Polycation-based DNA complexes for tumor-targeted gene delivery in vivo

Background Efficient and target-specific in vivo gene delivery is a major c hallenge in gene therapy. Compared to cell culture application, in vivo gen e delivery faces a variety of additional obstacles such as anatomical size constraints, interactions with biological fluids and extracellular matrix, and binding to a broad variety of non-target cell types. Methods Polycation-based vectors, including adenovirus-enhanced transferrin fection (AVET) and transferrin-polyethylenimine (Tf-PEI), were tested for g ene delivery into subcutaneously growing tumors after local and systemic ap plication. DNA biodistribution and reporter gene expression was measured in the major organs and in the tumor. Results Gene transfer after intratumoral application was 10-100 fold more e fficient with Tf-PEI/DNA or AVET complexes in comparison to naked DNA. Targ eted gene delivery into subcutaneously growing tumors after systemic applic ation was achieved using electroneutral AVET complexes and sterically stabi lized PEGylated Tf-PEI/DNA complexes, whereas application of positively cha rged polycation/DNA complexes resulted in predominant gene expression in th e lungs and was associated by considerable toxicity. Conclusion For systemic application, the physical and colloidal parameters of the transfection complexes, such as particle size, stability, and surfac e charge, determine DNA biodistribution, toxicity, and transfection efficac y. By controlling these parameters, DNA biodistribution and gene expression can be targeted to different organs. Copyright (C) 1999 John Wiley & Sons, Ltd.