Polycation-based DNA complexes for tumor-targeted gene delivery in vivo.
BACKGROUND
Efficient and target-specific in vivo gene delivery is a major challenge in gene therapy. Compared to cell culture application, in vivo gene delivery faces a variety of additional obstacles such as anatomical size constraints, interactions with biological fluids and extracellular matrix, and binding to a broad variety of non-target cell types.


METHODS
Polycation-based vectors, including adenovirus-enhanced transferrinfection (AVET) and transferrin-polyethylenimine (Tf-PEI), were tested for gene delivery into subcutaneously growing tumors after local and systemic application. DNA biodistribution and reporter gene expression was measured in the major organs and in the tumor.


RESULTS
Gene transfer after intratumoral application was 10-100 fold more efficient with Tf-PEI/DNA or AVET complexes in comparison to naked DNA. Targeted gene delivery into subcutaneously growing tumors after systemic application was achieved using electroneutral AVET complexes and sterically stabilized PEGylated Tf-PEI/DNA complexes, whereas application of positively charged polycation/DNA complexes resulted in predominant gene expression in the lungs and was associated by considerable toxicity.


CONCLUSIONS
For systemic application, the physical and colloidal parameters of the transfection complexes, such as particle size, stability, and surface charge, determine DNA biodistribution, toxicity, and transfection efficacy. By controlling these parameters, DNA biodistribution and gene expression can be targeted to different organs.
Kircheis
R
R
Boehringer Ingelheim Austria, Vienna, Austria.
Schüller
S
S
Brunner
S
S
Ogris
M
M
Heider
K H
KH
Zauner
W
W
Wagner
E
E
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D019496:Cancer Vaccines / Q000008:administration & dosage* / Q000737:chemistry; D004355:Drug Stability; D004563:Electrochemistry; D005260:Female; D015870:Gene Expression; D018390:Gene Targeting; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D015316:Genetic Therapy; D005822:Genetic Vectors; D051379:Mice; D008805:Mice, Inbred A; D008811:Mice, Inbred DBA; D009374:Neoplasms, Experimental / Q000235:genetics / Q000628:therapy; D010316:Particle Size; D011073:Polyamines; D000071228:Polyelectrolytes; D014162:Transfection; D019444:Vaccines, DNA / Q000008:administration & dosage* / Q000737:chemistry
D019496:Cancer Vaccines; D011073:Polyamines; D000071228:Polyelectrolytes; D019444:Vaccines, DNA