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.

Selecting a randomization method for a multi-center clinical trial with stochastic recruitment considerations.

Background: The design of a multi-center randomized controlled trial (RCT) involves multiple considerations, such as the choice of the sample size, the number of centers and their geographic location, the strategy for recruitment of study participants, amongst others. There are plenty of methods to sequentially randomize patients in a multi-center RCT, with or without considering stratification factors. The goal of this paper is to perform a systematic assessment of such randomization methods for a multi-center 1:1 RCT assuming a competitive policy for the patient recruitment process.

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.

Using viral sequence diversity to estimate time of HIV infection in infants.

Age at HIV acquisition may influence viral pathogenesis in infants, and yet infection timing (i.e. date of infection) is not always known.

Central and peripheral lung deposition of fluticasone propionate dry powder inhaler formulations in humans characterized by population pharmacokinetics.

This study aimed to gain an in-depth understanding of the pulmonary fate of three experimental fluticasone propionate (FP) dry powder inhaler formulations which differed in mass median aerodynamic diameters (MMAD; A-4.5 µm, B-3.8 µm and C-3.

Oncology dose optimization paradigms: knowledge gained and extrapolated from approved oncology therapeutics.

There has been increasing attention to dose optimization in the development of targeted oncology therapeutics. The current report has analyzed the dose selection approaches for 116 new molecular entities (NMEs) approved for oncology indications by the US FDA from 2010 to August 2021, with the goal to extract learnings about the ways to select the optimal dose. The analysis showed that: (1) the initial label dose was lower than the maximum tolerated dose (MTD) or maximum studied dose (MSD) in Phase 1 for the majority of approved NMEs, and that the MTD approach is no longer the mainstay for dose selection; (2) there was no dose ranging or optimization beyond Phase 1 dose escalation for ~ 80% of the NMEs; (3) integrated dose/exposure-response analyses were commonly used to justify the dose selection; (4) lack of dose optimization led to dose-related PMRs/PMCs in 14% of cases, but 82% of these did not result in change of the initial label dose; and (5) depending on properties of the NME and specific benefit/risk considerations for the target patient population, there could be different dose selection paradigms leading to identification of the appropriate clinical dose.

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.

The Beauty is a beast: Does leachate from the invasive terrestrial plant affect aquatic food webs?

Invasive alien species are a major threat to ecosystems. Invasive terrestrial plants can produce allelochemicals which suppress native terrestrial biodiversity. However, it is not known if leached allelochemicals from invasive plants growing in riparian zones, such as , also affect freshwater ecosystems.

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.

X-ray crystal structure of [ Ag][OTf]·5CD: a monoanionic bis-phosphinimine ligand supported tris-ilver complex.

The compound bis-{μ-2,5-bis-[-(4-iso-propyl-phen-yl)-,-di-phenyl-phospho-r-im-i-do-yl]pyrrol-1-ido-κ :':''}tris-ilver(I) tri-fluoro-methane-sulfonate deuterated benzene penta-solvate, [Ag(CHNP)](CFOS)·5CD, (I), was synthesized from two equivalents of Na [ = 2,5-(4- PrCHN=PPh)CHN] and three equivalents of AgOTf (OTf = OSOCF). High-quality crystals of (I) formed with five deuterated benzene solvent mol-ecules in the asymmetric unit. Notably, the bond lengths and angles between the three silver atoms are markedly different, unlike in most other reported tris-ilver complexes that tend to form three equivalent metal centers.

Allochthonous resources are less important for faunal communities on highly productive, small tropical islands.

Ecosystems are interconnected by energy fluxes that provide resources for the inhabiting organisms along the transition zone. Especially where in situ resources are scarce, ecosystems can become highly dependent on external resources. The dependency on external input becomes less pronounced in systems with elevated in situ production, where only consumer species close to the site of external input remain subsidized, whereas species distant to the input site rely on the in situ production of the ecosystem.

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.

Can Pharmacokinetic Studies Assess the Pulmonary Fate of Dry Powder Inhaler Formulations of Fluticasone Propionate?

In the context of streamlining generic approval, this study assessed whether pharmacokinetics (PK) could elucidate the pulmonary fate of orally inhaled drug products (OIDPs). Three fluticasone propionate (FP) dry powder inhaler (DPI) formulations (A-4.5, B-3.

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.

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.

Synthesis and aggregation behaviour of single-chain, 1,32-alkyl-branched bis(phosphocholines) - part 2: lateral chain length triggers self-assembling from sheets to fibres to vesicles.

Six single-chain, 1,32-alkyl-branched bis(phosphocholines) PC-C32(1,32Cm)-PC have been synthesized as model lipids for naturally occurring archaeal membrane lipids. The preparation of these bipolar amphiphiles bearing lateral alkyl chains of different lengths (C4-C15) was realized using a Cu-catalyzed Grignard bis-coupling reaction of various primary alkyl-branched bromides as side parts and a 1,22-dibromide as the centre part. The aggregation behaviour of these bolalipids in water was initially investigated by differential scanning calorimetry and transmission electron microscopy.

Bolalipid-Doped Liposomes: Can Bolalipids Increase the Integrity of Liposomes Exposed to Gastrointestinal Fluids?

The use of archaeal lipids and their artificial analogues, also known as bolalipids, represents a promising approach for the stabilization of classical lipid vesicles for oral application. In a previous study, we investigated the mixing behavior of three single-chain alkyl-branched bolalipids ( = 3, 6, 9) with either saturated or unsaturated phosphatidyl-cholines. We proved, that the bolalipids and show miscibility with 1-palmitoyl-2-oleoyl--glycero-3-phosphocholine (POPC) and 1,2-dioleoyl--glycero-3-phosphocholine (DOPC).

Azide-Modified Membrane Lipids: Miscibility with Saturated Phosphatidylcholines.

In this study, we describe the miscibility of four azide-modified membrane phospholipids (azidolipids) with conventional phospholipids. The azidolipids bear an azide group at different positions of the -1 or -2 alkyl chain and they further differ in the type of linkage (ester vs ether) of the -2 alkyl chain. Investigations regarding the miscibility of the azidolipids with bilayer-forming phosphatidylcholines will evaluate lipid mixtures that are suitable for the production of stable azidolipid-doped liposomes.

The Use of Artificial Gel Forming Bolalipids as Novel Formulations in Antimicrobial and Antifungal Therapy.

The alarming growth of multi-drug resistant bacteria has led to a quest for alternative antibacterial therapeutics. One strategy to circumvent the already existing resistance is the use of photodynamic therapy. Antimicrobial photodynamic therapy (aPDT) involves the use of non-toxic photosensitizers in combination with light and in situ oxygen to generate toxic radical species within the microbial environment which circumvents the resistance building mechanism of the bacteria.

Salmonella enterica persister cells form unstable small colony variants after in vitro exposure to ciprofloxacin.

Persistence phenotype and small colony variants (SCVs) can be part of a bacterial bet-hedging strategy for survival under environmental stresses, such as antimicrobial exposure. These phenotypes are of particular concern in persistent and relapsing infections, since cells resume to normal growth after cessation of the stressful condition. In this context, we found persisters and unstable SCVs as phenotypic variants of Salmonella enterica that were able to survive ciprofloxacin exposure.