CN111939138A - Method for preparing taxol nano-drug by taking apoferritin as carrier and recovering taxol - Google Patents
Method for preparing taxol nano-drug by taking apoferritin as carrier and recovering taxol Download PDFInfo
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Abstract
The invention relates to a method for preparing a taxol nano-drug taking apoferritin as a carrier and recovering taxol. Paclitaxel is the most excellent natural broad-spectrum and highly effective antitumor drug which is found at present, but the clinical application of paclitaxel is limited due to the poor water solubility and the lack of targeting property. The apoferritin is hollow cage-shaped protein formed by self-assembly of 24 protein subunits, and the nano cage-shaped protein can load paclitaxel into the nano cage-shaped protein through depolymerization and recombination of the protein subunits to form the paclitaxel nano drug taking the apoferritin as a carrier. When preparing paclitaxel nano-drugs, expensive paclitaxel is wasted because it cannot be recovered due to low loading rate. The invention provides a method for recovering paclitaxel after preparing a paclitaxel nano-drug, which can greatly reduce the preparation cost and realize the recovery and reuse of the paclitaxel.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a method for preparing a taxol nano-drug by taking apoferritin as a carrier and recovering taxol.
Background
Cancer remains a significant cause of human death, while chemotherapy is one of the most effective means for treating cancer in the clinic, and the use of excellent chemotherapeutic drugs is the key to the success of chemotherapy. Paclitaxel is a broad-spectrum and efficient anticancer drug, is the most excellent natural antitumor drug found at present, and is widely used for treating cancers such as breast cancer, ovarian cancer, partial head and neck cancer, lung cancer and the like in clinic.
However, because the water solubility of the paclitaxel is very poor, the commercially available paclitaxel injection mainly adopts the volume ratio of the polyoxyethylene castor oil to the ethanol to be miscible and dissolved, so that the water solubility of the paclitaxel is increased, but the polyoxyethylene castor oil can generate serious toxic and side effects in a human body; and because the taxol lacks the targeting property, the injection can also cause serious adverse effects on other normal cells, organs and tissues. The apoferritin is a nano hollow cage-shaped structure formed by self-assembly of 24 protein subunits, the nano cage has good water solubility, strong biocompatibility, good in-vivo stability and uniform and ideal size, and the apoferritin has targeting property and can be specifically combined with transferrin receptor 1(TfR1) overexpressed in tumor cells. In addition, the protein can load paclitaxel into a nano cage to form a paclitaxel nano medicament taking apoferritin as a carrier by regulating depolymerization and recombination of protein subunits, the paclitaxel nano medicament greatly improves the water solubility of the paclitaxel, enhances the targeting property of the paclitaxel, and is an ideal nano medicament.
However, when preparing the taxol nano-drug using apoferritin as a carrier, the loading rate of taxol is low, generally 12% -18%, most of taxol is wasted because of not being utilized, which results in an increase in the cost of preparing the taxol nano-drug. Recovery of unused paclitaxel is therefore a key to cost reduction.
Disclosure of Invention
The invention aims to improve the water solubility of paclitaxel, increase the targeting property of paclitaxel, relieve the adverse reaction on human body, and reduce the toxic and side effects of paclitaxel on normal cells, organs and tissues as much as possible, and provides a paclitaxel nano-drug taking apoferritin as a carrier, which not only improves the water solubility of paclitaxel to 100%, but also can be specifically combined with TfR1 and enter tumor cells under the mediation of TfR1, effectively inhibits the growth, migration and diffusion of the tumor cells, can greatly improve the treatment effect of cancer, and realizes the targeted treatment and accurate treatment of cancer. In addition, in the process of preparing the taxol nano-drug, the unused taxol is recovered, the cost for preparing the nano-drug is greatly reduced, and the recovery and the reutilization of the taxol are realized.
To solve the above technical problems, the present invention provides the following technical solutions:
the invention provides a preparation method of a taxol nano-drug taking apoferritin as a carrier, which comprises the following steps:
(1) cloning and expressing apoferritin;
(2) separating and purifying apoferritin;
(3) preparing taxol nanometer medicine with apoferritin as carrier and recovering unused taxol
Preferably, the ferritin preparation method in step (1) comprises the following steps:
a. constructing an apoferritin cage expression engineering bacterium: the apoferritin encoding gene was cloned into a plasmid vector and transformed into competent cells. Screening positive monoclonal transformant through antibiotic resistance to obtain engineering bacteria expressing apoferritin;
b. expression of apoferritin: inoculating engineering bacteria expressing apoferritin into a culture medium, adding IPTG (isopropyl-beta-D-thiogalactoside) to induce expression when the OD600 value of the bacteria liquid reaches a certain value, and centrifugally collecting bacteria.
Preferably, the engineering bacteria in the step a heterologously express apoferritin through escherichia coli;
preferably, the plasmid vector in step a is pET-20b (+);
preferably, the antibiotic in step a is ampicillin.
Preferably, the OD600 value in step b is 0.6-0.8;
preferably, the final concentration of IPTG in step b is 0.5 mM;
preferably, the induction temperature in step b is 30 ℃;
preferably, the induction time in step b is 6-8 h;
preferably, the centrifugal speed in the step b is 10000 rpm;
preferably, the centrifugation time in step b is 30 min.
Preferably, the separation and purification of apoferritin in step (2) mainly comprises the following steps:
c. crushing the collected engineering bacteria expressing the target protein, collecting supernatant, thermally treating the supernatant, and centrifuging again to obtain the supernatant which is crude apoferritin;
d. and purifying the crude protein to obtain refined protein.
Preferably, the disruption in step c is ultrasonication;
preferably, the crushing time in step c is 30 min;
preferably, the temperature of the heat treatment in the step c is 60 ℃;
preferably, the heat treatment time in step c is 10 min;
preferably, the centrifugal rotation speed of the step c is 10000 rpm;
preferably, the centrifugation time in step c is 30 min.
Preferably, the chromatography in step d is affinity chromatography or gel filtration chromatography;
preferably, the chromatographic column in step d is a nickel column or a Superdex 200 gel filtration chromatographic column.
Preferably, the preparation of the taxol nano-drug with apoferritin as a carrier in the step (3) mainly comprises the following steps:
e. mixing the apoferritin solution and paclitaxel solution according to a certain molar ratio, adjusting pH of the solution to 2.5-3, slowly stirring, adjusting pH of the solution to 7.0-7.5 again to obtain mixed solution of apoferritin-paclitaxel, free paclitaxel, denatured apoferritin, etc.;
f. and e, averagely dividing the mixed solution finally obtained in the step e into a plurality of groups, respectively putting the groups into dialysis bags for dialysis for different times, taking out the mixed solution, continuously dialyzing the supernatant after centrifugation, accumulating and dialyzing for a certain time, detecting the amount of the paclitaxel in the paclitaxel nano-drug, and calculating the encapsulation efficiency. The encapsulation efficiency was 100% of the amount of paclitaxel encapsulated in the apoferritin cage/total amount of paclitaxel
g. Dissolving the precipitate obtained by centrifugation in organic solvent, shaking, mixing thoroughly, centrifuging to obtain supernatant, and detecting the amount of paclitaxel in the supernatant. Removing organic solvent from the supernatant to obtain pure paclitaxel.
Preferably, all processes in step e are carried out at 4 ℃ and all processes are stirred slowly;
preferably, the paclitaxel solution in step e is a solution of paclitaxel dissolved in absolute ethanol;
preferably, the molar ratio of step e is 1: 200;
preferably, the stirring time in step e is 10 min.
Preferably, in step f, the supernatant is adjusted to pH 2.5-3 again, centrifuged again, and part of the supernatant is subjected to HPLC to detect the amount of paclitaxel in the apoferritin-paclitaxel;
preferably, the cut-off value of the dialysis bag of step f is 6-8 kDa;
preferably, the dialysis time of step f is 18 h;
preferably, the centrifugal speed of step f is 6000 rpm;
preferably, the centrifugation time in step f is 10 min.
Preferably, the organic solvent of step g is absolute ethanol;
preferably, the centrifugation speed of the step g is 10000 rpm;
preferably, the centrifugation time of step g is 10 min;
preferably, the method for removing the organic solvent in the step g is vacuum drying.
As a preferred technical scheme, the preparation method of the taxol nano-drug with the apoferritin as the carrier comprises the following steps:
cloning and expressing apoferritin: the apoferritin encoding gene was cloned into a pET-20b (+) plasmid vector and transformed into E.coli competent cells. Screening positive monoclonal transformant through ampicillin to obtain engineering bacteria expressing apoferritin; and (3) expressing the recombinant protein, inoculating the engineering bacteria expressing the apoferritin into an LB culture medium containing ampicillin, adding IPTG (isopropyl-beta-thiogalactoside) for induction expression when the OD600 value of the bacteria liquid reaches 0.6-0.8, and centrifugally collecting bacteria.
Separating and purifying the apoferritin: crushing engineering bacteria expressing apoferritin, centrifuging, collecting supernatant, heat treating the supernatant at 60 deg.C for 10min, centrifuging again, collecting supernatant, and performing affinity chromatography with nickel column and gel filtration chromatography to obtain pure apoferritin.
Mixing the apoferritin solution with paclitaxel dissolved in solvent such as anhydrous alcohol at a molar ratio of 1: 200, adjusting pH of the mixed solution to 2.5, slowly stirring for 10min, and re-adjusting pH of the solution to 7.0-7.5 to obtain mixed solution of apoferritin-carried paclitaxel nano drug, free paclitaxel, denatured apoferritin, etc. And (3) putting the mixed solution into a dialysis bag, dialyzing to remove free paclitaxel, taking out after dialyzing for 12-18h, centrifuging at 6000rpm for 10min to obtain supernatant, namely the paclitaxel nano-drug taking ferritin as a carrier, and detecting the content of paclitaxel in the paclitaxel nano-drug by HPLC. And (3) resuspending the precipitate obtained by dialysis by using an organic solvent such as absolute ethyl alcohol, fully shaking, centrifugally collecting supernatant, and removing the organic solvent in the supernatant to obtain a pure paclitaxel product.
The invention has the beneficial effects that: (1) the invention provides a method for preparing taxol nano-drugs; (2) the paclitaxel nano-drug prepared by the invention has the effect of targeting tumor cells, and provides a precondition for realizing accurate treatment of the drug; the invention (3) provides a simple and feasible method for recovering unused paclitaxel, and reduces the production cost. Therefore, the invention has great potential in the field of biological medicine and has good application prospect.
Drawings
FIG. 1: in example 2 apoferritin was purified by nickel column affinity chromatography of the fractions eluted.
FIG. 2: characterization of the pure apoferritin obtained in example 2. FIG. 2A is a size exclusion chromatogram of apoferritin; FIG. 2B is a transmission electron micrograph of apoferritin; figure 2C is a circular dichroism map of apoferritin.
FIG. 3: characterization of paclitaxel nano-drug with ferritin as carrier was prepared in example 3. FIG. 3A is a size exclusion chromatogram of a nano-drug of paclitaxel using apoferritin as a carrier; FIG. 3B is a circular dichroism spectrum of a paclitaxel nano-drug using apoferritin as a carrier; fig. 3C is a dynamic light scattering characterization particle size distribution diagram of the paclitaxel nano-drug using apoferritin as a carrier.
FIG. 4: the flow chart of the preparation of the taxol nano-drug taking ferritin as a carrier and the recovery of the taxol in the embodiment 3 is shown.
FIG. 5: the release profile of paclitaxel in the paclitaxel nano-drug using apoferritin as a carrier in example 4.
FIG. 6: the survival rate of SMMC-7721 cells in example 5 is determined by the effect of paclitaxel nano-drugs with different concentrations and apoferritin as a carrier.
FIG. 7: the flow cytometer in example 6 examined the binding ability of SMMC-7721 cells to HFtn, HFtn-PTX nanoparticles.
FIG. 8: in example 7, after the action of paclitaxel and a paclitaxel nano-drug using apoferritin as a carrier, the SMMC-7721 cells are detected by a flow cytometer, wherein A is an apoptosis characteristic diagram of each group, and B is apoptosis rate statistics.
Examples of the embodiments
The invention will be further explained and illustrated with reference to specific examples, which are, however, to be understood as being given by way of illustration only and not in any way limitative of the invention.
Example 1. cloning and expression of apoferritin;
the apoferritin encoding gene was cloned into a pET-20b (+) plasmid vector and transformed into E.coli BL21 competent cells. Screening positive monoclonal transformant through ampicillin to obtain engineering bacteria expressing apoferritin; inoculating the engineering bacteria expressing the apoferritin into an LB culture medium containing ampicillin, adding IPTG (isopropyl-beta-D-thiogalactoside) for induction expression when the OD600 value of the bacteria liquid reaches 0.6-0.8, adding IPTG (isopropyl-beta-thiogalactoside) with the final concentration of 0.5mM for induction expression for 6-8h, and centrifuging at 10000rpm for 5-8min to collect bacteria.
Example 2. isolation and purification of apoferritin;
ultrasonically crushing engineering bacteria expressing apoferritin, centrifuging, collecting supernatant, thermally treating the supernatant at 60 deg.C for 10min, centrifuging again, collecting supernatant, and performing nickel column affinity chromatography and gel filtration chromatography to obtain pure apoferritin.
Collecting engineering bacteria expressing apoferritin, ultrasonically crushing for 30-40min, centrifuging at 10000rpm for 30min, collecting supernatant, heat treating the supernatant at 60 deg.C for 10min, centrifuging at 10000rpm for 30min, collecting supernatant, subjecting to nickel column affinity chromatography, eluting with gradient imidazole solution (5mM, 10mM, 20mM, 250mM) to obtain impurity protein and target recombinant protein, collecting eluate, analyzing protein components in the eluate by SDS-PAGE, and purifying the target protein eluate again by gel filtration chromatography to obtain pure apoferritin.
Example 3 preparation of Taxol Nanomedicine with apoferritin as Carrier and recovery of Taxol
Mixing the apoferritin solution and paclitaxel dissolved in solvents such as absolute ethanol according to a molar ratio of 1: 200 to form a mixed solution, adjusting the pH of the mixed solution to 2.5, slowly stirring for 10min, and then adjusting the pH of the solution to 7.0-7.5 again to obtain a mixed solution of a paclitaxel nano-drug, free paclitaxel, denatured apoferritin and the like with apoferritin as a carrier. Putting the mixed solution into a dialysis bag with a cut-off value of 6-8kDa, dialyzing to remove free paclitaxel, taking out after dialyzing for 12-18h, centrifuging at 6000rpm for 10min to obtain a supernatant, namely the paclitaxel nano-drug taking ferritin as a carrier, taking part of the supernatant, readjusting the pH to 2.5 to re-release the paclitaxel in the apoferritin into the solution, and detecting the content of the paclitaxel in the paclitaxel nano-drug by HPLC. And (3) resuspending the precipitate obtained by dialysis by using an organic solvent such as absolute ethyl alcohol, fully shaking, centrifugally collecting supernatant, and removing the organic solvent in the supernatant to obtain a pure paclitaxel product.
Example 4 stability and in vitro Release of Taxol Nandrugcompounds with apoferritin as Carrier
Placing paclitaxel nanometer medicine into dialysis bag (molecular weight cut-off is 6-8kDa), placing into PBS buffer solution with pH of 7.4, and incubating at 37 deg.C. Samples were taken at incubation times 0, 0.5, 1, 2, 3, 4, 6, 8, 12, 24, 48, 60 hours and the released paclitaxel was quantified by HPLC. Paclitaxel release amount-total amount of released paclitaxel/paclitaxel. The results are shown in fig. 5, and the paclitaxel nano-drug using apoferritin as the carrier is relatively stable at pH 7.4. However, paclitaxel in the paclitaxel nano-drug is easier to release at pH 5.0, and the result shows that the release form of the paclitaxel nano-drug is pH-dependent.
Example 5 in vitro cytotoxicity study of Taxol Nandrugs with apoferritin as Carrier
In order to study the in vitro cytotoxicity of the taxol nano-drug taking the apoferritin as the carrier, SMMC-7721 was seeded in a 96-well plate at a density of 5000 cells per well, and after 24 hours of culture at 37 ℃, the taxol with the taxol content of 1-5000ng/mL and the taxol nano-drug taking the apoferritin as the carrier were added into the same well for 48 hours of culture. Wash 2 times with PBS, incubate 4h after addition of MTT, centrifuge carefully remove supernatant, add dimethyl sulfoxide, and measure uv absorbance at 570 nm. The result shows that the toxicity of the taxol nano-drug taking the apoferritin as the carrier is lower than that of the taxol naked drug. The same phenomenon is also observed in other drug-loaded systems, which may be related to the fact that paclitaxel enters cells through passive diffusion, while the paclitaxel nano-drug taking apoferritin as a carrier enters cells through an endocytosis mechanism mediated by transferrin receptor 1(TfR 1).
Example 6 targeting of Taxol Nanomedicines with apoferritin as vehicle
SMMC-7721 cells were seeded in well plates to grow to 1X 105About one cell, trypsinized, washed 3 times with pre-chilled PBS, and added with 50. mu.g/mL FITC-labeled HFtn and HFtn-PTX sodiumRice granules, 4 degrees C were incubated for 45min after using 0.3% BSA/PBS to wash cells 3 times, the cells were suspended in PBS, by flow cytometry to detect the fluorescence intensity. As shown, the fluorescence intensities of the two groups of FITC-labeled HFtn and HFtn-PTX nanoparticles are substantially equivalent, much higher than that of the PBS blank control group. This suggests that HFtn and HFtn-PTX nanoparticles can rapidly bind to receptors and enter cells, and this result also demonstrates that whether the HFtn nanocages are loaded with drugs does not affect the binding of nanoparticles to receptors.
Example 8 in vitro apoptosis study of Taxol Nandrugs with apoferritin as Carrier
In order to study the in vitro apoptosis characteristics of the taxol nano-drug taking apoferritin as a carrier, an Annexin V-FITC apoptosis kit is used for testing. SMMC-7721 at 4X 10 per well5The density of individual cells was plated in 6-well plates, and after 24 hours of incubation at 37 ℃ HFtn-PTX, PTX with a paclitaxel content of 6. mu.g/mL were added to different wells for 24 hours to add a blank culture group as a control. Cells were collected and suspended in binding buffer provided by Annexin V-FITC apoptosis kit, then 5. mu.L of Annexin V-FITC was added to each cell suspension and incubated at room temperature for 15min, followed by 5. mu.L of propidium iodide. Double-stained cells were immediately analyzed by flow cytometry. The results show that: apoptosis was evident in the PTX group and HFtn-PTX group compared to the control group, with apoptosis more evident in the HFtn-PTX group, which may be related to factors such as the HFtn-PTX nanoparticles binding to cells, entering cells and releasing drugs at a faster rate than the PTX particles.
Claims (8)
1. A method for preparing taxol nano-drugs with apoferritin as a carrier and recovering taxol is characterized in that the preparation method comprises the following steps: mixing the apoferritin solution with paclitaxel solution, adjusting pH to 2.5-3.0, stirring, adjusting pH to 7.0-7.5 to obtain mixed solution of apoferritin-paclitaxel, free paclitaxel, and denatured apoferritin; and (3) putting the obtained mixed solution into a dialysis bag for dialysis, taking out a dialysis sample, and centrifuging to obtain a supernatant, namely the taxol nano-drug taking the apoferritin as a carrier. Re-suspending and precipitating with anhydrous ethanol, shaking sufficiently, centrifuging again, and removing organic solvent in supernatant to obtain paclitaxel.
2. The method for preparing the taxol nano-drug with apoferritin as a carrier and recovering taxol according to claim 1, wherein the apoferritin is human heavy chain ferritin.
3. The method for preparing the taxol nano-drug using apoferritin as a carrier and recovering the taxol according to claim 2, wherein the amino acid sequence of the human heavy chain ferritin is shown as SEQ ID No.2, and the nucleic acid sequence is shown as SEQ ID No. 1.
4. The method for preparing the apoferritin-carried paclitaxel nano drug and recovering paclitaxel according to claim 1, wherein the molar ratio of apoferritin to paclitaxel is 1: 200.
5. The method for preparing a apoferritin-carried paclitaxel nano drug and recovering paclitaxel according to claim 1, wherein the preparation process is performed at 4 ℃.
6. The method for preparing the apoferritin-carried paclitaxel nano drug and recovering paclitaxel according to claim 1, wherein the cut-off value of dialysis bag is 6-8kDa, and dialysis time is 12-18 h.
7. The method for preparing a apoferritin-carried paclitaxel nano drug and recovering paclitaxel according to claim 1, wherein the method for removing organic solvent is vacuum drying.
8. The method of any one of claims 1-7, wherein the method comprises preparing a nano-drug of paclitaxel using apoferritin as a carrier and recovering paclitaxel.
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| CN112826943A (en) * | 2021-01-14 | 2021-05-25 | 齐鲁工业大学 | Protein nano-carrier, carrier loaded with targeting substance, preparation method and application |
| CN114668771A (en) * | 2022-03-18 | 2022-06-28 | 南京林业大学 | Preparation method and application of ferritin nanoparticles loaded with adriamycin and ursolic acid together |
| CN114984217A (en) * | 2022-06-21 | 2022-09-02 | 南京林业大学 | Preparation method and application of aptamer ferritin nanoparticles co-loaded with paclitaxel and manganese phthalocyanine |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112426534A (en) * | 2020-12-07 | 2021-03-02 | 南京林业大学 | Ferritin nanoparticle with C-terminal modified tumor penetrating peptide RGERPPR, and preparation method and application thereof |
| CN112426534B (en) * | 2020-12-07 | 2021-09-24 | 南京林业大学 | Ferritin nanoparticle with C-terminal modified tumor penetrating peptide RGERPPR, and preparation method and application thereof |
| CN112826943A (en) * | 2021-01-14 | 2021-05-25 | 齐鲁工业大学 | Protein nano-carrier, carrier loaded with targeting substance, preparation method and application |
| CN114668771A (en) * | 2022-03-18 | 2022-06-28 | 南京林业大学 | Preparation method and application of ferritin nanoparticles loaded with adriamycin and ursolic acid together |
| CN114668771B (en) * | 2022-03-18 | 2022-12-06 | 南京林业大学 | Preparation method and application of ferritin nanoparticles loaded with adriamycin and ursolic acid together |
| CN114984217A (en) * | 2022-06-21 | 2022-09-02 | 南京林业大学 | Preparation method and application of aptamer ferritin nanoparticles co-loaded with paclitaxel and manganese phthalocyanine |
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