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Structure optimization of dendritic lipopeptide based gene vectors with the assistance from molecular dynamic simulation


Disulfide modified, lipopeptides assemblies with arginine-rich dendritic periphery provide a promising platform for effective gene transfer. The dendritic arginine peptides that mimic cell-penetrating peptides of virus envelop are vital for complexation, interaction with physical barriers, and final gene release. Here, we report three lipopeptides with different generation dendritic periphery (R1LS, R2LS and R3LS), and each of them contains a dioleoyl-L-lysinate hydrophobic tail. Such molecules were proven to self-assemble in aqueous solution with different morphology, size, and surface zeta potential. R2LS and R3LS assemblies showed spherical and spindle shape with zeta potential of 27.2 and 32.8 mV, respectively. They exhibited complete condensation of pDNA at low N/P ratio, while R1LS assemblies displayed fiber pattern and relatively low electric potential of 10.9 mV with poor DNA binding ability. In the cellular viability experiment, R1LS and R2LS have no significant cytotoxicity even at high dosage, while R3LS showed conspicuous toxicity. As gene vectors, R2LS presented high gene transfection efficiency either in the presence or absence of serum, which increased by 58.7 % than liposome 2000 and PEI in the condition of 10 % fetal bovine serum for Hela cells. While R3LS showed good results just without serum and R1LS were unserviceable in all situations. Moreover, molecular dynamic simulation was exploited to analyze the kinestate of signal molecule and interactions of multiple molecules, which could assist us to well understand the experimental phenomena. The simulation results indicated that R2LS molecule has a better flexibility, which was favor to interact with cell membrane. And it could generate a tight integration in self-assembly while R1LS and R3LS assemblies have large molecular interval, which led to a controllable release of cargos for R2LS in reductive environment. In summary, the generation of dendrimer in lipopeptides is vital for gene transfer effect. For optimization, structure-function relationship is necessary to study, and the molecular dynamic simulation is an effective strategy to screen the molecular structure and even predict experimental results.

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Publication details

The article was received on 08 Oct 2018, accepted on 29 Nov 2018 and first published on 30 Nov 2018

Article type: Paper
DOI: 10.1039/C8TB02650E
Citation: J. Mater. Chem. B, 2018, Accepted Manuscript
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    Structure optimization of dendritic lipopeptide based gene vectors with the assistance from molecular dynamic simulation

    H. Liang, A. Hu, X. Chen, R. Jin, K. Wang, B. Ke and Y. Nie, J. Mater. Chem. B, 2018, Accepted Manuscript , DOI: 10.1039/C8TB02650E

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