Hydrogen bonding regulates the rigidity of liposome-encapsulated chlorin photosensitizers

Liposomal formulations facilitate the administration of hydrophobic drugs, avoiding precipitation and aggregation phenomena when injected in polar solvents. The integration of the photosensitizer into the liposome may alter the fluidity of the system and, thus, modify the delivery process of the drug. Such a change has been observed for the liposomal formulation of Temoporfin, which is one of the most potent chlorin photosensitizers employed in photodynamic therapy. Here, all-atom molecular dynamics simulations have been performed to identify the nature of the intermolecular interactions that might be responsible of the different lipids freedom of motion when the drug is introduced in the bilayer. It is found that Temoporfin participates as a hydrogen donor in strong hydrogen-bonding interactions with the polar groups of the phospholipids. The theoretical analysis suggests that the rigidity of drug/liposome complexes can be modulated by considering the different hydrogen-bond ability of the photosensitizer and the carrier material.M.D.V. thanks the Marie Curie Actions, within the Innovative Training Network-European Join Doctorate in Theoretical Chemistry and Computational Modelling TCCM-ITN-EJD-642294, for financial support. L.G. and J.J.N. thank the University of Vienn

Assessment of fluidity of different invasomes by electron spin resonance and differential scanning calorimetry

The aim of this study was to investigate the influence of membrane-softening components (terpenes/terpene mixtures, ethanol) on fluidity of phospholipid membranes in invasomes, which contain besides phosphatidylcholine and water, also ethanol and terpenes. Also mTHPC was incorporated into invasomes in order to study its molecular interaction with phospholipids in vesicular membranes. Fluidity of bilayers was investigated by electron spin resonance (ESR) using spin labels 5- and 16-doxyl stearic acid and by differential scanning calorimetry (DSC). Addition of 1% of a single terpene/terpene mixture led to significant fluidity increase around the C16 atom of phospholipid acyl chains comprising the vesicles. However, it was not possible to differentiate between the influences of single terpenes or terpene mixtures. Incorporation of mTHPC into the bilayer of vesicles decreased fluidity near the C16 atom of acyl chains, indicating its localization in the inner hydrophobic zone of bilayers. These results are in agreement with DSC measurements, which showed that terpenes increased fluidity of bilayers, while mTHPC decreased fluidity. Thus, invasomes represent vesicles with very high membrane fluidity. However, no direct correlation between fluidity of invasomes and their penetration enhancing ability was found, indicating that besides fluidity also other phenomena might be responsible for improved skin delivery of mTHPC

New cationic nanovesicular systems containing lysine-based surfactants for topical administration: Toxicity assessment using representative skin cell lines

Many strategies for treating diseases require the delivery of drugs into the cell cytoplasm following internalization within endosomal vesicles. Thus, compounds triggered by low pH to disrupt membranes and release endosomal contents into the cytosol are of particular interest. Cationic nanovesicles have attracted considerable interest as effective carriers to improve the delivery of biologically active molecules into and through the skin. In this study, lipid-based nanovesicles containing three different cationic lysine-based surfactants were designed for topical administration. We used representative skin cell lines and in vitro assays to assess whether the cationic compounds modulate the toxic responses of these nanocarriers. The nanovesicles were characterized in both water and cell culture medium. In general, significant agglomeration occurred after 24 h incubation under cell culture conditions. We found different cytotoxic responses among the formulations, which depended on the surfactant,cell line (3T3, HaCaT, and THP-1) and endpoint assayed (MTT, NRU, and LDH). Moreover, no potential phototoxicity was detected in fibroblast or keratinocyte cells, whereas only a slight inflammatory response was induced, as detected by IL-1a and IL-8 production in HaCaT and THP-1 cell lines, respectively. A key finding of our research was that the cationic charge position and the alkyl chain length of the surfactants determine the nanovesicles resulting toxicity. The charge on the a-amino group of lysine increased the depletion of cell metabolic activity, as determined by the MTT assay, while a higher hydrophobicity tends to enhance the toxic responses of the nanovesicles. The insights provided here using different cell lines and assays offer a comprehensive toxicological evaluation of this group of new nanomaterials

Pharmaceutical stability aspects of nanomedicines

Nanomedicine48857-86

Penetration enhancer-containing vesicles for cutaneous drug delivery

The function of vesicles as topical delivery systems is controversial with variable effects being reported in relation to the type of vesicles and their composition. A wide variety of lipids and surfactants can be used to prepare vesicles, and vesicle composition and preparation method influence their physicochemical properties (size, charge, lamellarity, thermodynamic state, deformability) and, therefore, their efficacy as drug delivery systems. In this chapter, composition, preparation, and results obtained by using penetration enhancer-containing vesicles, liposomes prepared by associating different penetration enhancers to phospholipids, are described. These systems have shown to improve cutaneous drug delivery, thanks to a combination of properties of vesicle carriers and penetration enhancers