Peptide Dendrimer/Lipid Hybrid Systems Are Efficient DNA Transfection Reagents: Structure鈥揂ctivity Relationships Highlight the Role of Charge Distribution Across Dendrimer Generations
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- 作者：Albert Kwok ; Gabriela A. Eggimann ; Jean-Louis Reymond ; Tamis Darbre ; Florian Hollfelder
- 刊名：ACS Nano
- 出版年：2013
- 出版时间：May 28, 2013
- 年：2013
- 卷：7
- 期：5
- 页码：4668-4682
- 全文大小：859K
- 年卷期：v.7,no.5(May 28, 2013)
- ISSN：1936-086X
文摘
Efficient DNA delivery into cells is the prerequisite of the genetic manipulation of organisms in molecular and cellular biology as well as, ultimately, in nonviral gene therapy. Current reagents, however, are relatively inefficient, and structure鈥揳ctivity relationships to guide their improvement are hard to come by. We now explore peptide dendrimers as a new type of transfection reagent and provide a quantitative framework for their evaluation. A collection of dendrimers with cationic and hydrophobic amino acid motifs (such as KK, KA, KH, KL, and LL) distributed across three dendrimer generations was synthesized by a solid-phase protocol that provides ready access to dendrimers in milligram quantities. In conjunction with a lipid component (DOTMA/DOPE), the best reagent, G1,2,3-KL ((LysLeu)8(LysLysLeu)4(LysLysLeu)2LysGlySerCys-NH2), improves transfection by 6鈥?0-fold over commercial reagents under their respective optimal conditions. Emerging structure鈥揳ctivity relationships show that dendrimers with cationic and hydrophobic residues distributed in each generation are transfecting most efficiently. The trigenerational dendritic structure has an advantage over a linear analogue worth up to an order of magnitude. The success of placing the decisive cationic charge patterns in inner shells rather than previously on the surface of macromolecules suggests that this class of dendrimers significantly differs from existing transfection reagents. In the future, this platform may be tuned further and coupled to cell-targeting moieties to enhance transfection and cell specificity.