CN117547600B - Preparation and application of liposome vaccine targeting HDAC - Google Patents
Preparation and application of liposome vaccine targeting HDAC Download PDFInfo
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- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
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Abstract
The invention belongs to the field of biological medicine, and in particular relates to a preparation method and application of a liposome vaccine containing an HDAC inhibitor, pam2-MUC1 antigen peptide and alpha-GalCer, wherein the liposome is prepared by the following method: 1) The HDAC inhibitors SAHA, pam2-MUC1 antigen peptide, α -GalCer adjuvant, choline, cholesterol were dissolved in the organic solvent methanol/dichloromethane (volume ratio 1:1), respectively, and then these 5 ingredients were mixed in a molar ratio and ensured to be sufficiently dissolved (choline: cholesterol: pam2-MUC1 antigen peptide: alpha-GalCer adjuvant: saha=10:8: 2:1: 2) Spin-drying the dissolved mixture into a film by a spin-steaming instrument; 3) And (3) hydrating, namely adding a certain volume of ultrapure water or PBS into a round-bottomed flask for forming a film, and carrying out ultrasonic treatment for 30min for hydrating to finally obtain the target liposome vaccine. The liposome vaccine is combined with the anti-angiogenesis lytic peptide, so that the effects of tumor immunotherapy can be achieved in a synergistic manner from multiple aspects such as epigenetic regulation, tumor vaccine and anti-angiogenesis, and the use concentration of anti-tumor drugs is reduced, so that the toxic and side effects of the anti-tumor drugs are reduced. The invention provides a new treatment idea and direction for the limitation of the clinical tumor immunotherapy at present.
Description
Technical Field
The invention belongs to the field of biological medicine, and relates to preparation of a liposome vaccine targeting HDAC and application of the liposome vaccine in the field of liver cancer treatment in cooperation with an anti-angiogenesis split peptide.
Background
Liver cancer, represented by hepatocellular carcinoma (hepatocellular carcinoma, HCC), is the fifth most common cancer worldwide, and is also the second leading cause of cancer death. The immune system has been widely accepted in inhibiting the occurrence and development of liver cancer, and the tumor immunotherapy is currently combined with targeting drugs and chemotherapeutics to treat malignant tumors, so that a clinically significant therapeutic effect is obtained, and the treatment using anti-tumor immune response is a big support for cancer treatment. However, many patients with cancer including liver cancer have congenital or secondary immune tolerance after receiving tumor immunotherapy, resulting in poor therapeutic effects. Highly effective anti-tumor immune responses require very high levels of regulation, and there is a great clinical need to develop new methods to augment tumor immunotherapy, particularly malignant highly metastatic cancers. Research shows that histone deacetylase inhibitors (HDACi) can effectively inhibit proliferation of various malignant tumors (such as lymphoma, breast cancer, liver cancer, colon cancer and the like), 5 HDAC drugs are marketed in batches before the day of the expiration, namely vorinostat, romidepsin, belinostat, panobinostat and sitagliptin, and are mainly used for treating blood cancer or breast cancer. In recent years, more and more studies have found that HDAC inhibitors have significant effects in enhancing tumor immunotherapy, such as HDAC6 inhibitors improving patient response to immunotherapy and reducing invasiveness of breast cancer. Other preclinical studies have also demonstrated that many HDAC inhibitors, including broad-spectrum HDAC inhibitors and subtype-selective HDAC inhibitors, exhibit good in vitro and in vivo anti-tumor activity and tumor immunomodulation, not only significantly inhibit tumor growth in vivo, but also activate anti-tumor immunity by activating T cells, alleviating the inhibitory immune microenvironment and affecting macrophage polarization.
Clinical outcome of tumor immunotherapy depends on the presence of tumor-specific antigens, which is central to T lymphocyte-based tumor immunotherapy. Research shows that the fragments generated by killing tumors by the cytotoxic drugs can become tumor antigens for activating immune systems and promote the anti-tumor effect of the PD-1 monoclonal antibodies or the immunotherapeutic drugs such as tumor vaccines. The lytic peptide is a very potential anti-tumor drug which achieves an anti-tumor effect mainly by lysing tumor cell membranes, so that the peptide has a therapeutic effect on various tumors including chemotherapy-resistant tumor cells. The research shows that the intratumoral injection of the lytic peptide can enhance the therapeutic effect of the PD-1 monoclonal antibody on the far-end tumor, and the fact that the lytic peptide can enhance the immune curative effect of the PD-1 monoclonal antibody by lysing tumor cells or not is proved. The applicant has developed a VEGFR-targeted lytic peptide in the early stage, which can effectively target VEGFR protein on the cell surface, and can inhibit proliferation and anti-angiogenesis of tumor at the same time. Therefore, the cracking peptide is combined with tumor immunotherapy, and is expected to enhance the immunotherapy effect to a greater extent.
Although existing immunotherapy has achieved significant results in the field of tumor treatment, the unique advantages of tumor vaccines have attracted attention from the scientific and medical industries. Tumor vaccines can target intracellular antigens other than tumor-specific surface antigens and even potentially elicit new tumor-specific T cell responses. However, the number of clinical trials of cancer vaccines currently being developed is limited, and their therapeutic efficacy and detailed and well-defined principles require further exploration by researchers. Research shows that the liposome as vaccine adjuvant can raise cell mediated immune response and strengthen body fluid, and is favorable to raising vaccine effect. Further research shows that the encapsulation of Pam 2 -MUC1 polypeptide and alpha-GalCer liposome can significantly improve the IgG antibody titer in mice, suggesting that the liposome is expected to be a very effective liposome vaccine for resisting Pam 2 -MUC1, however the anti-tumor treatment effect of the liposome has not been reported so far.
Tumor immunotherapy is a very complex procedure, and how to effectively use the sharps to exert the greatest effect thereof has been a focus and difficulty of attention of scientists. The adoption of multifactor synergistic activation of the immune system in vivo and the exertion of the anti-tumor effect are expected to become effective tools for solving clinical immune escape or immune tolerance.
Disclosure of Invention
Although tumor immunotherapy has shown great promise in cancer treatment, only a small percentage of people can get obvious therapeutic effects in specific clinical applications. How to improve the immune response of tumor immunotherapy, and thus the therapeutic effect, has been the direction of scientists. The technical problem to be solved by the invention is to provide a preparation method of an anti-tumor liposome vaccine containing Pam 2 -MUC1 antigen peptide, HDAC inhibitor SAHA and alpha-GalCer adjuvant and an application of the anti-tumor liposome vaccine in combination with anti-angiogenesis cleavage peptide, wherein a specific structure diagram is shown in figure 1. The technical scheme for solving the technical problems is as follows:
1. Preparing antitumor liposome vaccine with uniform size. The nano liposome structure formed by mixing an HDAC inhibitor SAHA, pam 2 -MUC1 antigen peptide, alpha-GalCer adjuvant, cholesterol and choline according to a certain proportion is specifically prepared as follows: choline, cholesterol, pam 2 -MUC1 antigen peptide, SAHA, α -GalCer were dissolved in dichloromethane/methanol (volume ratio 1:1), respectively, and then in a molar ratio of 10:8:2:2:1, and then placing the mixture in a round bottom flask, and performing reduced pressure spin drying to form a film. The proportion of the liposome is obtained through earlier literature investigation and cytotoxicity screening after SAHA introduction. Then, a certain volume of PBS or ultrapure water H2O is added, ultrasonic (53 Hz,90% power) is carried out for 30 hours in an ultrasonic instrument at 25 ℃, every 10 minutes of ultrasonic is carried out in the ultrasonic process, 1 minute is carried out in a cyclone instrument, and 3 times are carried out alternately until a uniformly dispersed suspension which can be seen by naked eyes is formed. Centrifugation was performed using an ultracentrifuge at 10000rpm for 30min to allow the liposomes to precipitate sufficiently, the supernatant was discarded, the precipitated liposomes were resuspended in PBS again, the size of the liposomes was measured using a particle sizer, the average particle size of the liposomes was about 177nm (pdi=0.462) as measured by the particle sizer, and the potential detection revealed that the liposomes were positively charged, more conducive to penetration of negatively charged cell membranes, as shown in fig. 2.
2. Application of liposome vaccine in anti-liver cancer treatment
Firstly, we verify that the HDAC inhibitor SAHA and the anti-angiolytic peptide have anti-liver cancer effect, and as shown in figures 3A-D, the two medicaments have anti-tumor effect in different liver cancer cells and have inhibition effect on normal cells at higher concentration. Then, in order to improve the curative effect and reduce the toxicity, the liposome is taken as a carrier to wrap Pam 2 -MUC1 antigen peptide capable of activating tumor immune response and an adjuvant alpha-GalCer for enhancing the immune effect, so that the liposome has stronger immune response effect, and meanwhile, the liposome wraps SAHA, so that the liposome has the effect of killing tumor cells and reduces the toxicity. As shown in FIG. 3E, the liposome has strong anti-tumor effect at low concentration after wrapping SAHA, but has no toxicity to normal cells. Therefore, the liposome vaccine obtained by the invention has the double effects of killing tumors and activating immune response. The anti-angiogenesis lytic peptide reported by the inventor in the prior period can resist tumor microvessels and lyse tumor cells so as to achieve the dual anti-tumor effect. By utilizing the characteristics, the lytic peptide is combined with the liposome vaccine of the invention, and firstly, apoptosis and cell cycle experiments prove that the lytic peptide combined with the liposome vaccine wrapped with SAHA can obviously cause apoptosis and cell cycle arrest of liver cancer cells in the G2 phase, as shown in figures 4 and 5. We also demonstrated that the liposomes have an effect of inhibiting intracellular HDAC activity by WB, as shown in fig. 6. Then, constructing a subcutaneous tumor animal model of liver cancer, firstly injecting a lytic peptide into tumor in an animal body to enable the tumor cells to be lysed to release new antigens, then injecting a liposome vaccine into the abdominal cavity of the animal, and activating tumor immune response in the body by cooperating with the new antigens to enhance the anti-tumor immune response effect. As shown in fig. 7-8, the liposome can effectively inhibit tumor proliferation, prolong the life cycle of mice, and the medicine has no remarkable toxicity and does not cause the change of the body weight of mice. Further immunohistochemical experiments and loss analysis show that the liposome vaccine prepared by the invention can remarkably improve immune response in mice, cause proliferation of anti-tumor immune related cells CD4 +、CD8+、CD11b+ and CD11c +, and simultaneously can cause expression of immune related cytokines such as TNF-alpha and IFN-gamma. Further proving our hypothesis as shown in fig. 9-10.
Compared with the prior art, the invention has obvious technical progress. The invention combines the liposome vaccine without tumor killing effect with the SAHA of the HDAC inhibitor to form a novel multifunctional nano liposome vaccine, so that the novel multifunctional nano liposome vaccine has dual effects of anti-tumor activity and immune response activation. The cytotoxicity experiment proves that the liposome vaccine containing SAHA has specific and obvious capability of killing liver cancer cells, and the liposome vaccine without SAHA can not effectively kill liver cancer cells. The western blot experiment proves that the liposome vaccine can effectively inhibit the activity of HDAC in cells, further influence the related signal paths, and induce apoptosis and cell cycle retardation of tumor cells. Animal tumor suppression experiments prove that the liposome vaccine wrapping SAHA has more remarkable tumor suppression effect than liposome vaccine without SAHA, and the synergistic intra-tumor administration of the anti-angiogenesis lytic peptide can remarkably suppress the proliferation of tumors in mice, but does not influence the change of the weight of the mice. Further HE staining experiments prove that the SAHA-containing liposome vaccine cooperates with the anti-angiogenesis lytic peptide, so that the weight of the mice is not reduced, the internal organs of the mice are not damaged, and the effectiveness and safety of the medicine in treating liver cancer are proved. The research result provides a new reference for developing novel anti-tumor vaccine in future and providing curative effect of clinical tumor immunotherapy.
Drawings
Fig. 1 is: the nano liposome structure and the anti-angiogenesis cleavage peptide structure diagram of the invention;
fig. 2 is: the structure characterization diagram of the nano liposome is shown in the specification;
fig. 3 is: toxicity patterns of the nano liposome drug in liver cancer cells and normal cells;
Fig. 4 is: the nano liposome induces apoptosis patterns of liver cancer cells;
Fig. 5 is: the nano liposome of the invention causes a liver cancer cell cycle arrest diagram;
fig. 6 is: the nanoliposome of the invention has an influence diagram on the acetylation level of HDAC protein substrates in liver cancer cells;
Fig. 7 is: the nano liposome has the effect of inhibiting tumor growth in a mouse liver cancer model;
Fig. 8 is: graph of the influence of nanoliposomes of the invention on mouse body weight during dosing;
Fig. 9 is: the nano-lipid of the invention can cause the expression of anti-tumor immune cells in tumor tissues
Fig. 10 is: the nano-lipid can enhance the expression of anti-tumor immune factors in mice.
Detailed Description
The principles and features of the present invention are described below with reference to the drawings, the examples are illustrated for the purpose of illustrating the invention and are not to be construed as limiting the scope of the invention.
Example 1: preparation of nanoliposome comprising SAHA, pam 2 -MUC1 polypeptide, alpha-GalCer adjuvant.
The synthetic route of Pam 2 -MUC1 polypeptide has been reported in the literature, and the synthetic route of the polypeptide used in the present invention is strictly carried out in accordance with the literature. The nano liposome structure is prepared by mixing SAHA, pam2-MUC1 antigen peptide, alpha-GalCer adjuvant, cholesterol and choline according to a certain proportion, and is specifically prepared as follows: choline, cholesterol, pam 2 -MUC1 antigen, SAHA, α -GalCer were dissolved in dichloromethane/methanol (volume ratio 1:1), respectively, and then in a molar ratio of 10:8:2:2:1, and then placing the mixture in a round bottom flask, and performing reduced pressure spin drying to form a film. Then, a volume of PBS or ddH2O was added and ultrasound (53 Hz,90% power) was performed in an sonicator at 25℃for 30 hours, every 10 minutes during the sonication, and 1 minute was vortexed in the vortexing instrument, alternating 3 times until a macroscopically homogeneously dispersed suspension was formed. Centrifuging with an ultracentrifuge at 10000rpm for 30min to precipitate liposome, discarding supernatant, re-suspending the precipitated liposome with PBS, measuring the particle size of the liposome with a particle size analyzer, and detecting the average particle size of the liposome with a particle size of 177nm (PDI=0.462), wherein the liposome is positively charged as detected by electric potential detection, and is more helpful for penetrating negatively charged cell membrane.
Example 2: synthesis preparation of antiangiogenic lytic peptides
The synthetic route of the anti-angiogenic cleavage peptide has been reported in patent and literature, and the synthetic route of the polypeptide used in the invention is strictly carried out according to literature, and polypeptide molecules with accurate structure and single component are obtained. Therefore, the synthetic route of the polypeptide is not described in detail.
Example 3: detection of killing action of nanoliposomes of the invention on different cells
Cytotoxicity experiments were determined by CCK8 cytotoxicity experiments. Cells were seeded at 8×10 3 in 96-well plates, after 24 hours, nanoliposomes containing SAHA, pam2-MUC1 polypeptide and α -GalCer adjuvant, nanoliposomes containing Pam 2 -MUC1 polypeptide and α -GalCer adjuvant, and anti-angiogenic polypeptides were incubated with hepatoma Huh7 cells, hepG2 cells, hep3B cells and normal LO2 cells, respectively, at different concentration gradients for 48 hours, CCK8 was added to each well of cells and incubation was continued for 1 hour. Absorbance was measured at 450nm using an enzyme-labeled instrument. Wherein the untreated cell viability was 100%. The results show that the nanoliposome of the present invention comprising HDAC has a remarkable antitumor effect, but has no remarkable toxicity to normal cells, as shown in fig. 3. Meanwhile, the anti-angiogenesis lytic peptide has very obvious inhibition effect on liver cancer cells. But liposome vaccines without SAHA have no significant toxicity to tumor cells. The results indicate that nanoliposome vaccines comprising SAHA have more pronounced anti-tumor selective toxicity.
Example 4: the nano liposome vaccine of the invention has the effects on apoptosis and cell cycle arrest of liver cancer cells.
In order to evaluate whether the nanoliposome vaccine causes apoptosis of tumor cells, an Annexin V-FITC apoptosis detection kit is adopted, and the apoptosis condition caused by medicines is detected by a flow cytometer. As shown in fig. 5, the drug did significantly induce apoptosis of tumor cells, as shown in fig. 4.
For cell cycle experiments, cells treated with drug for 24 hours were collected, first incubated with 70% glacial ethanol overnight at-20 ℃, PI stained, and then analyzed by flow cytometry. The results show that nanoliposomes can significantly induce cell cycle arrest in G1 phase of tumor cells, as shown in FIG. 5.
Example 5: nanolipids can significantly increase the substrate acetylation level of HDAC
Immunoblotting experiments (WB) were used to study the effect of SAHA-containing liposome vaccines on the level of HDAC substrate acetylation after treatment of tumor cells at different dosing concentrations. Repeated WB experiments show that the designed liposome can obviously cause up-regulation of the acetylation level of the HDAC histone substrate, and as shown in fig. 6, it is revealed that our drugs can obviously inhibit the activity of tumor cell HDAC.
Example 6: mouse subcutaneous liver cancer model, nano liposome in vivo tumor inhibition and safety evaluation
To further verify the in vivo anti-tumor effect of the nanoliposome, we constructed a mouse subcutaneous liver cancer model, and after the mouse subcutaneous tumor size was about 150mm 3, the intervention experiment was started, i.e., mice were divided into 5 groups, PBS group, SAHA group (2, 6,10,14 days of administration, intraperitoneal injection, 1 mg/kg) anti-angiogenic lytic peptide group (every 1 day of administration, 2 weeks, 2 mg/kg), SAHA-containing nanoliposome group (2, 6,10,14 days of intraperitoneal injection, liposome containing about SAHA1 mg/kg), nanoliposome+anti-angiogenic lytic peptide group (2 mg/kg of intratumoral injection on days 1,3,5,7,9,11,13, and nanoliposome administration on days 2,6,10, 14). Tumor size was assessed after 2 weeks. As shown in fig. 7, the nano-liposome combined anti-angiogenesis lytic peptide has the strongest anti-tumor activity, and can remarkably prolong the life cycle of mice. Moreover, the drug does not affect the weight of mice during the administration period, thus proving the relative safety of the drug. Further immunohistochemistry and cell flow type ELISA experiments prove that the liposome vaccine can effectively cause proliferation of anti-tumor immune cells in tumor tissues, as shown in figure 8, enhance expression of the anti-tumor immune cells in mice, as shown in figure 9, and expression of anti-tumor cytokines, as shown in figure 10.
The foregoing description of the preferred embodiments of the invention is not intended to limit the invention to the precise form disclosed, and any such modifications, equivalents, and alternatives falling within the spirit and scope of the invention are intended to be included within the scope of the invention.
Claims (3)
1. The application of the liposome vaccine in preparing an anti-tumor drug is characterized in that the liposome vaccine comprises an HDAC inhibitor, pam 2 -MUC1 antigen peptide and alpha-GalCer, and the preparation method of the liposome vaccine is as follows: preparing liposome by adopting a film hydration method, respectively dissolving an HDAC inhibitor SAHA, pam 2 -MUC1 antigen peptide, alpha-GalCer adjuvant, cholesterol and choline in an organic solvent methanol/dichloromethane, wherein the volume ratio of the two organic solvents is 1:1, and taking choline: cholesterol: pam 2 -MUC1 antigen peptide: alpha-GalCer adjuvant: SAHA=10:8:2:1:2, and then spin-drying the mixture in a spin-steaming instrument to form a film, preparing liposome vaccine by adopting PBS or ultrapure water hydration ultrasound, centrifuging at a high speed at 10000rpm for 30 minutes, removing non-encapsulated free molecules, and re-suspending and centrifuging again by using ultrapure water to precipitate to obtain the required liposome vaccine, wherein the sequence of Pam 2 -MUC1 antigen peptide is Pam 2 -lysine-glycine-alanine-proline-aspartic acid-valine-arginine-proline-alanine-proline-glycine, and the antitumor drug is a drug for treating liver cancer.
2. The use according to claim 1, wherein said liposome vaccine promotes apoptosis and cell cycle arrest in liver cancer cells by inhibiting HDAC activity in liver cancer cells, resulting in up-regulation of the level of acetylation of HDAC specific substrate histone H3, as compared to a liposome vaccine without SAHA.
3. The use according to claim 1, wherein the liposome vaccine is combined with an anti-angiogenic lytic peptide QR-KLU, which kills tumor cells and releases tumor neoantigens by intratumoral administration, activates the in vivo anti-tumor immune system, and cooperates with the liposome vaccine in a mouse tumor model, enhancing the in vivo tumor immunotherapy effect.
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