Abstract:This paper presents a new hybrid lipid that fuses the ideas of molecular tethering of lipid tails used by archaea and the integration of cholesterol groups used by eukaryotes, thereby leveraging two strategies employed by nature to increase lipid packing in membranes. Liposomes comprised of pure hybrid lipids exhibited a 5-30-fold decrease in membrane leakage of small ions and molecules compared to liposomes that used only one strategy (lipid tethering or cholesterol incorporation) to increase membrane integri… Show more
“…Archaea-like or archaea-inspired BAs are well-known in this regard. Their membrane spanning ether linked lipid backbone along with hydrophilic head groups stabilize the liposomal membrane (Benvegnu et al, 2005;Mahmoud et al, 2015;Jacobsen et al, 2017;Koyanagi et al, 2017;Leriche et al, 2017Leriche et al, , 2018. Liposomal stability enhancement is not limited to archaea-type BAs.…”
Section: Stability Of Ba-containing Nanostructuresmentioning
Bolaamphiphiles (BAs) are structurally segmented molecules with rich assembly characteristics and diverse physical properties. Interest in BAs as standalone active agents or as constituents of more complex therapeutic formulations has increased substantially in recent years. The preorganized amphiphilicity of BAs allows for a range of biological activities including applications that rely on multivalency. This review summarizes BA-related research in biomedically relevant areas. In particular, we review BA-related literature in four areas: gene delivery, antimicrobial materials, hydrogels, and prodrugs. We also discuss several distinguishing characteristics of BAs that impact their utility as biomedically relevant compounds.
“…Archaea-like or archaea-inspired BAs are well-known in this regard. Their membrane spanning ether linked lipid backbone along with hydrophilic head groups stabilize the liposomal membrane (Benvegnu et al, 2005;Mahmoud et al, 2015;Jacobsen et al, 2017;Koyanagi et al, 2017;Leriche et al, 2017Leriche et al, , 2018. Liposomal stability enhancement is not limited to archaea-type BAs.…”
Section: Stability Of Ba-containing Nanostructuresmentioning
Bolaamphiphiles (BAs) are structurally segmented molecules with rich assembly characteristics and diverse physical properties. Interest in BAs as standalone active agents or as constituents of more complex therapeutic formulations has increased substantially in recent years. The preorganized amphiphilicity of BAs allows for a range of biological activities including applications that rely on multivalency. This review summarizes BA-related research in biomedically relevant areas. In particular, we review BA-related literature in four areas: gene delivery, antimicrobial materials, hydrogels, and prodrugs. We also discuss several distinguishing characteristics of BAs that impact their utility as biomedically relevant compounds.
“…[7][8][9] However, liposomal retention of small neutral drugs, such as nucleoside analogs, still remains a challenge because small uncharged molecules diffuse quickly through membranes and, therefore, typically cannot be retained in conventional liposomal formulation. 10 Previously, we reported the design and synthesis of tetraether lipids (such as GMGTPC-CP, Fig. 1) that mimic many membrane properties found in archaeal organisms.…”
Section: Membrane Permeability Tetraether Lipids Nucleoside Drug Lipomentioning
confidence: 99%
“…This result could be attributed to the higher degree of packing offered by tetraether lipids. 10 In addition, molecular parameters typically used to assess lipophilicity (tPSA, SASA, and SA) were not sufficient to predict the relative membrane permeability of the nucleoside-based drugs. This work, thus, reveals that certain chemical features of pyrimidone-based drugs such as fluorine atoms and hydrogen bond donor groups can strongly influence membrane permeability.…”
Section: Membrane Permeability Tetraether Lipids Nucleoside Drug Lipomentioning
Although liposomal nanoparticles are one of the most versatile class of drug delivery systems, stable liposomal formulation of small neutral drug molecules still constitutes a challenge due to the low drug retention of current lipid membrane technologies. In this study, we evaluate the encapsulation and retention of seven nucleoside analog-based drugs in liposomes made of archaea-inspired tetraether lipids, which are known to enhance packing and membrane robustness compared to conventional bilayer-forming lipids. Liposomes comprised of the pure tetraether lipid generally showed improved retention of drugs (up to 4-fold) compared with liposomes made from a commercially available diacyl lipid. Interestingly, we did not find a significant correlation between the liposomal leakage rates of the molecules with typical parameters used to assess lipophilicity of drugs (such logD or topological polar surface area), suggesting that specific structural elements of the drug molecules can have a dominant effect on leakage from liposomes over general lipophilic character.
“…These synthetic lipids have shown great potential for biotechnological applications and especially in the field of liposomal drug/gene delivery 20–24 . Unlike extracted lipid mixtures, synthetic lipids offer the advantage of complete control of membrane lipid composition and, therefore, allow for systematic evaluation of the effects on membrane permeability of specific lipid structural features (e.g., tethering of lipid sidechains 18 , incorporation of rings in the tethered lipid sidechain 16 , inclusion of different polar headgroups 15 , and incorporation of different untethered sidechains 25 ). Using the structure of natural Archaeal lipids as inspiration, we developed successive generations of tetraether lipids with reduced membrane permeability to small ions or organic solutes when compared to commercial bilayer-forming lipids 25 .…”
Section: Introductionmentioning
confidence: 99%
“…Unlike extracted lipid mixtures, synthetic lipids offer the advantage of complete control of membrane lipid composition and, therefore, allow for systematic evaluation of the effects on membrane permeability of specific lipid structural features (e.g., tethering of lipid sidechains 18 , incorporation of rings in the tethered lipid sidechain 16 , inclusion of different polar headgroups 15 , and incorporation of different untethered sidechains 25 ). Using the structure of natural Archaeal lipids as inspiration, we developed successive generations of tetraether lipids with reduced membrane permeability to small ions or organic solutes when compared to commercial bilayer-forming lipids 25 . While membranes comprised of tetraether lipids show great stability in typical bilayer membrane disrupting conditions, the stability of these biomimetic membranes has never been reported under fusogenic conditions.Figure 1Chemical structure of bipolar tetraether lipids GMGTPC , GMGTPE and GMGTPA .…”
A major challenge in liposomal research is to minimize the leakage of encapsulated cargo from either uncontrolled passive permeability across the liposomal membrane or upon fusion with other membranes. We previously showed that liposomes made from pure Archaea-inspired bipolar tetraether lipids exhibit exceptionally low permeability of encapsulated small molecules due to their capability to form more tightly packed membranes compared to typical monopolar lipids. Here, we demonstrate that liposomes made of synthetic bipolar tetraether lipids can also undergo membrane fusion, which is commonly accompanied by content leakage of liposomes when using typical bilayer-forming lipids. Importantly, we demonstrate calcium-mediated fusion events between liposome made of glycerolmonoalkyl glycerol tetraether lipids with phosphatidic acid headgroups (GMGTPA) occur without liposome content release, which contrasts with liposomes made of bilayer-forming EggPA lipids that displayed ~80% of content release under the same fusogenic conditions. NMR spectroscopy studies of a deuterated analog of GMGTPA lipids reveal the presence of multiple rigid and dynamic conformations, which provide evidence for the possibility of these lipids to form intermediate states typically associated with membrane fusion events. The results support that biomimetic GMGT lipids possess several attractive properties (e.g., low permeability and non-leaky fusion capability) for further development in liposome-based technologies.
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