AMD3100 Conjugates as Components of Targeted Nonviral Gene Delivery Systems:Synthesis and in Vitro Transfection Efficiency of CXCR4-Expressing Cells

摘要

We describe the synthesis of a series of AMD3100-lipid and AMD3100-polycationic conjugates which were used as components of targeted lipoplexes (in conjunction with(poly)cationic lipids)and polyplexes,respectively,for mediating specific gene transfer into cells expressing CXCR4 which displays a high affinity for AMD3100.Transfection studies were investigated with suspension CXCR4(+)human lymphoma Jurkat cells and with adherent CXCR4(-)human glioblastoma T98G and human lung carcinoma A549 cells lines in order to demonstrate a receptor-mediated endocytosis pathway and to minimize nonspecific transfection pathways.Altogether,our results show that polyplexes formulated with AMD-labeled polymers constitute,under certain conditions,specific gene transfer systems into suspension CXCR4(+)Jurkat cells.This is more particularly the case when the nonspecific transfection pathways are minimized(i.e.for NIP<=2.5 AMD-labeled polyplexes)and in the presence of phorbol myristate acetate which triggers CXCR4 receptor endocytosis of the AMD-labeled polyplexes to a larger extent than that of their respective nonlabeled ones.Although encouraging,the transfection specificities and efficiencies obtained with these compounds should however be improved.This study also illustrates the difficulties to demonstrate and to obtain a specific and efficient gene transfer system with cationized ligand-labeled DNA particles which also provide receptor-independent nonspecific gene transfer to cells,and more particularly to adherent cells.