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Tumor-targeted gene transfer with DNA polyplexes.

Manfred Ogris¹, Ernst Wagner

¹Pharmaceutical Biology-Biotechnology, Center of Drug Research, Ludwig-Maximilians-University Munich, Germany.

Somatic Cell and Molecular Genetics

|May 31, 2003

Summary

Systemic gene delivery requires nonviral vectors like polyethylenimine (PEI) polyplexes. Shielding PEI with polyethylene glycol (PEG) and ligands like transferrin (Tf) enables targeted tumor gene delivery.

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Area of Science:

Biomedical Engineering
Nanotechnology
Molecular Biology

Background:

Systemic gene delivery is crucial for treating widespread diseases like cancer metastases.
Nonviral vectors, including DNA polyplexes and lipoplexes, are under development for therapeutic gene delivery.
Effective systemic circulation requires masking the surface charge of DNA complexes to prevent adverse interactions.

Purpose of the Study:

To develop and evaluate receptor-targeted, surface-shielded polyethylenimine (PEI) polyplexes for systemic gene delivery.
To investigate the influence of surface shielding (PEG) and targeting ligands (transferrin, EGF) on gene transfer efficiency and biodistribution.
To compare the tumor-targeting capabilities of modified PEI polyplexes with unmodified PEI polyplexes.

Main Methods:

Polyethylenimine (PEI) was complexed with DNA to form polyplexes.
PEI polyplexes were shielded with polyethylene glycol (PEG) and conjugated with targeting ligands (transferrin [Tf] or epidermal growth factor [EGF]).
Gene transfer efficiency and biodistribution were assessed following systemic administration in vivo, with a focus on tumor targeting.

Main Results:

Receptor-targeted, PEG-shielded Tf-PEI polyplexes demonstrated efficient gene transfer into tumor cell lines in a receptor- and cell-cycle-dependent manner.
Systemic administration of surface-shielded Tf-PEI polyplexes resulted in preferential gene delivery to subcutaneous tumors.
Unshielded, positively charged PEI polyplexes primarily directed gene transfer to the lung.

Conclusions:

Surface shielding and ligand conjugation of PEI polyplexes are critical for achieving targeted systemic gene delivery to distant tumors.
Modified PEI polyplexes offer a promising strategy for overcoming barriers to systemic gene therapy.
The biodistribution of nonviral gene vectors can be significantly influenced by surface properties and targeting moieties.

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