Perturbations in mitochondrial metabolism associated with defective cardiolipin biosynthesis: An in-organello real-time NMR study.

Mitochondria are central to cellular metabolism; hence, their dysfunction contributes to a wide array of human diseases. Cardiolipin, the signature phospholipid of the mitochondrion, affects proper cristae morphology, bioenergetic functions, and metabolic reactions carried out in mitochondrial membranes. To match tissue-specific metabolic demands, cardiolipin typically undergoes an acyl tail remodeling process with the final step carried out by the phospholipid-lysophospholipid transacylase tafazzin.

Investigation of keratolytic impact of synthetic bolalipids on skin penetration of a model hydrophilic permeant.

Synthetic single-chain bolalipids (SSCBs) are novel excipients in drug delivery, with potential as stabilizers or solubilizers. However, their impact on skin barrier function has not been comprehensively studied. Therefore, two SSCBs (PC-C24-PC and PC-C32-PC) were studied in aqueous systems for their impact on penetration of a model permeant into porcine skin.

Mitochondrial Structure and Function in Human Heart Failure.

Despite clinical and scientific advancements, heart failure is the major cause of morbidity and mortality worldwide. Both mitochondrial dysfunction and inflammation contribute to the development and progression of heart failure. Although inflammation is crucial to reparative healing following acute cardiomyocyte injury, chronic inflammation damages the heart, impairs function, and decreases cardiac output.

Perturbations in mitochondrial metabolism associated with defective cardiolipin biosynthesis: An real-time NMR study.

Mitochondria are central to cellular metabolism; hence, their dysfunction contributes to a wide array of human diseases including cancer, cardiopathy, neurodegeneration, and heritable pathologies such as Barth syndrome. Cardiolipin, the signature phospholipid of the mitochondrion promotes proper cristae morphology, bioenergetic functions, and directly affects metabolic reactions carried out in mitochondrial membranes. To match tissue-specific metabolic demands, cardiolipin typically undergoes an acyl tail remodeling process with the final step carried out by the phospholipid-lysophospholipid transacylase tafazzin.

Functional diversity among cardiolipin binding sites on the mitochondrial ADP/ATP carrier.

Lipid-protein interactions play a multitude of essential roles in membrane homeostasis. Mitochondrial membranes have a unique lipid-protein environment that ensures bioenergetic efficiency. Cardiolipin (CL), the signature mitochondrial lipid, plays multiple roles in promoting oxidative phosphorylation (OXPHOS).

Mitochondria in disease: changes in shapes and dynamics.

Mitochondrial structure often determines the function of these highly dynamic, multifunctional, eukaryotic organelles, which are essential for maintaining cellular health. The dynamic nature of mitochondria is apparent in descriptions of different mitochondrial shapes [e.g.

The role of phospholipids in drug delivery formulations - Recent advances presented at the Researcher's Day 2023 Conference of the Phospholipid Research Center Heidelberg.

This Focus on Meetings contribution summarizes recent advances in the research on phospholipids and their applications for drug delivery and analytical purposes that have been presented at the hybrid Researcher's Day 2023 Conference of the Phospholipid Research Center (PRC), held on July 3-5, 2023, in Bad Dürkheim, Germany. The PRC is a non-profit organization focused on expanding and sharing scientific and technological knowledge of phospholipids in pharmaceutical and other applications. This is accomplished by, e.

Conserved cardiolipin-mitochondrial ADP/ATP carrier interactions assume distinct structural and functional roles that are clinically relevant.

The mitochondrial phospholipid cardiolipin (CL) promotes bioenergetics via oxidative phosphorylation (OXPHOS). Three tightly bound CLs are evolutionarily conserved in the ADP/ATP carrier (AAC in yeast; adenine nucleotide translocator, ANT in mammals) which resides in the inner mitochondrial membrane and exchanges ADP and ATP to enable OXPHOS. Here, we investigated the role of these buried CLs in the carrier using yeast Aac2 as a model.

Development and in vivo validation of phospholipid-based depots for the sustained release of bupivacaine.

By direct deposition of the drug at the local site of action, injectable depot formulations - intended for treatment of a local disease or for local intervention - are designed to limit the immediate exposure of the active principle at a systemic level and to reduce the frequency of administration. To overcome known drawbacks in the production of some marketed phospholipid-based depots, here we propose to manufacture drug-loaded negatively charged liposomes through conventional technologies and to control their aggregation mixing a solution of divalent cations prior to administration. We identified phosphatidylglycerol (PG) as the most suitable phospholipid for controlled aggregation of the liposomes and to modulate the release of the anesthetic bupivacaine (BUP) from liposomal depots.

Azide- and diazirine-modified membrane lipids: Physicochemistry and applicability to study peptide/lipid interactions via cross-linking/mass spectrometry.

Although the incorporation of photo-activatable lipids into membranes potentially opens new avenues for studying interactions with peptides and proteins, the question of whether azide- or diazirine-modified lipids are suitable for such studies remains controversial. We have recently shown that diazirine-modified lipids can indeed form cross-links to membrane peptides after UV activation and that these cross-links can be precisely determined in their position by mass spectrometry (MS). However, we also observed an unexpected backfolding of the lipid's diazirine-containing stearoyl chain to the membrane interface challenging the potential application of this modified lipid for future cross-linking (XL)-MS studies of protein/lipid interactions.

Investigating bolalipids as solubilizing agents for poorly soluble drugs: Effects of alkyl chain length on solubilization and cytotoxicity.

Synthetic single-chain bolalipids with symmetrical headgroups have shown potential in various pharmaceutical applications, such as the stabilization of liposome bilayers. Despite their amphiphilic character, synthetic bolalipids have not yet been investigated for their suitability as solubilizing agents for poorly soluble drug compounds. In this study, three synthetic single-chain bolalipids with increasing alkyl chain lengths (C22, C24 and C26) were investigated.

A Diazirine-Modified Membrane Lipid to Study Peptide/Lipid Interactions - Chances and Challenges.

Although incorporation of photo-activatable lipids into membranes potentially opens up novel avenues for investigating interactions with proteins, the question of whether diazirine-modified lipids are suitable for such studies, remains under debate. Focusing on the potential for studying lipid/peptide interactions by cross-linking mass spectrometry (XL-MS), we developed a diazirine-modified lipid (DiazPC), and examined its behaviour in membranes incorporating the model α-helical peptide LAVA20. We observed an unexpected backfolding of the diazirine-containing stearoyl chain of the lipid.

Influence of a single ether bond on assembly, orientation, and miscibility of phosphocholine lipids at the air-water interface.

How does a small change in the structure of a phospholipid affect its supramolecular assembly? In aqueous suspensions, the substitution of one ester linkage in DPPC (1,2-dipalmitoyl-sn-glycero-3-phosphocholine) by an ether linkage alters its phase behaviour completely. To unravel the effect of replacing a phospholipid's ester linkage by an ether linkage in lipid monolayers, we characterized pure monolayers of the model lipid DPPC and its sn-2 ether analogue PHPC (1-palmitoyl-2-O-hexadecyl-sn-glycero-3-phosphocholine) as well as mixtures of both by measurements of surface pressure-molecular area (π-Amol) isotherms. In addition, we used infrared reflection absorption spectroscopy (IRRAS) to study lipid condensation, lipid chain orientation, headgroup hydration, and lipid miscibility in all samples.

The Phospholipid Research Center: Current Research in Phospholipids and Their Use in Drug Delivery.

This review summarizes the research on phospholipids and their use for drug delivery related to the Phospholipid Research Center Heidelberg (PRC). The focus is on projects that have been approved by the PRC since 2017 and are currently still ongoing or have recently been completed. The different projects cover all facets of phospholipid research, from basic to applied research, including the use of phospholipids in different administration forms such as liposomes, mixed micelles, emulsions, and extrudates, up to industrial application-oriented research.

An Azidolipid Monolayer - Transitions, Miscibility, and UV Reactivity Studied by Infrared Reflection Absorption Spectroscopy.

In this study, we characterized monolayers of an azide-modified lipid at the air-water interface, pure and in its mixtures with the model lipid DPPC, with the aim of proving its potential to be applied for photo-cross-linking with other molecules. We chose a phospholipid bearing a terminal azide group in one of its hydrophobic tails to study its monolayer characteristics with the Langmuir film balance technique. Furthermore, we performed infrared reflection absorption spectroscopy (IRRAS) to get detailed insights into the organization of those monolayers as well as high-resolution mass spectrometry (HRMS) to see the effects of UV-irradiation on the lipids' chemical structure and organization.

Assessment of the applicability of HLB values for natural phospholipid emulsifiers for preparation of stable emulsions.

Natural phospholipid (PL) excipients are native, biocompatible and relatively inexpensive alternatives to synthetic emulsifiers. A well-known PL excipient is lecithin, which primarily contains phosphatidylcholine (PC) and (depending on the purity grade) also contains a well-defined mixture of other PLs with a fatty acid composition, which reflects their natural source. Since all of these lipid species are emulsifiers, natural PLs can be considered as a mixture of (co-) emulsifiers.

Tuning the Thickness of a Biomembrane by Stapling Diamidophospholipids with Bolalipids.

In a biological membrane, proteins require specific lipids of distinctive length and chain saturation surrounding them. The active tuning of the membrane thickness therefore opens new possibilities in the study and manipulation of membrane proteins. Here, we introduce the concept of stapling phospholipids to different degrees of interdigitation depth by mixing 1,3-diamidophospholipids with single-chain bolalipids.

The role of liposomes in clinical nanomedicine development. What now? Now what?

The rapid rise in interest in 'nanomedicines' in the academic world over the last twenty years and the claims of success led to calls for reflection. The main body of text of this Commentary will be on answering the question: 'where to go with nanomedicines'? Research priorities for the future will be outlined based on experience with the most successful nanomedicines family within the broad field of nanomedicine so far: liposomes. An analysis of currently clinically tested, approved and marketed liposome-drug combinations provides these insights.

Evaluation of Hydrogenated Soybean Phosphatidylcholine Matrices Prepared by Hot Melt Extrusion for Oral Controlled Delivery of Water-Soluble Drugs.

The aims of this study were to prepare hydrogenated soybean phosphatidylcholine (HSPC) matrices by hot melt extrusion and to evaluate resulting matrix potential to extend drug release in regard to drug loading and solubility for oral drug delivery of water-soluble drugs. The liquid crystalline nature of HSPC powder allowed its extrusion at 120°C, which was below its capillary melting point. Model drugs with a wide range of water solubilities (8, 20 and 240 mg/mL) and melting temperatures (160-270°C) were used.

Study on the in situ aggregation of liposomes with negatively charged phospholipids for use as injectable depot formulation.

Compared to conventional parenteral formulations injectable depot formulations, owing to a sustained drug release, offer several advantages, such as a reduced dosing frequency - and consequent improved compliance - or a predictable release profile. Additionally, fluctuations in the drug blood level may be smoothened and consequently side effects reduced. Because of their capability to encapsulate water soluble drugs and their very low toxicity profile liposomes comprising phospholipids, most certainly represent a vehicle of choice for subcutaneous (s.

Review - An update on the use of oral phospholipid excipients.

The knowledge and experiences obtained with oral phospholipid excipients is increasing continuously. Nevertheless the present number of oral products using these excipients as essential excipient is very limited. This is remarkable to note, since phospholipids play a significant role in the food uptake mechanisms of the GI tract and these mechanisms could be translated into suitable dosage forms and corresponding drug delivery strategies.

Molecular imaging of brain localization of liposomes in mice using MALDI mass spectrometry.

Phospholipids have excellent biocompatibility and are therefore often used as main components of liposomal drug carriers. In traditional bioanalytics, the in-vivo distribution of liposomal drug carriers is assessed using radiolabeled liposomal constituents. This study presents matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) as an alternative, label-free method for ex-vivo molecular imaging of liposomal drug carriers in mouse tissue.

Molecular insights into the formation of drug-monoacyl phosphatidylcholine solid dispersions for oral delivery.

Phospholipid-based formulations provide a key technology to formulate poorly water-soluble drugs. A recent interest has been in using phospholipids with a high content of monoacyl phosphatidylcholine (monoacyl PC) due to its ability to form mixed micelles of mono- and di-acylphospholipids upon aqueous dispersion. The present work focused on binary drug- monoacyl PC systems (at about equimolar ratio) with respect to screening of solid dispersion feasibility.

Amorphous drug dispersions with mono- and diacyl lecithin: On molecular categorization of their feasibility and UV dissolution imaging.

There is a growing interest in drug-phospholipid complexes and similar formulations that are mostly solid dispersions with high drug load. This study aims to explore the feasibility of such phospholipid-based solid dispersions as well as to characterize them. A particular aim was to compare monoacyl phosphatidylcholine (PC) with the diacyl excipient.