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Tissue-dependent factors affect gene delivery to tumors in vivo
B Smrekar1, L Wightman, M F Wolschek
1Boehringer Ingelheim Austria, Dr Boehringer Gasse 5-11, Vienna, Austria.
Abstract:
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.
Insights
Tumor vascularization and macrophage infiltration significantly impact gene delivery. Well-vascularized tumors with low macrophage infiltration show high gene expression, while poor vascularization or high macrophage infiltration hinders delivery.
Area of Science:
- Gene therapy
- Nanomedicine
- Tumor biology
Background:
- Systemic gene delivery to tumors remains challenging.
- Understanding tumor-specific factors influencing gene delivery is crucial for therapeutic development.
Purpose of the Study:
- To investigate the impact of tumor microenvironment factors on systemic gene delivery using polyethylenimine/DNA complexes.
- To identify reasons for differential gene delivery efficiency across various tumor models.
Main Methods:
- Systemic application of surface-shielded transferrin-polyethylenimine/DNA and EGF-PEG-PEI/DNA complexes in mouse tumor models (Neuro2a, Huh-7, HepG2, M-3 melanoma, KB, 518A2, A549, SW480).
- Analysis of tumor vascularization, blood vessel density, and macrophage infiltration.
- Assessment of DNA uptake and gene expression levels in different tumor types.
Main Results:
- High DNA uptake and gene expression observed in well-vascularized Neuro2a, Huh-7, and HepG2 tumors with low macrophage infiltration.
- Significant DNA uptake but low gene expression in M-3 melanoma, attributed to necrosis and high macrophage infiltration.
- No DNA uptake or gene expression in poorly vascularized KB, 518A2, A549, and SW480 tumors.
Conclusions:
- Tumor vascularization is a key factor for DNA uptake in systemic gene delivery.
- Necrosis and macrophage infiltration can lead to DNA degradation, reducing gene expression.
- Tissue-dependent factors significantly influence the efficacy of in vivo gene delivery.