CN116463366A - mRNA for treating cancer and application thereof in preparing anticancer drugs - Google Patents
mRNA for treating cancer and application thereof in preparing anticancer drugs Download PDFInfo
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Abstract
The invention discloses mRNA for treating cancer and application thereof in preparing anticancer drugs, wherein the mRNA for treating cancer is DNase1L3mRNA or GC-DNase mRNA, and the base sequence of DNase1L3mRNA is shown as SEQ ID NO. 1; the base sequence of the GC-DNase mRNA is shown as SEQ ID NO. 2. The two mRNAs for treating cancer of the invention firstly take ecDNA as a target point of cancer treatment, play an anti-tumor role by reducing the ecDNA content in tumors, and in an established cancer animal model, including hepatocellular carcinoma, breast cancer and lung cancer, the two mRNAs are treated to obviously reduce the tumor volume, slow down the growth of the tumors and prolong the survival time of mice.
Description
Technical Field
The invention belongs to the field of biological medicine, and in particular relates to mRNA for treating cancer and application thereof in preparing anticancer drugs.
Background
ecDNA was first discovered in 1964 when chromosomes of higher organisms were studied by Alix Bassel and Yasuo Hoota. Scientists have found that ecDNA is present in large amounts in many cancer types in humans, while the presence of ecDNA is hardly observed in normal tissues. Oncogene amplification is a common type of cancer mutation that can occur in homogeneously stained areas within the chromosome or extrachromosomally. The presence of extrachromosomal DNA (ecDNA) in nearly half of cancer types, compared to other local amplifications, amplification of ecDNA carrying oncogenes is closely related to a worse prognosis for cancer patients. Oncogene amplification is a means for cancer cell survival, and since ecDNA is necessary for maintaining oncogene expression, and elimination of ecDNA affects cancer cell survival, some cancer cells are ecDNA-philic, which makes ecDNA an important meaning as a therapeutic target for cancer. Reducing ecDNA in tumor cells would make a remarkable contribution to the field of cancer treatment.
mRNA drugs have received increasing attention over the last decade. The transmission and transcription mechanism of mRNA medicine can overcome the limitation of traditional medicine, and provides a new way for treating diseases dependent on protein expression. Through decades of research and development, mRNA drugs have had the following advantages: 1. safety, mRNA is neither infectious nor integrated into the genome, there is no potential risk of infection or causing genetic mutation, and antigenicity is weak, adverse reactions such as allergy are not likely to occur, mRNA can also be degraded by cells, and in vivo half-life can be regulated by using various modifications and delivery methods; 2. the mRNA has high curative effect, is the smallest genetic carrier, can be more stable through proper modification, and can be efficiently translated into protein; 3. the production is convenient, mRNA is mainly produced by in vitro transcription reaction, the cost is low, the yield is high, and the method has the potential of mass production; 4. flexibility unlike traditional drugs, mRNA drugs can easily change their sequence to accommodate different therapeutic needs. mRNA drugs need to be delivered to the cell interior via vectors in order to be transcribed and translated. Common vectors are divided into viral vectors and non-viral vectors. Among them, viral vectors, though highly efficient in delivery, have safety problems such as immunogenicity and toxicity, which limit their clinical applications. Non-viral vectors mainly include lipid-based delivery systems, polymer-based nanoparticles, and inorganic nanoparticles. Among them, lipid Nanoparticles (LNP) are one of the most widely used non-viral delivery systems for oligonucleotide drugs and mRNA drugs, and their advantages include easy production, biodegradability, ability to protect RNA molecules from RNase degradation and renal clearance, promotion of endocytosis, and inhibition of degradation of endosomes. In recent years, mRNA drugs have made tremendous progress in treating tumors. Compared with the traditional micromolecule chemical medicine, the mRNA medicine has the advantages of more accurate target point, higher specificity and selectivity, strong plasticity, low toxic and side effect, no permanent influence on DNA of patients and the like. By 3 months of 2023, more than 20 mRNA antitumor drugs enter clinical trials worldwide, and several mRNA drugs have been proved to be effective in inhibiting tumor growth and diffusion and also have a certain curative effect on metastatic cancers. Although mRNA for tumor treatment is not available in batches at present, a few medicines enter phase II clinic and the development trend is very rapid. In the future, tumor treatment based on mRNA technology will come to be a brand new development opportunity and will become an important direction for tumor treatment in the future.
Disclosure of Invention
The object of the present invention is to overcome the deficiencies of the prior art and to provide mRNA for the treatment of cancer.
It is a second object of the present invention to provide the use of mRNA for the treatment of cancer in the preparation of an anticancer drug.
It is a third object of the present invention to provide a pharmaceutical complex comprising the mRNA for the treatment of cancer as described above.
The technical scheme of the invention is summarized as follows:
the mRNA for treating cancer is DNase1L3mRNA or GC-DNase mRNA, and the base sequence of the DNase1L3mRNA is shown as SEQ ID NO. 1; the base sequence of the GC-DNase mRNA is shown as SEQ ID NO. 2.
The cancer is liver cancer, lung cancer or breast cancer.
Use of mRNA for treating cancer in the preparation of an anticancer agent.
The drug complex comprising the mRNA for treating cancer is prepared by compounding the mRNA for treating cancer with one or more lipids to prepare a liposome, a lipid nanoparticle or a lipid complex.
The invention has the advantages that:
the two mRNAs for treating cancer of the invention firstly take ecDNA as a target point of cancer treatment, play an anti-tumor role by reducing the ecDNA content in tumors, and in an established cancer animal model, including hepatocellular carcinoma, breast cancer and lung cancer, the two mRNAs are treated to obviously reduce the tumor volume, slow down the growth of the tumors and prolong the survival time of mice.
Drawings
FIG. 1 is a graph showing tumor growth curve of a liver cancer model mouse;
FIG. 2 is a graph showing tumor growth curves of mice with lung cancer models.
FIG. 3 is a graph showing tumor growth in mice with breast cancer models.
FIG. 4 is a survival curve of liver cancer model mice.
FIG. 5 is a survival curve of mice with lung cancer models.
FIG. 6 is a survival curve of breast cancer model mice.
FIG. 7 shows the immunohistochemical staining pathology scores of tumor tissues of mice with liver cancer model.
FIG. 8 is a tumor tissue immunohistochemical staining pathology score of lung cancer model mice.
FIG. 9 is a tumor tissue immunohistochemical staining pathology score of breast cancer model mice.
FIG. 10 shows the ecDNA content statistics of tumor tissues of model mice of examples 2,3 and 4.
Detailed Description
The invention is further illustrated by the following examples.
Example 1
The mRNA for treating cancer is DNase1L3mRNA or GC-DNase mRNA, and the base sequence of the DNase1L3mRNA is shown as SEQ ID NO. 1; the base sequence of the GC-DNase mRNA is shown as SEQ ID NO. 2.
DNase1L3mRNA or GC-DNase mRNA is synthesized artificially.
mRNA is produced by in vitro transcription. Firstly, respectively synthesizing a DNA template sequence SEQ ID NO.3 of DNase1L3mRNA and a DNA template sequence SEQ ID NO.4 of GC-DNase mRNA, respectively cloning the DNA template sequences into a plasmid vector pUC57-mini-Kana-BsmBI free-terminator-T7 released-100A-BspQI (commercially available), performing in vitro transcription, and purifying to obtain DNase1L3mRNA and GC-DNase mRNA.
Example 2
Preparation of mRNA-LNP lipid nanoparticle (DNase 1L3mRNA and GC-DNase mRNA, respectively)
LNP encapsulation of in vitro synthesized mRNA was performed by LNP encapsulation delegated to nobanol marine bioscience instruments (Shanghai). The company adopts a FlowOrigin M1 lipid nanoparticle kit, and performs mRNA encapsulation by eliminating a microfluidic nano drug delivery platform of a microfluidic series to obtain mRNA-LNP lipid nanoparticles for intravenous injection administration of the tail of a mouse.
Example 3
Evaluation of therapeutic efficacy of patient-derived tumor xenograft liver cancer model in mRNA-treated SCID mice (mRNA DNase1L3mRNA and GC-DNase mRNA, respectively)
8 fresh surgical tumor tissues (F0) were taken and frozen immediately after surgery in 8 patients without any additional treatment. According to the declaration of helsinki, each patient signed a written informed consent and was done after approval by the university ethical committee of south opening. Subcutaneously implanting fragments of F0 tissue into 8 SCID mice of 4-6 weeks of age, respectively, when tumor size reaches 100-200mm 3 Taking out tumor tissue of mice as F1, taking out 2 samples of F1, implanting another 16 SCID mice of 4-6 weeks old under skin to realize in vivo transfer as F2, continuing to transfer to F3, and when F3 tumor size reaches 100-200mm 3 At this time, the mice from different patients with tumors were randomly divided into a control group, a DNase1L3 mRNA-treated group and a GC-DNase mRNA-treated group, each group having 8 mice. Then, every 5 days, 100. Mu.l of the lipid nanoparticle containing 3. Mu.g of mRNA-LNP/100. Mu.l of physiological saline was intravenously injected into the tail of each of the treatment group mice, and 100. Mu.l of physiological saline was intravenously injected into the tail of the control group mice. Tumor volume was measured every 3 days and tumor growth curves were plotted, see figure 1, while survival of mice was recorded for 60 days and survival curves were plotted, see figure 4. After the completion of the experiment, the mice were dissected, tumor tissues were fixed with formalin, immunohistochemical staining was performed, see fig. 7, histopathological analysis, and ecDNA content analysis of tumor tissue sites, see fig. 10.
Compared with the mice in the control group, the tumor volume of the mice in the two groups of mRNA (the mRNA is DNase1L3mRNA and GC-DNase mRNA respectively) treatment group is obviously reduced, the tumor growth speed is reduced, and the survival period of the mice is also obviously prolonged. Meanwhile, the histopathological analysis results show that the expression level of the protein encoded by the corresponding mRNA drug at the tumor part is increased, and the expression level of the protein markers related to malignant evolution of the tumor, including Vimentin, twist1 and Zeb1 is obviously reduced. Furthermore, ecDNA content at tumor tissue sites was significantly reduced in the mRNA treated group.
Example 4
Evaluation of the efficacy of treatment of lung cancer models in BALB/c-nude mice by mRNA treatment (DNase 1L3mRNA and GC-DNase mRNA, respectively)
Lung cancer cell a549 grows to reach more than 80% of the culture dish bottom. Vigorous cell viability was observed, cells were digested with trypsin, and washed with PBS. The cells were counted by a cell counting plate and resuspended with pre-chilled PBS. BALB/c-nude mice aged 6-8 weeks were selected and subcutaneously injected 1X 10 6 A549 cells and were randomly divided into a control group, DNase1L3 mRNA-treated group and GC-DNase mRNA-treated group, each group of 6 mice. Then, every 5 days, 100. Mu.l of the lipid nanoparticle containing 3. Mu.g of mRNA-LNP/100. Mu.l of physiological saline was intravenously injected into the tail of each of the treatment group mice, and 100. Mu.l of physiological saline was intravenously injected into the tail of the control group mice. Tumor volume was measured every 3 days and tumor growth curves were plotted, see fig. 2, while survival of mice was recorded for 60 days and survival curves were plotted, see fig. 5. After the completion of the experiment, the mice were dissected, tumor tissues were fixed with formalin, immunohistochemical staining was performed, see fig. 8, histopathological analysis, and ecDNA content analysis of tumor tissue sites, see fig. 10.
Compared with the mice in the control group, the tumor volume of the mice in the two groups of mRNA (the mRNA is DNase1L3mRNA and GC-DNase mRNA respectively) treatment group is obviously reduced, the tumor growth speed is reduced, and the survival period of the mice is also obviously prolonged. Meanwhile, the histopathological analysis results show that the expression level of the protein encoded by the corresponding mRNA drug at the tumor part is increased, and the expression level of the protein markers related to malignant evolution of the tumor, including Vimentin, twist1 and Zeb1 is obviously reduced. Furthermore, ecDNA content at tumor tissue sites was significantly reduced in the mRNA treated group.
Example 5
Evaluation of the therapeutic efficacy of the breast cancer model in mRNA-treated BALB/c-nude mice (mRNA DNase1L3mRNA and GC-DNase mRNA, respectively)
MDA-MB-231 breast cancer cells (1X 10) 7 Cells) were subcutaneously injected into each flank of 4-6 week old BALB/c-nude mice. Mice were randomly divided into 3 groups: namely a control group, a DNase1L3 mRNA-treated group and a GC-DNase mRNA-treated group, each group comprising 6 mice. Then, every 5 days, 100. Mu.l of the lipid nanoparticle containing 3. Mu.g of mRNA-LNP/100. Mu.l of physiological saline was intravenously injected into the tail of each of the treatment group mice, and 100. Mu.l of physiological saline was intravenously injected into the tail of the control group mice. Tumor volume was measured every 3 days and tumor growth curves were plotted, see fig. 3, while survival of mice was recorded for 60 days and survival curves were plotted, see fig. 6. After the completion of the experiment, the mice were dissected, tumor tissues were fixed with formalin, immunohistochemical staining was performed, see fig. 9, histopathological analysis, and ecDNA content analysis of tumor tissue sites, see fig. 10.
Compared with the mice in the control group, the tumor volume of the mice in the two groups of mRNA (the mRNA is DNase1L3mRNA and GC-DNase mRNA respectively) treatment group is obviously reduced, the tumor growth speed is reduced, and the survival period of the mice is also obviously prolonged. Meanwhile, the histopathological analysis results show that the expression level of the protein encoded by the corresponding mRNA drug at the tumor part is increased, and the expression level of the protein markers related to malignant evolution of the tumor, including Vimentin, twist1 and Zeb1 is obviously reduced. Furthermore, ecDNA content at tumor tissue sites was significantly reduced in the mRNA treated group.
Experiments prove that the liposome or the lipid complex prepared by the mRNA of the invention according to the conventional technical means in the field can also be used for preparing the drug complex of the mRNA for treating cancer.
Claims (4)
1. The mRNA for treating cancer is characterized in that the mRNA is DNase1L3mRNA or GC-DNase mRNA, and the base sequence of the DNase1L3mRNA is shown as SEQ ID NO. 1; the base sequence of the GC-DNase mRNA is shown as SEQ ID NO. 2.
2. mRNA for use in the treatment of cancer according to claim 1, characterized in that the cancer is liver cancer, lung cancer or breast cancer.
3. Use of the mRNA of claim 1 for the treatment of cancer in the manufacture of an anticancer drug.
4. A pharmaceutical complex comprising the mRNA for treating cancer according to claim 1, characterized in that the mRNA for treating cancer is complexed with one or more lipids to make a liposome, a lipid nanoparticle or a lipid complex.
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