CN111450045B - Double-layer gel storage, preparation method and application of preparation for preventing tumor recurrence after preparation - Google Patents
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Abstract
The invention relates to a double-layer gel storage, a preparation method thereof and application of a preparation for preventing tumor recurrence after preparation, belonging to the technical field of biological medicines. The double-layer gel storage comprises an outer layer gel storage and an inner layer gel storage, wherein the outer layer gel storage is wrapped outside the inner layer gel storage; the outer layer gel storage reservoir comprises 28-38 parts by mass of phospholipid, 62-70 parts by mass of glyceride and 1-8 parts by mass of cosolvent, and the inner layer gel storage reservoir comprises 40-55 parts by mass of phospholipid, 40-55 parts by mass of glyceride and 5-20 parts by mass of cosolvent; the outer layer gel storage and the inner layer gel storage also comprise an anti-tumor drug. The invention prepares phospholipid and glyceride gel precursors with different proportions into double-layer gel for programmed release of drugs; the gel precursor preparation with different properties adopts a double-barrel syringe to obtain the effect of a double-layer gel drug storage by injection, and the preparation can be quickly gelated when meeting water to simultaneously realize the programmed release of different drugs, thereby meeting the requirement of effective drug combination.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to a double-layer gel storage, a preparation method thereof and application of a preparation for preventing tumor recurrence after preparation.
Background
The recurrence and metastasis of tumors are severely life-threatening to the patient. Especially in the case of very aggressive tumors, the mortality rate after recurrence and metastasis is high.
Although surgical resection is a common approach in the treatment of solid tumors at present, surgery is not radical for small tumor cells that are invisible to the naked eye. These surgical areas still have residual tumor cells that can lead to recurrence in situ. Some patients have tumor cells in their blood before surgery, and these cells will follow the blood to other sites. The tumor at the primary site is surgically removed and these scattered tumor cells can also cause metastasis.
In addition to surgical resection, clinically used means include chemotherapy and radiotherapy. Relatively large doses of chemotherapeutic drugs can cause great toxicity to the body, and chemotherapy is not ideal as a local treatment means.
In recent years, the monitoring and elimination of tumor cells in the body by means of the immune system has become a big hot spot for preventing the recurrence and metastasis of tumors. However, even with the help of immunotherapeutic drugs, the adverse immune microenvironment of the tumor patient himself can impair the efficacy of the immunotherapeutic drug to a large extent.
Disclosure of Invention
The invention solves the problem that the preparation in the prior art can not well prevent the tumor recurrence and metastasis, and provides a double-layer gel storage. The double-layer gel reservoir comprises an outer layer gel reservoir and an inner layer gel reservoir, wherein the outer layer gel reservoir is wrapped outside the inner layer gel reservoir; the outer layer gel storage reservoir comprises 28-38 parts by mass of phospholipid, 62-70 parts by mass of glyceride and 1-8 parts by mass of cosolvent, and the inner layer gel storage reservoir comprises 40-55 parts by mass of phospholipid, 40-55 parts by mass of glyceride and 5-20 parts by mass of cosolvent; the outer layer gel storage and the inner layer gel storage also comprise an anti-tumor drug. The invention prepares phospholipid and glyceride gel precursors with different proportions into double-layer gel for programmed release of drugs; the preparation can be quickly gelated when meeting water to realize the programmed release of different medicines simultaneously, thereby meeting the requirement of effective medicine combination.
According to a first aspect of the present invention, there is provided a bilayer gel reservoir comprising an outer layer gel reservoir and an inner layer gel reservoir, the outer layer gel reservoir being wrapped around the outside of the inner layer gel reservoir; the outer layer gel storage reservoir comprises 28-38 parts by mass of phospholipid, 62-70 parts by mass of glyceride and 1-8 parts by mass of cosolvent, and the inner layer gel storage reservoir comprises 40-55 parts by mass of phospholipid, 40-55 parts by mass of glyceride and 5-20 parts by mass of cosolvent; the outer layer gel storage and the inner layer gel storage also comprise an anti-tumor drug.
Preferably, the antitumor drug in the outer layer gel storage is a chemotherapeutic drug, and the antitumor drug in the inner layer gel storage is an antitumor antibody drug;
preferably, the chemotherapeutic agent is loaded on the photothermal agent.
Preferably, the chemotherapeutic drug is doxorubicin, paclitaxel, gemcitabine, or sorafenib; the anti-tumor antibody drug is a PD-1 antibody, a PD-L1 antibody or a CD47 antibody.
Preferably, the outer gel reservoir further comprises a photothermal agent;
preferably, the photothermal agent is graphene, indocyanine green or gold nanoparticles.
Preferably, the photothermal agent in the outer gel reservoir is 0.6 to 1 part by mass.
Preferably, the phospholipid is soybean lecithin or egg yolk lecithin; the glyceride is diglyceride, triolein or cholesylglyceride; the cosolvent is absolute ethyl alcohol, methanol, propylene glycol or polyethylene glycol.
According to another aspect of the present invention, there is provided a method of fabricating a bilayer gel reservoir, comprising the steps of:
(1) mixing 28-38 parts by mass of phospholipid, 62-70 parts by mass of glyceride and 1-8 parts by mass of cosolvent to obtain an outer-layer gel precursor preparation, and then adding an anti-tumor drug into the outer-layer gel precursor preparation; mixing 40-55 parts by mass of phospholipid, 40-55 parts by mass of glyceride and 5-20 parts by mass of cosolvent to obtain an inner-layer gel precursor preparation, and then adding an anti-tumor drug into the inner-layer gel precursor preparation;
(2) and (2) respectively filling the outer layer gel precursor and the inner layer gel precursor which are obtained in the step (1) and added with the antitumor drugs into a syringe barrel of a double-barrel syringe, then pushing the inner layer gel precursor into water, gelatinizing the inner layer gel precursor with water to form inner layer gel, and then pushing the outer layer gel precursor to form outer layer gel outside the inner layer gel, so as to obtain the double-layer gel storage.
Preferably, the anti-tumor drug added into the outer layer gel precursor preparation is a chemotherapeutic drug, and the anti-tumor drug added into the inner layer gel precursor preparation is an anti-tumor antibody drug; after the antitumor antibody medicament and amphiphilic polymer form nano particles, freeze-drying the nano particles, and then adding the freeze-dried nano particles into an inner-layer gel precursor preparation;
preferably, the chemotherapeutic agent is loaded on the photothermal agent.
Preferably, step (1) further comprises the step of adding a photothermal agent after adding the anti-tumor drug to the outer layer gel precursor formulation;
preferably, the photothermal agent is graphene, indocyanine green or gold nanoparticles.
According to another aspect of the present invention, there is provided the use of any one of the bilayer gel depots for the preparation of a postoperative tumor recurrence prevention formulation or a postoperative tumor metastasis prevention formulation.
Generally, compared with the prior art, the above technical solution conceived by the present invention mainly has the following technical advantages:
(1) the invention prepares phospholipid and glyceride gel precursors with different proportions into double-layer gel for programmed release of drugs; the gel precursor preparation with different properties adopts a double-barrel syringe to obtain the effect of a double-layer gel drug storage by injection, and the preparation can be quickly gelated when meeting water to simultaneously realize the programmed release of different drugs, thereby meeting the requirement of effective drug combination.
(2) The outer layer gel storage in the invention has the function of quick release or light-operated release, and the inner layer gel storage has the long-term slow release performance. The inclusion objects in the drug-loaded double-layer gel precursor preparation can be uniformly dispersed; the viscosity is low and can be used for injection; after entering a human body, the hydrogel can act with body fluid, the inner layer gel can quickly form gel, and the gelation rate of the outer layer gel is slightly slow, so that double-layer gel is formed, the programmed release of the drug can be realized, and the requirement of combined medication is met; the biocompatibility is good, the inflammatory reaction of the organism can not be caused, and the toxic and side effects of the medicine are avoided; the frequency of medication can be reduced; the cost is low, the preparation method is simple, and the industrialization is easy; can be used for preventing tumor recurrence and metastasis after operation.
(3) In the invention, the outer layer gel storage comprises 28-38 parts by mass of phospholipid and 62-70 parts by mass of glyceride, and the inner layer gel storage comprises 40-55 parts by mass of glyceride and 40-55 parts by mass of glyceride; due to the different ratio of phospholipids to glycerides, the resulting gel phase transition temperature is significantly different. In a certain temperature range, the outer layer gel reaches the phase transition temperature, and the outer layer drug is quickly released. At this time, the inner layer gel does not reach the phase transition temperature, and the inner layer drug is still slowly released.
(4) Preferably, the outer layer gel reservoir also comprises chemotherapeutic drugs, the inner layer gel reservoir also comprises antibody drugs, and the outer layer gel reservoir rapidly releases the chemotherapeutic drugs after reaching the phase transition temperature. The chemotherapy drug can kill part of tumor cells, thereby activating the immune system of the body, and the immune activation state is more beneficial to the function of the inner layer antibody drug. The inner layer antibody medicine which is slowly released kills the tumor by the immune blocking therapy when the immune system is active, and is cooperated with the chemotherapy of the outer layer.
(5) Preferably, the outer reservoir further includes a photothermal agent that converts light energy into thermal energy by externally applied laser radiation, such that the temperature of the entire outer gel is raised above the phase transition temperature and below the phase transition temperature of the inner gel. Thereby realizing light-operated medicine release and gradual medicine release. And the temperature is controlled within the temperature range of the tumor thermotherapy, and the thermotherapy can be assisted to kill the tumor better.
Drawings
FIG. 1 is a diagram of a bilayer gel reservoir of the present invention.
FIG. 2 is a rheological diagram of the phase transition temperature of the gel of the inner and outer layers.
Fig. 3 is a graph of the effect of light-operated temperature rise of the outer gel.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention. In addition, the technical features involved in the embodiments of the present invention described below may be combined with each other as long as they do not conflict with each other.
Example 1
A double-layer gel storage reservoir for preventing relapse after tumor operation is prepared from the following two raw materials in percentage by weight: the first, 35 parts by mass of soybean lecithin, 65 parts by mass of glycerol dioleate and 5 parts by mass of absolute ethyl alcohol are marked as LG 35/65. And the second, 50 parts by mass of soybean lecithin, 50 parts by mass of glycerol dioleate and 10 parts by mass of absolute ethyl alcohol, which are marked as LG 50/50.
The preparation steps are as follows:
s1: mixing 35 parts by mass of phospholipid, 65 parts by mass of glyceride and an anti-tumor drug, adding 5 parts by mass of cosolvent, uniformly mixing on a mixer to completely dissolve the phospholipid and the glyceride to obtain an outer-layer gel precursor, mixing 50 parts by mass of phospholipid, 50 parts by mass of glyceride and the anti-tumor drug, adding 10 parts by mass of cosolvent, uniformly mixing on the mixer to completely dissolve the phospholipid and the glyceride to obtain an inner-layer gel precursor;
s2: and (4) respectively filling the inner layer gel precursor and the outer layer gel precursor obtained in the step (S1) into a syringe barrel of a double-barrel syringe, then pushing the inner layer gel precursor into water, gelling the inner layer gel precursor with water to form inner layer gel, and then pushing the outer layer gel precursor, wherein the outer layer gel can wrap the formed inner layer gel, so that the double-layer gel storage bin is obtained. As shown in fig. 1.
Example 2
A double-layer gel storage reservoir for preventing relapse after tumor operation is prepared from the following two raw materials in percentage by weight: the first, 36 parts by mass of soybean lecithin, 64 parts by mass of glycerol dioleate and 8 parts by mass of absolute ethyl alcohol are marked as LG 36/64. And secondly, 45 parts by mass of soybean lecithin, 55 parts by mass of glycerol dioleate and 5 parts by mass of absolute ethyl alcohol, which are marked as LG 45/55.
The preparation steps are as follows:
s1: mixing 36 parts by mass of phospholipid, 64 parts by mass of glyceride and an anti-tumor drug, adding 8 parts by mass of cosolvent, uniformly mixing on a mixer to completely dissolve the phospholipid and the glyceride to obtain an outer-layer gel precursor, mixing 45 parts by mass of phospholipid, 55 parts by mass of glyceride and the anti-tumor drug, adding 5 parts by mass of cosolvent, uniformly mixing on the mixer to completely dissolve the phospholipid and the glyceride to obtain an inner-layer gel precursor;
s2: and (4) respectively filling the inner layer gel precursor and the outer layer gel precursor obtained in the step (S1) into a syringe barrel of a double-barrel syringe, then pushing the inner layer gel precursor into water, gelling the inner layer gel precursor with water to form inner layer gel, and then pushing the outer layer gel precursor, wherein the outer layer gel can wrap the formed inner layer gel, so that the double-layer gel storage bin is obtained. As shown in fig. 1.
Example 3
A double-layer gel storage reservoir for preventing relapse after tumor operation is prepared from the following two raw materials in percentage by weight: the first, 38 parts by mass of soybean lecithin, 62 parts by mass of glycerol dioleate and 5 parts by mass of absolute ethyl alcohol are marked as LG 38/62. And the second, 40 parts by mass of soybean lecithin, 60 parts by mass of glycerol dioleate and 8 parts by mass of absolute ethyl alcohol, which are marked as LG 40/60.
The preparation steps are as follows:
s1: mixing 38 parts by mass of phospholipid, 62 parts by mass of glyceride and an anti-tumor drug, adding 5 parts by mass of cosolvent, uniformly mixing in a mixer to completely dissolve the phospholipid and the glyceride to obtain an outer-layer gel precursor, mixing 40 parts by mass of phospholipid, 60 parts by mass of glyceride and the anti-tumor drug, adding 8 parts by mass of cosolvent, uniformly mixing in the mixer to completely dissolve the phospholipid and the glyceride to obtain an inner-layer gel precursor;
s2: and (4) respectively filling the inner layer gel precursor and the outer layer gel precursor obtained in the step (S1) into a syringe barrel of a double-barrel syringe, then pushing the inner layer gel precursor into water, gelling the inner layer gel precursor with water to form inner layer gel, and then pushing the outer layer gel precursor, wherein the outer layer gel can wrap the formed inner layer gel, so that the double-layer gel storage bin is obtained. As shown in fig. 1.
Example 4
1.25mg of sorafenib solid powder is added into 1.25mL of the outer-layer gel precursor LG 35/65, and the mixture is directly mixed by a rotator to obtain the outer-layer gel precursor. The inner layer gel entraps the antibody drug, and the specific method comprises the following steps:
s1: weighing 1g of soybean lecithin SPC in a 10ml EP tube, and adding distilled water to 4 g; mixing for about 20min by using a shaking table to form a coarse dispersion body;
s2: performing ultrasonic treatment on the crude dispersion by using an ice bath probe for about 5min, wherein the power is 30%, and the ultrasonic treatment is stopped for 3s after 2s, so that SPC nanoparticles can be obtained;
s3: 200ul (5mg) of the nanoparticles were sonicated while 300ul (2mg/ml) of an IgG aqueous solution was added to the resulting nanoparticles, and the prepared nanoparticles were lyophilized, followed by addition of 1.25ml of LG 50/50 and mixing with a rotator overnight.
Example 5
1mg of sorafenib was weighed out and dissolved in a solution of PEG-400: ethanol ═ 1: 1. 1mg of graphene is taken and added into the sorafenib solution drop by an ultrasonic dispersion method. Firstly carrying out ultrasonic treatment for 1h, then uniformly mixing for 24h (200rpm,37 ℃) by a shaking table to ensure that the mixture is fully adsorbed. Subsequently, centrifugation was carried out at 3000rpm for 15min to remove the unloaded sorafenib. Freeze-drying the preparation, and then adding 1ml of LG 35/65 to obtain the outer-layer gel precursor loaded with graphene and sorafenib, wherein the sorafenib is loaded on the graphene.
Example 6
The invention selects two gel precursors with larger phase transition temperature difference to realize gradual drug release. The outer layer gel reaches the phase transition temperature to generate phase transition, and the inner layer gel does not generate phase transition. The phase transition temperatures of LG 35/65 and LG 50/50 were measured using a high speed rotational rheometer. The strain was measured under the conditions of 25-80 ℃ and 5% strain at f 2 Hz. As a result, as shown in FIG. 2, the phase transition temperature of LG 35/65 was about 39.5 ℃ and the phase transition temperature of LG 50/50 was about 57 ℃. The phase transition temperature difference between the two is large, and gradual drug release can be realized.
Example 7
The heating performance of the double-layer gel storage reservoir coated with the photothermal material is explored. The double-barrel syringe is used for preparing double-layer gel with the volume of 100ul of each layer, wherein the outer layer gel is used for encapsulating 80ug of graphene material. The gels were irradiated with 808nm laser light for 10 minutes, and the temperature rise was recorded. As shown in FIG. 3, the temperature-raising effect of the gel was significantly different under different laser power conditions. Within a certain range, the greater the power, the more the temperature rises. Therefore, the temperature of the gel on the outer layer can be realized by controlling the power, and the prepared double-layer gel storage reservoir coated with the photothermal material has a good heating effect with controllable power.
Example 8
10 days before treatment, mice were inoculated subcutaneously with 4T1-luc breast cancer cells 1X 10 near the right mammary gland6. When the tumor volume reaches 300mm3At the time, it is surgically removed 90% of the tumors, different preparations were implanted at the surgical site, respectively, and recorded as 0 d. Wherein the outer layer can be coated with chemotherapeutic drugs, such as adriamycin, paclitaxel, gemcitabine, sorafenib, etc. The outer layer can also be coated with photo-thermal preparations such as indocyanine green, gold nanoparticles, graphene and the like. The inner layer may carry antibody drugs such as PD-L1, aCD47 antibody, and the like. And irradiating gel implantation part with 808nm laser for 20min each time on 0,2,4, and 6 days. And (3) inspecting the tumor recurrence condition by adopting a small animal imager through the tumor fluorescence intensity. The result shows that the double-layer gradual drug release gel has better tumor recurrence prevention effect.
It will be understood by those skilled in the art that the foregoing is only a preferred embodiment of the present invention, and is not intended to limit the invention, and that any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the scope of the present invention.
Claims (9)
1. A bilayer gel reservoir comprising an outer layer gel reservoir and an inner layer gel reservoir, the outer layer gel reservoir being wrapped around the outer portion of the inner layer gel reservoir; the outer layer gel storage reservoir comprises 28-38 parts by mass of phospholipid, 62-70 parts by mass of glyceride and 1-8 parts by mass of cosolvent, and the inner layer gel storage reservoir comprises 40-55 parts by mass of phospholipid, 40-55 parts by mass of glyceride and 5-20 parts by mass of cosolvent; the outer layer gel storage and the inner layer gel storage also comprise an anti-tumor drug.
2. The bilayer gel reservoir of claim 1, wherein the anti-neoplastic drug in the outer layer gel reservoir is a chemotherapeutic drug and the anti-neoplastic drug in the inner layer gel reservoir is an anti-neoplastic antibody drug.
3. The bilayer gel reservoir of claim 2, wherein the chemotherapeutic drug is loaded on the photothermal agent.
4. The bilayer gel depot of claim 2, wherein the chemotherapeutic is doxorubicin, paclitaxel, gemcitabine or sorafenib; the anti-tumor antibody drug is a PD-1 antibody, a PD-L1 antibody or a CD47 antibody.
5. The bilayer gel reservoir of claim 1, further comprising a photothermal agent in the outer layer gel reservoir.
6. The bilayer gel reservoir of claim 5, wherein the photothermal agent is graphene, indocyanine green, or gold nanoparticles.
7. The bilayer gel reservoir of claim 5, wherein the photothermal agent in the outer layer gel reservoir is 0.6 to 1 part by mass.
8. A bilayer gel depot according to claim 1, wherein the phospholipid is soy lecithin or egg lecithin; the glyceride is diglyceride, triolein or cholesylglyceride; the cosolvent is absolute ethyl alcohol, methanol, propylene glycol or polyethylene glycol.
9. Use of a bilayer gel depot according to any one of claims 1 to 8 for the preparation of a postoperative prevention of tumor recurrence or a postoperative prevention of tumor metastasis.
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