 1.81±0.37 | 4.46±0.54 |
| 1:8 | 82.41±4.16 | 80.23±2.82 | 2.46±0.12 | 5.38±0.42 |
| 1:10 | 87.25±2.32 | 85.21±2.36 | 2.87±0.15 | 6.27±0.15 |
| 1:12 | 92.13±2.72 | 92.28±2.42 | 3.32±0.12 | 7.48±0.22 |
| 1:14 | 88.13±4.71 | 90.21±3.32 | 3.19±0.18 | 7.52±0.31 |
The result shows that the encapsulation efficiency and the drug loading capacity show the phenomenon of increasing first and then flatting along with the increase of the drug-fat ratio, and when the drug-fat ratio is more than 1:12, the encapsulation efficiency and the drug loading capacity are not increased along with the increase of the drug-fat ratio, so the optimal drug-fat ratio is selected to be 1: 12.
1.4 feed ratio of glyceryl monostearate to lecithin
And (3) taking the encapsulation efficiency and the drug loading rate as indexes, keeping other components unchanged, and respectively inspecting the influence of the ratio of the glyceryl monostearate to the lecithin of 3:1, 2:1, 1:1 and 1:2 on the preparation of the SLN. And respectively weighing the glyceryl monostearate and the lecithin according to different feeding ratios. The amount of glyceryl monostearate was 300 mg. In addition, 400mg of dodecyl maltoside was weighed out to prepare a 1.3% aqueous phase solvent. Weighing DSPE-PEG2000-Galactose8mg, docetaxel 12.5mg and curcumin 12.5mg, and adding 15ml ethanol to prepare oil phase. Organic phase and aqueous phase 1: 2. The ultrasonic treatment time is 1 min. The results of the SLN preparations with different ratios of glycerol monostearate to lecithin are shown in Table 4.
Table 4 results of the effect of glycerol monostearate and lecithin dosing on SLN drug loading (LE%) and encapsulation efficiency (EE%) (n ═ 3).
| Batch charging ratio | EE% (dox) | EE% (curcumin) | LE% (doxycycline) | LE% (curcumin) |
| 3:1 | 80.58±3.91 | 80.14±5.39 | 2.81±0.83 | 6.75±0.58 |
| 2:1 | 91.51±3.66 | 89.74±5.61 | 3.26±0.97 | 7.65±0.17 |
| 1:1 | 87.18±4.25 | 89.24±3.12 | 3.27±0.19 | 7.51±0.43 |
| 1:2 | 72.34±4.38 | 82.71±3.81 | 3.02±0.71 | 6.30±0.17 |
The results show that the encapsulation efficiency and the drug loading capacity are firstly increased and then decreased with the increase of the feed ratio, and the encapsulation efficiency and the drug loading capacity are not decreased with the increase of the feed ratio when the feed ratio is more than 2:1, so that the optimum feed ratio is 2: 1.
1.5 volume ratio of oil phase to aqueous phase
And (3) taking the encapsulation efficiency and the drug loading rate as indexes, keeping other components unchanged, and respectively inspecting the influence of the volume ratio of the oil phase to the water phase of 1:2, 1:3 and 1:4 on the preparation of the SLN. 300mg of glyceryl monostearate, 150mg of lecithin, 8mg of DSPE-PEG2000-Galactose, 12.5mg of docetaxel and 12.5mg of curcumin are respectively weighed, and 15ml of ethanol is added to prepare an oil phase. In addition, 400mg of dodecyl maltoside was weighed out to prepare a 1.3% aqueous phase solvent. Emulsification is carried out according to the volume ratio of different oil phases and water phases. The ultrasonic treatment time is 1 min. The results of the different volume ratios SLN preparations are shown in Table 5.
Table 5 effect of volume ratio of oil phase and water phase on SLN drug loading (LE%) and encapsulation efficiency (EE%) (n ═ 3).
| Volume ratio of oil phase to water phase | EE% (dox) | EE% (curcumin) | LE% (doxycycline) | LE% (curcumin) |
| 1:2 | 92.55±4.63 | 92.74±3.61 | 3.21±0.38 | 7.55±0.67 |
| 1:3 | 86.33±5.63 | 88.53±2.88 | 3.01±0.61 | 7.35±0.47 |
| 1:4 | 82.36±5.63 | 85.61±3.87 | 2.81±0.45 | 6.93±0.79 |
The results show that the encapsulation efficiency and drug loading were highest at a volume ratio of 1:2, so the volume ratio of oil phase to water phase was chosen to be 1: 2.
1.6 selection of emulsification temperature
The encapsulation efficiency and the drug loading rate are taken as indexes, other components are kept unchanged, and the influence of the emulsification temperature of 70 ℃, 75 ℃ and 80 ℃ on the preparation of the SLN is respectively examined. 300mg of glyceryl monostearate, 150mg of lecithin, 8mg of DSPE-PEG2000-Galactose, 12.5mg of docetaxel and 12.5mg of curcumin are respectively weighed. In addition, 400mg of dodecyl maltoside was weighed out to prepare a 1.3% aqueous phase solvent. Oil phase, aqueous phase 1: 2. Emulsification was performed at different temperatures. The ultrasonic treatment time is 1 min. The results of SLN preparations at different emulsification temperatures are shown in Table 6.
Table 6 results of the effect of different emulsification temperatures on SLN drug loading (LE%) and encapsulation efficiency (EE%) (n ═ 3).
| Emulsification temperature (. degree.C.) | EE% (dox) | EE% (curcumin) | LE% (doxycycline) | LE% (curcumin) |
| 70 | 97.54±1.68 | 91.74±6.41 | 3.26±0.47 | 6.90±0.17 |
| 75 | 91.67±4.10 | 98.31±0.92 | 3.04±0.66 | 7.22±0.75 |
| 80 | 93.31±3.64 | 97.38±2.48 | 2.98±0.43 | 7.03±0.81 |
The results show that the encapsulation efficiency and the drug loading rate of the curcumin tend to increase along with the increase of the temperature, but the docetaxel is opposite, and the final selected emulsifying temperature is 70 ℃ under the comprehensive consideration.
1.7 ultrasonic time screening
And (3) taking the encapsulation efficiency and the drug loading capacity as indexes, keeping other components unchanged, and respectively inspecting the influence of ultrasonic time of 2min, 5min and 10min on the preparation of the SLN. 300mg of glyceryl monostearate, 150mg of lecithin, 8mg of DSPE-PEG2000-Galactose, 12.5mg of docetaxel and 12.5mg of curcumin are respectively weighed. In addition, 400mg of dodecyl maltoside was weighed out to prepare a 1.3% aqueous phase solvent. Oil phase, aqueous phase 1: 2. The emulsification temperature was 70 ℃. Emulsification was performed at different sonication times. The results of SLN preparations at different sonication times are shown in Table 7.
Table 7 results of the effect of different sonication times on SLN drug loading (LE%) and encapsulation efficiency (EE%) (n ═ 3).
The results show that the encapsulation efficiency and the drug loading rate of the curcumin and the docetaxel are in an ascending trend along with the prolonging of the ultrasonic time, and the ultrasonic time is finally 10 min.
1.8 amount of DSPE-PEG2000-Galactose
The influence of the DSPE-PEG2000-Galactose dosage of 8mg, 16mg and 32mg on the preparation of the SLN is respectively examined by taking the encapsulation rate and the drug loading capacity as indexes and keeping other components unchanged. 300mg of glyceryl monostearate, 150mg of lecithin, 12.5mg of docetaxel and 12.5mg of curcumin are respectively weighed. In addition, 400mg of dodecyl maltoside was weighed out to prepare a 1.3% aqueous phase solvent. Oil phase, aqueous phase 1: 2. The emulsification temperature was 70 ℃. Performing ultrasonic treatment for 10 min. The results of the different DSPE-PEG2000-Galactose dose SLN preparations are shown in Table 8.
Table 8 effect of DSPE-PEG2000-Galactose dosage on SLN drug loading (LE%) and encapsulation efficiency (EE%) (n ═ 3).
The results show that the encapsulation rate and drug loading of curcumin and docetaxel have no obvious change with the increase of the dosage of DSPE-PEG2000-Galactose, because DSPE-PEG2000-Galactose is a substrate targeting SGLT1 in intestinal tract, the membrane permeability of SLN is supposed to be improved with the increase of the dosage, and 32mg is selected by comprehensively considering the dosage of DSPE-PEG 2000-Galactose.
1.9 Process verification
In summary, the optimal recipe is: 300mg of glyceryl monostearate, 150mg of lecithin, 32mg of DSPE-PEG2000-Galactose, 12.5mg of docetaxel and 12.5mg of curcumin are respectively weighed and added into 15ml of ethanol, and the mixture is heated to be completely dissolved to prepare an oil phase. And weighing 30ml of dodecyl maltoside aqueous solution with the concentration of 1.3%, heating in a water bath to the same temperature as the organic phase to form a water phase, injecting the organic phase into the water phase in the water bath at 70 ℃ at the stirring speed of 1000r/min, continuously stirring for 1h to volatilize the organic solvent, carrying out physical examination and concentration to 30ml, uniformly mixing, carrying out ultrasonic emulsification by using a probe for 10min to obtain a transparent nano emulsion, and cooling the obtained nano emulsion in an ice-water bath to obtain the nano emulsion.
Three batches of samples were prepared in parallel, the particle size, potential, encapsulation efficiency, drug loading were determined as shown in table 9, and the particle size potential is shown in fig. 1.
Table 9 particle size, potential, encapsulation efficiency and drug loading results for three batches of SLN nanoparticles.
The results show that the process is stable and reliable.
1.10 encapsulation efficiency and drug loading rate determination method
The free drug amount of SLN is separated by a dialysis bag method, and free curcumin and docetaxel content are measured by an HPLC method to calculate the encapsulation rate and drug loading amount of the SLN.
Chromatographic conditions
A chromatographic column: c18(250 mm. times.4.6 mm,5 μm); mobile phase methanol-water (78: 22); detection wavelength of 422 (curcumin) and 228nm (docetaxel); the flow rate is 1.0 ml/min; the column temperature is 35 ℃; the sample volume was 10. mu.l.
And (3) total drug quantity determination, precisely absorbing 1ml of nanoparticles, dissolving the nanoparticles in a 10ml measuring flask, adding methanol, performing ultrasonic demulsification, and fixing the volume. The solution was filtered through a 0.22 μm microporous membrane and assayed.
And (3) measuring the content of the non-encapsulated drugs, namely precisely measuring 2ml of SLN, placing the SLN in a dialysis bag, fastening two ends of the SLN, placing the SLN in 50ml of 10% ethanol PBS solution, shaking for 24 hours at 37 ℃, and taking 2ml of the SLN to be detected.
Encapsulation Efficiency (EE)% (M)General assembly-MSwimming device)/MGeneral assembly×100％
Drug Loading (DL)% (M)General assembly-MSwimming device)/MLipid×100％
Example 7 chemotherapy in combination with photodynamic therapy
To evaluate the potential of targeted SLN chemotherapy in combination with photodynamic anti-tumor, we incubated targeted SLN and its components docetaxel and curcumin with lung cancer a549 cells, and examined the cell inhibition rate and the production of reactive oxygen species by the cells with or without laser irradiation. The cell inhibition rate experiment is determined by an MTT method, and the active oxygen is determined by a DCFH-DA kit.
The experiment totally divided into 5 groups, namely Laser, docetaxel + curcumin, targeting SLN, Laser + docetaxel + curcumin and Laser + targeting SLN. The doses were 2. mu.g/ml.
The experimental result is shown in fig. 2, compared with the group without laser, the cell inhibition rate of the component docetaxel + curcumin under the irradiation of the laser is obviously improved (68.2 ± 3.4% vs 52.5 ± 4.8%). The active oxygen measurement result shows that the OD value of the generated amount of the active oxygen after laser irradiation is 2.24 +/-0.28, which indicates that the curcumin generates the active oxygen under the laser irradiation and generates the synergistic anti-tumor effect through PDT and chemotherapy. The inhibition rate of cells under the irradiation of laser light in the targeted SLN group is 88.6 +/-4.3% (70.2 +/-5.5% in the non-laser group), and the active oxygen measurement result shows that the OD value of the generated amount of the active oxygen after the irradiation of the laser light is 3.53 +/-0.39, which indicates that the preparation group can also produce stronger synergistic cytotoxicity through the PDT of the curcumin and the chemotherapy of the docetaxel. In addition, the inhibition rate of the nanoparticle group was higher than that of the component docetaxel + curcumin group, probably due to the increased cell accumulation of the nanoparticles.
Example 8 pharmacokinetic Studies
In order to investigate the effect of targeted nanoparticles on improving oral bioavailability, we used SD rats as a model to orally administer docetaxel and curcumin as bulk drugs, non-targeted SLN nanoparticles and targeted SLN nanoparticles, and simultaneously measured the concentrations of docetaxel and curcumin in plasma, and performed the drawing of a drug-time curve and the calculation of corresponding pharmacokinetic parameters according to the measured concentrations, respectively (table 10). The results are shown in fig. 3, where docetaxel and curcumin were rapidly absorbed into the blood from the intestinal tract after gavage. Area under the drug-time curve (AUC) for the non-targeted SLN group relative to the bulk drug group0-24) Is obviously higher than the raw material medicine group, and is respectively improved by 1.8 times (docetaxel) and 1.9 times (curcumin). The SLN nanoparticles can improve the oral absorption of docetaxel and curcumin, which is probably related to the improvement of the stability and the membrane permeability of the preparation.
The targeted SLN nanoparticle group exhibits a higher AUC than non-targeted SLN nanoparticles0-241.6 fold (docetaxel) and 2 fold (curcumin), respectively, with the results shown in figure 3 and table 10; and when the target SLN nano-particle and the DSPE-PEG2000-Galactose are co-administered, the AUC0-24The reduction was 2 fold (docetaxel) and 2.2 fold (curcumin), and the results are shown in fig. 4 and table 11. The intestinal SGLT1 transporter mediates the transmembrane transport of SLN nanoparticles, and high oral bioavailability is realized.
Table 10 pharmacokinetic parameters of curcumin and docetaxel after oral administration of bulk drug, non-targeted SLN nanoparticles and targeted nanoparticles (administration dose 20mg/kg, n ═ 6).
Table 11 curcumin and docetaxel pharmacokinetic parameters after co-oral administration of targeted SLN nanoparticles and DSPE-PEG2000-Galactose (dose 20mg/kg, n ═ 6).
Is compared with target SLN (p.o.) -8mg
In addition, we studied the pharmacokinetic behavior of SLN at different DSPE-PEG2000-Galactose doses, and the results showed that AUC with increasing DSPE-PEG2000-Galactose doses0-24Also with the increase (docetaxel 1.5-1.8 times, curcumin 1.4-1.8 times), see fig. 5 and table 12.
Table 12 curcumin and docetaxel pharmacokinetic parameters after oral administration of different targeting material dose SLN nanoparticles (administration dose 20mg/kg, n ═ 6).
Is compared with target SLN (p.o.) -8mg
The results show that increasing the dosage of the targeting material (increasing the number of transporter recognition groups) contributes to the increase of AUC of SLN nanoparticles by SGL10-24And oral bioavailability.
Claims (9)
1. An intestinal SGLT1 targeted docetaxel-curcumin solid lipid nanoparticle comprises the following raw materials in percentage by mass: 200-400mg of glycerin monostearate, 100-300mg of lecithin, 10-25mg of docetaxel, 10-25mg of curcumin, 5-40mg of targeting material and 240-450mg of dodecyl maltoside.
2. The intestinal SGLT1 targeted docetaxel-curcumin solid lipid nanoparticle of claim 1, wherein said targeting material is DSPE-PEG2000-Galactose, stearoyl Galactose or oleoyl Galactose.
3. The preparation method of intestinal SGLT1 targeted docetaxel-curcumin solid lipid nanoparticle as claimed in claim 1, specifically comprising the following steps: weighing glyceryl monostearate, lecithin, targeting material, docetaxel and curcumin according to the mass ratio, adding ethanol, heating to completely dissolve, and preparing into an oil phase; in addition, weighing dodecyl maltoside according to the mass ratio to prepare an aqueous solution, and heating the aqueous solution in a water bath to the same temperature (70 ℃) as the oil phase to form a water phase; injecting the oil phase into the water phase in 70 deg.C water bath at stirring speed of 1000r/min, continuously stirring for 1 hr to volatilize organic solvent, concentrating to 30ml, mixing well, ultrasonic emulsifying with probe for 10min to obtain transparent nano emulsion, and cooling the obtained nano emulsion in ice water bath.
4. The preparation method of intestinal SGLT1 targeted docetaxel-curcumin solid lipid nanoparticle as claimed in claim 3, wherein said targeting material is preferably DSPE-PEG2000-Galactose, and the addition amount is 32 mg.
5. The preparation method of intestinal SGLT1 targeted docetaxel-curcumin solid lipid nanoparticles as claimed in claim 3, wherein the amount of said dodecyl maltoside is preferably 400 mg.
6. The preparation method of intestinal SGLT1 targeted docetaxel-curcumin solid lipid nanoparticles as claimed in claim 3, wherein the ratio of the sum of docetaxel and curcumin to glyceryl monostearate is a drug-to-lipid ratio, and the drug-to-lipid ratio is preferably 1: 12.
7. The preparation method of intestinal SGLT1 targeted docetaxel-curcumin solid lipid nanoparticles as claimed in claim 3, wherein the dosage ratio of glyceryl monostearate and lecithin is preferably 2: 1.
8. The preparation method of intestinal SGLT1 targeted docetaxel-curcumin solid lipid nanoparticles as claimed in claim 3, wherein the volume ratio of the oil phase and the water phase is preferably 1: 2.
9. The intestinal SGLT1 targeted docetaxel-curcumin solid lipid nanoparticle as claimed in any one of claims 1 to 8, for use in non-small cell lung cancer, pancreatic cancer or breast cancer chemotherapy in combination with photodynamic therapy.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN103784421A (en) * | 2014-02-27 | 2014-05-14 | 哈尔滨医科大学 | Curcumin and piperine carried solid lipid nanoparticles and preparation method thereof |
-
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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| CN103784421A (en) * | 2014-02-27 | 2014-05-14 | 哈尔滨医科大学 | Curcumin and piperine carried solid lipid nanoparticles and preparation method thereof |
Non-Patent Citations (3)
| Title |
|---|
| HARISH PAWAR ET AL: "Folic acid functionalized long-circulating coencapsulated docetaxel and curcumin solid lipid nanoparticles: In vitro evaluation, pharmacokinetic and biodistribution in rats" * |
| 匡健 等: "肠道药物转运体对药物吸收的研究进展" * |
| 李岩: "半乳糖化纳米粒提高伊马替尼口服生物利用度的研究" * |
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| CN115227682B (en) * | 2022-07-25 | 2023-12-22 | 天津市医药科学研究所(天津市医药与健康研究中心) | Preparation method of powder aerosol for targeted small-airway slow-release delivery of COPD (chronic obstructive pulmonary disease) therapeutic drug |
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