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Polymer Based Systems for Tumor-Targeted Gene Delivery

Nature Biotechnology volume 17, page 15 (1999)Cite this article

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DNA complexed with transferrin-polyethylenimine (Tf-PEI) conjugates1,2, that combine the gene transfer efficiency of PEI3 with the specific mechanism of receptor-mediated endocytosis, were applied. Systemic application of optimized surface-shielded Tf-PEI800/DNA complexes into the tail vein of Neuro2A-bearing mice resulted in preferential gene delivery into the distantly growing subcutaneous tumors.4,5 In contrast, application of standard DNA/Tf-PEI800 complexes caused gene transfer primarily to the lung and also toxicity. Biophysical parameters of the transfection complexes, such as surface charge, particle size, modification with targeting ligand, and molecular weight of the polymeric carrier (PEI 800 vs. PEI25 or PEI22), were found to strongly influence in vivo DNA biodistribution, toxicity, and gene transfer efficacy.

Two major mechanisms are considered to contribute to the tumor-specific targeting as found in our model: passive targeting (by shielding the surface of complexes from undesired interaction) and active targeting (by a cell surface receptor ligand such as Tf). Passive targeting can be achieved by masking the surface charge of complexes through covalent coating DNA/Tf-PEI800 complexes with polyethylenglycol (PEG), resulting in a reduced plasma and erythrocyte binding. Prolonged circulation in blood allows extravasation of DNA complexes into distant tumor tissue which is an area of vascular leakiness. Shielding of charges in PEI25 or PEI22 complexes by linkage of sufficient Tf ligand also leads to preferential delivery into tumors, even in the absence of PEGylation.

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References

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  1. Boehringer-Ingelheim Austria, Cancer Vaccines, Dr. Boehringergasse 5–11, Vienna, A-1121, Austria

    Ernst Wagner

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  1. Ernst Wagner
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Wagner, E. Polymer Based Systems for Tumor-Targeted Gene Delivery. Nat Biotechnol 17 (Suppl 4), 15 (1999). https://doi.org/10.1038/70131

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