| siRNA(small interfering RNA)drugs in the gene-related diseases(such as cancer)treatment has a very broad application prospects,but its own characteristics such as strong negative charge and easily degraded by nuclease are in the face of a huge challenge when applied in the clinic.The one-dimensional mechanism of single-agent therapy often leads to the activation of alternating pathways leading to chemotherapy-resistant and tumor recurrence,and the molecular complexity of cancer also suggests that the use of single gene therapy may not be sufficient to prevent the progression of most cancers.Therefore,the use of nucleic acid and anti-cancer drug combination therapy system may be a more promising treatment.In order to solve the problems above,this paper designed an anti-tumor system for co-delivery of siRNA and curcumin based on disulfide cross-linked targeting peptide micelles.The in vitro and in vivo experiments demonstrated that the constructed vector could effectively deliver siRNA and curcumin into the target cells,which significantly improved the anti-tumor effect of single drug and achieved the goal of targeting cancer cells and anti-tumor synergisticly.The research work of the study mainly includes three aspects as follows:1 Construction of disulfide cross-linked targeting polypeptide nanoparticles for the carrier.First,the a-lactalbumin is hydrolyzed to form polypeptide,and the hydrophobic drug curcumin is encapsulated into its hydrophobic core by hydrophobic action in the process of assembling to form micelles.In order to improve the targeting of the vector,enhance the aggregation of the drug at the tumor site,and modify the integrin αvβ3 target peptide CRGDK on its surface.In order to further improve the anticancer effect of the system,the experiment by disconnecting the disulfide bond of the protein itself,exposing-SH,and-SH modified siPlkl(Plkl,polo-like kinase 1)mismatched cross-linked intermolecular disulfide bond,not only improve the stability of micelles,but also successfully loaded siPlkl,block tumor cell cycle.2 Response of Targeted Polypeptide Nanoparticles Based on Tumor Microenvironmental Response.To investigate the administration strategy of targeting nanometer micelles.The results show that when the vector enters the loop,the targeting peptide first leads the micelles to the tumor tissue and cells,enters the cells through endocytosis,enters the lysosome and enters the cytoplasm with the lower pH through the proton sponge effect;The strong reduction of GSH in tumor cells causes the micellar degradation,the release of siPlkl and curcumin,to achieve targeted synergistic anti-cancer effect.3 Study on the Effect of Targeted Polypeptide Nanoparticles Based on Tumor Microenvironment.The experiment results show that the disulfide cross-linked targeting peptide nanometer micelles can effectively kill tumor cells;increase aggregation in the tumor tissue,block cell cycle,inhibit tumor growth and prolong the survival time of mice.In conclusion,the nanometer micelles have targeted and glutathione responsive,and this paper provides a direction for co-delivery of siRNA and chemotherapeutic drug to form synergistic anticancer system. |
