Novel pegylated liposomal formulation of docetaxel with 3-n-pentadecylphenol derivative for cancer therapy.

The taxanes are commonly used in the treatment of many types of cancer. The disadvantages of using taxanes in therapy are their low solubility in water, the toxicity or relatively poor pharmacokinetics of existing formulations. Using liposomes as carriers would help in overcoming these problems, however, their use is limited by the low incorporation efficiency of taxane molecules within bilayer and by subsequent drug crystallization. Most of published taxanes liposomal formulations use natural soy phosphatidylcholine (PC) as main liposomes lipid. This allows a relatively good drug retention during the liposomes storage, but on the other hand, the use of liposomes with more liquid bilayer facilitates fast drug release after its intravenous administration. In order to decrease the drug release from liposomes in circulation, we used pegylated HSPC (hydrogenated soy PC) liposomes containing a novel synthetic 3-n-pentadecylphenol derivative - KW101, that showed a remarkably stabilizing action for the docetaxel (DTX) dopped HSPC liposomes over 30 days, expressed by the inhibition of DTX crystallization. The resulting liposomes with DTX showed similar cytotoxicity on MCF-7 and MDA-MB-231 breast cancer cell lines and higher toxicity in drug-resistant NCI/ADR-RES cell line in comparison with the free DTX. Moreover, this formulation has good pharmacokinetics in mice, in comparison to control pegylated DTX formulation composed of egg phosphatidylcholine (ePC). This novel liposomal formulation of docetaxel consisting of HSPC with the stabilizing compound KW101, appears to be a promising carrier for DTX cancer therapy.

Prediction of Chronic Inflammation for Inhaled Particles: the Impact of Material Cycling and Quarantining in the Lung Epithelium.

On a daily basis, people are exposed to a multitude of health-hazardous airborne particulate matter with notable deposition in the fragile alveolar region of the lungs. Hence, there is a great need for identification and prediction of material-associated diseases, currently hindered due to the lack of in-depth understanding of causal relationships, in particular between acute exposures and chronic symptoms. By applying advanced microscopies and omics to in vitro and in vivo systems, together with in silico molecular modeling, it is determined herein that the long-lasting response to a single exposure can originate from the interplay between the newly discovered nanomaterial quarantining and nanomaterial cycling between different lung cell types. This new insight finally allows prediction of the spectrum of lung inflammation associated with materials of interest using only in vitro measurements and in silico modeling, potentially relating outcomes to material properties for a large number of materials, and thus boosting safe-by-design-based material development. Because of its profound implications for animal-free predictive toxicology, this work paves the way to a more efficient and hazard-free introduction of numerous new advanced materials into our lives.

Laurdan emission study of the cholesterol-like effect of long-chain alkylresorcinols on the structure of dipalmitoylphosphocholine and sphingomyelin membranes.

Long-chain alkylresorcinols (ARs) are commonly found in plant and bacteria cells, and they exhibit a wide variety of biological effects, including antifungal, antitumor, and antiphrastic activities. The cholesterol (Chol)-like effect of ARs with hydrocarbon side-chain lengths ranging from C15 to C25 on the structure of pure and Chol-doped dipalmitoylphosphocholine (DPPC) and sphingomyelin (SM) membranes was investigated by Laurdan fluorescence spectroscopy. The Laurdan emission generalized polarization parameter was analyzed as a function of the temperature and excitation wavelength in DPPC (or SM)/Chol, DPPC (or SM)/AR, and DPPC/Chol/AR systems. It was found that AR incorporation into both DPPC and SM bilayers induces an increase in the temperature of the main lipid phase transition, similar to the effect of Chol molecule incorporation. The phase separation, lipid-chain ordering, and membrane hydration are discussed for the AR-mixed membranes and compared with DPPC (or SM)/Chol membranes.

Phase separation in phosphatidylcholine membrane caused by the presence of a pyrimidine analogue of fluphenazine with high anti-multidrug-resistance activity.

Phenothiazine compounds are known as effective inhibitors of a multidrug resistance (MDR) of tumor cells to chemotherapeutic agents. This group consists of many important substances used in human medicine such as antipsychotic drugs in the case of fluphenazine (FPh) or chlorpromazine (CPZ). Fluphenazine was on the World Health Organization (WHO) list of Essential Medicines of 2009, and its new pyrimidine analog (FPh-prm) presented in this work has been documented to have a high anti-MDR activity. In order to discover the character of alterations of the lipid bilayer structure caused by the presence of FPh-prm inside the lipid membrane, which is responsible for the essential increase of an anti-MDR activity of FPh-prm, microcalorimetric (differential scanning calorimetry), Laurdan fluorescence, (31)P nuclear magnetic resonance spectroscopy (NMR), and attenuated total reflectance Fourier transfer infrared spectroscopy (FTIR-ATR) were used for dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) liposomes mixed with a different concentration of amine analogue. It was stated that the formation of domains with different content of FPh-prm/DPPC can be a reason for the membrane-related mechanism of chemoprevention associated with the inhibition of the outward transport of anticancer drugs by the glycoprotein P (Pgp) in cancer cells by the pyrimidine analog of FPh. To our best knowledge, this report is the first to show the bilayer structure of domains formed by incomplete miscibility of fluphenazine-related compounds and phospholipid molecules. Our results provide a sound basis for the design of future modifications of anti-MDR drugs by providing very effective inhibitors of the pump activity of Pgp.