CN111012761A - Drug-loaded microsphere, anti-tumor drug and preparation method - Google Patents
Drug-loaded microsphere, anti-tumor drug and preparation method Download PDFInfo
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- CN111012761A CN111012761A CN201911345192.9A CN201911345192A CN111012761A CN 111012761 A CN111012761 A CN 111012761A CN 201911345192 A CN201911345192 A CN 201911345192A CN 111012761 A CN111012761 A CN 111012761A
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Abstract
The invention discloses a drug-loaded microsphere, an anti-tumor drug and a preparation method thereof, relating to the technical field of tumor treatment. The drug-loaded microsphere comprises a loading matrix and an active factor, wherein the active factor is adsorbed on the loading matrix; the active factor includes any one of or a combination of both a chemokine and a cytokine. The drug-loaded microspheres can chemotactic the transfer of tumor cells and immune effector cells by loading a chemotactic factor on a drug-loaded matrix, promote the targeted killing of the tumor cells by the immune effector cells, and promote the migration of the immune effector cells into tumors and the proliferation or survival of the immune effector cells by loading the cytokine on the drug-loaded matrix, thereby realizing the immunotherapy of the tumors. The preparation method of the drug-loaded microsphere is simple and easy to popularize and apply. The drug-loaded microspheres can be used for preparing anti-tumor drugs which target tumor cells.
Description
Technical Field
The invention relates to the technical field of tumor treatment, in particular to a drug-loaded microsphere, an anti-tumor drug and a preparation method thereof.
Background
Immunotherapy is the most promising strategy for tumor therapy in clinical applications. The basic principle of tumor immunotherapy is to control tumors by biologically enhancing the function of autoimmune effector cells or adoptively inhibiting tumor-reactive cells. For solid tumors, an important part of the curative effect of tumor immunotherapy is that immune effector cells migrate into tumors and are in direct contact with tumor cells, so that the tumor cells are killed.
Inside the tumor, tumor cells, stromal cells and the like can secrete a plurality of chemotactic factors, but most of the chemotactic factors have the functions of promoting immunosuppressive cells to migrate into the tumor, and the chemotactic factors capable of promoting immune effector cells to migrate are less, so that the immune effector cells for killing the tumor cannot effectively reach the inside of the tumor, and the common curative effect of tumor immunotherapy on solid tumors is poor. In addition, the existing loaded chemotherapeutic drugs have low efficiency, and the existing tumor immunotherapy cannot improve the tumor immunosuppression microenvironment and can not reverse the tumor immune escape.
In view of this, the invention is particularly proposed.
Disclosure of Invention
The invention aims to provide a drug-loaded microsphere, an anti-tumor drug and a preparation method thereof so as to solve the technical problems.
The invention is realized by the following steps:
the drug-loaded microsphere comprises a loading matrix and an active factor, wherein the active factor is adsorbed on the loading matrix; the active factor includes any one of or a combination of both a chemokine and a cytokine.
The invention provides a drug-loaded microsphere, which adsorbs active factors through a loaded matrix. When the drug-loaded microsphere is used, on one hand, the drug-loaded microsphere is introduced into a tumor through the arterial cannula, and can simultaneously achieve the dual effects of embolizing tumor blood vessels and adjusting tumor immune microenvironment, so that tumor immune escape is reduced; on the other hand, the method of directly injecting the drug-carrying microspheres in the tumor body is adopted, the loaded active factors are slowly released, the relatively stable local concentration is achieved, immune effector cells are continuously attracted to migrate into the tumor body, and the curative effects of cellular immunotherapy and immune checkpoint antibody therapy can be enhanced. Therefore, compared with the existing microspheres carrying chemotherapeutic drugs, the drug-carrying microspheres have better clinical application prospect. The migration of immune effector cells in a targeted tumor body can be promoted by loading chemotactic factors and cytokines in the drug-loaded microspheres.
In a preferred embodiment of the present invention, the above-mentioned chemokine is a chemokine which promotes migration of immune effector cells into tumor, proliferation or survival of immune effector cells;
preferably, the chemokine comprises any one of CCL19, CXCL9, CXCL10 and CCL3 and combinations of chemokines;
preferably, the chemokine is CXCL 10.
The chemotactic factor is a small molecule secretory protein capable of chemotactic immune cells to directionally move, and the chemotactic factor CCL19 is expressed on T cells and various tumor cells. CCL19 can chemotact CD4+ and CD8+ T cells to infiltrate tumors, mediate immune cells to release cytokines, and inhibit tumor proliferation, migration and invasion.
CXCL9 is a small molecule protein produced by gamma-interferon-induced monocytes and belongs to the chemokine α -subfamily (CXC family), and CXCL9 chemokine has been shown to chemotact inflammatory cell migration, induce inflammatory responses, promote neovascularization growth, and inhibit neovascularization growth induced by fibroblast growth factor and vascular endothelial growth factor.
CXCL9 and CXCL10 can activate and chemotaxis effector lymphocytes such as T lymphocytes, NK cells.
CXCL10, also known as interferon gamma inducible protein 10, belongs to the non-ELR class of the CXC chemokine superfamily and is involved in a variety of autoimmune diseases. CXCL10 can inhibit the formation of hematopoietic cell colony, chemotaxis monocyte, activate T cell and natural killer cell, stimulate the T cell to adhere to endothelial cell and the cell fusion mediated by natural killer cell, inhibit angiogenesis, etc. The primary target cells are activated T lymphocytes. Human fibroblasts, monocytes, endothelial cells, parenchymal hepatocytes, keratinocytes and HL60 and U937 cell lines all expressed CXCL10 under induction of interferon gamma.
CCL3 is also called macrophage inflammatory protein 1-aMIP-1 α, and a plurality of cells in a human body have the capacity of secreting CCL 3. CCL3 has CCR1, CCR5 and CCR9 in the receptors of the human body, the receptors belong to G protein coupled receptors, after the two receptors are specifically combined, waterfall-like cell activation is generated so as to induce chemotactic inflammatory cells to reach an effect site, CCL3 has chemotactic effect on monocytes, neutrophils and the like, also has the role in NK cell and NTL mediated cell lysis, has the role in local immune processes of inflammation and tumor, and mediates the release of other cytokines.
In the aspect of tumor immunity, CCL3 can promote a mononuclear macrophage cell system to generate MIP-3 α to strengthen chemotactic effect on DC, and can directly or indirectly promote CD4+ T, CD8+ T to release inflammatory cytokines to reduce and prevent tumor growth, but CCL3 can also promote angiogenesis of a tumor focus area, and enhance adhesion of cancer cells and vascular endothelium to enable metallo-proteinase hydrolytic activity to be up-regulated to promote tumor metastasis.
The invention provides the medicine carrying microspheres loaded with the chemotactic factors, thereby chemotactic the transfer of tumor cells and immune effector cells, promoting the immune effector cells to kill the tumor cells in a targeted way, and realizing the immunotherapy of tumors.
The drug-loaded microspheres can be introduced into tumors through arterial cannulas, and simultaneously achieve the dual functions of embolizing tumor blood vessels and regulating tumor immune microenvironment, thereby providing a new embolization agent for tumor interventional therapy. The drug-loaded microsphere can also be combined with other immunotherapy such as Car-T cells and immune checkpoint PD-1/PD-L1 monoclonal antibodies in a form of loading corresponding chemokines for direct intratumoral injection, so as to promote migration of immune effector cells into tumors and achieve a synergistic effect. The slow release of the loaded chemotactic factors and cytokines can be realized by directly injecting the drug-loaded microspheres in a tumor body, and the possibility is provided for developing the chemotactic factors and cytokine therapeutic drugs directly injected in the tumor body.
In a preferred embodiment of the present invention, the cytokine is a cytokine that promotes migration of immune effector cells into tumors, and promotes proliferation or survival of immune effector cells;
preferably, the cytokine includes any one of interleukins, interferons, tumor necrosis factors and growth factors and combinations of cytokines.
Preferably, the cytokine includes any one of interleukins and interferons and a combination of cytokines.
More preferably, the interleukin is IL-2 or IL-7.
The cell factors can promote the migration of immune effector cells into the tumor and promote the proliferation or survival of the immune effector cells, thereby realizing the immunotherapy of the tumor.
In a preferred embodiment of the present invention, the material of the supporting substrate is a polymer material or a colloid material.
In a preferred embodiment of the present invention, the material of the supporting substrate is a polymer material;
the high molecular polymer material is selected from chitin, cellulose, polyamino acid, polyvinyl alcohol, polylactic acid, polycaprolactone or polyphosphazene;
preferably, the loaded matrix is attached to the active agent by physical adsorption.
The loaded substrate is loaded with active factors in a physical adsorption mode, so that the effect has the characteristic of easy operation in clinical application.
A method for preparing drug-loaded microspheres, comprising: mixing the load matrix and the active factor and standing. The active factor is loaded on the loading matrix by mixing the loading matrix with the active factor.
In the preferred embodiment of the present invention, the mixing and standing time is 30-40 min. Mixing and standing for 30-40min to make the active factors adsorbed on the loading matrix in a physical adsorption or covalent connection mode to form the drug-loaded microspheres.
An antitumor drug contains drug-loaded microspheres. The drug-loaded microspheres are coated in the anti-tumor drug to specifically inhibit or kill targeted tumor cells.
In a preferred embodiment of the present invention, the tumor is selected from: adenoma, lymphoma, intestinal cancer, liver cancer, head and neck cancer, or colon cancer. Preferably, the tumor is selected from liver cancer or colon cancer. Experiments prove that the drug-loaded microspheres and the antitumor drug provided by the invention can promote T cells to infiltrate into colon cancer, so that immunotherapy is realized.
In a preferred embodiment of the present invention, the anti-tumor drug is in a dosage form selected from tablets, granules, bagged steeping drug, oral liquid, capsules, dripping pills, mixtures, tinctures, enemas, films or injections.
The dosage form of the antitumor drug can be adjusted according to the needs. Preferably, the injection is an injection, so that the clinical injection application is convenient.
The invention has the following beneficial effects:
the invention provides a drug-loaded microsphere, an anti-tumor drug and a preparation method thereof, the drug-loaded microsphere can chemotaxis the transfer of tumor cells and immune effector cells through a drug-loaded matrix-loaded chemotactic factor, promotes the immune effector cells to kill the tumor cells in a targeted manner, and the drug-loaded matrix-loaded cytokine can promote the immune effector cells to migrate into the tumor, promotes the immune effector cells to proliferate or survive, thereby realizing the immunotherapy of the tumor. The clinical drug delivery treatment of the drug-loaded microsphere can be achieved through direct tumor injection or arterial intubation infusion, the slow release of the loaded chemotactic factor and cytokine can be realized through direct tumor injection, the relatively stable local concentration is achieved, immune cells are continuously attracted to migrate to the tumor, and the curative effects of cellular immunotherapy and immune checkpoint antibody therapy are enhanced. Compared with the existing microspheres carrying chemotherapeutic drugs, the drug-carrying microspheres have better clinical application prospect. The arterial cannula perfusion has the dual functions of embolism effect and tumor immune microenvironment regulation, and plays a role in immunotherapy. The preparation method is simple and easy to popularize and apply. The drug-loaded microspheres can be used for preparing anti-tumor drugs which target tumor cells.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained according to the drawings without inventive efforts.
FIG. 1 is a typical flow cytometer analysis of four treatment groups in Experimental example 1;
FIG. 2 is a graph showing the tumor infiltration of CD4 after treatment in four groups of mice in Experimental example 1+And CD8+Statistical plots of T cell numbers (T-test, P < 0.001, n-5).
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
The features and properties of the present invention are described in further detail below with reference to examples.
Example 1
This example provides a method for preparing drug-loaded microspheres. The loaded substrate (Callispher, 100-4Mixing the loaded matrix with 0.1ug of CXCL10, standing and loading for 30min to obtain the drug-loaded microsphere loaded with CXCL 10.
Experimental example 1
In this experimental example, the drug-loaded microspheres prepared in example 1 were used to perform a mouse colon cancer treatment experiment. The method specifically comprises the following steps:
(1) and (3) culture passage of the cells: the mouse CT26 colon cancer cell line used in the experiment is cultured in RPMI1640 containing 10% inactivated fetal calf serumIn nutrient medium, the mixture is placed in 5 percent CO at 37 DEG C2Culturing in an incubator, and changing the culture solution every other day. 0.15% Trypsin [ containing 0.02% ethylenediaminetetraacetic acid (EDTA) ] in Phosphate Buffered Saline (PBS)]The cells were passaged by digestion, 1 passage every 3 days, and cells in the logarithmic growth phase were collected for experiments.
(2) Establishing a mouse tumor model: collecting cells in logarithmic growth phase, adjusting cell concentration to 2.5 × 106One per ml. BALB/C mice were prepared for dorsal skin, and 0.2ml (5X 10) of cell suspension was injected subcutaneously into the right dorsal skin of the mice5Cells/side), the formation of nodules was observed daily, and the presence of hard-textured nodules at the site to be inoculated was considered to be nodules. Measuring the length (a) and the width (b) of the tumor body by using a vernier caliper, wherein the volume of the tumor body is as the formula V ═ a × b2And/2.
(3) Mouse treatment: when the tumors of step (2) grew to about 5cm in diameter, the tumor-bearing mice were divided into four groups (5 mice per group): a blank control group (group A), a matrix-loaded treatment group (group B), a chemokine CXCL10 treatment group (group C) and a drug-loaded microsphere treatment group (group D). Group A intratumorally injected with 0.1mL of PBS; group B intratumoral injection of PBS0.1mL + Supported matrix of example 1X 104A plurality of; group C injected PBS0.1mL + CXCL100.1ug; group D injection of PBS0.1mL + drug-loaded microspheres from example 1 (loaded matrix 1X 10)4Individual + cxcl100.1 ug).
(4) Tumor infiltrating lymphocyte and spleen lymphocyte collection: five days after treatment, the mice were killed by cervical dislocation, the lateral tumors and spleens were removed, minced, collagenase, hyaluronidase and dnase were diluted in RPMI1640 medium and added to the tumor tissue, and incubated at 37 ℃ for 2 hours. The tumor tissue was then transferred to a clean glass dish and ground, and the cell suspension was filtered through a 40 μm filter to remove debris and cell clumps. The cell suspension is washed and resuspended for standby.
(5) Flow cytometry analysis: adjusting the cell concentration of the prepared cell suspension to 5.0 × 106Adding 100 mu l of cell suspension into each EP tube, adding corresponding fluorescence labeled detection antibody according to the instruction, mixing uniformly, incubating for 30min at 4 ℃ in dark place, washing away unbound antibody by PBS, adding 500 mu l of PBS liquid, mixing uniformly, labeling CD45, CD4 and CD8 antibodies, transferring to flow-type tube, and loading on top of the tubeDetecting CD4+And CD8+The number of T cells.
The flow cytometry analysis results of the 4 treatment groups are shown in FIG. 1, and the tumor infiltration CD4 of the four groups of mice after treatment+And CD8+The statistical results of T cell numbers are shown in fig. 2 (T test, P < 0.001, n-5), and in fig. 2, A, B, C and CD4 of group D, from left to right+Number of T cells A, B, C and CD8 of group D+The number of T cells. As shown in fig. 1 and 2, the chemokine CXCL10 loaded with the polymer material can significantly improve CD4+T cells and CD8+The number of T cells, namely the infiltration of the T cells into the tumor can be promoted during the intratumoral injection, thereby realizing the immunotherapy of the tumor.
The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. The drug-loaded microsphere is characterized by comprising a loading matrix and an active factor, wherein the active factor is adsorbed on the loading matrix; the active factors include any one or a combination of both of chemokines and cytokines.
2. The drug-loaded microsphere of claim 1, wherein the chemokine is one that promotes migration of immune effector cells into a tumor, proliferation or survival of immune effector cells;
preferably, the chemokine comprises any one of CCL19, CXCL9, CXCL10 and CCL3 and a combination of chemokines of more;
preferably, the chemokine is CXCL 10.
3. The drug-loaded microsphere of claim 1 or 2, wherein the cytokine is a cytokine that promotes migration of immune effector cells into a tumor, proliferation or survival of immune effector cells;
preferably, the cytokine comprises any one of interleukin, interferon, tumor necrosis factor and growth factor and the combination of a plurality of cytokines;
preferably, the cytokine comprises any one of interleukin and interferon and the combination of a plurality of cytokines;
more preferably, the interleukin is IL-2 or IL-7.
4. The drug-loaded microsphere of claim 1, wherein the material of the loading matrix is a polymeric or colloidal material.
5. The drug-loaded microsphere of claim 4, wherein the material of the loading matrix is a high molecular polymer material or a colloidal material;
the high molecular polymer material is selected from chitin, cellulose, polyamino acid, polyvinyl alcohol, polylactic acid, polycaprolactone or polyphosphazene;
preferably, the loaded matrix is attached to the active factor by physical adsorption.
6. The method for preparing drug-loaded microspheres according to any one of claims 1 to 5, wherein the method comprises the following steps: mixing and standing the loaded matrix and the active factors.
7. The method according to claim 6, wherein the mixing is allowed to stand for 30 to 40 min.
8. An antitumor agent comprising the drug-loaded microsphere according to any one of claims 1 to 5.
9. Antineoplastic drug according to claim 8, characterized in that said tumor is selected from: adenoma, lymphoma, intestinal cancer, liver cancer, head and neck cancer, or colon cancer.
10. The antitumor drug as claimed in claim 8, wherein the dosage form of the antitumor drug is selected from tablets, granules, bagged steeping drug, oral liquid, capsules, dripping pills, mixtures, tinctures, enemas, films or injections.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114354943A (en) * | 2021-12-27 | 2022-04-15 | 中南大学湘雅医院 | Immune therapy efficacy prediction marker and prediction model construction and application |
| CN115154618A (en) * | 2022-07-19 | 2022-10-11 | 杭州准星医学科技有限公司 | Mesoporous silica sustained-release preparation for cancerous ascites and preparation method thereof |
| CN117466986A (en) * | 2023-10-30 | 2024-01-30 | 中南大学 | Preparation method of chemokine CCL3 and application of chemokine CCL3 in preparation of tumor immunotherapy drugs |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1362623A (en) * | 2002-01-21 | 2002-08-07 | 陕西超英生物医学研究开发有限公司 | Multiple immunological microsphere and its prepn techn and detection method |
| CN1676121A (en) * | 2004-03-29 | 2005-10-05 | 中国人民解放军军事医学科学院毒物药物研究所 | Slow-release micro-ball formulation for tissue, organ local therapy, and its preparing method and use |
| CN109303761A (en) * | 2018-11-21 | 2019-02-05 | 首玺(广州)医疗科技有限责任公司 | A kind of load has chitosan microball composition of the Stem Cell Activity factor and its preparation method and application |
-
2019
- 2019-12-24 CN CN201911345192.9A patent/CN111012761A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1362623A (en) * | 2002-01-21 | 2002-08-07 | 陕西超英生物医学研究开发有限公司 | Multiple immunological microsphere and its prepn techn and detection method |
| CN1676121A (en) * | 2004-03-29 | 2005-10-05 | 中国人民解放军军事医学科学院毒物药物研究所 | Slow-release micro-ball formulation for tissue, organ local therapy, and its preparing method and use |
| CN109303761A (en) * | 2018-11-21 | 2019-02-05 | 首玺(广州)医疗科技有限责任公司 | A kind of load has chitosan microball composition of the Stem Cell Activity factor and its preparation method and application |
Non-Patent Citations (9)
| Title |
|---|
| YANA WANG ET AL.: ""Engineering chemoattractant gradients using chemokine-releasing polysaccharide microspheres"", 《BIOMATERIALS》 * |
| 任博等: ""聚磷腈微球搭载生长因子时间缓释对骨髓间充质干细胞粘附和增殖的影响"", 《中国运动医学杂志》 * |
| 吴孟超等: "《中国外科年鉴》", 31 August 2016 * |
| 张昌菊: "《医学免疫学》", 31 January 2010, 世界图书出版公司 * |
| 易诚青等: ""装载趋化因子CXCL13的中空羟基磷灰石微球对间充质干细胞的趋化效应研究"", 《上海交通大学学报（医学版）》 * |
| 曾晓华等: ""白细胞介素2葡聚糖微球并碘油栓塞治疗肝癌的动物实验"", 《介入放射学杂志》 * |
| 王伟: "《肿瘤药剂学》", 30 November 2016, 江苏凤凰科学技术出版社 * |
| 韦超等: "《药剂学》", 31 August 2012, 河南科学技术出版社 * |
| 韩明勇等: "《肿瘤分子靶向治疗学》", 31 August 2008, 济南出版社 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114354943A (en) * | 2021-12-27 | 2022-04-15 | 中南大学湘雅医院 | Immune therapy efficacy prediction marker and prediction model construction and application |
| CN115154618A (en) * | 2022-07-19 | 2022-10-11 | 杭州准星医学科技有限公司 | Mesoporous silica sustained-release preparation for cancerous ascites and preparation method thereof |
| CN117466986A (en) * | 2023-10-30 | 2024-01-30 | 中南大学 | Preparation method of chemokine CCL3 and application of chemokine CCL3 in preparation of tumor immunotherapy drugs |
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