Application Of Redox Responsive Branched Polyamide Amine Derivatives In Tumor Therapy

Cationic polymer as a carrier for tumor therapy is one of the research hotspots in the field of biological materials in recent years. The outer end of the cationic polymer containing a large number of genes can be modified, it can efficiently load drug and gene therapy after modification of functional molecules, It precisely delivers drugs and genes to tumor cells in order to inhibiting the proliferation of tumor cells and killing tumor cells. Although many achievements has been gained in this area, there are many problems restricting the application. Firstly as a gene vector, the transfection efficiency of cationic polymer is much lower than that of virus vector, and low transfection efficiency will inevitably affect the effectiveness of tumor therapy. Secondly, Single gene therapy is time-consuming, and the treatment effect is not as good as the traditional drug chemotherapy.GSH-responsive cationic polymers containing disulfide linkages have been synthesized and used for gene therapy to tumors. These redox cationic polymers can condense DNA and form the compact complexes. After enter the cellular cytoplasm, the high GSH concentration results in the breakage of disulfide bonds and the rapid unpacking of DNA from the complexes. This result can not only increase the transfection efficiency due to the DNA release from the complexes, but also reduce the cytotoxicity because of avoiding the intracellular accumulation of the high-molecular-weight cationic polymers. In view of this, various functional hyperbranched polymers based on the hyperbranched polyamide amine have been constructed. First of all, a targeted gene conveying system is constructed based on the hyperbranched polyamide amine modified with folate to solve the problem of non targeting, low transfer rate and high toxicity of traditional gene vector. What’s more, the blood compatibility of the materials has been studied so as to provide reference for clinical application. Secondly, a gene and drug co-delivery carrier consisting the hyperbranched polyamide amine and poly(ethylene glycol)- poly(lactic acid) is constructed by amidation reaction. through in vitro vector transfection efficiency and drug load effect, and the biocompatibility of the gene and drug co-delivery vector is investigated in order to construct a delivery system which has good biocompatibility and comprehensive effect of gene therapy and chemical therapy. The co-delivery vector can overcome the drawbacks of single drug therapy and improve the effect of treatment of tumors. The main research contents of this paper is mainly divided into the following two aspects.1.Folate-targeting redox hyperbranched poly(amido amine)s delivering MMP-9 si RNA for cancer therapyThe hyperbranched polyamide amine modified with folate(FA-PAAs) was synthesized by michael addition reaction and amidation reaction. Its physical and chemical properties are well analyzed by 1H NMR, UV-2550 spectrophotometer, dynamic light scattering(particle size and ζ-potential), TEM and so on. The redox response of FA-PAAs was demonstrated by gel permeation chromatography(GPC). The binding ability of FA-PAAs to p EGFP was studied by the gel electrophoresis assay. In vitro assays have been carried out to confirm the target ability of FA-PAAs, and western blot and apoptosis assays display the effective inhibition to MCF-7 cells. In addition, the biocompatibility including blood compatibility of FA-PAAs is also assayed to confirm the safety of the obtained gene carrier.2.Based on hyperbranched polyamide amine characterized by poly(ethylene glycol)-poly(lactic acid) for drug and gene co-deliveryThe well-defined hyperbranched polyamide amine derivatives based on PAAs, named as m PEG-PLA-PAAs is synthesized by the modification of m PEG-PLA, and their physical and chemical properties are well characterized by 1H NMR, fourier transform infrared(FTIR), gel permeation chromatography(GPC), dynamic light scattering(particle size and ζ-potential), TEM and so on. The obtained products are studied for DNA binding and transfection. It is found that, m PEG-PLA-PAAs exhibit strong DNA condensation. Through a series of in vitro experiments, m PEG-PLA-PAAs may be used as drug and gene co-carrier.