Coupling Of The Targeting Ligand ¦Â-cyclodextrin - Low Molecular Weight Polyethylenimine As A Gene Vector System

Gene therapy is that, the occurrence, development and progress of disease is interfereed in by deliverying human normal or therapeutic gene into target cells in order to substitute to defect or correct the fault in genic structure or ruction or to kill the pathological cells or to increase the ability of cleaning the pathological cells. One of the most important technique is to develop effective and safe gene delivery vectors.The gene delivery vectors applied in gene therapy are mainly divided into the viral carrier and the non-viral carrier. Viral vectors are used widely for gene delivery system in cancer gene therapy for clinical application because of its highly efficient gene delivery. But there are some disadvantage, they are immunogenic (repeat administration is dangerous), insertional mutagenesis in host genome, limited capacity of delivery DNA, limited scale of production and caused malignant transformation of the cells . Non-viral vectors have some safety advantages over viral vectors, including low immunogenecity, the absence of endogenous virus recombination, low production cost and reproducibility.The application of non-viral vectors to human has, however, been held back by the poor efficiency of their delivery gene to cells.Polyethylenimine (PEI) is one of the most efficient and widely studied synthetic carriers for delivery of plasmid DNA into cells in vitro and in vivo. The high transfection efficiency of PEI/DNA complexes has been ascribed to the capacity of PEI to buffer endosomes, which protects DNA from nuclease degradation and facilitates endosomal escape of PEI/DNA complexes ("proton sponge hypothesis"). Further studies have shown that the transfection efficiency and cytotoxicity of PEI/DNA formulations are highly dependent on the molecular weight of PEI. PEI can make erythrocyte aggregate and bind non-specificly with albumin in blood . Transgene efficiency is lowly applied in vivo. So modification of PEI is needed.In this study,beta-cyclodextrin (β-CyD) has been choosen to as the backbond for connecting low molecular weight polyethylenimine (PEI). CyDs can disrupt biological membranes by complexation with phospholipids and cholesterols. These effects have been suggested to assist cell uptake of polyamidoamine dendrimer/DNA particles and intracellular trafficking of DNA molecules. The resulting polymer (PEI-P-CyD) displayed good transduction efficiency with no detectable toxicity. In order to further improve the efficiency, folic acid,targeting Her-2 receptor oligopetide and norethindrone were conjugated to PEI-β-CyD. The copolymer showed low cytotoxicity and high transfection efficiency and domonstrated good speciality targeting for tumor cells afer conjugated these ligands.