Chemistry and Physics of Lipids最新文献

The aim of this study was to construct a bifunctional liposome with hepatic-targeting capacity by modifying with a targeting ligand and an intracellular tumor reduction response functional group to deliver drugs precisely to focal liver tissues and release them in large quantities in hepatocellular carcinoma cells. This could improve drug efficacy and reduce toxic side effects at the same time. First, the bifunctional ligand for liposome was successfully obtained by chemically synthesizing it from the hepatic-targeting glycyrrhetinic acid (GA) molecule, cystamine, and the membrane component cholesterol. Then the ligand was used to modify the liposomes. The particle size, PDI and zeta potential of the liposomes were determined with a nanoparticle sizer, and the morphology was observed by transmission electron microscopy. The encapsulation efficiency and drug release behavior were also determined. Further, the stability in vitro of the liposomes and the changes in the simulated reducing environment were determined. Finally, the antitumor activity in vitro and cellular uptake efficiency of the drug-loaded liposomes were investigated by performing cellular assays. The results showed that the prepared liposomes had a uniform particle size of 143.6 ± 2.86 nm with good stability and an encapsulation rate of 84.3 ± 2.1 %. Moreover, the particle size of the liposomes significantly increased and the structure was destroyed in a DTT reducing environment. Cellular experiments showed that the modified liposoes had better cytotoxic effects on hepatocarcinoma cells than both normal liposomes and free drugs. This study has great potential for tumor therapy and provides novel ideas for the clinical use of oncology drugs in dosage forms.

Liposomes with enhanced elasticity have been proven to increase the efficiency of drug transport across the skin. The understanding of the background physicochemical processes driving the liposome viscoelastic properties is an essential feature for the design of effective formulations involving different lipids and additive molecules. In this work we use field-cycled nuclear magnetic resonance relaxometry to analyze both the mechanical properties of liposome membranes, and their relationship with the involved molecular dynamics. Different liposomal formulations were considered. We show a correlation between the molecular dynamical regime and mesoscopic physical parameters that define the expected deformability of the vesicles. Results strongly suggest that the purity of the used lipids may influence the elastic properties of the membranes in an appreciable way. Common features in the behaviour of the involved dynamic variables were identified by comparing formulations with surfactants of similar molecular weight.

Galactolipids are the main lipids from plant photosynthetic membranes and they can be digested by pancreatic lipase related protein 2 (PLRP2), an enzyme found in the pancreatic secretion in many animal species. Here, we used transmission Fourier-transform infrared spectroscopy (FTIR) to monitor continuously the hydrolysis of galactolipids by PLRP2, in situ and in real time. The method was first developed with a model substrate, a synthetic monogalactosyl diacylglycerol with 8-carbon acyl chains (C8-MGDG), in the form of mixed micelles with a bile salt, sodium taurodeoxycholate (NaTDC). The concentrations of the residual substrate and reaction products (monogalactosylmonoglyceride, MGMG; monogalactosylglycerol, MGG; octanoic acid) were estimated from the carbonyl and carboxylate vibration bands after calibration with reference standards. The results were confirmed by thin layer chromatography analysis (TLC) and specific staining of galactosylated compounds with thymol and sulfuric acid. The method was then applied to the lipolysis of more complex substrates, a natural extract of MGDG with long acyl chains, micellized with NaTDC, and intact chloroplasts isolated from spinach leaves. After a calibration performed with α-linolenic acid, the main fatty acid (FA) found in plant galactolipids, FTIR allowed quantitative measurement of chloroplast lipolysis by PLRP2. A full release of FA from membrane galactolipids was observed, that was not dependent on the presence of bile salts. Nevertheless, the evolution of amide vibration band in FTIR spectra suggested the interaction of membrane proteins with NaTDC and lipolysis products.

Naturally occurring psychedelics have been used for a long time as remedies or in religious ceremonies and recreational activities. Recent studies have proven the therapeutic potential of some psychedelic compounds to safely treat a wide range of diseases such as anxiety, depression, migraine, and addiction. It is hypothesized that psychedelic compounds like tryptamines can exert their effects by two possible mechanisms: binding to the transmembrane serotonin receptor and/or modifying the properties of the neuronal membrane that can alter the conformational equilibrium and desensitize receptors. The impact of three different tryptamine class compounds with a tertiary amine (dimethyltryptamine, bufotenine, and 5-MeO-DMT) in both neutral and charged forms on a model bilayer lipid membrane are studied using all-atom MD simulations. All compounds partition into the bilayer, and change membrane properties, but to different extents. We determine the tendency of compounds to partition into the membrane by free energy calculations. Neutral tryptamines partition into the bilayer almost completely. Dimethyltryptamine and 5-MeO-DMT cross the membrane spontaneously during the simulation time, but bufotenine does not, although it has the maximum effect on the structural properties of the membrane. However, protonated compounds partition partially into the bilayer and cannot pass through the middle of the membrane during the simulation time. In this way, subtle alteration of chemical structure can play a significant role in the improvement or deterioration of partitioning of these compounds into the bilayer and their passage across the membrane.

Antibody-functionalized targeted nanocarriers have shown great–potential for minimizing the chemoresistance and systemic toxicity of cancer chemotherapies. The combination of chemotherapy and photothermal therapy has great potential in improving therapeutic effect. However, cetuximab-modified nanoparticles based lipids for chemo-phototherapy of EGFR overexpressing colorectal carcinoma (CRC) have seldom been investigated. Hence, this study aimed to fabricate cetuximab-conjugated and near infrared (NIR) light-responsive hybrid lipid-polymer nanoparticles (abbreviated as Cet-CINPs) for targeted delivery of irinotecan. Cet-CINPs were prepared with copolymer PLGA and various lipids DSPE-PEG, DSPE-PEG-Mal, lecithin as carriers. Cetuximab was conjugated on the surface of nanoparticles to achieve targeting anti-tumor efficacy. Cet-CINPs were characterized in terms of morphology (spherical), size (119 nm), charge (−27.2 mV), drug entrapment efficiency (43.27 %), and antibody conjugation efficiency (70.87 %). Cet-CINPs showed preferable photothermal response, pH/NIR-triggered drug release behavior, enhanced cellular uptake and ROS level compared with free ICG and CINPs. Meanwhile, in vitro cytotoxicity assay showed that Cet-CINPs with NIR irradiation had a higher cytotoxicity against Lovo cells than non-targeted or non-NIR activated nanoparticles. The IC₅₀ values of Cet-CINPs with NIR irradiation was 22.84 ± 1.11 μM for 24 h and 5.01 ± 1.06 μM for 48 h, respectively. These investigations demonstrate that Cet-CINPs with good tumor-targeting ability and enhanced antitumor activity, are a promising multifunctional nanoplatform for CRC therapy.

Ergosterol (Ergo) and cholesterol contribute to performances of liposomes by increasing membrane packing density and physical stability. However, as these sterols can reduce membrane flexibility, they can lower skin permeability of liposomes. We synthesized ergosterol ester (Ergo-Est) containing unsaturated fatty acid different from Ergo in size and physical properties. In this work, we investigated effects of Ergo-Est and Ergo on physical properties of liposomes. We incorporated Ergo, Ergo-oleate (EO^18:1), Ergo-linoleate (EL^18:2), and Ergo-linolenate (ELn^18:3) into the liposomal membrane of egg phosphatidylcholine and soybean lecithin. Ergo-Est did not reduce membrane fluidity as much as Ergo. Nevertheless, Ergo-Est increased membrane packing density and physical stability of liposomes. EL^18:2 and ELn^18:3 almost maintained membrane flexibility and skin permeability of liposomes, while Ergo significantly reduced them. Skin permeation test demonstrated that EL^18:2 and ELn^18:3 liposomes permeated to the dermis, whereas Ergo liposome mostly remained in the stratum corneum. This is the first report to show that EL^18:2 and ELn^18:3 can be efficient sterol compounds for flexible liposome formulation.

Macrocycle-based amphiphiles are capable of self-assembling into multidimensional nano-architecture with defined dimensions for various applications. Herein we report the synthesis, physio-chemical characterizations and oral drug delivery profiling of resorcinarene-based amphiphilic supramolecular macrocycle. The macrocycle was synthesized in two-step reaction and characterized using ¹H NMR, Mass spectrometry and IR spectroscopic techniques. The synthesized macrocycle was assessed for vesicles formation, checked for biocompatibility and then Amphotericin B (Amp-B) was entrapped in macrocycle-based vesicles. The drug loaded vesicles were characterized for shape, size, homogeneity, drug entrapment, surface charge, in-vitro release profile and stability. Amp-B loaded macrocycle based vesicles were examined in rabbits for in-vivo bioavailability and compared with plan drug suspension. The synthesized macrocycle was non-toxic in normal mouse fibroblast cells, compatible with blood and safe in mice. The drug loaded macrocycle based vesicles appeared spherical with 279.4 nm size and − 12.2 mV zeta potential loading 85.45 % drug. The drug loaded vesicles storage stability for 30 days and gastric fluid stability for 1 h were it retained nearly 90 % drug at 30th day and 83.79 % drug at 1 h in gastric fluid. Oral bioavailability of Amp-B in rabbits was markedly enhanced when delivered in synthesized macrocycle based vesicles in comparison with plan drug suspension. Results of this study indicate that the synthesized star shaped tetra-tailed supramolecular amphiphile could be used as an efficient nanocarrier for enhancing oral bioavailability of drugs with solubility and bioavailability issues like Amp-B.

In some dermal diseases with evident skin dehydration and desquamation, the natural ratio of CER[NP]:CER[AP] is altered in the extracellular matrix of the stratum corneum by increasing the concentration of CER[AP]. The extracellular matrix of the stratum corneum is composed of several stacked lipid bilayers. Molecular dynamics simulations were used to investigate the molecular nanostructure of CER[NP], CER[AP], cholesterol and lignoceric acid models of the extracellular matrix of the stratum corneum with a nativelike CER[NP]:CER[AP] 2:1 ratio and a CER[NP]:CER[AP] ratio of 1:2. Despite the very minor chemical difference between CER[NP] and CER[AP], which is only a single OH group, it was possible to observe differences between the structural influence of the two ceramides. In the models with 1:2 ratio, the higher CER[AP] content leads to a larger inclination of the acyl chains and a smaller overlap in the lamellar midplane, with a small increase of the repeat distance compared to the model with higher CER[NP] concentration. Because CER[AP] forms more H-bonds than CER[NP], the total number of hydrogen bonds in the headgroup region is larger in the models with higher CER[AP] concentration, reducing the mobility of the lipids towards the centre of the bilayer and resulting in less overlap and increased tilt angles.

Metformin hydrochloride (MET) is commonly used in diabetes treatment. Recently, it has gained interest for its anticancer potential against a wide range of cancers. Owing to its hydrophilic nature, the delivery and clinical actions of MET are limited. Therefore, the present work aims to develop MET-encapsulated NLCs using the hot-melt emulsification and probe-sonication method. The optimization was accomplished by 3³ BB design wherein lipid ratio, surfactant concentration, and sonication time were independent variables while the PS (nm), PDI, and EE (%) were dependent variables. The PS, PDI, % EE and ZP of optimized _GMSMET-NLCs were found to be 114.9 ± 1.32 nm, 0.268 ± 0.04 %, 60.10 ± 2.23 %, and ZP − 15.76 mV, respectively. The morphological features, DSC and PXRD, and FTIR analyses suggested the confirmation of formation of the NLCs. Besides, optimized _GMSMET-NLCs showed up to 88 % MET release in 24 h. Moreover, _GMSMET-NLCs showed significant cell cytotoxicity against KB oral cancer cells compared with MET solution as shown by the reduction of IC₅₀ values. Additionally, _GMSMET-NLCs displayed significantly increased intracellular ROS levels suggesting the _GMSMET-NLCs induced cell death in KB cells. _GMSMET-NLCs can therefore be explored to deliver MET through different routes of administration for the effective treatment of oral cancer.

Lipids play pivotal roles in cancer biology. Lipids have a wide range of biological roles, especially in cell membrane synthesis, serve as energetic molecules in regulating energy-demanding processes; and they play a significant role as signalling molecules and modulators of numerous cellular functions. Lipids may participate in the development of cancer through the fatty acid signalling pathway. Lipids consumed in the diet act as a key source of extracellular pools of fatty acids transported into the cellular system. Increased availability of lipids to cancer cells is due to increased uptake of fatty acids from adipose tissues. Lipids serve as a source of energy for rapidly dividing cancerous cells. Surviving requires the swift synthesis of biomass and membrane matrix to perform exclusive functions such as cell proliferation, growth, invasion, and angiogenesis. FATPs (fatty acid transport proteins) are a group of proteins involved in fatty acid uptake, mainly localized within cells and the cellular membrane, and have a key role in long-chain fatty acid transport. FATPs are composed of six isoforms that are tissue-specific and encoded by a specific gene. Previous studies have reported that FATPs can alter fatty acid metabolism, cell growth, and cell proliferation and are involved in the development of various cancers. They have shown increased expression in most cancers, such as melanoma, breast cancer, prostate cancer, renal cell carcinoma, hepatocellular carcinoma, bladder cancer, and lung cancer. This review introduces a variety of FATP isoforms and summarises their functions and their possible roles in the development of cancer.