Drug–lipid interaction evaluation: why a 19th century solution?

Ribeiro, Marta M. B.; Melo, Manuel N.; Serrano, Isa; Santos, Nuno C.; Castanho, Miguel A. R. B.

doi:10.1016/j.tips.2010.06.007

Cited by 32 publications

(24 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Successful interaction between a CPP-cargo complex and lipid membranes is known to be a crucial element in the design of drug delivery systems [15]: if the complex shows higher membrane affinity the translocation is more likely to occur [45][46][47]. The results in Figs 2-4 and S3-S5 indicate that the presence of peptide is mandatory for ssDNA interaction with membranes.…”

Section: Partition Of Cpp : Ssdna Complexes To Lipid Membranesmentioning

confidence: 91%

Nucleic acid delivery by cell penetrating peptides derived from dengue virus capsid protein: design and mechanism of action

et al. 2013

Self Cite

View full text Add to dashboard Cite

Cell penetrating peptides (CPPs) can be used as drug delivery systems for different therapeutic molecules. In this work two novel CPPs, pepR and pepM, designed from two domains of the dengue virus (DENV) capsid protein, were studied for their ability to deliver nucleic acids into cells as non-covalently bound cargo. Translocation studies were performed by confocal microscopy in HepG2, BHK and HEK cell lineages, astrocytes and peripheral blood mononuclear cells. Combined studies in HepG2 cells, astrocytes and BHK cells, at 4 and 37°C or using specific endocytosis inhibitors, revealed that pepR and pepM use distinct internalization routes: pepM translocates lipid membranes directly, while pepR uses an endocytic pathway. To confirm these results, a methodology was developed to monitor the translocation kinetics of both peptides by real-time flow cytometry. Kinetic constants were determined, and the amount of nucleic acids delivered was estimated. Additional studies were performed in order to understand the molecular bases of the peptide-mediated translocation. Peptide-nucleic acid and peptide-lipid membrane interactions were studied quantitatively based on the intrinsic fluorescence of the peptides. pepR and pepM bound ssDNA to the same extent. Partition studies revealed that both peptides bind preferentially to anionic lipid membranes, adopting an a-helical conformation. However, fluorescence quenching studies suggest that pepM is deeply inserted into the lipid bilayer, in contrast with pepR. Moreover, only pepM is able to promote the fusion and aggregation of vesicles composed of zwitterionic lipids. Altogether, the results show that DENV capsid protein derived peptides serve as good templates for novel CPP-based nucleic acid delivery strategies, defining different routes for cell entry.

show abstract

Section: Partition Of Cpp : Ssdna Complexes To Lipid Membranesmentioning

confidence: 91%

Nucleic acid delivery by cell penetrating peptides derived from dengue virus capsid protein: design and mechanism of action

et al. 2013

Self Cite

View full text Add to dashboard Cite

show abstract

“…LUVs have a lipid packing close to planar membrane due to their larger radii of curvature relative to molecular dimensions and are more stable than other vesicles, making them ideal mammalian membrane models. Also, LUVs inner and outer layers display similar superficial areas (Ribeiro et al, 2010). These vesicles can be easily produced with different biologically relevant lipid compositions (e.g., presence of charged phospholipids or different cholesterol content), accounting for the contributions of hydrophobic and electrostatic interactions, membrane fluidity, and phase separation, or can even be prepared directly from lipids extracted from a certain type of cell.…”

Section: Methodsmentioning

confidence: 97%

Translocating the blood-brain barrier using electrostatics

Ribeiro¹,

Domingues²,

Freire³

et al. 2012

Front. Cell. Neurosci.

Self Cite

View full text Add to dashboard Cite

Mammalian cell membranes regulate homeostasis, protein activity, and cell signaling. The charge at the membrane surface has been correlated with these key events. Although mammalian cells are known to be slightly anionic, quantitative information on the membrane charge and the importance of electrostatic interactions in pharmacokinetics and pharmacodynamics remain elusive. Recently, we reported for the first time that brain endothelial cells (EC) are more negatively charged than human umbilical cord cells, using zeta-potential measurements by dynamic light scattering. Here, we hypothesize that anionicity is a key feature of the blood-brain barrier (BBB) and contributes to select which compounds cross into the brain. For the sake of comparison, we also studied the membrane surface charge of blood components—red blood cells (RBC), platelets, and peripheral blood mononuclear cells (PBMC). To further quantitatively correlate the negative zeta-potential values with membrane charge density, model membranes with different percentages of anionic lipids were also evaluated. From all the cells tested, brain cell membranes are the most anionic and those having their lipids mostly exposed, which explains why lipophilic cationic compounds are more prone to cross the blood-brain barrier.

show abstract

“…The oil/water or octanol/water partitioning coefficients (K OW ) have been common criteria for the assessment of membrane permeability 27 . In many cases K OW can be accurately predicted just from the chemical structure 28,29 .…”

mentioning

confidence: 99%

Effects on Membrane Lateral Pressure Suggest Permeation Mechanisms for Bacterial Quorum Signaling Molecules

et al. 2011

View full text Add to dashboard Cite

Quorum sensing is an intricate example of ‘social’ behavior in microbial communities mediated by small secreted molecules (autoinducers). The mechanisms of membrane permeation remain elusive for many of them. Here we present the assessment of membrane permeability for three natural autoinducers and five synthetic analogs based on their polarity, surface activity, affinity for lipid monolayers and ability to induce lateral pressure changes in the inner E. coli membrane sensed by the bacterial tension-activated channel MscS. AI-1 (N-(3-Oxodecanoyl)-L-homoserine lactone) is surface-active, it robustly inserts into lipid monolayers, indicating strong propensity toward membranes. When presented to membrane patches from the cytoplasmic side, AI-1 transiently shifts MscS’s activation curve toward higher tensions due to intercalation into the cytoplasmic leaflet followed by redistribution to the opposite side. Indole showed no detectable surface activity at the air-water interface, but produced a moderate increase of lateral pressure in monolayers and was potent at shifting activation curves of MscS, demonstrating transients on sequential additions. AI-2 (4,5-dihydroxy-2,3-pentanedione, DPD) showed little activity at the interfaces, correspondingly with no effect on MscS activation. After chemical modification with isobutyl, hexyl or heptyl chains, AI-2 displayed strong surface activity. Hexyl and especially heptyl AI-2 induced robust transient shifts of MscS activation curves. The data strongly suggest that both AI-1 and indole are directly permeable through the membrane. AI-2, more hydrophilic, shows low affinity toward lipids and thus requires a transport system, whereas alkyl analogs of AI-2 should permeate the membrane directly.

show abstract

Drug–lipid interaction evaluation: why a 19th century solution?

Cited by 32 publications

References 49 publications

Nucleic acid delivery by cell penetrating peptides derived from dengue virus capsid protein: design and mechanism of action

Nucleic acid delivery by cell penetrating peptides derived from dengue virus capsid protein: design and mechanism of action

Translocating the blood-brain barrier using electrostatics

Effects on Membrane Lateral Pressure Suggest Permeation Mechanisms for Bacterial Quorum Signaling Molecules

Contact Info

Product

Resources

About