CN112220758A - Preparation of meltable hydrogel drug-loaded microspheres with photo-thermal responsiveness and application of microspheres in cell amplification - Google Patents

Preparation of meltable hydrogel drug-loaded microspheres with photo-thermal responsiveness and application of microspheres in cell amplification Download PDF

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Publication number
CN112220758A
CN112220758A CN202011110047.5A CN202011110047A CN112220758A CN 112220758 A CN112220758 A CN 112220758A CN 202011110047 A CN202011110047 A CN 202011110047A CN 112220758 A CN112220758 A CN 112220758A
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hydrogel
photo
microspheres
drug
thermal
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赵远锦
寿鑫
沈贤
孙维健
王月桐
商珞然
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Wenzhou Research Institute Of Chinese Academy Of Sciences Wenzhou Institute Of Biomaterials And Engineering
Second Affiliated Hospital and Yuying Childrens Hospital of Wenzhou Medical University
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Wenzhou Research Institute Of Chinese Academy Of Sciences Wenzhou Institute Of Biomaterials And Engineering
Second Affiliated Hospital and Yuying Childrens Hospital of Wenzhou Medical University
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Abstract

The invention relates to a preparation method of a meltable hydrogel drug-loaded microsphere with photo-thermal responsiveness and application thereof in cell amplification, firstly, the hydrogel microsphere is prepared by utilizing the properties of heating and dissolving the hydrogel and solidifying when meeting cold; dissolving a photo-thermal responsive material and hydrogel in hot water to obtain a uniform photo-thermal responsive material-hydrogel aqueous solution, dispersing the prepared photo-thermal responsive material-hydrogel aqueous solution into an oil phase containing an emulsifier under the stirring condition to obtain a water-in-oil type emulsion, cooling the emulsion, and then respectively carrying out suction filtration and washing by using diethyl ether and water to obtain photo-thermal responsive material-hydrogel microspheres; the antibody drug loaded microspheres obtain the meltable hydrogel drug loaded microspheres with photo-thermal responsiveness. The hydrogel microspheres obtained by the invention have near infrared light response and thermal responsiveness, are loaded with antibodies required by tumor immunotherapy, can carry out controllable release of medicaments, and have the capacity of being applied to tumor therapy.

Description

Preparation of meltable hydrogel drug-loaded microspheres with photo-thermal responsiveness and application of microspheres in cell amplification
Technical Field
The invention relates to the field of biological materials, in particular to preparation of a meltable hydrogel drug-loaded microsphere with photo-thermal responsiveness and application of the microsphere in cell amplification.
Background
With the aging of the population and the deterioration of the living environment, tumors have become one of the major diseases that endanger human health. The common tumor treatment schemes comprise surgical excision, radiotherapy, chemotherapy and the like, and the treatment methods have the problems of large wound, easy relapse and the like. With the intensive study of the mechanisms of tumorigenesis and development, various new tumor treatment regimens have entered the clinic. The tumor immunotherapy is a new tumor treatment scheme, is a powerful tumor killing treatment means for enhancing the self anti-tumor capacity by activating the autoimmune system of a tumor patient, and has the advantages of small side effect, wide adaptation diseases and the like. However, the tumor immunosuppressive microenvironment in tumor patients invariably impairs the killing process of T cells against tumors. Therefore, the selection of effective strategies to counteract the tumor immunosuppression microenvironment and enhance the tumor killing activity of human endogenous immune cells has important significance.
The micro-carrier drug release system can be used for the sustained release of the drug and maintaining the drug concentration to fluctuate within a small range. However, most drug release systems are prepared from common hydrogel, and the drug loaded in the hydrogel is often released through the internal cross-linked network structure of the hydrogel material in a free diffusion manner, so that the release efficiency is low, and the intelligence is not sufficient. Therefore, specific materials with response capability, such as biomedical materials responding to physiological signals or external stimuli (such as pH, temperature and light), are introduced into the drug sustained-release microcarrier, so that the drug sustained-release microcarrier can be used as an intelligent drug-loading platform for tumor immunotherapy, and has a wide application prospect in tumor immunotherapy.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a preparation method of a meltable hydrogel drug-loaded microsphere with photo-thermal responsiveness and an application of the microsphere in cell amplification aiming at the defects of the prior art.
The invention is based on a microcarrier drug release system, and generates the photo-thermal responsive hydrogel drug-loaded microspheres with uniform size by an emulsion stirring method. The hydrogel microspheres obtained by the invention have near infrared light response and thermal responsiveness, are loaded with antibodies required by tumor immunotherapy, can carry out controllable release of medicaments, and have the capacity of being applied to tumor therapy.
In order to achieve the purpose, the technical scheme provided by the invention is as follows:
a meltable hydrogel drug-loaded microsphere with photo-thermal responsiveness, which comprises the following steps:
(1) preparing hydrogel microspheres: firstly, preparing hydrogel microspheres by utilizing the properties of heating and dissolving the hydrogel and solidifying the hydrogel in the presence of cold;
(2) preparing photo-thermal responsive material-hydrogel microspheres: dissolving a photo-thermal responsive material and hydrogel in hot water to obtain a uniform photo-thermal responsive material-hydrogel aqueous solution, dispersing the prepared photo-thermal responsive material-hydrogel aqueous solution into an oil phase containing an emulsifier under the stirring condition to obtain a water-in-oil type emulsion, cooling the emulsion, and then respectively carrying out suction filtration and washing by using diethyl ether and water to obtain photo-thermal responsive material-hydrogel microspheres;
(3) antibody drug loading of microspheres: soaking the photo-thermal responsive material-hydrogel microspheres prepared in the step (2) in an antibody drug solution for a period of time; after soaking, washing with a proper amount of PBS buffer solution for several times, and storing at room temperature in a dark state to obtain the meltable hydrogel drug-loaded microspheres with photo-thermal responsiveness.
Further, the photo-thermal response material is one or more than two materials selected from MXene, black phosphorus quantum dots and graphene quantum dots.
Furthermore, the hydrogel material is selected from one or more than two of gelatin hydrogel, agarose gel and matrigel.
Furthermore, in the photo-thermal responsive material-hydrogel microspheres, the proportion of the hydrogel material is 0.5% -5% v/v.
Furthermore, in the photo-thermal response material-hydrogel microspheres, the concentration of the photo-thermal response material is 10ug/ml to 500 ug/ml.
Further, the soaking time in the step (3) is 24 hours.
Further, the antibody drug is a monoclonal antibody, and is selected from one or more of anti-CD3 and anti-CD28, and the concentration of the antibody is 10-100 ng/ml.
The meltable hydrogel drug-carrying microspheres with photo-thermal responsiveness are applied to preparation of cell amplification drugs, and the drugs are loaded in the hydrogel microspheres, so that the hydrogel microspheres can be used for activation of immune cells of tumor patients and anti-tumor therapy of autoimmune cells of the tumor patients in-situ injection, intravenous injection, oral administration, perfusion and other modes.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides a photo-thermal response meltable hydrogel drug-loaded microsphere, which has the advantages of simple preparation process and easily available raw materials, and can be obtained by extracting a large amount of animal tissues. Under the irradiation of near infrared light, the hydrogel microspheres prepared by the invention convert the near infrared light into heat to melt, so that immune stimulation type antibody medicines loaded inside are released, and the hydrogel microspheres can be used for activating immune cells of tumor patients and treating autoimmune cells for anti-tumor.
Compared with the performance of the existing material, the photo-thermal responsive hydrogel microsphere prepared by the invention has the characteristics of high response rate and obvious response characteristic change. The prepared photo-thermal responsive meltable gelatin microsphere has the advantages of good biocompatibility, a large amount of loaded drugs, intelligent controllable release and the like. In addition, the near infrared light can promote the release of antibody drugs, and the released antibody can also activate T cells, so that the T cells infiltrate into the tumor and the elimination of the tumor cells is promoted.
Drawings
FIG. 1: the photo-thermal response characteristic of the hydrogel microsphere and the near-infrared light response characteristic of the MXene-doped hydrogel microsphere.
FIG. 2: and (3) loading and releasing the hydrogel microspheres, and carrying out a fluorescence image of the hydrogel microspheres along with the drug release of the near infrared light irradiation.
FIG. 3: and (3) expanding the T cells by the gelatin microspheres, co-culturing the gelatin microspheres in the T cells, and counting the T cells to observe the growth condition of the T cells.
FIG. 4: and (3) detecting the killing of the T cells after the gelatin microspheres are amplified on the breast cancer cells MDA-MB-231, and detecting the killing condition of the MDA-MB-231 cells by a CCK-8 method.
Detailed Description
The present invention will be described in further detail with reference to specific examples. The following examples are intended to illustrate the invention only and are not intended to limit the scope of the invention.
Example 1: preparation of gelatin microspheres
A certain amount of gelatin is weighed and heated to be dissolved in 15ml of deionized water to prepare 6% gelatin water solution as a water phase. Mixing liquid paraffin and petroleum ether according to different volume ratios, and adding a certain amount of oil-soluble emulsifier to obtain an oil phase. The oil phase is preheated to the operating temperature, the aqueous phase is added into a container, and micro-droplets of the gelatin gel are generated by shearing with magnetic stirring. Slowly cooling the obtained water-in-oil gelatin gel to below 20 ℃ under mechanical stirring, solidifying the gel to form microspheres, and sequentially performing suction filtration and washing by using petroleum ether, ethanol and distilled water to obtain the gelatin microspheres. The results show that brief irradiation of the hydrogel microspheres with near infrared light can significantly increase the temperature of the microspheres (fig. 1).
Example 2: preparation of photo-thermal responsive meltable MXene-gelatin drug-loaded microspheres
(1) Dissolving MXene and gelatin microsphere in hot water to obtain uniform MXene-gelatin water solution, dispersing the water phase into oil phase containing emulsifier under stirring to obtain water-in-oil emulsion, cooling the emulsion, and respectively filtering with diethyl ether and water to obtain MXene-gelatin microsphere.
(2) Antibody drug loading of microspheres:
soaking the MXene-gelatin microspheres prepared in the step 1) in an antibody drug solution for 24 hours. After soaking, washing with a proper amount of PBS buffer solution for several times, and storing at room temperature in a dark state.
Wherein the concentration of MXene is 10ug/ml-500 ug/ml. The proportion of gelatin was 0.5% (v/v). The antibody drug is a monoclonal antibody, and is selected from one or more of anti-CD3 and anti-CD28, and the concentration of the antibody is 10 ng/ml.
Example 3: drug loading and release
And soaking the prepared gelatin microspheres in a solution containing antibody drugs or BSA-FITC. After soaking, 10 gelatin microsphere samples are taken respectively, dispersed in 1.5ml of PBS buffer solution, and irradiated by infrared laser, and the residual quantity of embedded drug molecules in the gelatin microspheres is represented by reading the fluorescence value of the microspheres because BSA-FITC is green fluorescence. After each test, 1ml of new PBS buffer solution was used to replace the buffer solution of the microspheres, so as to study the release of the microspheres under natural conditions, the results show that the near infrared irradiation also promotes the release of the drug (FIG. 2).
Example 4: extraction and culture of peripheral blood-derived T cells
Collecting 10ml of peripheral blood of the volunteer, diluting the peripheral blood with equal volume of physiological saline, slowly adding the diluted peripheral blood into a centrifuge tube filled with 5ml of lymphocyte separation liquid, and centrifuging for 20min at 400 g. After the centrifugation is finished, the middle leucocyte layer is absorbed, physiological saline is added to 10ml, 300g is centrifuged for 5min, and the supernatant is discarded. Washing buffer was added to the cell pellet and the cells were counted, and T cell culture medium (containing IL-2) was added at a cell density of 1X 106/ml, and fresh culture medium was replenished every 3 days. The proliferation rate of T cells was characterized by counting T cells, and as a result, it was found that gelatin microsphere-activated T cells proliferated faster and the number of T cells obtained was greater (fig. 3).
Example 5: in vitro killing experiment of T cells
The breast cancer cell strain MDA-MB-231 is added according to the proportion of 1.5 multiplied by 10 per hole5Cells are inoculated into a 6-well plate, T cells treated by gelatin drug-loaded microspheres are added according to different proportions, and the ratio of E to T is from 1:5 to 5: 1. The negative control group had only tumor cells and no T cells. At 37 ℃ 5% CO2Incubate in incubator for 6 hours. After culturing for 24 and 48 hours respectively, adding a CCK-8 reagent into the culture solution, detecting the absorbance value of the culture solution by using a microplate reader after 60min, and evaluating the activity of the tumor cells. As shown in the results of FIG. 4, the CCK-8 results show that the T cells expanded by the hydrogel microspheres have stronger tumor killing capacity.
The above description is only a preferred embodiment of the present invention, and should not be taken as limiting the invention in any way, and any person skilled in the art can make any simple modification, equivalent replacement, and improvement on the above embodiment without departing from the technical spirit of the present invention, and still fall within the protection scope of the technical solution of the present invention.

Claims (8)

1. A meltable hydrogel drug-loaded microsphere with photo-thermal responsiveness is characterized in that: the preparation method comprises the following steps:
(1) preparing hydrogel microspheres: firstly, preparing hydrogel microspheres by utilizing the properties of heating and dissolving the hydrogel and solidifying the hydrogel in the presence of cold;
(2) preparing photo-thermal responsive material-hydrogel microspheres: dissolving a photo-thermal responsive material and hydrogel in hot water to obtain a uniform photo-thermal responsive material-hydrogel aqueous solution, dispersing the prepared photo-thermal responsive material-hydrogel aqueous solution into an oil phase containing an emulsifier under the stirring condition to obtain a water-in-oil type emulsion, cooling the emulsion, and then respectively carrying out suction filtration and washing by using diethyl ether and water to obtain photo-thermal responsive material-hydrogel microspheres;
(3) antibody drug loading of microspheres: soaking the photo-thermal responsive material-hydrogel microspheres prepared in the step (2) in an antibody drug solution for a period of time; after soaking, washing with a proper amount of PBS buffer solution for several times, and storing at room temperature in a dark state to obtain the meltable hydrogel drug-loaded microspheres with photo-thermal responsiveness.
2. The photothermal responsive meltable hydrogel drug-loaded microsphere of claim 1, wherein: the photo-thermal response material is one or more than two materials selected from MXene, black phosphorus quantum dots and graphene quantum dots.
3. The photothermal responsive meltable hydrogel drug-loaded microsphere of claim 1, wherein: the hydrogel material is selected from one or more than two of gelatin hydrogel, agarose gel and matrigel.
4. The photothermal responsive meltable hydrogel drug-loaded microsphere of claim 1, wherein: in the photo-thermal responsive material-hydrogel microspheres, the proportion of the hydrogel material is 0.5-5% v/v.
5. The photothermal responsive meltable hydrogel drug-loaded microsphere of claim 1, wherein: in the photo-thermal response material-hydrogel microspheres, the concentration of the photo-thermal response material is 10ug/ml-500 ug/ml.
6. The photothermal responsive meltable hydrogel drug-loaded microsphere of claim 1, wherein: the soaking time in the step (3) is 24 hours.
7. The photothermal responsive meltable hydrogel drug-loaded microsphere of claim 1, wherein: the antibody drug is a monoclonal antibody, is selected from one or more of anti-CD3 and anti-CD28, and has the concentration of 10-100 ng/ml.
8. The use of the photo-thermo-responsive meltable hydrogel drug-loaded microspheres of claim 1 in the preparation of a cell amplification drug, characterized in that: the hydrogel microspheres are loaded with drugs, and can be used for activating immune cells of tumor patients and treating autoimmune cells of tumor patients in-situ injection, intravenous injection, oral administration, perfusion and other modes.
CN202011110047.5A 2020-10-16 2020-10-16 Preparation of meltable hydrogel drug-loaded microspheres with photo-thermal responsiveness and application of microspheres in cell amplification Pending CN112220758A (en)

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