CN115779091A - Application of Erbin gene in platelet in preparation of colorectal cancer lung metastasis drug - Google Patents
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Images
Abstract
The invention relates to application of Erbin genes in platelets in preparation of drugs for colorectal cancer lung metastasis, and specifically relates to targeted reduction of Erbin expression in platelets. The invention develops a series of colorectal cancer lung metastasis medicaments through discovery of the new target spot, wherein the platelet medicament is easy to separate and modify and has great potential in tumor metastasis treatment.
Description
Technical Field
The invention relates to the technical field of disease treatment and detection, in particular to application of Erbin genes in platelets in preparation of drugs for treating colorectal cancer lung metastasis.
Background
Platelets are small fragments of anucleate discocytes released into the peripheral blood by bone marrow Megakaryocytes (MK). Meanwhile, platelets obtain organelles such as alpha granules, dense granules, lysosomes, microtubules and mitochondria from megakaryocytes. Platelets in normal circulating blood are in a non-adhesive "resting" state, and when a blood vessel is damaged, the platelets are activated after being contacted with adhesive proteins (such as fibrinogen) or soluble platelet agonists (such as ADP and thrombin), and then, the intra-platelet granular substances release bioactive molecules (such as vascular endothelial growth factor, vascular endostatin, von Willebrand factor, P-selectin, fibrinogen and the like) to further activate platelet surface integrin alpha IIb beta 3 (GPIIb/IIIa) receptors, enhance the binding of the receptors with ligands such as fibrinogen, mediate platelet adhesion and aggregation, and play an important role in maintaining blood vessel integrity and hemostasis.
Thrombosis is one of the common clinical manifestations of malignant tumors. The interaction between platelets and tumor cells greatly promotes metastasis of the tumor cell blood vessels. For example, platelets protect tumor cells from mechanical damage caused by blood flow shear forces; p-selectin released by platelets mediates the adhesion of tumor cells to vascular endothelial cells to help tumor cells exude; tumor cells activate platelets by a direct or indirect mechanism, and the activated platelets mediate EMT-like transformation of the tumor cells and promote angiogenesis.
Platelets are considered to be important "inflammatory cells" because they are present in high numbers and release inflammatory mediators. Platelets, like red blood cells, are restricted to the circulation and do not enter lymphatic vessels, where they interact primarily with white blood cells in solid organs, driving and regulating host inflammatory responses and immune responses. Platelets, acting as similar "immune cells", can function as: 1) Platelets release large amounts of soluble cytokines, directly killing infected cells; 2) Platelets enhance their interaction with immune cells by adhering to various immune cells; 3) Platelets express and secrete CD40 and CD154, affecting Dendritic Cell (DCs) maturation and T cell activation; 4) Platelets encapsulate pathogens by inducing Neutrophil Extracellular Traps (NETs).
Overall, the role of platelets as "immune cells" in the tumor microenvironment in tumor metastasis is of further concern.
Colorectal cancer is the top three malignant tumors ranked worldwide, and despite the great advances in diagnostic and therapeutic techniques, colorectal cancer patients who have developed distant metastases still have poor prognosis. The colorectal cancer lung metastasis cases in China account for 32.9% of all colorectal cancer metastatic patients, while the initial lung metastasis cases reach 24.5%, wherein about 9.4-12.2% of lung metastasis patients are suitable for local radical treatment including R0 surgery (complete resection), radiotherapy and ablation treatment. Colorectal cancer lung metastasis cases account for 32.9% of all colorectal cancer metastatic patients, and most lung metastasis patients cannot be treated radically, so immunotherapy may be another option for lung metastasis patients. However, there still exists a lack of target molecules, and a targeting therapeutic medium which is simple in operation and convenient in autograft.
Disclosure of Invention
In order to solve the technical problems, the invention discovers for the first time that the conditional deletion of the Erbin of the megakaryocyte or the platelet can obviously inhibit the lung metastasis of the colorectal cancer by exploring the effect of the Erbin gene in a tumor immune microenvironment, thereby providing the medicine for the lung metastasis of the colorectal cancer.
The first purpose of the invention is to provide the application of Erbin gene in platelets in preparing drugs for preventing or treating colorectal cancer lung metastasis, and critically, the Erbin gene in platelets is reduced in a targeted manner.
Furthermore, the substance for reducing the Erbin expression in the platelets in a targeted mode is an Erbin inhibitor or a substance containing the Erbin inhibitor, and is selected from one or two of siRNA and shRNA.
Furthermore, the substance containing the Erbin inhibitor is a nano vesicle with surface modified cyclic peptide RGD and loaded with the Erbin inhibitor inside.
It is a second object of the invention to provide a vaccine formulation for the treatment of colorectal cancer lung metastases comprising platelets treated in vitro to reduce Erbin gene expression. The targeted knockdown/knockdown Erbin platelets are injected into an individual suffering from colorectal cancer metastasis through vein injection, the colorectal cancer metastasis can be obviously inhibited, and the platelets are used as medicines and have the advantages of easy separation and easy in-vitro modification.
Further, the platelets are autologous or allogeneic. The autologous platelets are preferred, and are modified and then infused back into the body of a patient due to immune resistance caused by immunotherapy, so that the autologous platelets are more easily accepted by the body and are less prone to immune storm formation. The non-self cells may cause the attack of immune cells of the receptor itself, cause rejection reaction, lead to undesirable treatment effect and even cause inflammation storm.
Further, the step of in vitro treatment for reducing the Erbin gene expression comprises the steps of in vitro separation of platelets and treatment of the platelets with an Erbin inhibitor or a substance containing an Erbin inhibitor.
The third purpose of the invention is to provide the application of platelets subjected to the in vitro treatment of Erbin gene expression reduction in the preparation of drugs for treating colorectal cancer lung metastasis.
The fourth purpose of the invention is to provide a detection kit for colorectal cancer lung metastasis, wherein a detection sample of the detection kit is platelets isolated in vitro, and the detection kit comprises a reagent for detecting the content of acyl carnitine. The invention researches the characteristics, particularly the metabolic characteristics, of the platelet lacking or underexpressing Erbin, and discovers that the platelet lacking or underexpressing Erbin can secrete a large amount of acylcarnitine which is a lipid metabolite for the first time, so that the acylcarnitine secretion amount of the platelet can be used as a biomarker for detecting colorectal cancer lung metastasis.
Further, the detection kit also comprises a reagent for activating the blood platelet.
Furthermore, when the detection kit is used for monitoring the treatment effect of a patient, platelets in peripheral blood of the patient to be detected are separated, the content of acyl carnitine in the supernatant is detected after the platelets are activated, and if the content of the acyl carnitine is increased, a certain treatment effect is indicated.
By means of the scheme, the invention at least has the following advantages:
(1) The invention is based on a mouse with a platelet deletion Erbin gene (namely, only the platelet of the mouse is deleted with the Erbin gene, but not all the platelets are deleted), and a new target molecule for treating colorectal cancer lung metastasis, namely the Erbin gene in the platelet, is determined through in vitro and in vivo experiments. Based on the discovery of the new target, a new medicine for colorectal cancer lung metastasis is provided, and the medicine targets the Erbin gene of platelets, can promote plasma cells in individuals to secrete antibodies, and promotes effector T cells in individuals to kill tumors.
(2) Aiming at the discovered colorectal cancer lung metastasis treatment target, the invention also provides a platelet medicine. Because immune rejection reaction exists in immunotherapy, platelets taken from an individual are modified in vitro and Erbin is knocked down and then are infused back into the body of the patient, so that the immune rejection reaction and other adverse reactions can be obviously reduced. The mode of targeted therapy against platelets has the following advantages: the blood platelet is easy to separate and obtain, and the blood platelet is easy to modify.
(3) The invention discovers that the platelets can secrete more acyl Carnitine through the mouse with the platelet lacking Erbin genes, and in order to confirm the effect of the acyl Carnitine on colorectal cancer lung metastasis in mechanism research, the invention confirms that the acyl Carnitine (L-Carnitine) can inhibit the colorectal cancer metastasis in a mode of injecting the acyl Carnitine into the abdominal cavity in the mouse with the colorectal cancer lung metastasis. Therefore, a kit for detecting colorectal cancer lung metastasis is provided, if the curative effect of a patient receiving treatment needs to be monitored, besides the number and the size of lung metastasis foci through traditional imaging, the kit can also be realized by taking blood platelets of the patient, and detecting the content of secreted acyl carnitine after in vitro activation.
The foregoing description is only an overview of the technical solutions of the present invention, and in order to make the technical solutions of the present invention more clearly understood and to implement them in accordance with the contents of the description, the following description is made with reference to the preferred embodiments of the present invention and the accompanying detailed drawings.
Drawings
In order that the present disclosure may be more readily and clearly understood, reference will now be made in detail to the present disclosure, examples of which are illustrated in the accompanying drawings.
FIG. 1 shows the result of the verification of the entrance of nanovesicles into platelets;
FIG. 2 shows Erbin L/L (ii) a Identifying the expression of Erbin in the platelet of pf4cre mice and control mice;
fig. 3 is a graph of the results of erbb inhibiting colorectal cancer lung metastasis in targeted platelets; the colorectal cancer lung metastasis condition of the A.cKO mice and the control mice has a large lung tissue appearance; B. (A) HE scan of the graph; C. quantitatively counting tumors in the maximum area of lung tissues (HE staining) of two groups of mice (the number n of the mice in each group is more than or equal to 5) in the picture (A) under a mirror; D. (A) Lung weight/body weight in the graph; E. colorectal cancer lung metastasis in wild-type mice, cKO mice, and wild-type mice receiving cKO mouse platelets, with gross lung tissue; F. (E) HE scan of the graph; G. (E) Lung weight/body weight in the graph; H. quantitatively counting tumors in the maximum area of lung tissues (HE staining) of three groups of mice (the number n of the mice in each group is more than or equal to 5) in the image (E) under a mirror; I. colorectal cancer lung metastasis in wild-type mice, cKO mice, and wild-type mice that received cKO mouse megakaryocytes, with gross lung tissue; J. (I) HE scan of the graph; K. (I) Lung weight/body weight in the graph; l, quantitatively counting tumors in the maximum area of lung tissues (HE staining) of three groups of mice (the number n of the mice in each group is more than or equal to 5) in the picture (I) under a mirror; m. wild type, cKO mice and mice receiving nanovesicle-encapsulated siErbin for colorectal cancer lung metastasis, lung tissue gross appearance;
FIG. 4 shows lung metastasis of colorectal cancer in wild type mice and cKO miceThe ratio of plasma cells, exhausted T cells, effector T cells, and the expression of megakaryocytes and characteristic molecules PD1/PDL1 on the megakaryocytes in the bone marrow and lung metastases of mice; wherein, A, wild type and cKO tumor-bearing mice mature megakaryocytes (CD 41) + CD42b + ) A ratio; B. all megakaryocyte CD41 in lung metastases of wild-type and cKO tumor-bearing mice + And the proportion of mature megakaryocytes; C. two groups of mice lung metastasis focus mesoplasmic cells (B220) - CD138 + ) A ratio; D. depleted T cells (CD 4) in lung metastases of two groups of mice + PD1 + ；CD8 + PD1 + ) A ratio; E. two groups of mice lung metastasis focus effector T cell CD4 + /CD8 + GranzB + ；CD4 + /CD8 + IFNγ + ；CD4 + /CD8 + Perforin + ) A ratio; F. mature megakaryocytes in bone marrow and lung metastases of two groups of mice express the ratio of PD1/PDL 1;
FIG. 5 is a graph of the ratio of plasma cells and the ratio of effector T cells in lung metastases of wild type mice, cKO mice and wild type mice receiving cKO megakaryocytes/platelets; wherein A, igA in wild type, cKO and wild type mouse lung metastases receiving cKO mouse platelets + /IgM + /IgG + CD138 + The proportion of cells; B. wild type, cKO and IgA in lung metastases of wild type mice receiving cKO mouse megakaryocytes + /IgM + /IgG + CD138 + The proportion of cells; C. (in panel a) and d. (in panel B) the proportion of effector T in lung metastases of three groups of mice;
FIG. 6 is a platelet non-target metabolomics analysis of wild type and cKO mice and a supernatant lipid metabolomics analysis of wild type and cKO mice secretion of platelets and activated platelets; wherein, a. Platelet non-target metabolomics analysis of wild type and cKO mice; B. wild-type and cKO mouse activated platelet supernatant lipid metabolomics analysis of differential metabolites (heat map); C. wild-type and cKO mouse platelet lipid metabolomics analysis of differential metabolites (heat map);
FIG. 7 shows that acylcarnitine inhibits lung metastasis of colorectal cancer in mice; wherein, the lung metastasis range of colorectal cancer lung metastasis models of A.WT, cKO mice and WT mice receiving acyl Carnitine L-Carnitine are in general appearance; B.HE diagram; C. lung weight/body weight; D. the number of lung metastases; E. the proportion of IgA + CD138+ cells, igM + CD138+ cells, and IgG + CD138+ cells in the three groups of mouse lung metastases; F. the proportion of exhausted T cells PD1+ CD8+ cells in the three groups of mouse lung metastases; G. the ratio of potent T cells Perforin + CD8+/CD4+ T cells in the lung metastases of three groups of mice.
Detailed Description
The present invention is further described below in conjunction with the following figures and specific examples so that those skilled in the art may better understand the present invention and practice it, but the examples are not intended to limit the present invention.
The following examples of the invention relate to the following materials:
the cRGD-PEG-P (TMC-DTC) has the following structural formula:
PEG-P(TMC-DTC)-PEI 1200 the structural formula is as follows:
the kit detects acyl carnitine in the platelet supernatant: palmityl-L-carbonitine;
in vivo injection of acylcarnitines: L-Carnitine inner salt
Example 1 preparation of nanovesicles surface-modified with cyclic peptide RGD and loaded with erbb inhibitor inside
Loading the bins into the nanomaterial with sirna (siErbin):
(1) Preparation of polymer nano vesicle coated siErbin
Separating platelets, and collecting platelets at 3 × 10 8 The ratio of/ml and polymer nano vesicle solution labeled with Cy5 fluorescence was calculated in a ratio of 9:1 interaction and centrifugation at 37 ℃ incubator for 2h to remove supernatant.
The polymer nano vesicle loaded with siRNA consists of two polymers, namely PEG-P (TMC-DTC) -PEI1200 and cRGD-PEG-P (TMC-DTC), and the two polymers can be self-assembled in a water phase after being mixed to form a polymer vesicle with disulfide cross-linking reduction response, the particle size is 40-50nm, the PDI is small, the stability is good, the nano vesicle can stably exist in a normal physiological environment to protect a medicament, and the medicament can be quickly released in a reduction environment. Meanwhile, the proton sponge effect of PEI can help the drug to escape from the endosome quickly to play a role, siRNA degradation is prevented from losing activity, and cRGD modified on the surface of the polymer vesicle can target platelets to mediate endocytosis.
Polymer (a): PEG-P (TMC-DTC) -PEI 1200 The siRNA is polyethylene glycol-poly (trimethylene carbonate-co-dithiolane trimethylene carbonate) -polyethyleneimine, has a certain positive charge, and can efficiently and stably load siRNA with negative charge through electrostatic interaction; the cRGD-PEG-P (TMC-DTC) is a cyclic polypeptide cRGDfc modified on the surface of a polymer, can be specifically combined with integrin, and targets platelets.
The specific process of loading siRNA is as follows: PEG-P (TMC-DTC) -PEI1200 and DMF solution (concentration is 40 mg/mL) of cRGD-PEG-P (TMC-DTC) are mixed according to a certain proportion (the molar ratio of the PEG-P to the cRGD-PEG-P is 80% and 20% in the experiment respectively), and then the mixture is slowly dripped into HEPES buffer solution containing siRNA (water phase: oil phase =9 1), after stirring for 5min, organic solvent and unloaded siRNA in the HEPES buffer solution are removed by dialysis.
(2) After the platelets and the nano vesicles with Cy5 labels are co-cultured and labeled with CD41 antibody for 30min, the platelets are specifically stained, and the CD41 is analyzed in a flow mode + Cy5 + The ratio of cells, and thus whether the material entered the platelets, are shown in FIG. 1. From the previous results, more than 95% of the vesicles entered the platelets.
Example 2
(1) The invention uses the transgenic mouse with megakaryocyte/platelet conditional deletion Erbin as experimental material (Erbin) loxp/loxp (ii) a pf4cre, hereinafter abbreviated cKO). The expression of Erbin and GAPDH in wild-type mice and megakaryocyte/platelet conditionally Erbin deficient mice were analyzed by immunoblotting for protein extraction, and the results are shown in FIG. 2.
(2) The first discovery that Erbin in targeted megakaryocyte/platelet can obviously inhibit colorectal cancer lung metastasis
A mouse colorectal cancer lung metastasis model is constructed by injecting mouse colorectal cancer cells MC38 into tail veins, and the effect of Erbin-regulated megakaryocytes/platelets in colorectal cancer metastasis is determined.
The results showed that 18 days after molding, the lung metastases were significantly less in the cKO mice than in the wild type mice (FIG. 3A). To further determine the effect of Erbin-deficient megakaryocytes/platelets in colorectal cancer lung metastasis, we adoptively administered megakaryocytes (fig. 3I-L) and platelets (fig. 3E-H) from the cKO mice to wild-type mice, respectively, and determined the function of Erbin-deficient megakaryocytes/platelets by comparing them to the non-recipient and cKO mice. The results show that both colorectal cancer lung metastases were significantly reduced in wild type mice that received either megakaryocytes or platelets from the cKO, and lung tissue was roughly looking close to the phenotype of the donor mouse (cKO) lung (fig. 3), suggesting that the erbb-deficient megakaryocytes/platelets inhibited colorectal cancer lung metastases.
Platelets are considered to have a strong clinical transformation potential as drug delivery vehicles in the treatment of various diseases. Because platelet surface integrin α IIb β 3 and α V β 3 receptor have high affinity for cyclic polypeptide RGD, we use nanovesicles (provided by professor of long-term chunking, university of suzhou, preparation methods mentioned above) with surface modified cyclic polypeptide RGD to encapsulate siRNA (siErbin) of Erbin, which specifically binds to platelet surface integrin receptor, targets platelet receptor, delivers siErbin into platelets, and knockdown Erbin gene therein.
Wild-type mice on the third day after tumor burden were injected with siErbin-encapsulated nanovesicles via tail vein, and then every 7 days, and observed for colorectal cancer lung metastasis on day 18 with wild-type mice and cKO mice that did not receive vesicles. The previous results showed that lung metastasis was significantly less in the group receiving vesicle-encapsulated siErbin (WT + crd-siErbin) than in the non-receiving group and the lung metastasis phenotype tended to be identical to that of the cKO group (fig. 3M) compared to the non-receiving and cKO groups.
(3) We found that more PDL1 was enriched in the cKO mice bone marrow and lung metastases low /PD1 low CD41 + CD42b + Mature megakaryocyte (FIGS. 4A and B), PD1 low B220 - CD138 + Plasma cells (FIG. 4C), IFN γ + CD8 + T cells and less depleted PD1 + CD8 + T cells (FIGS. 4D, E).
(4) After wild type mice received megakaryocyte platelets from cKO mice (FIG. 5A), more plasma cells were aggregated in recipient lung metastases (FIG. 5B), and CD8 was effected + T cells (fig. 5C, D).
Wild-type mice receiving cKO mouse platelets showed IgA in lung metastases compared to non-receiving groups + CD138 + ，IgM + CD138 + And IgG + CD138 + The ratio was significantly increased and converged to CKO mice, about 20-fold, 7-fold and 10-fold higher than the wild type non-recipient group. Receptor CD8 in wild-type lung metastases + IFNγ + The number of the plants is significantly increased by about 3 times that of wild type non-receiving group, namely, CD4 + IFNγ + The number was about 7 times that of the wild type non-receiving group.
Wild-type mice that received cKO mouse megakaryocytes had IgA in lung metastases compared to the non-receiving group + CD138 + ，IgM + CD138 + And IgG + CD138 + The ratio was significantly increased and converged to CKO mice, approximately 3-fold, 3-fold and 3-fold higher than in the wild type non-recipient group. CD8 in receptor wild-type lung metastases + IFNγ + The number of the plants is remarkably increased by about 6 times that of wild type non-receiving group, and the number of the plants is CD4 + IFNγ + The number was about 4 times that of the wild type non-receiving group.
This suggests that megakaryocytes/platelets in cKO mice promote the production of more plasma cells and T-effector cells in recipient wild-type mice, and that the increase in T-effector cells promotes tumor killing.
(5) Analysis of non-target metabolomics (fig. 6A) and classical lipidomics (fig. 6B, C) choking mice with platelet supernatant (fig. 6B) and platelets (fig. 6C) in which the abundance of acylcarnitine was significantly higher than in the control group.
Platelet analysis of wild type and cKO mice by non-target metabolomics showed that the differential metabolic pathways are enriched on lipid-associated metabolic pathways; lipid metabolomics analysis showed that the differential lipid metabolite within platelets of wild type and cKO mice was Acar (acylcarnitines); the differential lipid metabolite in the supernatant after platelet activation of wild type and cKO mice was Acar; and are both more abundant in cKO mouse platelets and in the cKO mouse platelet supernatant.
(6) The acylcarnitine inhibits the lung metastasis of colorectal cancer of a mouse, increases plasma cells in a lung metastasis focus, reduces exhausted CD8+ T cells and increases effector T cells.
To verify whether the above we found that more platelet-secreting acylcarnitines in the cKO mice were the key factor for inhibiting colorectal cancer metastasis, we found that acylcarnitines significantly inhibited colorectal cancer pulmonary metastasis in wild-type mice by intraperitoneal injection of acylcarnitine L-Carnitine (abbreviated as LC) to a colorectal cancer pulmonary metastasis model in wild-type mice, and that phenotypes and cKO mouse phenotypes converged (fig. 7A-D), the number of plasma cells in the lung metastasis foci of wild-type colorectal cancer pulmonary metastasis mice receiving acylcarnitines was significantly smaller, and converged to the cKO mice (fig. 7E); depletion T cells PD1+ CD8+ T cells were significantly reduced, converging with the cKO (fig. 7F); CD8+ T cells with a killing effect IFN + CD8+/CD4+ T, perforin + CD8+/CD4+ T cells were significantly increased, converging with the cKO (fig. 7G).
It should be understood that the above examples are only for clarity of illustration and are not intended to limit the embodiments. Other variations and modifications will be apparent to persons skilled in the art in light of the above description. This need not be, nor should it be exhaustive of all embodiments. And obvious variations or modifications of the invention may be made without departing from the spirit or scope of the invention.
Claims (10)
1. The application of Erbin gene in platelets in preparing colorectal cancer lung metastasis medicaments is characterized in that: the target reduces the expression of Erbin in platelets.
2. Use according to claim 1, characterized in that: the substance for reducing the Erbin expression in the platelet in a targeted mode is an Erbin inhibitor or a substance containing the Erbin inhibitor.
3. Use according to claim 2, characterized in that: the Erbin inhibitor is selected from siRNA and/or shRNA.
4. Use according to claim 2, characterized in that: the substance containing the Erbin inhibitor is a nano vesicle with the surface modified with cyclic peptide RGD and the interior loaded with the Erbin inhibitor.
5. A vaccine formulation for treating colorectal cancer lung metastasis, comprising: the vaccine formulation includes platelets treated in vitro to reduce Erbin gene expression.
6. The vaccine formulation of claim 5, wherein: the platelets are autologous or allogeneic.
7. The vaccine formulation of claim 5, wherein: the step of in vitro treatment for reducing the Erbin gene expression comprises the steps of in vitro separation of platelets and treatment of the platelets by an Erbin inhibitor or a substance containing the Erbin inhibitor.
8. Application of platelets subjected to in vitro treatment for reducing Erbin gene expression in preparation of medicaments for lung metastasis of colorectal cancer.
9. A detection kit for colorectal cancer lung metastasis, characterized in that: the detection kit comprises a reagent for detecting the content of acyl carnitine, and a detection sample is platelets separated in vitro.
10. The test kit according to claim 9, characterized in that: the detection kit also comprises a reagent for activating the blood platelet.
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