CN113662940A - Self-assembled nano material of metformin hydrochloride and TGF-beta inhibitor - Google Patents
Self-assembled nano material of metformin hydrochloride and TGF-beta inhibitor Download PDFInfo
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Abstract
The invention discloses a self-assembled nano material of metformin hydrochloride and a TGF-beta inhibitor. The nanometer material has the advantages of uniform granularity and good dispersibility, and the preparation method has the advantages of simple operation, mildness, greenness and easy scale production. Animal experiment results show that the nano material can obviously inhibit the growth and metastasis of breast cancer tumors. The nano material also has the characteristics of high safety and easy storage, and has important application prospect in the field of future tumor treatment.
Description
Technical Field
The invention belongs to the field of nano material preparation and biomedicine, and particularly relates to a self-assembled nano material of metformin hydrochloride and a TGF-beta inhibitor.
Background
Tumor microenvironment refers to the overall function and network structure of tumor cells and their surrounding non-tumor cells, and includes their functional interactions in addition to the dynamic microenvironment in which these cells are located. The tumor microenvironment provides guarantee for the growth of the tumor, and simultaneously helps the tumor to avoid an immune defense line, and finally results in uncontrollable malignant growth and metastasis of the tumor.
Transforming growth factor beta (TGF-beta) is a multifunctional cytokine and also an important component of the tumor microenvironment. Abnormal activation of TGF-beta signal channel can not only promote the proliferation and metastasis of tumor cells, but also regulate and shape the tumor microenvironment. TGF-beta promotes the conversion of the naive T cells to Treg subgroups by inhibiting the differentiation of the naive T cells to effector phenotypes, inhibits the antigen presenting function of dendritic cells, shapes immunosuppressive microenvironment and helps tumor cells to escape from the host's immune killing effect. TGF-beta can also induce tumor cells and endothelial cells to produce various extracellular matrices, such as matrix metalloproteinase MMP-2, providing a favorable microenvironment for invasion and migration of tumor cells. In addition, the effect of TGF-beta on stimulating angiogenesis is also beneficial to promoting malignant change and metastasis of tumors. Therefore, blocking TGF- β signaling pathways in the tumor microenvironment is of great significance for remodeling the tumor microenvironment, and for controlling tumor progression and metastasis.
LY3200882 is a potent and highly selective TGF-beta inhibitor, and can effectively inhibit TGF-beta related pathways in a concentration-dependent manner in tumor tissues in vitro and tumor models in vivo, remodel tumor microenvironment, and exert an anti-tumor effect.
In view of the above, the invention utilizes the co-assembly of metformin and a TGF-beta inhibitor LY3200882 to construct a nano-drug MLY NPs capable of remodeling tumor microenvironment, and the nano-drug MLY NPs can be applied to the treatment of breast cancer.
Disclosure of Invention
The invention aims to provide a self-assembled nano material of metformin hydrochloride and a TGF-beta inhibitor.
In order to achieve the purpose, the invention adopts the following technical scheme:
the self-assembled nano material of the metformin hydrochloride and the TGF-beta inhibitor is self-assembled into quasi-circular particles by the metformin hydrochloride and the TGF-beta inhibitor LY3200882, and the average diameter of the nano material is 10 nm, and the hydration radius of the nano material is 20 nm.
The preparation method of the nano material comprises the following steps:
(1) dissolving metformin hydrochloride and a TGF-beta inhibitor LY3200882 in dimethyl sulfoxide according to the molar ratio of 1:1, and carrying out ultrasonic treatment to uniformly mix the metformin hydrochloride and the TGF-beta inhibitor LY 3200882;
(2) adding the mixture obtained in the step (1) into secondary water, and stirring and reacting for 15-30 min at the temperature of 25 ℃ and the speed of 250 rpm;
(3) and after the reaction is finished, centrifuging the reaction solution, dialyzing the precipitate by using a dialysis bag, replacing the dialysate every 4 hours for 1 time, and dialyzing for 4 days to obtain the nano material MLY NPs.
The application of the nano material in preparing a nano preparation for inhibiting the growth and metastasis of breast cancer.
The self-assembled nano material of the metformin hydrochloride and the TGF-beta inhibitor, which is obtained by the invention, has the function of regulating and controlling the tumor microenvironment, and can be used for treating breast cancer.
The invention has the following remarkable advantages:
(1) the preparation method of the nano material has the advantages of simple preparation process, less time consumption, low energy consumption, mildness, greenness and easiness in large scale, has good universality and provides good reference for preparation of other self-assembly nano materials.
(2) The TGF-beta inhibitor LY3200882 is a hydrophobic drug, the metformin hydrochloride is a highly hydrophilic drug, and the two drugs act through hydrogen bonds, so that the formed nano material has good water solubility, namely the water solubility of the TGF-beta inhibitor LY3200882 can be improved by combining the metformin hydrochloride with the TGF-beta inhibitor LY3200882, and the possibility is provided for the TGF-beta inhibitor LY3200882 to be widely used in clinic.
(3) The nano material MLY NPs prepared by the method can be applied to preparing a nano preparation for inhibiting the growth and metastasis of breast cancer, has the characteristics of high safety and easy preservation, and has important application prospect in the field of future tumor treatment.
Drawings
FIG. 1 is a TEM image and DLS image of nanomaterial MLY NPs.
FIG. 2 is a graph of the change of breast cancer versus tumor volume in mice of different treatment groups.
FIG. 3 is the result of H & E staining of breast cancer tumor tissues of mice of different treatment groups. FIG. 1 shows a physiological saline solution group; FIG. 2 Met group; FIG. 3 shows group LY; FIG. 4 shows the Met/LY group; FIG. 5 is a set of MLY NPs; fig. 6 is a partially enlarged view of fig. 5.
Fig. 4 is an in vivo bioluminescence image of a lung metastasis model of breast cancer in mice of different treatment groups.
Figure 5 is a photograph of pulmonary nodules in mice after treatment.
Figure 6 is statistical data for pulmonary nodules in mice after treatment.
Detailed Description
In order to make the present invention more comprehensible, the technical solutions of the present invention are further described below with reference to specific embodiments, but the present invention is not limited thereto.
Example 1 preparation of metformin and TGF-beta inhibitor LY3200882 self-assembled nanomaterials MLY NPs
0.0046g of metformin hydrochloride is fully dissolved in 12 mL of DMSO, 0.0120 g of TGF-beta inhibitor LY3200882 is fully dissolved in 12 mL of DMSO, then the two solutions are mixed according to the molar ratio of the materials being 1:1, and ultrasonic treatment is carried out at room temperature to ensure that the two solutions are uniformly mixed. Then, the mixed solution diluted 4.6 times was added dropwise into a beaker containing 100 mL of secondary water, and the reaction was stirred at 250 rpm for 15 min to 30 min at room temperature. And dialyzing the precipitate obtained by centrifuging the obtained reaction solution (dialysis bag MWCO 8000-14000), replacing the dialyzate for 1 time every 4 hours, and dialyzing for 4 days to obtain the nano-material MLY NPs. The storage was carried out at 4 ℃.
The obtained nano-material MLY NPs were subjected to morphology characterization by using Hitachi HT7700 transmission electron microscope, and the results are shown in FIG. 1. As can be seen from FIG. 1, the synthesized nano-material MLY NPs are quasi-circular particles with uniform size and average diameter of 10 nm. The hydration radius of the nano material MLY NPs is measured by a particle sizer, the average particle size is 20 nm, and the average particle size is basically consistent with the result of an electron microscope.
Example 2 Effect of nanomaterial MLY NPs on tumor growth inhibition of 4T1 tumor-bearing mice
We constructed a breast cancer 4T1 tumor-bearing mouse model (mouse purchased from Shanghai Si Laike laboratory animals, LLC) for investigating the therapeutic effect of the nano-drug MLY NPs in vivo, when the tumor volume of the mouse is about 100 mm3At this time, the mice were randomly divided into 5 groups, and physiological saline (150 μ L), Met (12.2 mg/kg) solution, LY solution (2.9 mg/kg), Met/LY solution (12.2 mg/kg Met, 2.9 mg/kg LY 3200882), or MLY NPs solution (15 mg/kg) were administered separately by tail vein injection. The injection is given every two days for a total of 6 treatments. As shown in FIG. 2, the relative tumor volumes of the Met/LY and MLY NPs treated mice were 5.3 and 2.8, respectively, 14 days after treatmentP <0.05), the relative tumor volumes of the mice of the normal saline, Met and LY treatment groups are 11.8, 6.6 and 8.2 respectively; these results demonstrate that MLY NPs effectively inhibit tumor growth. In addition, after the treatment is finished, the tumor tissue is subjected to H&E staining to further observe the antitumor effect of each group from a pathological perspective. As shown in fig. 3, the MLY NPs treated group exhibited a distinct tumor cell apoptotic morphology compared to the individual treated groups: cell nuclei are collapsed, lysed, and cell nuclei are fragmented.
Example 3 Effect of Nano-materials MLY NPs on inhibiting metastasis of in vivo Breast cancer tumor
100 mu L of mouse-derived breast cancer cell Luc-4T1 (5X 10) expressing luciferase6One/ml, purchased from south-beijing cobber limited) was inoculated into the lungs of female Balb/C mice by tail vein injection (mice purchased from shanghai sleek laboratory animals, llc). Is connected in seriesOn day 7 post-breed, mice were randomized into 5 groups (n = 6): saline group (150 μ L), Met group (12.2 mg/kg), LY3200882 group (2.9 mg/kg), Met/LY3200882 group (12.2 mg/kg Met, 2.9 mg/kg LY 3200882), MLY NPs group (15 mg/kg). The tail vein was dosed once every two days for 12 days. Mice were imaged at preset time points using the lumine XRMS series iii imaging system (perkin elmer, usa) to observe metastasis of cancer cells. D-fluorescein sodium salt was administered intraperitoneally at a fluorescein/body weight concentration of 150 mg/kg prior to bioluminescence imaging. As shown in fig. 4, the fluorescence signal was strongest in the lungs of mice in the saline group at day 14, and the tumor had spread to other tissues, with distinct and uncontrolled multiple metastases at day 20; mice treated with Met, LY, Met/LY showed significant metastasis on day 20; compared with each control group, the fluorescence signal of the lungs of the mice in the MLY NPs group is the weakest, and the spread sites are fewer. And photographing the lung and counting the number of tumor nodules after living body imaging is finished. As shown in FIG. 5, the lungs of the saline group were filled with tumor nodules of various sizes, and both lungs were rough and significantly swollen; the lungs of Met and LY groups were seen as multiple tumor nodules of varying sizes. Compared with the group 3, the lung tumor nodules of the Met/LY and MLY NPs treatment group are fewer, wherein the number of the lung tumor nodules of the Met/LY group is 3.1 times that of the MLY NPs (P)<0.01) (fig. 6), while the latter lung surface is also smoother. These results together demonstrate that MLY NPs can effectively inhibit the metastasis of breast cancer cells 4T1 in a lung metastasis model of breast cancer.
The above description is only a preferred embodiment of the present invention, and all equivalent changes and modifications made in accordance with the claims of the present invention should be covered by the present invention.
Claims (3)
1. A self-assembled nano material of metformin hydrochloride and TGF-beta inhibitor is characterized in that: the nano material is self-assembled into round-like particles by metformin hydrochloride and a TGF-beta inhibitor LY3200882, the average diameter is 10 nm, and the hydration radius is 20 nm.
2. A method for preparing the nanomaterial of claim 1, wherein: the method comprises the following steps:
dissolving metformin hydrochloride and a TGF-beta inhibitor LY3200882 in dimethyl sulfoxide according to the molar ratio of 1:1, and carrying out ultrasonic treatment to uniformly mix the metformin hydrochloride and the TGF-beta inhibitor LY 3200882;
secondly, adding the mixture obtained in the step one into secondary water, and stirring and reacting for 15-30 min at the speed of 250 rpm under the condition of room temperature;
and thirdly, after the reaction is finished, performing centrifugal treatment on the reaction liquid, dialyzing the precipitate by using a dialysis bag, replacing the dialyzate for 1 time every 4 hours, and dialyzing for 4 days to obtain the nano material MLY NPs.
3. Use of the nanomaterial of claim 1 in the preparation of a nano-formulation for inhibiting the growth and metastasis of breast cancer.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6475521B1 (en) * | 1998-03-19 | 2002-11-05 | Bristol-Myers Squibb Co. | Biphasic controlled release delivery system for high solubility pharmaceuticals and method |
| CN104644649A (en) * | 2013-11-21 | 2015-05-27 | 广东泰禾医药科技有限公司 | Medicinal composition for inhibiting IGF-1 signal transduction pathway |
| CN110448549A (en) * | 2019-09-16 | 2019-11-15 | 福州大学 | A kind of nano material of Metformin hydrochloride and 7-Ethyl-10-hydroxycamptothecin self assembly |
| CN112707902A (en) * | 2020-03-23 | 2021-04-27 | 杭州阿诺生物医药科技有限公司 | TGF-beta receptor inhibitors |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6475521B1 (en) * | 1998-03-19 | 2002-11-05 | Bristol-Myers Squibb Co. | Biphasic controlled release delivery system for high solubility pharmaceuticals and method |
| CN104644649A (en) * | 2013-11-21 | 2015-05-27 | 广东泰禾医药科技有限公司 | Medicinal composition for inhibiting IGF-1 signal transduction pathway |
| CN110448549A (en) * | 2019-09-16 | 2019-11-15 | 福州大学 | A kind of nano material of Metformin hydrochloride and 7-Ethyl-10-hydroxycamptothecin self assembly |
| CN112707902A (en) * | 2020-03-23 | 2021-04-27 | 杭州阿诺生物医药科技有限公司 | TGF-beta receptor inhibitors |
Non-Patent Citations (1)
| Title |
|---|
| WAHDAN-ALASWAD, R等: "Metformin attenuates transforming growth factor beta (TGF-beta) mediated oncogenesis in mesenchymal stem-like/claudin-low triple negative breast cancer", 《CELL CYCLE》 * |
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