Injectable liposomal docosahexaenoic acid alleviates atherosclerosis progression and enhances plaque stability.

Atherosclerosis is a chronic inflammatory vascular disease that is characterized by the accumulation of lipids and immune cells in plaques built up inside artery walls. Docosahexaenoic acid (DHA, 22:6n-3), an omega-3 polyunsaturated fatty acid (PUFA), which exerts anti-inflammatory and antioxidant properties, has long been purported to be of therapeutic benefit to atherosclerosis patients. However, large clinical trials have yielded inconsistent data, likely due to variations in the formulation, dosage, and bioavailability of DHA following oral intake. To fully exploit its potential therapeutic effects, we have developed an injectable liposomal DHA formulation intended for intravenous administration as a plaque-targeted nanomedicine. The liposomal formulation protects DHA against chemical degradation and increases its local concentration within atherosclerotic lesions. Mechanistically, DHA liposomes are readily phagocytosed by activated macrophages, exert potent anti-inflammatory and antioxidant effects, and inhibit foam cell formation. Upon intravenous administration, DHA liposomes accumulate preferentially in atherosclerotic lesional macrophages and promote polarization of macrophages towards an anti-inflammatory M2 phenotype, resulting in attenuation of atherosclerosis progression in both ApoE-/- and Ldlr-/- experimental models. Plaque composition analysis demonstrates that liposomal DHA inhibits macrophage infiltration, reduces lipid deposition, and increases collagen content, thus improving the stability of atherosclerotic plaques against rupture. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) further reveals that DHA liposomes can partly restore the complex lipid profile of the plaques to that of early-stage plaques. In conclusion, DHA liposomes offer a promising approach for applying DHA to stabilize atherosclerotic plaques and attenuate atherosclerosis progression, thereby preventing atherosclerosis-related cardiovascular events.

Safety, pharmacokinetics and tissue penetration of PIPAC paclitaxel in a swine model.

INTRODUCTION: Peritoneal carcinomatosis is difficult to treat. Pressurized Intra-Peritoneal Aerosolised Chemotherapy (PIPAC) is a novel method of delivering chemotherapy to the peritoneal cavity, aiming for homogenous and deeper drug distribution. To date, limited chemotherapeutics have been used with promising results. Here, we evaluate the pharmacokinetics, peritoneal tissue drug concentration, penetration, and short-term safety of PIPAC using solvent-based paclitaxel in swine to guide clinical trials. MATERIALS AND METHODS: PIPAC solvent-based paclitaxel was administered at 60, 30, and 15mg/m2 for 3 cohorts. Each PIPAC procedure was followed by intravenous (IV) administration of the same dose of solvent-based paclitaxel on Day 7, serving as control for pharmacokinetic comparison in the same pig. Safety and toxicity were evaluated by clinical assessment, blood counts and biochemistry. Blood samples were taken for pharmacokinetic analysis. Peritoneal biopsies were taken to measure tissue paclitaxel concentrations and distribution. RESULTS: 12 Yorkshire x Landrace pigs underwent trial procedures. With PIPAC, there was linear pharmacokinetics and lower systemic exposure to paclitaxel compared to IV administration. MALDI-MSI demonstrated concentration of paclitaxel at the peritoneal surface, with estimated 2 mm penetration. PIPAC paclitaxel had favorable toxicity profile. The most significant adverse event was neutropenia which was dose dependent, with absolute neutrophil count <1.0 × 103/µL seen at the highest dose. One pig developed grade 2 hypersensitivity reaction during IV infusion and one death occurred during the PIPAC procedure, likely from anaphylaxis; these are known potential adverse events mandating standard precautions and monitoring. CONCLUSION: PIPAC paclitaxel at 15mg/m2 may be considered for a Phase I study.

Role of Electrochemistry in Desorption Ionization Mass Spectrometry (LS DESI MS) of Aqueous Samples Containing Electrolyte Salts.

The ionization of LS samples in desorption ionization mass spectrometry (LS DESI MS), supplied continuously through a LS interface separated in space from the spray emitter, was investigated in this work. The role of electrochemistry (EC) in the ionization process was addressed. The visual (observation) of the operation of the LS DESI MS system showed a thick spray plume generated by the electrosonic spray ionization (ESSI), forming a liquid cone at the LS interface. When the LS interface was grounded the cone collapsed and the MS ion signal was lost, indicating that the LS was carried to the MS inlet by the spray that emerged from the cone. Ion signals in a new in-line LS DESI MS system, in angled LS DESI MS, and in electrospray ionization (ESI) MS, which produced the most intense ion signals from methanol/water solutions, and in ESSI MS, of dopamine (DA), tyrosine (Tyr) and N,N-dimethyl-p-phenylenediamine (DMPA), were evaluated using methanol/water and aqueous (aq) solutions. In addition, the effect on ion signals of geometric parameters and the LS and the spray solution flow rates was tested in in-line LS DESI MS. Of the methods tested, the analysis of aq LS containing electrolytes was simplest by LS DESI MS. The signal intensity was higher in in-line than in angled LS DESI MS. In online electrochemistry (EC)/LS DESI MS, when 0 V was applied to the EC cell Tyr ion signal was detected only at low pH (2).

Merits of online electrochemistry liquid sample desorption electrospray ionization mass spectrometry (EC/LS DESI MS).

A new online electrochemistry/liquid sample desorption electrospray ionization mass spectrometry (EC/LS DESI MS) system with a simple electrochemical thin-layer flow-through cell was developed and tested using N,N-dimethyl-p-phenylenediamine (DMPA) as a model probe. Although oxidation of DMPA is observed as a result of ionization of LS in positive ion mode LS DESI, application of voltage to the online electrochemical (EC) cell in EC/LS DESI MS increases yields of oxidation products. An advantage of LS DESI MS is its sensitivity in aqueous electrolyte solutions, which improves efficiency of electrochemical reactions in EC/LS DESI MS. In highly conductive low pH aqueous buffer solutions, oxidation efficiency is close to 100%. EC/ESI MS typically requires mixed aqueous/organic solvents and low electrolyte concentrations for efficient ionization in MS, limiting efficiency of electrochemistry online with MS. Independently, the results verify higher electrochemical oxidation efficiency during positive mode ESI than during LS DESI.