Cancer Therapy Based On Lipid Nanoparticles Responding To Tumor Microenvironment

Nucleic acid delivery technology brings new hope for the treatment of malignant tumors and other diseases.Lipid nanoparticles(LNP),as a delivery carrier with stable delivery efficiency,high biosafety and abundant clinical practice,have been widely used in the field of cancer treatment.Lipid materials used mainly can be divided into two types currently,permanently cationic lipid and ionization cationic lipid,they have their own advantages and limitations of different.Ionizable lipids have a positive charge at pH less than their pKa,while no charge at pH greater than their pKa,which determines that LNPs with ionization cationic lipid are unstable in the environment of high pH(blood,interstitium fluid)for nucleic acid encapsulation,and affects theirs cell uptake efficiency.Although LNP made of lipids of permanent cations is highly efficient in cell uptake,it is not easy to disintegrate in cells to release the encapsulated nucleic acids,and its cytotoxicity is more significant.In order to overcome these shortcomings of LNPs,we designed a new type of LNP which responses ROS in the tumor microenvironment.It is permanent cationic LNP before responding,however,after being uptake into the cytoplasm of tumor cells,the benzene boric acid structure responses by ROS in the tumor cells,makes it become an ionization cationic LNP,and helps it disassembly and release the encapsulated nucleic acid.The details are as follows:LNP that can respond to ROS in a tumor microenvironment was synthesized and its response to hydrogen peroxide was detected by gel electrophoresis.a similar LNPs that cannot respond to ROS were synthesized and compared with it.The high efficiency of siRNA release in solution and cell uptake of this LNP was verified,and the transmembrane mode was demonstrated by inhibitor experiments to be alveolar protein-mediated endocytosis.Using the newly synthesized LNP,the Enhanced Green Fluorescent Protein(EGFP)expressed in MCF-7 cells was knocked out to verify its high gene knockout efficiency.In addition,polo-like Kinase 1(PLK1)was knocked out in MCF-7 cells,which affected the cell cycle and mitosis of MCF-7 cells,leading the apoptosis of MCF-7 cells,and finally achieved anti-tumor effect.Mice implanted with MCF-7 subcutaneous tumor were used as models,and PLK1-siRNA was transfected with that newly synthesized LNP by tail vein injection to verify the anti-tumor ability of PLK1-siRNA encapsulated by that L NP,and its anti-tumor mechanism and biosafety were verified by staining the viscera and tumor sections of mice.