Physical and Biological Properties of Cationic Triesters of Phosphatidylcholine

MacDonald, Robert C.; Ashley, Gary W.; Shida, Miho M.; Rakhmanova, Vera A.; Tarahovsky, Yury S.; Pantazatos, Dennis; Kennedy, Michael T.; Pozharski, Edwin; Baker, Kent A.; Jones, Ramoun D.; Rosenzweig, Howard S.; Choi, Kenneth L.; Qiu, Ruomeng; McIntosh, Thomas J.

doi:10.1016/s0006-3495(99)77095-5

Cited by 127 publications

(152 citation statements)

References 78 publications

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“…These data with the tripeptide headgroups are consistent with a structural model where a smectic phase is formed with the DNA chains located between the adjacent lipid bilayers within the multilamellar liposome. This structural model has been reported for complexes of DNA with DOTAP (25) and cationic triesters of phosphatidylcholine (26).…”

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confidence: 61%

Lipophilic Peptides for Gene Delivery

et al. 2008

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DNA transfections are widely performed in research laboratories and in vivo gene delivery holds the promise for curing many diseases. The synthetic carriers or vectors for DNA are typically cationic lipids. However, in biology, the recognition of nucleic acids by proteins involves both electrostatic and stacking contributions. As such we have prepared a series of new lipophilic peptide vectors that possess lysine and tryptophan amino acids for evaluation. These lipophilic peptides show minimal cytotoxicity and enhanced in vitro gene transfection activity.The complexation of cationic amphiphiles with DNA or RNA and the resulting supramolecular structures are of interest for the delivery of nucleic acids to cells. As such, a means to correct a defective gene, introduce a new gene, or knock-down a gene is provided for a specific in vitro or in vivo application (1-7). This complexation between cationic amphiphiles and nucleic acids is governed by electrostatic interactions between the positively charged amphiphiles and the negatively charged phosphate backbone of the nucleic acid and the hydrophobic chainchain packing forces between the individual assembled amphiphiles. In biology, the recognition of nucleic acids by proteins involves more than electrostatic interactions (8-10). Examination of these protein nucleic acid recognition motifs typically reveals structures rich in basic and aromatic amino acids that provide important electrostatic and stacking contributions to binding. With this inspiration in mind, we are designing peptide-based amphiphiles for gene delivery. Herein we describe a series of lipophilic peptides including the synthesis, physiochemical properties, cytotoxicity, and in vitro gene transfection activity.To mimic structural characteristics present in nucleic acid binding proteins, we selected the tripeptide Lys-Trp-Lys, KWK, to be the headgroup for the amphiphile because it possesses cationic charges and an aromatic side chain and is relatively small in size. Moreover, this peptide is known to bind DNA with a binding constant on the order of 10 4 M and is a model peptide used to study protein-nucleic acid interactions, and lysine and tryptophan provide important interactions in a number of structurally characterized DNA binding domains of proteins (11)(12)(13)(14). In addition, lysine-based small molecule amphiphiles and macromolecules (e.g., polylysine) are being explored and used for gene transfection (15)(16)(17)(18)(19)(20)(21)(22)(23)(24). In order to perform a systematic study to identify the key molecular components responsible for transfection © 2008 American Chemical Society * Correspondence should be addressed to M.W.G.; author E-mail: mgrin@bu.edu. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript activity with these new lipophilic peptides, we prepared a series of amphiphiles where the headgroup (charge, aliphatic content, aromatic content) and fatty acid chain length (C12:0, C14:0, C16:0, and C18:0) were varied. As shown in Figure ...

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confidence: 61%

Lipophilic Peptides for Gene Delivery

et al. 2008

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“…One possible answer to these questions is that the medium-chain lipid facilitates mixing of the lipoplex lipid with cellular lipid, which could lead to the neutralizing of the positive charge of the cationic lipid and facilitate release of DNA from the complex. 14,15 If that were the case, one might expect EDLPC to facilitate fusion (or at least lipid mixing) of cationic liposomes with anionic liposomes. We therefore compared the fusion of EDLPC/EDOPC (80/20/15), EDLPC/EDOPC (60/40/16.7), and pure EDOPC lipoplexes with phosphatidylglycerol-containing (anionic) liposomes.…”

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New strategy for transfection: mixtures of medium-chain and long-chain cationic lipids synergistically enhance transfection

Wang

MacDonald

2004

Gene Ther

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To date, the primary approach to improve the transfection properties of cationic lipids has been the synthesis of new kinds of cationic amphipaths or the inclusion of noncationic helper lipids. Here, it is reported that an alternative approach can be unusually effective, namely, the combination of two cationic lipid derivatives having the same head group but tails of different chain lengths. Particularly efficient was the combination of dilauroyl (12 carbon chain) and dioleoyl (18 carbon chain) homologues of O-ethylphosphatidylcholine.This mixture transfected DNA into human umbilical artery endothelial cells (HUAEC) more than 30-fold more efficiently than either compound separately. A unique advantage of this kind of combination agent is that transfection can be optimized either in the presence or absence of serum by adjusting the component ratio.

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“…These values are slightly higher than those for DPPC, which has a Tm around 41.3 °C and a corresponding enthalpy of 8.2 kcal/mol ( [7] and references therein). The thermodynamic behavior of these cationic triesters of phosphatidylcholine can be attributed to the net positive charge and the absence of intermolecular hydrogen bonding [98]. Furthermore, the overall polarity of the lipid is decreased, which may decrease the interfacial polarity.…”

Section: The Interdigitated Gel Phase In Cationic Lipidsmentioning

confidence: 99%