CN100479806C - Nanostructured liposome vector with highly effective antineoplastic activity - Google Patents
Nanostructured liposome vector with highly effective antineoplastic activity Download PDFInfo
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- CN100479806C CN100479806C CNB2006101556053A CN200610155605A CN100479806C CN 100479806 C CN100479806 C CN 100479806C CN B2006101556053 A CNB2006101556053 A CN B2006101556053A CN 200610155605 A CN200610155605 A CN 200610155605A CN 100479806 C CN100479806 C CN 100479806C
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Abstract
The invention relates to a nanometer liposome carrier with high-effect anti-tumor activity, which carries the anti-tumor Paclitaxel, while the liposome is formed by single lipid and liquid lipid, wherein, the liquid lipid is 5-20% of liposome, the Paclitaxel is 3.1-3.6% of solid liposome nanometer particles, and the diameter is 481-532nm. The invention has high-effect cell extraction and cell-pulp hold function via the nanometer liposome carrier, while the package on the anti-tumor drug whose molecule target is at the cell pulp can improve the adsorption of anti-tumor drug and improve the drug density at target part. The invention can improve the drug adsorption of tumor cell, reduce the drug distribution at normal cell, reduce the side effect and toxicity, and improve the effect.
Description
Technical field
The present invention relates to the preparation and the application of this meter structured lipid carrier in antineoplaston of nano structured lipid carrier.
Background technology
Tumor is the major disease that directly threatens human health always, and chemotherapy of tumors is because the molecular targeted property of medicine shortage itself, thereby great treatment problems such as cure rate is low, toxic and side effects is huge occur.By the suitable carriers technology, with the direct targeting pathological tissues of medicine (organ), cell and subcellular organelle one of important means that solves the low and toxic and side effects of cancer chemotherapy cure rate.Present scientist both domestic and external has obtained certain progress by carrier technique on the tissue (organ) of tumour medicine and cell-targeting, but the curative effect of making a breakthrough property not, its essence is that the molecular target of most antitumor drug is positioned at cell, so the research and development of molecular drug target (subcellular organelle) targeting vector material technology are the keys that breaks through the cancer chemotherapy bottleneck in the tumor cell.
The technological core of targeting vector design mainly comprises the focus internal organs targeting of carrier, and passes through the cell membrane in the focus internal organs on this basis, finishes the subcellular organelle targeting at molecular drug target.Current, researcher utilizes the characteristic of some receptor of tumor cell surface (as folacin receptor) overexpression, ligand modified carrier material is successfully applied to tissue (internal organs) targeted therapy of tumor.The subcellular organelle targeting is noticeable always, and it can increase substantially the targeted therapy effect of medicine.Be subjected to the restriction of carrier material and designs thereof theory and manufacturing technology, comprise the non-virus carrier gene therapy, never obtain breakthrough for many years.
The solid lipid drug-supplying system is the new colloidal drug-supplying system that grows up early 1990s, and it is after Emulsion, liposome, polymer nanoparticle, has the target controlling and releasing drug-supplying system of development potentiality.The solid lipid drug-supplying system adopts natural or synthetic lipid materials, is carrier as stearic acid, lecithin, monoglyceride etc., pharmaceutical pack is wrapped in the lipoid nuclear makes solid micelle drug-supplying system.It had both possessed polymeric drug delivery system controlled release, had avoided advantages such as drug leakage, and the toxicity that has had Emulsion, liposome again concurrently is low, good biocompatibility, advantage that bioavailability is high.But also there are some potential limitation in the solid lipid drug-supplying system, squeezes problems such as phenomenon as limited medicine carrying ability, the medicine of storage process.
The different liquid fatty of mixed form is as mixing lipid substrate in solid lipid, with this prepare novel nano structured lipid carrier (nanostructured lipid carrier, NLC).The adding of liquid fatty can be upset the lattice structure of solid lipid rule, increases the ratio of irregular crystal formation in the nanoparticle structure, and the spatial content of carrying fat-soluble medicine is increased, thereby improves the medicine carrying ability of carrier.By controlling liquid lipid ratio, also can make NLC under body temperature, keep the solid skeletal structure, realize that the NLC controlled delivery of pharmaceutical agents discharges.
Paclitaxel is the new type natural antitumor drug that extracts from the Ramulus et folium taxi cuspidatae bark, and its chemical constitution is a kind of tetracyclic diterpene compounds in the taxanes.It promotes microtubule polymerization by combining with the cell tubulin, suppresses its depolymerization, and cell mitogen is blocked, thereby suppresses tumor growth.Paclitaxel is solvable in methanol, ethanol, dimethyl sulfoxide organic solvents such as (DMSO), and the dissolubility in water is less than 0.03mg/mL.Therefore, although paclitaxel has good antineoplastic activity,, make its intravenous administration bring very big difficulty because the dissolubility in water is very little.For solving this difficult problem, people have added surfactant polyoxyethylene castor oil hydrogenated (Cremophor EL) in injection.Though polyoxyethylene hydrogenated Oleum Ricini can increase the water solublity of paclitaxel. can cause the multiple untoward reaction that comprises severe allergic reaction.Paclitaxel is made the nanoparticle drug-supplying system, can overcome above-mentioned difficulties, improve bioavailability, intensifier target is to curative effect.
Summary of the invention
An object of the present invention is to provide a kind of nano structured lipid carrier with highly effective antineoplastic activity, this is carrier loaded antitumor drug paclitaxel, its matrix material is made up of monoglyceride and liquid lipid, the ratio that wherein liquid lipid (oleic acid) accounts for matrix material is 5-20%, paclitaxel is 3.1%～3.6% of a pastille solid lipid nanoparticle, and the particle diameter of this nano structured lipid carrier is 481～532nm.This nano structured lipid carrier is compared with paclitaxel solution, can significantly improve the antitumor curative effect of medicine on cellular level.
Another object of the present invention provides a kind of preparation method with nano structured lipid carrier of highly effective antineoplastic activity, specifically realizes by following steps:
Precision takes by weighing 30mg matrix material and 1.5mg paclitaxel, places the 3mL dehydrated alcohol, 70 ℃ of dissolvings of water-bath.With the distilled water is decentralized photo, puts in 70 ℃ of water-baths.At 400rmin
-1Under the mechanical agitation condition, organic facies is injected the 30mL decentralized photo, stir 5min, obtain paclitaxel loaded nano structured lipid carrier dispersion liquid.Resultant paclitaxel loaded nano structured lipid carrier dispersion liquid 3molL
-1HCl solution is regulated pH to 1.2, with 20000rmin
-1Centrifugal 10min, precipitation adds 0.1% poloxamer (Poloxamer), and (w v) behind the redispersion, uses 1molL
-1NaOH solution is regulated pH to 7.0.Promptly obtain paclitaxel loaded nano structured lipid carrier.
Usefulness of the present invention is: be detained the nano structured lipid carrier of function by having efficient cellular uptake and cytoplasm, molecular target is positioned at sealing of cytoplasmic antitumor drug, can increase the picked-up of tumor cell greatly to antitumor drug, and the drug level at molecular drug target position.Increase the picked-up of tumor cell, help reducing the distribution of medicine, reduce the toxic and side effects of medicine at normal structure or cell to medicine; And the increase of the drug level at molecular drug target position helps improving the curative effect of antitumor drug.
Description of drawings
Fig. 1 is the medicine release in vitro curve of paclitaxel loaded oleic acid monoglyceride nano structured lipid carrier.
Fig. 2 contains the A549 cellular uptake fluorescence inverted microscope photo of 5% oleic monoglyceride nano structured lipid carrier for the FITC labelling.
Fig. 3 contains the A549 cellular uptake fluorescence inverted microscope photo of 10% oleic monoglyceride nano structured lipid carrier for the FITC labelling.
Fig. 4 contains the A549 cellular uptake fluorescence inverted microscope photo of 20% oleic monoglyceride nano structured lipid carrier for the FITC labelling.
The specific embodiment
The present invention is described further in conjunction with the accompanying drawings and embodiments.
Embodiment 1: paclitaxel loaded preparation and the application that contains 5% oleic monoglyceride nanostructured carrier
1) the paclitaxel loaded preparation that contains 5% oleic monoglyceride nanostructured carrier
Precision takes by weighing the 30mg matrix material (ratio of oleic acid and monoglyceride is: 0.5/9.5) and the 1.5mg paclitaxel, place the 3mL dehydrated alcohol, 70 ℃ of dissolvings of water-bath respectively.With the distilled water is decentralized photo, puts in 70 ℃ of water-baths.At 400rmin
-1Under the mechanical agitation condition, organic facies is injected the 30mL decentralized photo, stir 5min, obtain the monoglyceride nano structured lipid carrier dispersion liquid of 5% oleic acid content.Resultant nano structured lipid carrier dispersion liquid 3molL
-1HCl solution is regulated pH to 1.2, with 20000rmin
-1Centrifugal 10min, precipitation adds 0.1% poloxamer (Poloxamer) (w/v) behind the redispersion, uses 1molL
-1NaOH solution is regulated pH to 7.0.Promptly obtain paclitaxel loaded oleic acid monoglyceride nano structured lipid carrier.
Table 1 is the physicochemical properties such as particle diameter, surface potential and entrapment efficiency of preparation-obtained paclitaxel loaded oleic acid monoglyceride nano structured lipid carrier.
Table 1: the particle diameter of paclitaxel loaded nano structured lipid carrier, surface potential and entrapment efficiency.
The medicine release in vitro of paclitaxel loaded nano structured lipid carrier, realize in the following manner: get the centrifugal nano structured lipid carrier precipitation redispersion that obtains in 50mL PH7.4PBS (including the 2M sodium salicylate), vortex oscillation 3min, nanoparticle is uniformly dispersed, put into 37 ℃ of constant temperature water bath agitator constant temperature vibrations, frequency of oscillation is 60 min
-1At interval certain hour (0,1,2,4,8,12,24,48h) is drawn dispersion liquid 1mL, 20000rmin
-1Centrifugal 15min, supernatant is measured the drug level in the subsequent filtrate with aperture 0.22 μ m filtering with microporous membrane, HPLC, its result is referring to Fig. 1, Fig. 1 is for containing the medicine release in vitro curve of 5%, 10%, 15% oleic paclitaxel loaded oleic acid monoglyceride nano structured lipid carrier.
2) lung cancer A549 cell of monoglyceride oleic acid nano structured lipid carrier transhipment
The present invention adopts the oleic acid monoglyceride nano structured lipid carrier that contains fluorescein isothiocyanate (fitc) (FITC) and stearylamine chemistry grafting to carry out the transhipment research of lung cancer A549 cell.The oleic acid monoglyceride nano structured lipid carrier that contains fluorescein isothiocyanate (fitc) and stearylamine chemistry grafting prepares by the following method: precision takes by weighing the 27mg matrix material, and (ratio of oleic acid and monoglyceride is respectively: 0.5/9.5) with 4.5mg fluorescein isothiocyanate (fitc) and stearylamine chemistry grafting, place the 3mL dehydrated alcohol, 70 ℃ of dissolvings of water-bath.With the distilled water is decentralized photo, puts in 70 ℃ of water-baths.At 400rmin
-1Under the mechanical agitation condition, organic facies is injected the 30mL decentralized photo, stir 5min, obtain the dispersion liquid of FITC labelling oleic acid monoglyceride nano structured lipid carrier.The dispersion liquid 3molL of resultant FITC labelling oleic acid monoglyceride nano structured lipid carrier
-1HCl solution is regulated pH to 1.2, with 20000rmin
-1Centrifugal 10min, precipitation adds 0.1% poloxamer (Poloxamer) (w/v) behind the redispersion, uses 1molL
-1NaOH solution is regulated pH to 7.0.The gained dispersion liquid is used for lung cancer A549 cell transhipment research.
Get the A549 cell, in the RPMI RPMI-1640 that contains 10% calf serum of having an appointment, cultivate (5%CO
2, 37 ℃ of incubators).When cell reaches exponential phase, can inoculate.The trophophase cell of taking the logarithm after the PBS rinse, adds trypsinization and with the culture fluid dilution, by every hole 1 * 10
5The density of individual cell is inoculated in 24 well culture plates, and after the cell attachment growth in 24 well culture plates, (final concentration is 100 μ gmL to the oleic acid monoglyceride nano structured lipid carrier of adding FITC labelling
-1), hatch 1,2,4,12, behind the 24h, wash cell 3 times with PBS, the fluorescence inverted microscope is observed also and is taken pictures, and the result is presented at carrier and A549 cell and hatches altogether after one hour and just can observe fluorescence in cell, and wherein carrier and the A549 cell result of hatching altogether after 4 and 24 hours sees Fig. 2 a and 2b respectively.
3) antitumor curative effect of paclitaxel loaded oleic acid monoglyceride nano structured lipid carrier
With the lung cancer A549 cell is model, and the IC50 value (the half fatality rate of cell) after the antitumor curative effect of paclitaxel loaded oleic acid monoglyceride nano structured lipid carrier drug feeding system is hatched altogether by drug-supplying system and cell is estimated.The cell survival rate test adopts tetrazolium salts colorimetry (MTT Assay) to measure.After 24 orifice plates were cultivated the growth of 24h cell attachment in advance, the blank that adds variable concentrations respectively contained the suspension of 5% oleic monoglyceride nano structured lipid carrier; Dehydrated alcohol 1:1 (V/V)) and the paclitaxel loaded suspension that contains 5% oleic monoglyceride nano structured lipid carrier of variable concentrations (solvent is Cremophor:, and establish control wells, every group is repeated 3 times the paclitaxel solution of variable concentrations; After hatching 48 hours, every hole adds MTT solution 60 μ L and hatches abandoning supernatant after 4 hours, PBS solution flushing 2 times, and every hole adds DMSO 500 μ L, cessation reaction.With culture plate level vibration 10min, measure trap at the 570nm place with enzyme connection detector, calculate cell survival rate by (1) formula:
Cell survival rate (%)=A
570(sample)/A
570(contrast) * 100% (1)
A wherein
570(sample) is the trap of the cell behind the adding suspension, A
570(contrast) is the trap of the cell of blank.
The IC50 value of blank oleic acid monoglyceride nano structured lipid carrier, paclitaxel solution and the paclitaxel loaded oleic acid monoglyceride nano structured lipid carrier of being measured the results are shown in Table 2.
Table 2: the IC50 value of monoglyceride oleic acid nano structured lipid carrier, paclitaxel solution and paclitaxel loaded monoglyceride oleic acid nano structured lipid carrier
The result shows that containing 5% oleic monoglyceride nano structured lipid carrier is the hypotoxicity carrier material, and paclitaxel is through containing the antitumor curative effect that can improve after 5% oleic monoglyceride nano structured lipid carrier is sealed about 2.5 times.
Embodiment 2: paclitaxel loaded preparation and the application that contains 10% oleic monoglyceride nanostructured carrier
1) the paclitaxel loaded preparation that contains 10% oleic monoglyceride nanostructured carrier
1/9) and the 1.5mg paclitaxel precision takes by weighing the 30mg matrix material (ratio of oleic acid and monoglyceride is:, place the 3mL dehydrated alcohol, 70 ℃ of dissolvings of water-bath respectively.With the distilled water is decentralized photo, puts in 70 ℃ of water-baths.At 400rmin
-1Under the mechanical agitation condition, organic facies is injected the 30mL decentralized photo, stir 5min, obtain the monoglyceride nano structured lipid carrier dispersion liquid of 10% oleic acid content.Resultant nano structured lipid carrier dispersion liquid 3molL
-1HCl solution is regulated pH to 1.2, with 20000rmin
-1Centrifugal 10min, precipitation adds 0.1% poloxamer (Poloxamer) (w/v) behind the redispersion, uses 1molL
-1NaOH solution is regulated pH to 7.0.Promptly obtain paclitaxel loaded oleic acid monoglyceride nano structured lipid carrier.
The preparation-obtained paclitaxel loaded physicochemical properties such as particle diameter, surface potential and entrapment efficiency that contain 10% oleic monoglyceride nano structured lipid carrier see Table 1.
The paclitaxel loaded medicine release in vitro that contains 10% oleic monoglyceride nano structured lipid carrier, realize in the following manner: get the centrifugal nano structured lipid carrier precipitation redispersion that obtains in 50mL PH7.4PBS (including the 2M sodium salicylate), vortex oscillation 3min, nanoparticle is uniformly dispersed, put into 37 ℃ of constant temperature water bath agitator constant temperature vibrations, frequency of oscillation is 60 min
-1At interval certain hour (0,1,2,4,8,12,24,48h) is drawn dispersion liquid 1mL, 20000rmin
-1Centrifugal 15min, supernatant is measured the drug level in the subsequent filtrate with aperture 0.22 μ m filtering with microporous membrane, HPLC.Its result is referring to Fig. 1.
2) lung cancer A549 cell that contains 10% oleic monoglyceride nano structured lipid carrier is transported
The present invention adopts the oleic acid monoglyceride nano structured lipid carrier that contains fluorescein isothiocyanate (fitc) (FITC) and stearylamine chemistry grafting to carry out the transhipment research of lung cancer A549 cell.1/9) and the chemical grafting of 4.5mg fluorescein isothiocyanate (fitc) and stearylamine the oleic acid monoglyceride nano structured lipid carrier that contains fluorescein isothiocyanate (fitc) and stearylamine chemistry grafting prepares by the following method: precision takes by weighing the 27mg matrix material, and (ratio of oleic acid and monoglyceride is respectively:, place the 3mL dehydrated alcohol, 70 ℃ of dissolvings of water-bath.With the distilled water is decentralized photo, puts in 70 ℃ of water-baths.At 400rmin
-1Under the mechanical agitation condition, organic facies is injected the 30mL decentralized photo, stir 5min, obtain the dispersion liquid of FITC labelling oleic acid monoglyceride nano structured lipid carrier.The dispersion liquid 3molL of resultant FITC labelling oleic acid monoglyceride nano structured lipid carrier
-1HCl solution is regulated pH to 1.2, with 20000rmin
-1Centrifugal 10min, precipitation adds 0.1% poloxamer (Poloxamer) (w/v) behind the redispersion, uses 1molL
-1NaOH solution is regulated pH to 7.0.The gained dispersion liquid is used for lung cancer A549 cell transhipment research.
Get the A549 cell, in the RPMI1640 culture fluid that contains 10% calf serum of having an appointment, cultivate (5%CO
2, 37 ℃ of incubators).When cell reaches exponential phase, can inoculate.The trophophase cell of taking the logarithm after the PBS rinse, adds trypsinization and with the culture fluid dilution, by every hole 1 * 10
5The density of individual cell is inoculated in 24 well culture plates, and after the cell attachment growth in 24 well culture plates, (final concentration is 100 μ gmL to the oleic acid monoglyceride nano structured lipid carrier of adding FITC labelling
-1), hatch 1,2,4,12, behind the 24h, wash cell 3 times with PBS, the fluorescence inverted microscope is observed also and is taken pictures, and the result is presented at carrier and A549 cell and hatches altogether after one hour and just can observe fluorescence in cell, and wherein carrier and the A549 cell result of hatching altogether after 4 and 24 hours sees Fig. 3 a and 3b respectively.
3) the paclitaxel loaded antitumor curative effect that contains 10% oleic monoglyceride nano structured lipid carrier
With the lung cancer A549 cell is model, and the IC50 value (the half fatality rate of cell) after the antitumor curative effect of paclitaxel loaded oleic acid monoglyceride nano structured lipid carrier drug feeding system is hatched altogether by drug-supplying system and cell is estimated.The cell survival rate test adopts tetrazolium salts colorimetry (MTT Assay) to measure.After 24 orifice plates were cultivated the growth of 24h cell attachment in advance, the blank that adds variable concentrations respectively contained the suspension of 10% oleic monoglyceride nano structured lipid carrier; Dehydrated alcohol 1:1 (V/V)) and the paclitaxel loaded suspension that contains 10% oleic monoglyceride nano structured lipid carrier of variable concentrations (solvent is Cremophor:, and establish control wells, every group is repeated 3 times the paclitaxel solution of variable concentrations; After hatching 48 hours, every hole adds MTT solution 60 μ L and hatches abandoning supernatant after 4 hours, PBS solution flushing 2 times, and every hole adds DMSO 500 μ L, cessation reaction.With culture plate level vibration 10min, measure trap at the 570nm place with enzyme connection detector, calculate cell survival rate by (1) formula:
The IC50 value of blank oleic acid monoglyceride nano structured lipid carrier, paclitaxel solution and the paclitaxel loaded oleic acid monoglyceride nano structured lipid carrier of being measured the results are shown in Table 2
The result shows that containing 10% oleic monoglyceride nano structured lipid carrier is the hypotoxicity carrier material, and paclitaxel is through containing the antitumor curative effect that can improve after 10% oleic monoglyceride nano structured lipid carrier is sealed about 6.9 times.
Embodiment 3: paclitaxel loaded preparation and the application that contains 20% oleic monoglyceride nanostructured carrier
1) the paclitaxel loaded preparation that contains 20% oleic monoglyceride nanostructured carrier
2/8) and the 1.5mg paclitaxel precision takes by weighing the 30mg matrix material (ratio of oleic acid and monoglyceride is:, place the 3mL dehydrated alcohol, 70 ℃ of dissolvings of water-bath respectively.With the distilled water is decentralized photo, puts in 70 ℃ of water-baths.At 400rmin
-1Under the mechanical agitation condition, organic facies is injected the 30mL decentralized photo, stir 5min, obtain the monoglyceride nano structured lipid carrier dispersion liquid of 20% oleic acid content.Resultant nano structured lipid carrier dispersion liquid 3molL
-1HCl solution is regulated pH to 1.2, with 20000rmin
-1Centrifugal 10min, precipitation adds 0.1% poloxamer (Poloxamer) (w/v) behind the redispersion, uses 1molL
-1NaOH solution is regulated pH to 7.0.Promptly obtain paclitaxel loaded oleic acid monoglyceride nano structured lipid carrier.
The preparation-obtained paclitaxel loaded physicochemical properties such as particle diameter, surface potential and entrapment efficiency that contain 20% oleic monoglyceride nano structured lipid carrier see Table 1.
The paclitaxel loaded medicine release in vitro that contains 20% oleic monoglyceride nano structured lipid carrier, realize in the following manner: get the centrifugal nano structured lipid carrier precipitation redispersion that obtains in 50mL PH7.4PBS (including the 2M sodium salicylate), vortex oscillation 3min, nanoparticle is uniformly dispersed, put into 37 ℃ of constant temperature water bath agitator constant temperature vibrations, frequency of oscillation is 60 min
-1At interval certain hour (0,1,2,4,8,12,24,48h) is drawn dispersion liquid 1mL, 20000rmin
-1Centrifugal 15min, supernatant is measured the drug level in the subsequent filtrate with aperture 0.22 μ m filtering with microporous membrane, HPLC, and its result is referring to Fig. 1.
2) lung cancer A549 cell that contains 20% oleic monoglyceride nano structured lipid carrier is transported
The present invention adopts the oleic acid monoglyceride nano structured lipid carrier that contains fluorescein isothiocyanate (fitc) (FITC) and stearylamine chemistry grafting to carry out the transhipment research of lung cancer A549 cell.2/8) and the chemical grafting of 4.5mg fluorescein isothiocyanate (fitc) and stearylamine the oleic acid monoglyceride nano structured lipid carrier that contains fluorescein isothiocyanate (fitc) and stearylamine chemistry grafting prepares by the following method: precision takes by weighing the 27mg matrix material, and (ratio of oleic acid and monoglyceride is respectively:, place the 3mL dehydrated alcohol, 70 ℃ of dissolvings of water-bath.With the distilled water is decentralized photo, puts in 70 ℃ of water-baths.At 400rmin
-1Under the mechanical agitation condition, organic facies is injected the 30mL decentralized photo, stir 5min, obtain the dispersion liquid of FITC labelling oleic acid monoglyceride nano structured lipid carrier.The dispersion liquid 3molL of resultant FITC labelling oleic acid monoglyceride nano structured lipid carrier
-1HCl solution is regulated pH to 1.2, with 20000rmin
-1Centrifugal 10min, precipitation adds 0.1% poloxamer (Poloxamer) (w/v) behind the redispersion, uses 1molL
-1NaOH solution is regulated pH to 7.0.The gained dispersion liquid is used for lung cancer A549 cell transhipment research.
Get the A549 cell, in the RPMI RPMI-1640 that contains 10% calf serum of having an appointment, cultivate (5%CO
2, 37 ℃ of incubators).When cell reaches exponential phase, can inoculate.The trophophase cell of taking the logarithm after the PBS rinse, adds trypsinization and with the culture fluid dilution, by every hole 1 * 10
5The density of individual cell is inoculated in 24 well culture plates, and after the cell attachment growth in 24 well culture plates, (final concentration is 100 μ gmL to the oleic acid monoglyceride nano structured lipid carrier of adding FITC labelling
-1), hatch 1,2,4,12, behind the 24h, wash cell 3 times with PBS, the fluorescence inverted microscope is observed also and is taken pictures, and the result is presented at carrier and hatches altogether for the moment with the A549 cell and then just can observe fluorescence in cell, and wherein carrier and the A549 cell result of hatching altogether after 4 and 24 hours sees Fig. 4 a and 4b respectively.
3) the paclitaxel loaded antitumor curative effect that contains 20% oleic monoglyceride nano structured lipid carrier
With the lung cancer A549 cell is model, and the IC50 value (the half fatality rate of cell) after the antitumor curative effect of paclitaxel loaded oleic acid monoglyceride nano structured lipid carrier drug feeding system is hatched altogether by drug-supplying system and cell is estimated.The cell survival rate test adopts tetrazolium salts colorimetry (MTT Assay) to measure.After 24 orifice plates were cultivated the growth of 24h cell attachment in advance, the blank that adds variable concentrations respectively contained the suspension of 20% oleic monoglyceride nano structured lipid carrier; The paclitaxel loaded suspension that contains 20% oleic monoglyceride nano structured lipid carrier of paclitaxel solution of variable concentrations (solvent is Cremophor: dehydrated alcohol 1: 1 (V/V)) and variable concentrations, and establish control wells, every group is repeated 3 times; After hatching 48 hours, every hole adds MTT solution 60 μ L and hatches abandoning supernatant after 4 hours, PBS solution flushing 2 times, and every hole adds DMSO 500 μ L, cessation reaction.With culture plate level vibration 10min, measure trap at the 570nm place with enzyme connection detector, calculate cell survival rate by (1) formula:
The IC50 value of blank oleic acid monoglyceride nano structured lipid carrier, paclitaxel solution and the paclitaxel loaded oleic acid monoglyceride nano structured lipid carrier of being measured the results are shown in Table 2.
The result shows that containing 20% oleic monoglyceride nano structured lipid carrier is the hypotoxicity carrier material, and paclitaxel is through containing the antitumor curative effect that can improve after 20% oleic monoglyceride nano structured lipid carrier is sealed about 14.3 times.
Claims (2)
1. nano structured lipid carrier with highly effective antineoplastic activity, it is characterized in that: load antitumor drug paclitaxel, its matrix material is made up of monoglyceride and liquid lipid, liquid lipid accounts for the 5-20% of matrix material, paclitaxel is the 3.1%-3.6% of pastille solid lipid nanoparticle, particle diameter is 481～532nm, and described liquid lipid is selected oleic acid for use.
2. a kind of nano structured lipid carrier with highly effective antineoplastic activity according to claim 1 is characterized in that: realize by following steps:
Precision takes by weighing 30mg matrix material and 1.5mg paclitaxel, places the 3mL dehydrated alcohol, and 70 ℃ of dissolvings of water-bath are decentralized photo with the distilled water, put in 70 ℃ of water-baths, at 400rmin
-1Under the mechanical agitation condition, organic facies is injected the 30mL decentralized photo, stir 5min, obtain paclitaxel loaded nano structured lipid carrier dispersion liquid, resultant paclitaxel loaded nano structured lipid carrier dispersion liquid 3molL
-1HCl solution is regulated pH to 1.2, with 20000rmin
-1Centrifugal 10min, precipitation adds w/v and behind 0.1% the poloxamer redispersion, uses 1molL
-1NaOH solution is regulated pH to 7.0, promptly gets the purpose product.
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| CN105541762B (en) * | 2016-01-19 | 2018-06-19 | 沈阳药科大学 | Docetaxel-oleic acid prodrug and its nano structured lipid carrier and application |
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