Tumor-targeted gene delivery: an attractive strategy to use highly active effector molecules in cancer treatment.
We have developed surface-shielded ligand-polycation based gene delivery systems which are able to target gene expression to distant tumors after systemic application. Tumor-specific targeting is achieved by (1) incorporation of cell-binding ligands; and (2) shielding of the complexes from non-specific interactions with blood components and non-target cells. Shielding of polycation/DNA complexes can be achieved by coating with either polyethylene glycol or by incorporating the ligand transferrin at high densities. Following systemic application, surface-shielded DNA complexes coding for a highly active, yet highly toxic cytokine, tumor necrosis factor-alpha (TNFalpha), localized gene expression to distant tumors, resulting in hemorrhagic tumor necrosis and inhibition of tumor growth. TNFalpha activity was confined to the tumor without systemic TNF-related toxicity. These results indicate that targeted gene delivery may be an attractive strategy to use highly potent molecules in cancer treatment.
Kircheis
R
R
Boehringer Ingelheim Austria, Vienna, Austria.
Wightman
L
L
Kursa
M
M
Ostermann
E
E
Wagner
E
E
D000818:Animals; D015870:Gene Expression; D018390:Gene Targeting / Q000379:methods*; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D009374:Neoplasms, Experimental / Q000628:therapy*; D011094:Polyethyleneimine; D014168:Transferrin / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D014168:Transferrin; D014409:Tumor Necrosis Factor-alpha; D011094:Polyethyleneimine