Journal
MOLECULAR PHARMACEUTICS
Volume 12, Issue 3, Pages 716-730Publisher
AMER CHEMICAL SOC
DOI: 10.1021/mp5005349
Keywords
serine; gemini surfactants; mitochondria; transfection; complex size; complex surface charge; complex-membrane interactions
Funding
- Portuguese Foundation for Science and Technology [SFRH/BD/63288/2009, SFRH/BD/79077/2011, SFRH/BD/61193/2009]
- FEDER/COMPETE [PTDC/DTP-FTO/0265/2012, PEst-C/SAU/LA0001/2013-14, PTDC/QUI-QUI/115212/2009, Pest/C-QUI/UI0081/2013]
- Fundação para a Ciência e a Tecnologia [SFRH/BD/61193/2009, PTDC/DTP-FTO/0265/2012] Funding Source: FCT
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Gene delivery targeting mitochondria has the potential to transform the therapeutic landscape of mitochondrial genetic diseases. Taking advantage of the nonuniversal genetic code used by mitochondria, a plasmid DNA construct able to be specifically expressed in these organelles was designed by including a codon, which codes for an amino acid only if read by the mitochondrial ribosomes. In the present work, gemini surfactants were shown to successfully deliver plasmid DNA to mitochondria. Gemini surfactant-based DNA complexes were taken up by cells through a variety of routes, including endocytic pathways, and showed propensity for inducing membrane destabilization under acidic conditions, thus facilitating cytoplasmic release of DNA. Furthermore, the complexes interacted extensively with lipid membrane models mimicking the composition of the mitochondrial membrane, which predicts a favored interaction of the complexes with mitochondria in the intracellular environment. This work unravels new possibilities for gene therapy toward mitochondrial diseases.
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