Tissue-dependent factors affect gene delivery to tumors in vivo.
Systemic application of surface-shielded transferrin-polyethylenimine/DNA complexes leads to predominant DNA uptake and gene expression in Neuro2a tumors in syngeneic A/J mice. Similarly, high expression levels were found in Huh-7 and HepG2 human tumor xenografts in SCID mice after systemic application of surface-shielded EGF-PEG-PEI/DNA complexes. Significant DNA uptake but low gene expression were found in the M-3 melanoma while no DNA uptake and no gene expression were found in KB, 518A2, A549, and SW480 xenograft tumor models. To elucidate the reasons for these differences, the tumors were analyzed for vascularization and infiltration of macrophages. Neuro2a, Huh-7, and HepG2 tumors are well vascularized, with a high density of partially immature blood vessels and low numbers of infiltrating macrophages. The M-3 melanoma is well vascularized correlating with significant DNA uptake, however, necrosis and intensive infiltration by macrophages lead to rapid degradation of DNA. In contrast, the KB, 518A2, A549, and SW480 tumors are poorly vascularized, correlating with undetectable DNA uptake and gene expression. Using two different vector systems the data indicate that gene delivery to tumors in vivo is affected by tissue-dependent factors. Uptake of DNA into the tumor depends on vascularization of the tumor, while necrosis and macrophage infiltration may facilitate degradation of the DNA.
Smrekar
B
B
Boehringer Ingelheim Austria, Dr Boehringer Gasse 5-11, Vienna, Austria.
Wightman
L
L
Wolschek
M F
MF
Lichtenberger
C
C
Ruzicka
R
R
Ogris
M
M
Rödl
W
W
Kursa
M
M
Wagner
E
E
Kircheis
R
R
D000818:Animals; D004247:DNA / Q000378:metabolism; D004815:Epidermal Growth Factor / Q000235:genetics; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007275:Injections, Intravenous; D008264:Macrophages / Q000473:pathology; D051379:Mice; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D016513:Mice, SCID; D009369:Neoplasms / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D009374:Neoplasms, Experimental / Q000098:blood supply / Q000473:pathology / Q000628:therapy; D009389:Neovascularization, Pathologic; D011094:Polyethyleneimine; D014018:Tissue Distribution; D014162:Transfection / Q000379:methods*; D014168:Transferrin / Q000235:genetics*; D014407:Tumor Cells, Cultured
D014168:Transferrin; D004815:Epidermal Growth Factor; D011094:Polyethyleneimine; D004247:DNA