DNA Complexing Lipopolythiourea

Tranchant, Isabelle; Mignet, Nathalie; Crozat, Estelle; Leblond, Jeanne; Girard, Christian; Scherman, Daniel; Herscovici, Jean

doi:10.1021/bc049920n

Cited by 19 publications

(27 citation statements)

References 23 publications

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“…Despite this major drawback, DT3TU could be formulated with dipalmytoylphosphatidylcholine (DPPC) or PEG-lipid to avoid aggregation, and obtain a formal proof of concept of the maintained thiourea function capacity to interact with DNA in its lipidic form [19]. When associated to DT3TU, DNA was protected from DNAse-mediated degradation [19], and transfection of HeLa cells was achieved (Figure 1).…”

Section: Resultsmentioning

confidence: 99%

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Lipothioureas as Lipids for Gene Transfection: A Review

et al. 2011

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Non-viral gene therapy requires innovative strategies to achieve higher transfection efficacy. A few years ago, our group proposed bioinspired lipids whose interaction with DNA was not based on ionic interactions, but on hydrogen bonds. We thus developed lipids bearing a thiourea head which allowed an interaction with DNA phosphates through hydrogen bonds. After a proof of concept with a lipid bearing three thiourea functions, a molecular and cellular screening was performed by varying all parts of the lipids: the hydrophobic anchor, the spacer, the linker, and the thiourea head. Two lipothiourea-based structures were identified as highly efficient in vitro transfecting agents. The lipothioureas were shown to reduce non specific interactions with cell membranes and deliver their DNA content intracellularly more efficiently, as compared to cationic lipoplexes. These lipids could deliver siRNA efficiently and allowed specific cell targeting in vitro. In vivo, thiourea lipoplexes presented a longer retention time in the blood and less accumulation in the lungs after an intravenous injection in mice. They also induced luciferase gene expression in muscle and tumor after local administration in mice. Therefore, these novel lipoplexes represent an excellent alternative to cationic lipoplexes as transfecting agents. In this review we will focus on the structure activity studies that permitted the identification of the two most efficient thiourea lipids.

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Section: Resultsmentioning

confidence: 99%

“…Considering the above mentioned advantageous properties of the thiourea moiety, we therefore chose to incorporate this function at the polar head of a lipid, in order to form lipothiourea-based liposomes [19]. We could show that the thiourea function maintained its property of interacting with phosphates in a lipidic form.…”

Section: Introductionmentioning

confidence: 99%

Lipothioureas as Lipids for Gene Transfection: A Review

et al. 2011

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“…However, this does not reflect all the mechanisms of interaction between thiourea lipids and DNA as compound 1b which only bears thiourea functions is able to interact with DNA although less efficiently. The compounds from the "lysine" lipopolythiourea family [16][17][18] which are also able to compact DNA do not undergo acidic conditions during their synthesis which implies that DNA compaction does not necessarily need electrostatic interactions. The lysine structure of this family of compounds might induce rigidity in the lipid structure which surely affects the DNA compaction.…”

Section: Discussionmentioning

confidence: 99%

“…We demonstrated that different families of lipopolythioureas could compact DNA [16] and transfect cells [17]. We improved the structure of the lipids until the molecules were hydrophilic enough to be easily formulated.…”

Section: Introductionmentioning

confidence: 99%

Iminothiol/thiourea tautomeric equilibrium in thiourea lipids impacts DNA compaction by inducing a cationic nucleation for complex assembly

Breton¹,

Bessodes²,

Bouaziz³

et al. 2009

Biophysical Chemistry

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT2 Abstract: Our research on lipidic vectors for transfection led us to develop thiourea lipids able to interact with DNA. Hence, we developed a series of lipopolythioureas based on the strong hydrogen bond donor ability of thiourea. More recently we have reported a branched hydroxylated bis-thiourea derivative with interesting transfecting properties. The last step of the syntheses involved a strong acidic condition, leading to an unstable product upon storage.Therefore we designed a new synthesis in mild acidic conditions. Though they exhibit the same mass, the lipids obtained in the two different conditions differ by their interaction with DNA. We therefore explored the physicochemical properties of these two lipids by different means that we describe in this article. In order to insure easier and reliable 13 C-NMR studies of the thiourea group we have designed the synthesis of the corresponding 13 C-labelled thiourea lipids. We have thus shown that when the lipid was submitted to mildly acidic medium; only the thiourea group was observed; while a thiourea/charged and/or uncharged iminothiol tautomeric equilibrium formed when the last step of the synthesis was submitted to low pH. NMR experiments showed that this tautomeric equilibrium could not form in polar solvents. However, UV experiments on the liposomal form of the lipopolythiourea showed the presence of the tautomers. Lipid/DNA interaction consequently differed according to the acidic treatment applied. Eventually, these results revealed that on this particular thiourea lipid, electrostatic interactions due to cationic thioureas are likely to be responsible for DNA compaction and that this tautomeric form of the thiourea could be stabilised by hydrogen bonds in a supramolecular assembly. Nevertheless, this does not reflect a general thiourea lipid/DNA interaction as other thiourea lipids that are able to compact DNA do not undergo an acidic treatment during the final stage of their synthesis.

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“…We recently developed non cationic lipids based on a thiourea head group moiety (LPT) [16]. We investigated various lipid chain lengths, types of linker and structures of the head group in order to optimize the formulation and transfection properties [17].…”

Section: Introductionmentioning

confidence: 99%