Enhanced cellular uptake of a triplex-forming oligonucleotide by nanoparticle formation in the presence of polypropylenimine dendrimers.

Abstract

We used polypropylenimine dendrimers for delivering a 31 nt triplex-forming oligonucleotide (ODN) in breast, prostate and ovarian cancer cell lines, using 32P-labeled ODN. Dendrimers enhanced the uptake of ODN by approximately 14-fold in MDA-MB-231 breast cancer cells, compared with control ODN uptake. Dendrimers exerted their effect in a concentration- and molecular weight-dependent manner, with generation 4 (G-4) dendrimer having maximum efficacy. A similar increase in ODN uptake was found with MCF-7 and SK-BR-3 (breast), LNCaP (prostate) and SK-OV-3 (ovarian) cancer cells. The dendrimers had no significant effect on cell viability at concentrations at which maximum ODN uptake occurred. [3H]Thymidine incorporation showed that complexing the ODN with G-4 significantly increased the growth-inhibitory effect of the ODN. Western blot analysis showed a significant 65% reduction of c-myc protein level in ODN-G-4 treated cells compared with that of ODN-treated/control cells. Gel electrophoretic analysis showed that ODN remained intact in cells even after 48 h of treatment. The hydrodynamic radii of nanoparticles formed from ODN in the presence of the dendrimers were in the range of 130-280 nm, as determined by dynamic laser light scattering. Taken together, our results indicate that polypropylenimine dendrimers might be useful vehicles for delivering therapeutic oligonucleotides in cancer cells.

• Authors: Latha M Santhakumaran, Thresia Thomas, T J Thomas
• Journal: Nucleic acids research (Nucleic Acids Res) Vol. 32 Issue 7 Pg. 2102-12 ( 2004) ISSN: 1362-4962 [Electronic] England
• PMID: 15087489 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Oligonucleotides
• Phosphorus Radioisotopes
• Polypropylenes
• Proto-Oncogene Proteins c-myc
• triplex DNA
• DNA

Topics

• Cell Line, Tumor (drug effects, metabolism)
• Cell Survival (drug effects)
• DNA (chemistry, pharmacokinetics)
• Dose-Response Relationship, Drug
• Electrophoresis, Polyacrylamide Gel
• Female
• Humans
• Male
• Nanotechnology
• Oligonucleotides (chemistry, pharmacokinetics)
• Particle Size
• Phosphorus Radioisotopes
• Polypropylenes (administration & dosage, chemistry)
• Proto-Oncogene Proteins c-myc (metabolism)